Sample records for acid suppressive therapy

  1. Acid suppression and surgical therapy for Barrett's oesophagus.

    PubMed

    de Jonge, Pieter J F; Spaander, Manon C; Bruno, Marco J; Kuipers, Ernst J

    2015-02-01

    Gastro-oesophageal reflux disease is a common medical problem in developed countries, and is a risk factor for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Both proton pump inhibitor therapy and antireflux surgery are effective at controlling endoscopic signs and symptoms of gastro-oesophageal reflux in patients with Barrett's oesophagus, but often fail to eliminate pathological oesophageal acid exposure. The current available studies strongly suggest that acid suppressive therapy, both pharmacological as well as surgical acid suppression, can reduce the risk the development and progression in patients with Barrett's oesophagus, but are not capable of complete prevention. No significant differences have been found between pharmacological and surgical therapy. For clinical practice, patients should be prescribed a proton pump inhibitor once daily as maintenance therapy, with the dose guided by symptoms. Antireflux surgery can be a good alternative to proton pump inhibitor therapy, but should be primarily offered to patients with symptomatic reflux, and not to asymptomatic patients with the rationale to protect against cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study.

    PubMed

    Kilduff, Claire E; Counter, Melanie J; Thomas, Gareth A; Harrison, Nicholas K; Hope-Gill, Benjamin D

    2014-01-01

    Chronic cough affects more than 70 percent of patients with Idiopathic Pulmonary Fibrosis and causes significant morbidity. Gastroesophageal reflux is the cause of some cases of chronic cough; and also has a postulated role in the aetiology of Idiopathic Pulmonary Fibrosis. A high prevalence of acid; and more recently non-acid, reflux has been observed in Idiopathic Pulmonary Fibrosis cohorts. Therefore, gastroesophageal reflux may be implicated in the pathogenesis of cough in Idiopathic Pulmonary Fibrosis. Eighteen subjects with Idiopathic Pulmonary Fibrosis underwent 24-hour oesophageal impedance and cough count monitoring after the careful exclusion of causes of chronic cough other than gastroesophageal reflux. All 18 were then treated with high dose acid suppression therapies. Fourteen subjects underwent repeat 24-hour oesophageal impedance and cough count monitoring after eight weeks. Total reflux and acid reflux frequencies were within the normal range in the majority of this cohort. The frequencies of non-acid and proximal reflux events were above the normal range. Following high dose acid suppression therapy there was a significant decrease in the number of acid reflux events (p = 0.02), but an increase in the number of non-acid reflux events (p = 0.01). There was no change in cough frequency (p = 0.70). This study confirms that non-acid reflux is prevalent; and that proximal oesophageal reflux occurs in the majority, of subjects with Idiopathic Pulmonary Fibrosis. It is the first study to investigate the effect of acid suppression therapy on gastroesophageal reflux and cough in patients with Idiopathic Pulmonary Fibrosis. The observation that cough frequency does not improve despite verifiable reductions in oesophageal acid exposure challenges the role of acid reflux in Idiopathic Pulmonary Fibrosis associated cough. The finding that non-acid reflux is increased following the use of acid suppression therapies cautions against the widespread use

  3. Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study

    PubMed Central

    2014-01-01

    Background Chronic cough affects more than 70 percent of patients with Idiopathic Pulmonary Fibrosis and causes significant morbidity. Gastroesophageal reflux is the cause of some cases of chronic cough; and also has a postulated role in the aetiology of Idiopathic Pulmonary Fibrosis. A high prevalence of acid; and more recently non-acid, reflux has been observed in Idiopathic Pulmonary Fibrosis cohorts. Therefore, gastroesophageal reflux may be implicated in the pathogenesis of cough in Idiopathic Pulmonary Fibrosis. Methods Eighteen subjects with Idiopathic Pulmonary Fibrosis underwent 24-hour oesophageal impedance and cough count monitoring after the careful exclusion of causes of chronic cough other than gastroesophageal reflux. All 18 were then treated with high dose acid suppression therapies. Fourteen subjects underwent repeat 24-hour oesophageal impedance and cough count monitoring after eight weeks. Results Total reflux and acid reflux frequencies were within the normal range in the majority of this cohort. The frequencies of non-acid and proximal reflux events were above the normal range. Following high dose acid suppression therapy there was a significant decrease in the number of acid reflux events (p = 0.02), but an increase in the number of non-acid reflux events (p = 0.01). There was no change in cough frequency (p = 0.70). Conclusions This study confirms that non-acid reflux is prevalent; and that proximal oesophageal reflux occurs in the majority, of subjects with Idiopathic Pulmonary Fibrosis. It is the first study to investigate the effect of acid suppression therapy on gastroesophageal reflux and cough in patients with Idiopathic Pulmonary Fibrosis. The observation that cough frequency does not improve despite verifiable reductions in oesophageal acid exposure challenges the role of acid reflux in Idiopathic Pulmonary Fibrosis associated cough. The finding that non-acid reflux is increased following the use of acid suppression

  4. Use of acid-suppressive therapy before anti-reflux surgery in 2922 patients: a nationwide register-based study in Denmark.

    PubMed

    Lødrup, A; Pottegård, A; Hallas, J; Bytzer, P

    2015-07-01

    Guidelines recommend that patients with gastro-oesophageal reflux disease are adequately treated with acid-suppressive therapy before undergoing anti-reflux surgery. Little is known of the use of acid-suppressive drugs before anti-reflux surgery. To determine the use of proton pump inhibitors and H2 -receptor antagonists in the year before anti-reflux surgery. A nationwide retrospective study of all patients aged ≥18 undergoing first-time anti-reflux surgery in Denmark during 2000-2012 using data from three different sources: the Danish National Register of Patients, the Danish National Prescription Register, and the Danish Person Register. The study population thus included 2922 patients (median age: 48 years, 55.7% male). The annual proportion of patients redeeming ≥180 DDD of acid-suppressive therapy increased from 17.0% 5 years before anti-reflux surgery to 64.9% 1 year before. The probability for inadequate dosing 1 year before surgery (<180 DDD) was significantly increased for younger patients, patients operated in the period 2000-2003, patients who had not undergone pre-surgical manometry, pH- or impedance monitoring, and patients who had not redeemed prescriptions on NSAID or anti-platelet drugs. Compliance with medical therapy should be evaluated thoroughly before planning anti-reflux surgery, as a high proportion of patients receive inadequate dosing of acid-suppressive therapy prior to the operation. © 2015 John Wiley & Sons Ltd.

  5. Acid-Suppressive Therapy and Risk of Infections: Pros and Cons.

    PubMed

    Fisher, Leon; Fisher, Alexander

    2017-07-01

    This narrative review summarises the benefits, risks and appropriate use of acid-suppressing drugs (ASDs), proton pump inhibitors and histamine-2 receptor antagonists, advocating a rationale balanced and individualised approach aimed to minimise any serious adverse consequences. It focuses on current controversies on the potential of ASDs to contribute to infections-bacterial, parasitic, fungal, protozoan and viral, particularly in the elderly, comprehensively and critically discusses the growing body of observational literature linking ASD use to a variety of enteric, respiratory, skin and systemic infectious diseases and complications (Clostridium difficile diarrhoea, pneumonia, spontaneous bacterial peritonitis, septicaemia and other). The proposed pathogenic mechanisms of ASD-associated infections (related and unrelated to the inhibition of gastric acid secretion, alterations of the gut microbiome and immunity), and drug-drug interactions are also described. Both probiotics use and correcting vitamin D status may have a significant protective effect decreasing the incidence of ASD-associated infections, especially in the elderly. Despite the limitations of the existing data, the importance of individualised therapy and caution in long-term ASD use considering the balance of benefits and potential harms, factors that may predispose to and actions that may prevent/attenuate adverse effects is evident. A six-step practical algorithm for ASD therapy based on the best available evidence is presented.

  6. Triple antimicrobial therapy and acid suppression in dogs with chronic vomiting and gastric Helicobacter spp.

    PubMed

    Leib, Michael S; Duncan, Robert B; Ward, Daniel L

    2007-01-01

    Helicobacter pylori is a common cause of gastritis and peptic ulcers in humans. Many dogs, including those with gastritis and chronic vomiting, are infected with Helicobacter spp. Triple antimicrobial therapy will eradicate Helicobacter infection, improve gastritis, and reduce clinical signs. The addition of acid suppression medication will not improve results. Twenty-four pet dogs with chronic vomiting and gastric Helicobacter spp. Dogs were randomly assigned to triple antimicrobial therapy with or without famotidine. Gastroduodenoscopy was performed 4 weeks and 6 months after therapy. Helicobacter spp status was determined by histologic assessment of gastric mucosal biopsy specimens. Eradication rates for each treatment were not significantly different and combined were 75 and 42.9% at 4 weeks and 6 months, respectively. A greater improvement in gastritis scores occurred in dogs that became Helicobacter spp negative. Overall, the frequency of vomiting was reduced by 86.4%, but there were no differences between treatments. Eradication rates of Helicobacter spp with both treatments were not significantly different. Eradication rates at 6 months were modest, and more effective treatments should be developed. Acid suppression is not a necessary component of treatment protocols for dogs. Eradication of gastric Helicobacter spp was associated with improvement in gastritis scores. Dramatic reduction of the vomiting frequency occurred with both treatment protocols. Gastric Helicobacter spp may cause or contribute to chronic vomiting and gastritis in some dogs.

  7. Acid-suppressing therapies and subsite-specific risk of stomach cancer.

    PubMed

    Wennerström, E Christina M; Simonsen, Jacob; Camargo, M Constanza; Rabkin, Charles S

    2017-04-25

    Associations of stomach cancer risk with histamine type-2 receptor antagonists (H 2 RA) and proton-pump inhibitors (PPI) are controversial. We hypothesised that proximal extension of Helicobacter pylori infection from acid suppression would disproportionately increase cancers at proximal subsites. A total of 1 563 860 individuals in the Danish Prescription Drug Registry first prescribed acid-suppressive drugs 1995-2011 were matched to unexposed population-based controls. Hazard ratios (HR) were calculated by Cox proportional hazard regression for stomach cancers diagnosed more than one year after first prescription. There were 703 stomach cancers among H 2 RA-exposed individuals and 1347 among PPI-exposed. Restricted to individuals with five or more prescriptions, subsite-specific HRs for H 2 RA and PPI were 4.1 and 6.4 for proximal subsites vs 8.0 and 10.3 for distal subsites, respectively. Moderate exposures to acid-suppressive drugs did not favour proximal tumour localisation. Given confounding by indication, these findings do not resolve potential contribution to gastric carcinogenesis overall.

  8. Oropharyngeal flora in patients admitted to the medical intensive care unit: clinical factors and acid suppressive therapy.

    PubMed

    Frandah, Wesam; Colmer-Hamood, Jane; Mojazi Amiri, Hoda; Raj, Rishi; Nugent, Kenneth

    2013-05-01

    Acid suppression therapy in critically ill patients significantly reduces the incidence of stress ulceration and gastrointestinal (GI) bleeding; however, recent studies suggest that proton pump inhibitors (PPIs) increase the risk of pneumonia. We wanted to test the hypothesis that acid suppressive therapy promotes alteration in the bacterial flora in the GI tract and leads to colonization of the upper airway tract with pathogenic species, potentially forming the biological basis for the observed increased incidence of pneumonia in these patients. This was a prospective observational study on patients (adults 18 years or older) admitted to the medical intensive care unit (MICU) at a tertiary care centre. Exclusion criteria included all patients with a diagnosis of pneumonia at admission, with infection in the upper airway, or with a history of significant dysphagia. Oropharyngeal cultures were obtained on day 1 and days 3 or 4 of admission. We collected data on demographics, clinical information, and severity of the underlying disease using APACHE II scores. There were 110 patients enrolled in the study. The mean age was 49±16 years, 50 were women, and the mean APACHE II score was 9.8 ± 6.5. Twenty per cent of the patients had used a PPI in the month preceding admission. The first oropharyngeal specimen was available in 110 cases; a second specimen at 72-96 h was available in 68 cases. Seventy-five per cent of the patients admitted to the MICU had abnormal flora. In multivariate logistic regression, diabetes mellitus and PPI use were associated with abnormal oral flora on admission. Chronic renal failure and a higher body mass index reduced the frequency of abnormal oral flora on admission. Most critically ill patients admitted to our MICU have abnormal oral flora. Patients with diabetes and a history of recent PPI use are more likely to have abnormal oral flora on admission.

  9. Fatty Acids Suppress Autophagic Turnover in β-Cells*

    PubMed Central

    Las, Guy; Serada, Sam B.; Wikstrom, Jakob D.; Twig, Gilad; Shirihai, Orian S.

    2011-01-01

    Recent studies have shown that autophagy is essential for proper β-cell function and survival. However, it is yet unclear under what pathogenic conditions autophagy is inhibited in β-cells. Here, we report that long term exposure to fatty acids and glucose block autophagic flux in β-cells, contributing to their toxic effect. INS1 cells expressing GFP-LC3 (an autophagosome marker) were treated with 0.4 mm palmitate, 0.4 mm oleate, and various concentrations of glucose for 22 h. Kinetics of the effect of fatty acids on autophagy showed a biphasic response. During the second phase of autophagy, the size of autophagosomes and the content of autophagosome substrates (GFP-LC3, p62) and endogenous LC3 was increased. During the same phase, fatty acids suppressed autophagic degradation of long lived protein in both INS1 cells and islets. In INS1 cells, palmitate induced a 3-fold decrease in the number and the acidity of Acidic Vesicular Organelles. This decrease was associated with a suppression of hydrolase activity, suppression of endocytosis, and suppression of oxidative phosphorylation. The combination of fatty acids with glucose synergistically suppressed autophagic turnover, concomitantly suppressing insulin secretion. Rapamycin treatment resulted in partial reversal of the inhibition of autophagic flux, the inhibition of insulin secretion, and the increase in cell death. Our results indicate that excess nutrient could impair autophagy in the long term, hence contributing to nutrient-induced β-cell dysfunction. This may provide a novel mechanism that connects diet-induced obesity and diabetes. PMID:21859708

  10. Cough Suppressant and Pharmacologic Protussive Therapy

    PubMed Central

    Bolser, Donald C.

    2011-01-01

    Background Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis. Methods Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms “cough,” “double-blind placebo-controlled,” “antitussive,” “mucolytic,” “cough clearance,” “common cold,” “protussive,” “guaifenesin,” “glycerol,” and “zinc.” Results Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further. Conclusions These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants. PMID:16428717

  11. Molecular Mechanisms for Sweet-suppressing Effect of Gymnemic Acids*

    PubMed Central

    Sanematsu, Keisuke; Kusakabe, Yuko; Shigemura, Noriatsu; Hirokawa, Takatsugu; Nakamura, Seiji; Imoto, Toshiaki; Ninomiya, Yuzo

    2014-01-01

    Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca2+]i responses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3. PMID:25056955

  12. Effect of Timing of Proton Pump Inhibitor Administration on Acid Suppression.

    PubMed

    Furuta, Kenji; Adachi, Kyoichi; Aimi, Masahito; Shimura, Shino; Mikami, Hironobu; Nishimura, Nobuhiro; Ishimura, Norihisa; Ishihara, Shunji; Naora, Kohji; Kinoshita, Yoshikazu

    2016-01-01

    Esomeprazole has been reported to show a strong acid suppression following preprandial as compared to postprandial administration, though no known study has compared the acid suppressing effects of other proton pump inhibitors between those administrations. The aim of this study was to compare intragastric pH levels following pre- and postprandial administrations of rabeprazole and esomeprazole. In 15 Helicobacter pylori-negative healthy volunteers, we measured intragastric pH after 7 days of pre- and postprandial administrations of rabeprazole (10 mg) or esomeprazole (20 mg) using a 5-way crossover design. Preprandial administration of esomeprazole showed stronger acid suppression than postprandial administration. The values for percent time at pH >4.0 over a 24-hour period increased from 45.3% with postprandial administration of esomeprazole to 54.4% with preprandial administration, while the percent time at pH >4.0 during daytime was increased to a greater extent from 51.4 to 66.5% with preprandial administration (p = 0.05). On the other hand, the acid suppressing effect of rabeprazole was not influenced by the timing of administration. The acid suppressing effect of esomeprazole is influenced by administration timing. In contrast, the acid suppressing effect of rabeprazole is not augmented by preprandial administration. © 2015 S. Karger AG, Basel.

  13. Feeding by whiteflies suppresses downstream jasmonic acid signaling by eliciting salicylic acid signaling.

    PubMed

    Zhang, Peng-Jun; Li, Wei-Di; Huang, Fang; Zhang, Jin-Ming; Xu, Fang-Cheng; Lu, Yao-Bin

    2013-05-01

    Phloem-feeding whiteflies in the species complex Bemisia tabaci cause extensive crop damage worldwide. One of the reasons for their "success" is their ability to suppress the effectual jasmonic acid (JA) defenses of the host plant. However, little is understood about the mechanisms underlying whitefly suppression of JA-regulated defenses. Here, we showed that the expression of salicylic acid (SA)-responsive genes (EDS1 and PR1) in Arabidopsis thaliana was significantly enhanced during feeding by whitefly nymphs. Whereas upstream JA-responsive genes (LOX2 and OPR3) also were induced, the downstream JA-responsive gene (VSP1) was repressed, i.e., whiteflies only suppressed downstream JA signaling. Gene-expression analyses with various Arabidopsis mutants, including NahG, npr-1, ein2-1, and dde2-2, revealed that SA signaling plays a key role in the suppression of downstream JA defenses by whitefly feeding. Assays confirmed that SA activation enhanced whitefly performance by suppressing downstream JA defenses.

  14. Acid-suppressive Medication Use and the Risk for Nosocomial Gastrointestinal Bleeding

    PubMed Central

    Herzig, Shoshana J.; Vaughn, Byron P.; Howell, Michael D.; Ngo, Long H.; Marcantonio, Edward R.

    2011-01-01

    Background Acid-suppressive medications are increasingly prescribed for non-critically ill hospitalized patients, although the incidence of nosocomial gastrointestinal bleeding and magnitude of potential benefit from this practice are unknown. We aimed to define the incidence of nosocomial gastrointestinal bleeding outside of the intensive care unit, and examine the association between acid-suppressive medication and this complication. Methods We conducted a pharmacoepidemiologic cohort study of patients admitted to an academic medical center from 2004 through 2007, at least 18 years of age and hospitalized for 3 or more days. Admissions with a primary diagnosis of gastrointestinal bleeding were excluded. Acid-suppressive medication use was defined as any order for a proton-pump inhibitor or histamine-2-receptor antagonist. The main outcome measure was nosocomial gastrointestinal bleeding. A propensity matched generalized estimating equation was used to control for confounders. Results The final cohort included 78,394 admissions (median age = 56 years; 41% men). Acid-suppressive medication was ordered in 59% of admissions and nosocomial gastrointestinal bleeding occurred in 224 admissions (0.29%). After matching on the propensity score, the adjusted odds ratio for nosocomial gastrointestinal bleeding in the group exposed to acid-suppressive medication relative to the unexposed group was 0.63 (95% CI 0.42 to 0.93). The number-needed-to-treat to prevent one episode of nosocomial gastrointestinal bleeding was 770. Conclusions Nosocomial gastrointestinal bleeding outside of the intensive care unit was rare. Despite a protective effect of acid-suppressive medication, the number-needed-to-treat to prevent one case of nosocomial gastrointestinal bleeding was relatively high, supporting the recommendation against routine use of prophylactic acid-suppressive medication in noncritically ill hospitalized patients. PMID:21321285

  15. Effect of Thyrotropin Suppression Therapy on Bone in Thyroid Cancer Patients

    PubMed Central

    Hawley, Sarah T.; Haymart, Megan R.

    2016-01-01

    Background. The thyroid cancer incidence is rising. Despite current guidelines, controversy exists regarding the degree and duration of thyrotropin suppression therapy. Also, its potential skeletal effects remain a concern to physicians caring for thyroid cancer patients. We conducted a review of published data to evaluate existing studies focusing on the skeletal effects of thyrotropin suppression therapy in thyroid cancer patients. Materials and Methods. A systematic search of the PubMed, Ovid/Medline, and Cochrane Central Register of Controlled Trials databases was conducted. The retained studies were evaluated for methodological quality, and the study populations were categorized into premenopausal women, postmenopausal women, and men. Results. Twenty-five pertinent studies were included. Seven studies were longitudinal and 18 were cross-sectional. Of the 25 included studies, 13 were assigned an excellent methodological quality score. Three of 5 longitudinal studies and 3 of 13 cross-sectional studies reported decreased bone mineral density (BMD) in premenopausal women; 2 of 4 longitudinal studies and 5 of 13 cross-sectional studies reported decreased BMD in postmenopausal women. The remaining studies showed no effect on BMD. The only longitudinal study of men showed bone mass loss; however, cross-sectional studies of men did not demonstrate a similar effect. Conclusion. Studies to date have yielded conflicting results on the skeletal effects of thyrotropin suppression therapy and a knowledge gap remains, especially for older adults and men. Existing data should be cautiously interpreted because of the variable quality and heterogeneity. Identifying groups at risk of adverse effects from thyrotropin suppression therapy will be instrumental to providing focused and tailored thyroid cancer treatment. Implications for Practice: The standard treatment for thyroid cancer includes total thyroidectomy with or without radioactive iodine ablation, often followed by

  16. Effect of Thyrotropin Suppression Therapy on Bone in Thyroid Cancer Patients.

    PubMed

    Papaleontiou, Maria; Hawley, Sarah T; Haymart, Megan R

    2016-02-01

    The thyroid cancer incidence is rising. Despite current guidelines, controversy exists regarding the degree and duration of thyrotropin suppression therapy. Also, its potential skeletal effects remain a concern to physicians caring for thyroid cancer patients. We conducted a review of published data to evaluate existing studies focusing on the skeletal effects of thyrotropin suppression therapy in thyroid cancer patients. A systematic search of the PubMed, Ovid/Medline, and Cochrane Central Register of Controlled Trials databases was conducted. The retained studies were evaluated for methodological quality, and the study populations were categorized into premenopausal women, postmenopausal women, and men. Twenty-five pertinent studies were included. Seven studies were longitudinal and 18 were cross-sectional. Of the 25 included studies, 13 were assigned an excellent methodological quality score. Three of 5 longitudinal studies and 3 of 13 cross-sectional studies reported decreased bone mineral density (BMD) in premenopausal women; 2 of 4 longitudinal studies and 5 of 13 cross-sectional studies reported decreased BMD in postmenopausal women. The remaining studies showed no effect on BMD. The only longitudinal study of men showed bone mass loss; however, cross-sectional studies of men did not demonstrate a similar effect. Studies to date have yielded conflicting results on the skeletal effects of thyrotropin suppression therapy and a knowledge gap remains, especially for older adults and men. Existing data should be cautiously interpreted because of the variable quality and heterogeneity. Identifying groups at risk of adverse effects from thyrotropin suppression therapy will be instrumental to providing focused and tailored thyroid cancer treatment. The standard treatment for thyroid cancer includes total thyroidectomy with or without radioactive iodine ablation, often followed by thyrotropin suppression therapy. Despite current guidelines, controversy exists

  17. Identifying Risk Factors Associated with Inappropriate Use of Acid Suppressive Therapy at a Community Hospital

    PubMed Central

    Bodukam, Vijay; Saigal, Kirit; Bahl, Jaya; Wang, Yvette; Hanlon, Alexandra; Lu, Yinghui; Davis, Michael

    2016-01-01

    Purpose. By examining the prescribing patterns and inappropriate use of acid suppressive therapy (AST) during hospitalization and at discharge we sought to identify the risk factors associated with such practices. Methods. In this retrospective observational study, inpatient records were reviewed from January 2011 to December 2013. Treatment with AST was considered appropriate if the patient had a known specific indication or met criteria for stress ulcer prophylaxis. Results. In 2011, out of 58 patients who were on AST on admission, 32 were newly started on it and 23 (72%) were inappropriate cases. In 2012, out of 97 patients on AST, 61 were newly started on it and 51 (84%) were inappropriate cases. In 2013, 99 patients were on AST, of which 48 were newly started on it and 36 (75%) were inappropriate cases. 19% of the patients inappropriately started on AST were discharged on it in three years. Younger age, female sex, and 1 or more handoffs between services were significantly associated with increased risk of inappropriate AST. Conclusion. Our findings reflect inappropriate prescription of AST which leads to increase in costs of care and unnecessarily puts the patient at risk for potential adverse events. The results of this study emphasize the importance of examining the patient's need for AST at each level of care especially when the identified risk factors are present. PMID:27818680

  18. [Advances in postoperative thyroid-stimulating hormone suppression therapy in females with thyroid cancer].

    PubMed

    Song, F; Yi, H L

    2018-05-07

    Differentiated thyroid cancer is the most common malignant carcinoma in female population.Postoperative long-term thyroid-stimulating hormone(TSH) suppression therapy can reduce the risk of recurrence for differentiated thyroid cancer and control the progress of the disease, but it also induces simultaneously subclinical hypothyroidism and imposes negative effect on female. In addition to cardiovascular disease, TSH suppression therapy can lead to the alteration of sex hormone metabolism, menstrual disorder, poor influence on pregnancy and osteoporosis. This article reviews the recent studies on postoperative TSH suppression therapy in women with thyroid cancer.

  19. Indication of acid suppression therapy and predictors for the prophylactic use of protonpump inhibitors vs. histamine-2 receptor antagonists in a Malaysian tertiary hospital

    PubMed Central

    Oh, Ai L.; Tan, Andrew G.; Phan, Hui S.; Lee, Basil C.; Jumaat, Nafisah; Chew, Soo P.; Wong, Siok H.; Ting, Shee H.; Subramaniam, Theebaa

    2015-01-01

    Background: Proton-pump inhibitors (PPI) and histamine-2 receptor antagonists (H2RA) are common acid suppressants used in gastrointestinal disorders. The trend of usage in Malaysia has changed from predominantly H2RA to PPI from 2007 to 2008, 3.46 versus 2.87 and 2.99 versus 3.24 DDD (Defined Daily Dose)/1000 population/day respectively. This raises concerns as PPI overutilization amounts to higher cost expenditure and are associated with various untoward consequences such as Clostridium difficile-associated diarrhea, pneumonia, and osteoporosis. Objectives: To evaluate the indication of acid suppression therapy (AST) and to look for predictors associated with the prophylactic use of PPI as compared to H2RA. Methods: Data collection was conducted via a standardized surveillance form over a 2-month period in the general medical wards of Sarawak General Hospital. All patients who received at least one dose of PPI or H2RA in any dosage form were included in the study. Appropriateness of prophylaxis was determined using current available guidelines. Selected risk factors were analysed using simple logistic regression to look for predictors associated with the choice of PPI in prophylactic AST. Results: Out of 212 cases in the present cohort, about three quarters (75.5%, n=160) of acid suppressants were given as prophylaxis. Over half of these did not have appropriate indications for prophylactic AST (58.1%, n=93). Among all cases given prophylactic AST, 75.0% (n=120) of them were given PPI. Renal insufficiency was identified as the only predictor associated with the use of prophylactic PPI in preference to H2RA (OR=2.86, 95%CI 1.21:6.72, p=0.011). Conclusion: Inappropriate prophylactic AST is a major concern and may even be underestimated due to the lack of appropriate guidelines. More data is required to guide the selection between PPI and H2RA, specifically the more cost-effective use of H2RA in patients with lower gastrointestinal risk or in whom PPI has no clear

  20. L-Carnitine suppresses oleic acid-induced membrane permeability transition of mitochondria.

    PubMed

    Oyanagi, Eri; Yano, Hiromi; Kato, Yasuko; Fujita, Hirofumi; Utsumi, Kozo; Sasaki, Junzo

    2008-10-01

    Membrane permeability transition (MPT) of mitochondria has an important role in apoptosis of various cells. The classic type of MPT is characterized by increased Ca(2+) transport, membrane depolarization, swelling, and sensitivity to cyclosporin A. In this study, we investigated whether L-carnitine suppresses oleic acid-induced MPT using isolated mitochondria from rat liver. Oleic acid-induced MPT in isolated mitochondria, inhibited endogenous respiration, caused membrane depolarization, and increased large amplitude swelling, and cytochrome c (Cyt. c) release from mitochondria. L-Carnitine was indispensable to beta-oxidation of oleic acid in the mitochondria, and this reaction required ATP and coenzyme A (CoA). In the presence of ATP and CoA, L-carnitine stimulated oleic acid oxidation and suppressed the oleic acid-induced depolarization, swelling, and Cyt. c release. L-Carnitine also contributed to maintaining mitochondrial function, which was decreased by the generation of free fatty acids with the passage of time after isolation. These results suggest that L-carnitine acts to maintain mitochondrial function and suppresses oleic acid-mediated MPT through acceleration of beta-oxidation. Copyright (c) 2008 John Wiley & Sons, Ltd.

  1. Impact of regurgitation on health-related quality of life in gastro-oesophageal reflux disease before and after short-term potent acid suppression therapy.

    PubMed

    Kahrilas, Peter J; Jonsson, Andreas; Denison, Hans; Wernersson, Börje; Hughes, Nesta; Howden, Colin W

    2014-05-01

    Limited data exist on the impact of regurgitation on health-related quality of life (HRQOL) in gastro-oesophageal reflux disease (GORD). We assessed the relationship between regurgitation frequency and HRQOL before and after acid suppression therapy in GORD. We used data from two randomised trials of AZD0865 25-75 mg/day versus esomeprazole 20 or 40 mg/day in non-erosive reflux disease (NERD) (n=1415) or reflux oesophagitis (RO) (n=1460). The Reflux Disease Questionnaire was used to select patients with frequent and intense heartburn for inclusion and to assess treatment response. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was used to assess HRQOL. At baseline, 93% of patients in both the NERD and RO groups experienced regurgitation. Mean QOLRAD scores were similar for NERD and RO at baseline and at week 4 and disclosed decremental HRQOL with increasing frequency of regurgitation; a clinically relevant difference of >0.5 in mean QOLRAD scores was seen with regurgitation ≥4 days/week versus <4 days/week. The prevalence of frequent, persistent regurgitation (≥4 days/week) at week 4 among heartburn responders (≤1 day/week of mild heartburn) was 28% in NERD and 23% in RO. QOLRAD scores were higher among heartburn responders. There was a similar pattern of impact related to regurgitation frequency in heartburn responders compared with the group as a whole. Frequent regurgitation was associated with a clinically relevant, incremental decline in HRQOL beyond that associated with heartburn before and after potent acid suppression in both NERD and RO. NCT00206284 and NCT00206245.

  2. Acid suppressants for managing gastro-oesophageal reflux and gastro-oesophageal reflux disease in infants: a national survey.

    PubMed

    Bell, Jane C; Schneuer, Francisco J; Harrison, Christopher; Trevena, Lyndal; Hiscock, Harriet; Elshaug, Adam G; Nassar, Natasha

    2018-02-22

    To evaluate the diagnosis and management of reflux and gastro-oesophageal reflux disease (GORD) in infants aged <1 year presenting to general practitioners (GPs). A nationally representative, prospective, cross-sectional survey of GP activity in Australia, 2006-2016 (Bettering the Evaluation And Care of Health Study). Annually, a random sample of around 1000 GPs recorded details for 100 consecutive visits with consenting, unidentified patients. Diagnoses of reflux and GORD and their management including prescribing of acid-suppressant medicines (proton pump inhibitors (PPIs) and histamine receptor antagonists (H2RAs)) and counselling, advice or education. Of all infants' visits, 512 (2.7%) included a diagnosis of reflux (n=413, 2.2%) or GORD (n=99, 0.5%). From 2006 to 2016, diagnostic rates decreased for reflux and increased for GORD. Prescribing of acid suppressants occurred in 43.6% visits for reflux and 48.5% visits for GORD, similar to rates of counselling, advice or education (reflux: 38.5%, GORD: 43.4% of visits). Prescribing of PPIs increased (statistically significant only for visits for reflux), while prescribing of H2RAs decreased. Overprescribing of acid suppressants to infants may be occurring. In infants, acid-suppressant medicines are no better than placebo and may have significant negative side effects; however, guidelines are inconsistent. Clear, concise and consistent guidance is needed. GPs and parents need to understand what is normal and limitations of medical therapy. We need a greater understanding of the influences on GP prescribing practices, of parents' knowledge and attitudes and of the pressures on parents of infants with these conditions. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  3. Impact of regurgitation on health-related quality of life in gastro-oesophageal reflux disease before and after short-term potent acid suppression therapy

    PubMed Central

    Kahrilas, Peter J; Jonsson, Andreas; Denison, Hans; Wernersson, Börje; Hughes, Nesta; Howden, Colin W

    2014-01-01

    Objective Limited data exist on the impact of regurgitation on health-related quality of life (HRQOL) in gastro-oesophageal reflux disease (GORD). We assessed the relationship between regurgitation frequency and HRQOL before and after acid suppression therapy in GORD. Method We used data from two randomised trials of AZD0865 25–75 mg/day vs. esomeprazole 20 or 40 mg/day in non-erosive reflux disease (NERD) (n=1415) or reflux oesophagitis (RO) (n=1460). The Reflux Disease Questionnaire was used to select patients with frequent and intense heartburn for inclusion and to assess treatment response. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was used to assess HRQOL. Results At baseline, 93% of patients in both the NERD and RO groups experienced regurgitation. Mean QOLRAD scores were similar for NERD and RO at baseline and at week 4 and disclosed decremental HRQOL with increasing frequency of regurgitation; a clinically relevant difference of >0.5 in mean QOLRAD scores was seen with regurgitation ≥4 days/week vs. <4 days/week. The prevalence of frequent, persistent regurgitation (≥4 days/week) at week 4 among heartburn responders (≤1 day/week of mild heartburn) was 28% in NERD and 23% in RO. QOLRAD scores were higher amongst heartburn responders. There was a similar pattern of impact related to regurgitation frequency in heartburn responders as in the group as a whole. Conclusion Frequent regurgitation was associated with a clinically relevant, incremental decline in HRQOL beyond that associated with heartburn before and after potent acid suppression, in both NERD and RO. Clinical trial numbers NCT00206284 and NCT00206245. PMID:23831734

  4. Docosahexaenoic acid suppresses breast cancer cell metastasis by targeting matrix-metalloproteinases.

    PubMed

    Yun, Eun-Jin; Song, Kyung-Sub; Shin, Soyeon; Kim, Soyeon; Heo, Jun-Young; Kweon, Gi-Ryang; Wu, Tong; Park, Jong-Il; Lim, Kyu

    2016-08-02

    Breast cancer is one of the most prevalent cancers in women, and nearly half of breast cancer patients develop distant metastatic disease after therapy. Despite the significant advances that have been achieved in understanding breast cancer metastasis in the past decades, metastatic cancer is still hard to cure. Here, we demonstrated an anti-cancer mechanism of docosahexaenoic acid (DHA) that suppressed lung metastasis in breast cancer. DHA could inhibit proliferation and invasion of breast cancer cells in vitro, and this was mainly through blocking Cox-2-PGE2-NF-κB-MMPs cascades. DHA treatment significantly decreased Cox-2 and NF-κB expression as well as nuclear translocation of NF-κB in MDA-MB-231 cells. In addition, DHA also reduced NF-κB binding to DNA which may lead to inactivation of MMPs. Moreover, in vivo studies using Fat-1 transgenic mice showed remarkable decrease of tumor growth and metastasis to EO771 cells to lung in DHA-rich environment. In conclusion, DHA attenuated breast cancer progression and lung metastasis in part through suppressing MMPs, and these findings suggest chemoprevention and potential therapeutic strategy to overcome malignant breast cancer.

  5. Impact of adherence on duration of virological suppression among patients receiving combination antiretroviral therapy.

    PubMed

    Raboud, J M; Harris, M; Rae, S; Montaner, J S G

    2002-04-01

    To assess the effect of adherence to antiretroviral therapy on the duration of virological suppression after controlling for whether or not the patient ever attained a plasma viral load below the limit of detection of sensitive HIV-1 RNA assays. Data were combined from three randomized, blinded clinical trials (INCAS, AVANTI-2, and AVANTI-3) that compared the antiviral effects of two- and three-drug antiretroviral regimens. Virological suppression was defined as maintaining a plasma viral load below 1000 copies/mL. Adherence was defined prospectively and measured by patient self-report. Adherence did not have a major impact on the probability of achieving virological suppression for patients receiving dual therapy. However, for patients receiving triple therapy, adherence increased the probability of virological suppression, whether the plasma viral load nadir was above or below the lower limit of quantification. Compared to adherent patients with a plasma viral load nadir below the lower limit of quantification, the relative risk of virological failure was 3.0 for non-adherent patients with a nadir below the limit, 18.1 for adherent patients with a nadir above the limit, and 32.1 for non-adherent patients with a nadir above the limit. For patients receiving current three-drug antiretroviral regimens, adherence to therapy and plasma viral load nadir are important factors determining the duration of virological suppression.

  6. Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques

    PubMed Central

    Del Prete, Gregory Q.; Shoemaker, Rebecca; Oswald, Kelli; Lara, Abigail; Trubey, Charles M.; Fast, Randy; Schneider, Douglas K.; Kiser, Rebecca; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Freemire, Brandi; Keele, Brandon F.; Estes, Jacob D.; Quiñones, Octavio A.; Smedley, Jeremy; Macallister, Rhonda; Sanchez, Rosa I.; Wai, John S.; Tan, Christopher M.; Alvord, W. Gregory; Hazuda, Daria J.; Piatak, Michael

    2014-01-01

    Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4+ T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches. PMID:25182644

  7. Hyaluronic acid-modified zirconium phosphate nanoparticles for potential lung cancer therapy.

    PubMed

    Li, Ranwei; Liu, Tiecheng; Wang, Ke

    2017-02-01

    Novel tumor-targeting zirconium phosphate (ZP) nanoparticles modified with hyaluronic acid (HA) were developed (HA-ZP), with the aim of combining the drug-loading property of ZP and the tumor-targeting ability of HA to construct a tumor-targeting paclitaxel (PTX) delivery system for potential lung cancer therapy. The experimental results indicated that PTX loading into the HA-ZP nanoparticles was as high as 20.36%±4.37%, which is favorable for cancer therapy. PTX-loaded HA-ZP nanoparticles increased the accumulation of PTX in A549 lung cancer cells via HA-mediated endocytosis and exhibited superior anticancer activity in vitro. In vivo anticancer efficacy assay revealed that HA-ZP nanoparticles possessed preferable anticancer abilities, which exhibited minimized toxic side effects of PTX and strong tumor-suppression potential in clinical application.

  8. Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV-infected Chinese rhesus macaques.

    PubMed

    Ling, Binhua; Piatak, Michael; Rogers, Linda; Johnson, Ann-Marie; Russell-Lodrigue, Kasi; Hazuda, Daria J; Lifson, Jeffrey D; Veazey, Ronald S

    2014-01-01

    Viral reservoirs-persistent residual virus despite combination antiretroviral therapy (cART)-remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM) treated with intensive combination antiretroviral therapy (cART) and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA). SIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L-870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations. Upon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters. The ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations.

  9. Transmission calculation and intensity suppression for a proton therapy system

    NASA Astrophysics Data System (ADS)

    Chen, Wei; Yang, Jun; Qin, Bin; Liang, ZhiKai; Chen, Qushan; Liu, Kaifeng; Li, Dong; Fan, Mingwu

    2018-02-01

    A proton therapy project HUST-PTF (HUST Proton Therapy Facility) based on a 250 MeV isochronous superconducting cyclotron is under development in Huazhong University of Science and Technology (HUST). In this paper we report the main design features of the beam line in HUST-PTF project. The energy selection system (ESS) for energy modulation is discussed in detail, including the collimators, momentum slit and transmission calculation. Due to significant difference among the transmissions of ESS for different energies, the intensity suppression scheme by defocusing beam at high energies on collimators in the beam line is proposed and discussed. Finally, the ratios of beam intensities between low and high energies are expected to be controlled within 10 to meet the clinical requirement, and the beam optics of each energy step after intensity suppression is studied respectively.

  10. Dosimetric impact of a CT metal artefact suppression algorithm for proton, electron and photon therapies

    NASA Astrophysics Data System (ADS)

    Wei, Jikun; Sandison, George A.; Hsi, Wen-Chien; Ringor, Michael; Lu, Xiaoyi

    2006-10-01

    Accurate dose calculation is essential to precision radiation treatment planning and this accuracy depends upon anatomic and tissue electron density information. Modern treatment planning inhomogeneity corrections use x-ray CT images and calibrated scales of tissue CT number to electron density to provide this information. The presence of metal in the volume scanned by an x-ray CT scanner causes metal induced image artefacts that influence CT numbers and thereby introduce errors in the radiation dose distribution calculated. This paper investigates the dosimetric improvement achieved by a previously proposed x-ray CT metal artefact suppression technique when the suppressed images of a patient with bilateral hip prostheses are used in commercial treatment planning systems for proton, electron or photon therapies. For all these beam types, this clinical image and treatment planning study reveals that the target may be severely underdosed if a metal artefact-contaminated image is used for dose calculations instead of the artefact suppressed one. Of the three beam types studied, the metal artefact suppression is most important for proton therapy dose calculations, intermediate for electron therapy and least important for x-ray therapy but still significant. The study of a water phantom having a metal rod simulating a hip prosthesis indicates that CT numbers generated after image processing for metal artefact suppression are accurate and thus dose calculations based on the metal artefact suppressed images will be of high fidelity.

  11. Perfluorooctanoic Acid Exposure Suppresses T-independent Antibody Responses

    EPA Science Inventory

    Exposure to  3.75mg/kg of perfluoroocatnoic acid (PFOA) for 15d suppresses T-dependent antibody responses (TDAR), suggesting that T helper cells and/or B cells/plasma cells may be impacted. This study evaluated effects of PFOA exposure on the T cell-independent antibody response...

  12. Citric Acid Suppresses the Bitter Taste of Olopatadine Hydrochloride Orally Disintegrating Tablets.

    PubMed

    Sotoyama, Mai; Uchida, Shinya; Tanaka, Shimako; Hakamata, Akio; Odagiri, Keiichi; Inui, Naoki; Watanabe, Hiroshi; Namiki, Noriyuki

    2017-01-01

    Orally disintegrating tablets (ODTs) are formulated to disintegrate upon contact with saliva, allowing administration without water. Olopatadine hydrochloride, a second-generation antihistamine, is widely used for treating allergic rhinitis. However, it has a bitter taste; therefore, the development of taste-masked olopatadine ODTs is essential. Some studies have suggested that citric acid could suppress the bitterness of drugs. However, these experiments were performed using solutions, and the taste-masking effect of citric acid on ODTs has not been evaluated using human gustatory sensation tests. Thus, this study evaluated citric acid's taste-masking effect on olopatadine ODTs. Six types of olopatadine ODTs containing 0-10% citric acid were prepared and subjected to gustatory sensation tests that were scored using the visual analog scale. The bitterness and overall palatability of olopatadine ODTs during disintegration in the mouth and after spitting out were evaluated in 11 healthy volunteers (age: 22.8±2.2 years). The hardness of the ODTs was >50 N. Disintegration time and dissolution did not differ among the different ODTs. The results of the gustatory sensation tests suggest that citric acid could suppress the bitterness of olopatadine ODTs in a dose-dependent manner. Olopatadine ODTs with a high content of citric acid (5-10%) showed poorer overall palatability than that of those without citric acid despite the bitterness suppression. ODTs containing 2.5% citric acid, yogurt flavoring, and aspartame were the most suitable formulations since they showed low bitterness and good overall palatability. Thus, citric acid is an effective bitterness-masking option for ODTs.

  13. Association Between Response to Acid-Suppression Therapy and Efficacy of Antireflux Surgery in Patients With Extraesophageal Reflux.

    PubMed

    Krill, Joseph T; Naik, Rishi D; Higginbotham, Tina; Slaughter, James C; Holzman, Michael D; Francis, David O; Garrett, C Gaelyn; Vaezi, Michael F

    2017-05-01

    The effectiveness of antireflux surgery (ARS) varies among patients with extraesophageal manifestations of gastroesophageal reflux disease (GERD). By studying a cohort of patients with primary extraesophageal symptoms and abnormal physiologic markers for GERD, we aimed to identify factors associated with positive outcomes from surgery, and compare outcomes to those with typical esophageal manifestations of GERD. We performed a retrospective cohort study to compare adult patients with extraesophageal and typical reflux symptoms who underwent de novo ARS from 2004 through 2012 at a tertiary care center. All 115 patients (79 with typical GERD and 36 with extraesophageal manifestations of GERD) had evidence of abnormal distal esophageal acid exposure based on pH testing or endoscopy. The principle outcome was time to primary symptom recurrence after surgery, based on patient reports of partial or total recurrence of symptoms at follow-up visits. Patients were followed up for a median duration of 66 months (interquartile range, 52-77 mo). The median time to recurrence of symptoms in the overall cohort was 68 months (11.5 months in the extraesophageal cohort vs >132 months in the typical cohort). Symptom recurrence after ARS was associated with having primarily extraesophageal symptoms (adjusted hazard ratio, 2.34; 95% confidence interval, 1.31-4.17) and poor preoperative symptom response to acid-suppression therapy (AST) (hazard ratio, 3.85; 95% confidence interval, 2.05-7.22). Patients with primary extraesophageal symptoms who had a full or partial preoperative AST response experienced lower rates of symptom recurrence compared to patients with poor AST response (P < .01). The rate of symptom recurrence was lowest among patients with primary typical reflux symptoms who had a partial or full symptom response to AST (P < .01). The severity of acid reflux on pH testing, symptom indices, severity of esophagitis, and hiatal hernia size were not associated with symptom

  14. Growth Suppression and Therapy Sensitization of Breast Cancer.

    DTIC Science & Technology

    1997-07-01

    mutant jun. As shown in Figure 8, T47D breast cancer cells grown in the presence of 9- cis retinoic acid do become more sensitive to suppression by p53...SRI 1220. We have used the plasmid reactivation assay to demonstrate that repair of a cisplatin damaged plasmid is inhibited by 9- cis retinoic acid in...3 hr in vitro Sensitivity of T47D cells to 9- cis RA with 25 pM cisplatin) 120 --- 25- T47D 1220 M 100 - 11-gal O ,p53 "o 8.0 o. m 5 wR 80 T47D

  15. Risk of fracture and pneumonia from acid suppressive drugs.

    PubMed

    Eom, Chun-Sick; Lee, Sang-Soo

    2011-09-26

    A recently published systematic review and meta-analysis, incorporating all relevant studies on the association of acid suppressive medications and pneumonia identified up to August 2009, revealed that for every 200 patients, treated with acid suppressive medication, one will develop pneumonia. They showed the overall risk of pneumonia was higher among people using proton pump inhibitors (PPIs) [adjusted odds ratio (OR) = 1.27, 95% CI: 1.11-1.46, I(2) = 90.5%] and Histamine-2 receptor antagonists (H2RAs) (adjusted OR = 1.22, 95% CI: 1.09-1.36, I(2) = 0.0%). In the randomized controlled trials, use of H2RAs was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI: 1.01-1.48, I(2) = 30.6%). Another meta-analysis of 11 studies published between 1997 and 2011 found that PPIs, which reduce stomach acid production, were associated with increased risk of fracture. The pooled OR for fracture was 1.29 (95% CI: 1.18-1.41) with use of PPIs and 1.10 (95% CI: 0.99-1.23) with use of H2RAs, when compared with non-use of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30, 95% CI: 1.15-1.48) and of hip fracture risk (adjusted OR = 1.34, 95% CI: 1.09-1.66), whereas long-term H2RA use was not significantly associated with fracture risk. Clinicians should carefully consider when deciding to prescribe acid-suppressive drugs, especially for patients who are already at risk for pneumonia and fracture. Since it is unnecessary to achieve an achlorhydric state in order to resolve symptoms, we recommend using the only minimum effective dose of drug required to achieve the desired therapeutic goals.

  16. Selective scavenging of intra-mitochondrial superoxide corrects diclofenac-induced mitochondrial dysfunction and gastric injury: A novel gastroprotective mechanism independent of gastric acid suppression.

    PubMed

    Mazumder, Somnath; De, Rudranil; Sarkar, Souvik; Siddiqui, Asim Azhar; Saha, Shubhra Jyoti; Banerjee, Chinmoy; Iqbal, Mohd Shameel; Nag, Shiladitya; Debsharma, Subhashis; Bandyopadhyay, Uday

    2016-12-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat multiple inflammatory diseases and pain but severe gastric mucosal damage is the worst outcome of NSAID-therapy. Here we report that mitoTEMPO, a mitochondrially targeted superoxide (O 2 - ) scavenger protected as well as healed gastric injury induced by diclofenac (DCF), the most commonly used NSAID. Common existing therapy against gastric injury involves suppression of gastric acid secretion by proton pump inhibitors and histamine H 2 receptor antagonists; however, dyspepsia, vitamin B12 deficiency and gastric microfloral dysbalance are the major drawbacks of acid suppression. Interestingly, mitoTEMPO did not inhibit gastric acid secretion but offered gastroprotection by preventing DCF-induced generation of O 2 - due to mitochondrial respiratory chain failure and by preventing mitochondrial oxidative stress (MOS)-mediated mitopathology. MitoTEMPO even restored DCF-stimulated reduced fatty acid oxidation, mitochondrial depolarization and bioenergetic crisis in gastric mucosa. MitoTEMPO also prevented the activation of mitochondrial pathway of apoptosis and MOS-mediated proinflammatory signaling through NF-κB by DCF. Furthermore, mitoTEMPO when administered in rats with preformed gastric lesions expedited the healing of gastric injury and the healed stomach exhibited its normal physiology as evident from gastric acid and pepsin secretions under basal or stimulated conditions. Thus, in contrast to the existing antiulcer drugs, mitochondrially targeted O 2 - scavengers like mitoTEMPO may represent a novel class of gastroprotective molecules that does not affect gastric acid secretion and may be used in combination with DCF, keeping its anti-inflammatory action intact, while reducing its gastrodamaging effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Eradication of Barrett's mucosa with argon plasma coagulation and acid suppression: immediate and mid term results

    PubMed Central

    Van Laethem, J-L; Cremer, M; Peny, M; Delhaye, M; Deviere, J

    1998-01-01

    Background—Intestinal metaplastic mucosa in Barrett's oesophagus can be replaced by squamous epithelium after mucosal thermal ablation associated with acid suppression therapy. 
Aims—To assess whether restoration of squamous epithelium can be obtained after ablation of Barrett's oesophagus using argon plasma coagulation (APC) associated with proton pump inhibitor (PPI) therapy. 
Methods—Thirty one patients with Barrett's oesophagus received APC. Omeprazole (40 mg/day) was given from the first APC application to one month after completion of the treatment, then given symptomatically. Twenty four hour pH-metry was performed during endotherapy. 
Results—Complete re-epithelialisation was visualised at endoscopy in 25/31 patients (81%) after a mean number of 2.4 APC sessions (range 1-4). Only partial squamous re-epithelialisation was observed in three patients and three others had no eradication. At histological assessment, eradication of Barrett's oesophagus was only confirmed in 19/31 patients (61%) due to the presence of a few residual Barrett's glands under the new squamous epithelium. Complete eradication was related to a Barrett's oesophagus segment length of less than 4 cm and the absence of circumferential extension but not to the normalisation of oesophageal acid exposure under PPI therapy. Seventeen patients with apparently complete endoscopic and histological eradication of Barrett's oesophagus were re-evaluated at one year; eight (47%) disclosed relapsing islands of Barrett metaplasia despite continuous omeprazole therapy (10-40 mg/day). 
Conclusions—APC combined with 40 mg omeprazole daily can eradicate Barrett's mucosa with apparent squamous re-epithelialisation in the majority of patients even in the absence of normalisation of oesophageal acid exposure. However, one year after endotherapy for Barrett's oesophagus, relapse is frequent but limited in extent. 

 Keywords: Barrett's oesophagus; argon plasma coagulation; omeprazole

  18. Extracorporeal Shock Wave Therapy Suppresses the Early Proinflammatory Immune Response to a Severe Cutaneous Burn Injury

    DTIC Science & Technology

    2009-02-01

    Burn wound model Mice were anaesthetised using isoflurane inha- lation. After shaving the dorsum, the exposed skin was washed gently with room...Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn injury* Thomas A Davis, Alexander...S, Peoples GE, Tadaki D, Elster EA. Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn

  19. Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19.

    PubMed

    Shimatani, Tomohiko; Inoue, Masaki; Kuroiwa, Tomoko; Xu, Jing; Mieno, Hiroshi; Nakamura, Masuo; Tazuma, Susumu

    2006-01-01

    To improve clinical outcomes of the initial therapy for gastroesophageal reflux disease, intragastric pH should be above 4.0 for more than 20 hours a day (83.3%) and nocturnal gastric acid breakthrough, defined as 60 continuous minutes of intragastric pH below 4.0 at night, should be inhibited. A "step-down" therapy sometimes fails because of insufficient acid suppression. Therefore we compared the acid-suppressive effects of proton pump inhibitors. This was a prospective, randomized, open-label, 8-way crossover study. In 9 healthy Helicobacter pylori-negative cytochrome P450 (CYP) 2C19 homozygous extensive metabolizers, intragastric pH was measured for 24 hours on day 7 of treatment with rabeprazole, omeprazole, and lansoprazole orally administered once daily at reduced and standard doses. Compared with baseline data (7% [range, 5%-20%]), the median values of the 24-hour percent of time that intragastric pH was above 4.0 significantly increased but did not exceed 83.3% under any of the 7 regimens, which were as follows: 10 mg rabeprazole (51% [range, 28%-78%], P < .01), 20 mg rabeprazole (59% [range, 36%-83%], P < .01), 10 mg omeprazole (26% [range, 4%-33%], P < .05), 20 mg omeprazole (48% [range, 31%-73%], P < .01), 40 mg omeprazole (62% [range, 47%-87%], P < .01), 15 mg lansoprazole (34% [range, 5%-51%], P < .05), and 30 mg lansoprazole (56% [range, 20%-76%], P < .05). Significant differences were observed among 10, 20, and 40 mg omeprazole (10 mg versus 20 mg, P < .01; 10 mg versus 40 mg, P < .01; and 20 mg versus 40 mg, P < .05) and between 15 and 30 mg lansoprazole (P < .01), whereas no significant difference was observed between 10 and 20 mg rabeprazole. Nocturnal gastric acid breakthrough was observed under all regimens. Rabeprazole, omeprazole, and lansoprazole, given once daily at standard doses, cannot be expected to achieve ideal acid suppression for the initial therapy for gastroesophageal reflux disease in Helicobacter-negative CYP2C19 homozygous

  20. Oral contraceptive therapy for polycystic ovary disease after chronic gonadotropin-releasing agonist administration. Predictors of continued ovarian suppression.

    PubMed

    Elkind-Hirsch, K E; Anania, C; Malinak, R

    1996-09-01

    To study the beneficial effects of oral contraceptive (OC) therapy following gonadotropin-releasing hormone agonist (GnRH-a) administration in women with polycystic ovary disease (PCOD). Twenty-three hyperandrogenic women (aged 15-39) were randomized into two groups; GnRH-a (depot every 28 days) for six months or combination therapy (GnRH-a plus OC "addback") for six months. Following six months of treatment with either therapy, all patients received OC therapy for at least six months. The hormonal state was evaluated at three-month intervals. Hormone levels of luteinizing hormone (LH), testosterone (T) and free T remained suppressed within the normal range in 11 of 17 patients (65%) during the six months of OC only therapy, while the other six patients showed "escape" from suppression, with the LH, T and free T concentrations rising to pre-GnRH-a treatment levels. Use of OC addback therapy did not potentiate the long-acting therapeutic effect of GnRH-a pretreatment; three of six patients in the escape group were pretreated with combination therapy and three with GnRH-a only. In the majority of women with PCOD, OC therapy following GnRH-a administration was effective in maintaining ovarian androgen suppression. Failure to maintain ovarian suppression in this patient population was associated with higher elevations of baseline free T concentrations.

  1. Quality of healing of gastric ulcers: Natural products beyond acid suppression

    PubMed Central

    Kangwan, Napapan; Park, Jong-Min; Kim, Eun-Hee; Hahm, Ki Baik

    2014-01-01

    Gastric ulcer is a chronic disease featured with unexpected complications, including bleeding, stenosis and perforation, as well as a high incidence of recurrence. Clinical treatments for gastric ulcer have allowed the rapid development of potent anti-ulcer drugs during the last several decades. Gastric ulcer healing is successful with conventional treatments including H2-receptor antagonists, and proton pump inhibitors (PPIs) have been essential for ulcer healing and prevention of complications. Additionally, Helicobacter pylori eradication therapy is effective in reducing ulcer recurrence and leads to physiological changes in the gastric mucosa which affect the ulcer healing process. However, in spite of these advancements, some patients have suffered from recurrence or intractability in spite of continuous anti-ulcer therapy. A new concept of the quality of ulcer healing (QOUH) was initiated that considers the reconstruction of the mucosal structure and its function for preventing ulcer recurrence. Although several gastroprotection provided these achievements of the QOUH, which PPI or other acid suppressants did not accomplish, we found that gastroprotection that originated from natural products, such as a newer formulation from either Artemisia or S-allyl cysteine from garlic, were very effective in the QOUH, as well as improving clinical symptoms with fewer side effects. In this review, we will introduce the importance of the QOUH in ulcer healing and the achievements from natural products. PMID:24891974

  2. Quality of healing of gastric ulcers: Natural products beyond acid suppression.

    PubMed

    Kangwan, Napapan; Park, Jong-Min; Kim, Eun-Hee; Hahm, Ki Baik

    2014-02-15

    Gastric ulcer is a chronic disease featured with unexpected complications, including bleeding, stenosis and perforation, as well as a high incidence of recurrence. Clinical treatments for gastric ulcer have allowed the rapid development of potent anti-ulcer drugs during the last several decades. Gastric ulcer healing is successful with conventional treatments including H2-receptor antagonists, and proton pump inhibitors (PPIs) have been essential for ulcer healing and prevention of complications. Additionally, Helicobacter pylori eradication therapy is effective in reducing ulcer recurrence and leads to physiological changes in the gastric mucosa which affect the ulcer healing process. However, in spite of these advancements, some patients have suffered from recurrence or intractability in spite of continuous anti-ulcer therapy. A new concept of the quality of ulcer healing (QOUH) was initiated that considers the reconstruction of the mucosal structure and its function for preventing ulcer recurrence. Although several gastroprotection provided these achievements of the QOUH, which PPI or other acid suppressants did not accomplish, we found that gastroprotection that originated from natural products, such as a newer formulation from either Artemisia or S-allyl cysteine from garlic, were very effective in the QOUH, as well as improving clinical symptoms with fewer side effects. In this review, we will introduce the importance of the QOUH in ulcer healing and the achievements from natural products.

  3. Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid, a Farnesoid X Receptor Antagonist.

    PubMed

    Fujita, Kyosuke; Iguchi, Yusuke; Une, Mizuho; Watanabe, Shiro

    2017-04-01

    The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR. We observed that the dietary administration of UDCA in mice decreased the expression levels of SREBP1c and its target lipogenic genes. Alpha- and β-muricholic acids (MCA) and cholic acid (CA) were the major bile acids in the mouse liver but their contents decreased upon UDCA administration. The hepatic contents of chenodeoxycholic acid and deoxycholic acid (DCA) were relatively low but were not changed by UDCA. UDCA did not show FXR agonistic or antagonistic potency in in vitro FXR transactivation assay. Taking these together, we deduced that the above-mentioned change in hepatic bile acid composition induced upon UDCA administration might cause the relative increase in the FXR activity in the liver, mainly by the reduction in the content of β-MCA, a farnesoid X receptor antagonist, which suggests a mechanism by which UDCA suppresses lipogenesis and decreases the lipid contents in the mouse liver.

  4. DETERMINATION OF CARBOXYLIC ACIDS BY ION-EXCLUSION CHROMATOGRAPHY WITH NON-SUPPRESSED CONDUCTIVITY AND OPTICAL DETECTORS

    EPA Science Inventory

    Determination of carboxylic acids using non-suppressed conductivity and UV detections is described. The background conductance of 1-octanesulfonic acid, hexane sulfonic acid and sulfuric acid at varying concentrations was determined. Using 0.2 mM 1-octanesulfonic acid as a mobile...

  5. Mindfulness-based cognitive therapy for depressed individuals improves suppression of irrelevant mental-sets.

    PubMed

    Greenberg, Jonathan; Shapero, Benjamin G; Mischoulon, David; Lazar, Sara W

    2017-04-01

    An impaired ability to suppress currently irrelevant mental-sets is a key cognitive deficit in depression. Mindfulness-based cognitive therapy (MBCT) was specifically designed to help depressed individuals avoid getting caught in such irrelevant mental-sets. In the current study, a group assigned to MBCT plus treatment-as-usual (n = 22) exhibited significantly lower depression scores and greater improvements in irrelevant mental-set suppression compared to a wait-list plus treatment-as-usual (n = 18) group. Improvements in mental-set-suppression were associated with improvements in depression scores. Results provide the first evidence that MBCT can improve suppression of irrelevant mental-sets and that such improvements are associated with depressive alleviation.

  6. [Differentiation therapy for non-acidic gastroesophageal reflux disease].

    PubMed

    Lishchuk, N B; Simanenkov, V I; Tikhonov, S V

    2017-01-01

    To investigate the clinical and pathogenetic features of the non-acidic types of gastroesophageal reflux disease (GERD) and to evaluate the impact of combined therapy versus monotherapy on the course of this disease. The investigation enrolled 62 patients with non-acidic GERD. The follow-up period was 6 weeks. The patients were divided into 2 groups: 1) weakly acidic gastroesophageal refluxes (GER); 2) weakly alkaline GER. Then each group was distributed, thus making up 4 groups: 1) 19 patients with weakly acidic GER who received monotherapy with rabeprazole 20 mg/day; 2) 21 patients with weakly acidic GER had combined therapy with rabeprazole 20 mg and itopride; 3) 8 patients with weakly alkaline GER who received ursodeoxycholic acid (UDCA) monotherapy; and 4) 14 patients with weakly alkaline GER who had combined therapy with UDCA and itopride, The clinical symptoms of the disease, the endoscopic pattern of the upper gastrointestinal tract (GIT) mucosa, histological changes in the esophageal and gastric mucosa, and the results of 24-hour impedance pH monitoring were assessed over time. During differentiation therapy, the majority of patients reported positive clinical changes and an improved or unchanged endoscopic pattern. Assessment of impedance pH monitoring results revealed decreases in the overall number of GERs, the presence of a bolus in the esophagus, and the number of proximal refluxes. These changes were noted not only in patients taking proton pump inhibitors (PPIs), but also in those treated with UDCA monotherapy or combined PPI and prokinetic therapy. A differentiated approach to non-acidic GER treatment contributes to its efficiency. Adding the prokinetic itomed (itopride hydrochloride) to PPI therapy in a patient with weakly acidic GER enhances the efficiency of treatment, by positively affecting upper GIT motility. The mainstay of therapy for GERD with a predominance of weakly alkaline refluxes is UDCA, the combination of the latter and the

  7. Photodynamic therapy with simultaneous suppression of multiple treatment escape pathways (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Z.; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2016-03-01

    We introduce photoactivatable multi-inhibitor nanoliposomes (PMILs) for photodynamic tumor cell and microvessel damage in synchrony with photo-initiation of tumor-confined, multikinase inhibitor release. The PMIL is a biodegradable delivery system comprised of a nanoliposome carrying a photoactivable chromophore (benzoporphyrin derivative monoacid A, BPD) in its bilayer. A multikinase inhibitor-loaded PEG-PLGA nanoparticle is encapsulated within the liposome, which acts a barrier to nanoparticle erosion and drug release. Following intravenous PMIL administration, near infrared irradiation of tumors triggers photodynamic therapy and initiates tumor-confined drug release from the nanoparticle. This talk presents promising preclinical data in mouse models of pancreatic cancer utilizing this concept to suppress the VEGF and MET signaling pathways—both critical to cancer progression, metastasis and treatment escape. A single PMIL treatment using low doses of a multikanse inhibitor (cabozantinib, XL184) achieves sustained tumor reduction and suppresses metastatic escape, whereas combination therapy by co-administration of the individual agents has significantly reduced efficacy. The PMIL concept is amenable to a number of molecular inhibitors and offers new prospects for spatiotemporal synchronization of combination therapies whilst reducing systemic drug exposure and associated toxicities.

  8. Liquid L-thyroxine versus tablet L-thyroxine in patients on L- thyroxine replacement or suppressive therapy: a meta-analysis.

    PubMed

    Laurent, Irakoze; Tang, Siying; Astère, Manirakiza; Wang, Kan Ran; Deng, Shuhua; Xiao, Ling; Li, Qi Fu

    2018-03-23

    To compare the effectiveness of liquid L-T4 (L-thyroxine) and tablet L-T4 in patients on L-T4 replacement or suppressive therapy. The Cochrane Library, PubMed, Embase, and Web of Science databases were searched to identify relevant articles. All prospective or randomized controlled studies (RCTs) comparing liquid L-T4 and tablet L-T4 in patients on L-T4 replacement or suppressive therapy were included in the analysis. Overall, the initial search of the four databases identified 1278 published studies; of these, eight studies were ultimately included in the meta-analysis. TSH (thyroid stimulating hormone) levels were significantly suppressed in patients on liquid L-T4 compared with those on tablet L-T4, in patients on L-T4 suppressive therapy with L-T4 malabsorption (Mean Difference (MD) = -2.26, 95% Confidence Interval (CI): -3.59, -0.93; P = 0.0009)). However, liquid L-T4 and tablet L-T4 did not show a statistically significant difference in patients on L-T4 suppressive therapy without malabsorption (MD = 0.08, 95% CI: -0.31, 0.47; P = 0.69). TSH levels were significantly normalized in patients on liquid L-T4 compared with those on tablet L-T4, in Patients on L-T4 replacement therapy with L-T4 malabsorption (MD = -3.20, 95% CI: -5.08, -1.32; P = 0.0009). However, liquid L-T4 and tablet L-T4 did not show a statistically significant difference in patients on L-T4 replacement therapy without malabsorption (MD = 0.91, 95% CI: -0.03, 1.86; P = 0.06). Liquid L-T4 is more efficient than tablet L-T4 in patients on L-T4 replacement or suppressive therapy with malabsorption. No significant differences were observed in patients without malabsorption. Further studies should be conducted to verify these findings.

  9. Acid and non-acid reflux in patients refractory to proton pump inhibitor therapy: is gastroparesis a factor?

    PubMed

    Tavakkoli, Anna; Sayed, Bisma A; Talley, Nicholas J; Moshiree, Baharak

    2013-10-07

    To determine whether an increased number and duration of non-acid reflux events as measured using the multichannel intraluminal impedance pH (MII-pH) is linked to gastroparesis (GP). A case control study was conducted in which 42 patients undergoing clinical evaluation for continued symptoms of gastroesophageal reflux disease (both typical and atypical symptoms) despite acid suppression therapy. MII-pH technology was used over 24 h to detect reflux episodes and record patients' symptoms. Parameters evaluated in patients with documented GP and controls without GP by scintigraphy included total, upright, and supine number of acid and non-acid reflux episodes (pH < 4 and pH > 4, respectively), the duration of acid and non-acid reflux in a 24-h period, and the number of reflux episodes lasting longer than 5 min. No statistical difference was seen between the patients with GP and controls with respect to the total number or duration of acid reflux events, total number and duration of non-acid reflux events or the duration of longest reflux episodes. The number of non-acid reflux episodes with a pH > 7 was higher in subjects with GP than in controls. In addition, acid reflux episodes were more prolonged (lasting longer than 5 min) in the GP patients than in controls; however, these values did not reach statistical significance. Thirty-five patients had recorded symptoms during the 24 h study and of the 35 subjects, only 9% (n = 3) had a positive symptom association probability (SAP) for acid/non-acid reflux and 91% had a negative SAP. The evaluation of patients with a documented history of GP did not show an association between GP and more frequent episodes of non-acid reflux based on MII-pH testing.

  10. Targeted inhibition of p38alpha MAPK suppresses tumor-associated endothelial cell migration in response to hypericin-based photodynamic therapy.

    PubMed

    Hendrickx, Nico; Dewaele, Michael; Buytaert, Esther; Marsboom, Glenn; Janssens, Stefan; Van Boven, Maurits; Vandenheede, Jackie R; de Witte, Peter; Agostinis, Patrizia

    2005-11-25

    Photodynamic therapy (PDT) is an established anticancer modality and hypericin is a promising photosensitizer for the treatment of bladder tumors. We show that exposure of bladder cancer cells to hypericin PDT leads to a rapid rise in the cytosolic calcium concentration which is followed by the generation of arachidonic acid by phospholipase A2 (PLA2). PLA2 inhibition significantly protects cells from the PDT-induced intrinsic apoptosis and attenuates the activation of p38 MAPK, a survival signal mediating the up-regulation of cyclooxygenase-2 that converts arachidonic acid into prostanoids. Importantly, inhibition of p38alpha MAPK blocks the release of vascular endothelial growth factor and suppresses tumor-promoted endothelial cell migration, a key step in angiogenesis. Hence, targeted inhibition of p38alpha MAPK could be therapeutically beneficial to PDT, since it would prevent COX-2 expression, the inducible release of growth and angiogenic factors by the cancer cells, and cause an increase in the levels of free arachidonic acid, which promotes apoptosis.

  11. Fatal spontaneous Clostridium septicum gas gangrene: a possible association with iatrogenic gastric acid suppression.

    PubMed

    Wu, Yiru E; Baras, Alexander; Cornish, Toby; Riedel, Stefan; Burton, Elizabeth C

    2014-06-01

    The long-term use of proton pump inhibitors has been linked to an increased risk for the development of gastric polyps, hip fractures, pneumonia, and Clostridium difficile colitis. There is evidence that chronic acid suppression from long-term use of proton pump inhibitors poses some risk for the development of C difficile-associated diarrhea by decreasing the elimination of pathogenic microbes before reaching the lower gastrointestinal tract. Here we present a case of a 51-year-old woman with a recent history of abdominal pain and fever who presented to the emergency department with rapidly progressive spontaneous necrotizing fasciitis and gas gangrene and died within hours of presentation. Postmortem examination confirmed spreading tissue gas gangrene and myonecrosis. In addition, multiple intestinal ulcers containing Clostridium septicum were present at autopsy. This case illustrates a possible association between proton pump inhibitor therapy and fatal C septicum infection.

  12. Combination Therapy with Atorvastatin and Amlodipine Suppresses Angiotensin II-Induced Aortic Aneurysm Formation

    PubMed Central

    Takahashi, Kikuyo; Matsumoto, Yasuharu; Do.e, Zhulanqiqige; Kanazawa, Masanori; Satoh, Kimio; Shimizu, Takuya; Sato, Akira; Fukumoto, Yoshihiro; Shimokawa, Hiroaki

    2013-01-01

    Background Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. Methods and Results Experimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. Conclusions Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho

  13. Mindfulness-based cognitive therapy may reduce thought suppression in previously suicidal participants: findings from a preliminary study.

    PubMed

    Hepburn, Silvia R; Crane, Catherine; Barnhofer, Thorsten; Duggan, Danielle S; Fennell, Melanie J V; Williams, J Mark G

    2009-06-01

    Thought suppression is a strategy aimed at mental control that may paradoxically increase the frequency of unwanted thoughts. This preliminary study examined effects of mindfulness-based cognitive therapy (MBCT) on thought suppression and depression in individuals with past depression and suicidality. In a randomized controlled trial design, 68 participants were allocated to an MBCT group or a treatment-as-usual waitlist control. Measures of thought suppression and depression were taken pre- and post-treatment. MBCT did not reduce thought suppression as measured by the White Bear Suppression Inventory, but significantly reduced self-reported attempts to suppress in the previous week. Preliminary evidence suggests that MBCT for suicidality may reduce thought suppression, but differential effects on thought suppression measures warrant further studies.

  14. Acid-suppressive efficacy of a reduced dosage of rabeprazole: comparison of 10 mg twice daily rabeprazole with 20 mg twice daily rabeprazole, 30 mg twice daily lansoprazole, and 20 mg twice daily omeprazole by 24-hr intragastric pH-metry.

    PubMed

    Shimatani, Tomohiko; Inoue, Masaki; Kuroiwa, Tomoko; Xu, Jing; Tazuma, Susumu; Horikawa, Yoko; Nakamura, Masuo

    2005-07-01

    Rabeprazole achieves more potent acid suppression than other proton pump inhibitors. Therefore it is administered at reduced as well as high dosages in eradication therapy for Helicobacter pylori; however, there is incomplete assessment of the efficacy of a reduced dosage of rabeprazole as might be employed in therapy. In this study, we evaluated acid-suppressive efficacy of a reduced dosage of rabeprazole on day 7 by 24-hr pH-metry in 10 healthy male cytochrome P-450 2C19 extensive metabolizers without Helicobacterpylori infection and compared the results with those of high dosages of rabeprazole, lansoprazole, and omeprazole. Median intragastric pH value, pH >3 holding time ratio (pH>3HT), pH>4HT, pH>5HT, pH>6HT, and pH>7HT for 24 hr with rabeprazole, 10 mg twice daily, were not significantly different from those of rabeprazole, 20 mg twice daily, lansoprazole, 30 mg twice daily, and omeprazole, 20 mg twice daily. In conclusion, for acid-suppressive efficacy, a reduced dosage of rabeprazole is comparable to high dosages of rabeprazole, lansoprazole, and omeprazole.

  15. Hyaluronic Acid: A Boon in Periodontal Therapy

    PubMed Central

    Dahiya, Parveen; Kamal, Reet

    2013-01-01

    Hyaluronic acid is a naturally occurring linear polysaccharide of the extracellular matrix of connective tissue, synovial fluid, and other tissues. Its use in the treatment of the inflammatory process is established in medical areas such as orthopedics, dermatology, and ophthalmology. The Pubmed/Medline database was searched for keywords “Hyaluronic acid and periodontal disease” and “Hyaluronic acid and gingivitis” which resulted in 89 and 22 articles respectively. Only highly relevant articles from electronic and manual search in English literature were selected for the present review article. In the field of dentistry, hyaluronic acid has shown anti-inflammatory and anti-bacterial effects in the treatment of periodontal diseases. Due to its tissue healing properties, it could be used as an adjunct to mechanical therapy in the treatment of periodontitis. Further studies are required to determine the clinical efficacy of hyaluronic acid in healing of periodontal lesion. The aim of the present review, article is to discuss the role of hyaluronic acid in periodontal therapy. PMID:23814761

  16. On the suppression of plasma nonesterified fatty acids by insulin during enhanced intravascular lipolysis in humans.

    PubMed

    Carpentier, André C; Frisch, Frédérique; Cyr, Denis; Généreux, Philippe; Patterson, Bruce W; Giguère, Robert; Baillargeon, Jean-Patrice

    2005-11-01

    During the fasting state, insulin reduces nonesterified fatty acid (NEFA) appearance in the systemic circulation mostly by suppressing intracellular lipolysis in the adipose tissue. In the postprandial state, insulin may also control NEFA appearance through enhanced trapping into the adipose tissue of NEFA derived from intravascular triglyceride lipolysis. To determine the contribution of suppression of intracellular lipolysis in the modulation of plasma NEFA metabolism by insulin during enhanced intravascular triglyceride lipolysis, 10 healthy nonobese subjects underwent pancreatic clamps at fasting vs. high physiological insulin level with intravenous infusion of heparin plus Intralipid. Nicotinic acid was administered orally during the last 2 h of each 4-h clamp to inhibit intracellular lipolysis and assess insulin's effect on plasma NEFA metabolism independently of its effect on intracellular lipolysis. Stable isotope tracers of palmitate, acetate, and glycerol were used to assess plasma NEFA metabolism and total triglyceride lipolysis in each participant. The glycerol appearance rate was similar during fasting vs. high insulin level, but plasma NEFA levels were significantly lowered by insulin. Nicotinic acid significantly blunted the insulin-mediated suppression of plasma palmitate appearance and oxidation rates by approximately 60 and approximately 70%, respectively. In contrast, nicotinic acid did not affect the marked stimulation of palmitate clearance by insulin. Thus most of the insulin-mediated reduction of plasma NEFA appearance and oxidation can be explained by suppression of intracellular lipolysis during enhanced intravascular triglyceride lipolysis in healthy humans. Our results also suggest that insulin may affect plasma NEFA clearance independently of the suppression of intracellular lipolysis.

  17. A clinical data validated mathematical model of prostate cancer growth under intermittent androgen suppression therapy

    NASA Astrophysics Data System (ADS)

    Portz, Travis; Kuang, Yang; Nagy, John D.

    2012-03-01

    Prostate cancer is commonly treated by a form of hormone therapy called androgen suppression. This form of treatment, while successful at reducing the cancer cell population, adversely affects quality of life and typically leads to a recurrence of the cancer in an androgen-independent form. Intermittent androgen suppression aims to alleviate some of these adverse affects by cycling the patient on and off treatment. Clinical studies have suggested that intermittent therapy is capable of maintaining androgen dependence over multiple treatment cycles while increasing quality of life during off-treatment periods. This paper presents a mathematical model of prostate cancer to study the dynamics of androgen suppression therapy and the production of prostate-specific antigen (PSA), a clinical marker for prostate cancer. Preliminary models were based on the assumption of an androgen-independent (AI) cell population with constant net growth rate. These models gave poor accuracy when fitting clinical data during simulation. The final model presented hypothesizes an AI population with increased sensitivity to low levels of androgen. It also hypothesizes that PSA production is heavily dependent on androgen. The high level of accuracy in fitting clinical data with this model appears to confirm these hypotheses, which are also consistent with biological evidence.

  18. An Example of Genetically Distinct HIV Type 1 Variants in Cerebrospinal Fluid and Plasma During Suppressive Therapy

    PubMed Central

    Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars; Peterson, Julia; Shao, Wei; Spudich, Serena; Price, Richard W.; Palmer, Sarah

    2014-01-01

    We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system. PMID:24338353

  19. An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy.

    PubMed

    Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars; Peterson, Julia; Shao, Wei; Spudich, Serena; Price, Richard W; Palmer, Sarah

    2014-05-15

    We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system.

  20. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders.

    PubMed

    Richardson, Rose; Smart, Matthew; Tracey-White, Dhani; Webster, Andrew R; Moosajee, Mariya

    2017-02-01

    Between 5 and 70% of genetic disease is caused by in-frame nonsense mutations, which introduce a premature termination codon (PTC) within the disease-causing gene. Consequently, during translation, non-functional or gain-of-function truncated proteins of pathological significance, are formed. Approximately 50% of all inherited retinal disorders have been associated with PTCs, highlighting the importance of novel pharmacological or gene correction therapies in ocular disease. Pharmacological nonsense suppression of PTCs could delineate a therapeutic strategy that treats the mutation in a gene- and disease-independent manner. This approach aims to suppress the fidelity of the ribosome during protein synthesis so that a near-cognate aminoacyl-tRNA, which shares two of the three nucleotides of the PTC, can be inserted into the peptide chain, allowing translation to continue, and a full-length functional protein to be produced. Here we discuss the mechanisms and evidence of nonsense suppression agents, including the small molecule drug ataluren (or PTC124) and next generation 'designer' aminoglycosides, for the treatment of genetic eye disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Effect of gastric acid suppressants and prokinetics on peritoneal dialysis-related peritonitis

    PubMed Central

    Kwon, Ji Eun; Koh, Seong-Joon; Chun, Jaeyoung; Kim, Ji Won; Kim, Byeong Gwan; Lee, Kook Lae; Im, Jong Pil; Kim, Joo Sung; Jung, Hyun Chae

    2014-01-01

    AIM: To investigate the effect of gastric acid suppressants and prokinetics on peritonitis development in peritoneal dialysis (PD) patients. METHODS: This was a single-center, retrospective study. The medical records of 398 PD patients were collected from January 2000 to September 2012 and analyzed to compare patients with at least one episode of peritonitis (peritonitis group, group A) to patients who never had peritonitis (no peritonitis group, group B). All peritonitis episodes were analyzed to compare peritonitis caused by enteric organisms and peritonitis caused by non-enteric organisms. RESULTS: Among the 120 patients who met the inclusion criteria, 61 patients had at least one episode of peritonitis and 59 patients never experienced peritonitis. Twenty-four of 61 patients (39.3%) in group A and 15 of 59 patients (25.4%) in group B used gastric acid suppressants. Only the use of H2-blocker (H2B) was associated with an increased risk of PD-related peritonitis; the use of proton pump inhibitors, other antacids, and prokinetics was not found to be a significant risk factor for PD-related peritonitis. A total of 81 episodes of peritonitis were divided into enteric peritonitis (EP) or non-enteric peritonitis, depending on the causative organism, and gastric acid suppressants and prokinetics did not increase the risk of EP in PD patients. CONCLUSION: The use of H2B showed a trend for an increased risk of overall PD-related peritonitis, although further studies are required to clarify the effects of drugs on PD-related peritonitis. PMID:25057226

  2. Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fang, Zhong-Ze; Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian

    Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showedmore » that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4{sup +} naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. - Highlights: • CPT-11 is an effective anticancer drug, but induced toxicity limits its application in the clinic. • CPT-11 decreased IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes. • CPT-11 altered the composition of bile acid metabolites, notably DCA and TDCA in liver, bile and intestine. • DCA and TDCA potentiated CPT-11-induced suppression of IL-10 secretion by active CD4{sup +} naive T cells.« less

  3. Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation.

    PubMed

    Kaneko, Chihiro; Ogura, Jiro; Sasaki, Shunichi; Okamoto, Keisuke; Kobayashi, Masaki; Kuwayama, Kaori; Narumi, Katsuya; Iseki, Ken

    2017-03-01

    A high intake of fructose increases the risk for hyperuricemia. It has been reported that long-term fructose consumption suppressed renal uric acid excretion and increased serum uric acid level. However, the effect of single administration of fructose on excretion of uric acid has not been clarified. We used male Wistar rats, which were orally administered fructose (5g/kg). Those rats were used in each experiment at 12h after administration. Single administration of fructose suppressed the function of ileal uric acid excretion and had no effect on the function of renal uric acid excretion. Breast cancer resistance protein (BCRP) predominantly contributes to intestinal excretion of uric acid as an active homodimer. Single administration of fructose decreased BCRP homodimer level in the ileum. Moreover, diphenyleneiodonium (DPI), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), recovered the suppression of the function of ileal uric acid excretion and the Bcrp homodimer level in the ileum of rats that received single administration of fructose. Single administration of fructose decreases in BCRP homodimer level, resulting in the suppression the function of ileal uric acid excretion. The suppression of the function of ileal uric acid excretion by single administration of fructose is caused by the activation of Nox. The results of our study provide a new insight into the mechanism of fructose-induced hyperuricemia. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. DIBROMOACETIC ACID ATTENUATES A DIMETHYLDITHIOCARBAMATE-INDUCED SUPPRESSION OF THE RAT LH SURGE

    EPA Science Inventory

    DIBROMOACETIC ACID ATTENUATES A DITHIOCARBAMATE-INDUCED SUPPRESSION OF THE LH SURGE IN THE RAT. Jerome M. Goldman, Ashley S. Murr, Angela R. Buckelew, W. Keith McElroy and Janet M. Ferrell. Repro. Toxicol. Div., NHEERL, ORD, US EPA, RTP, NC

    At elevated concentrations, the ...

  5. Binocular Therapy for Childhood Amblyopia Improves Vision Without Breaking Interocular Suppression.

    PubMed

    Bossi, Manuela; Tailor, Vijay K; Anderson, Elaine J; Bex, Peter J; Greenwood, John A; Dahlmann-Noor, Annegret; Dakin, Steven C

    2017-06-01

    Amblyopia is a common developmental visual impairment characterized by a substantial difference in acuity between the two eyes. Current monocular treatments, which promote use of the affected eye by occluding or blurring the fellow eye, improve acuity, but are hindered by poor compliance. Recently developed binocular treatments can produce rapid gains in visual function, thought to be as a result of reduced interocular suppression. We set out to develop an effective home-based binocular treatment system for amblyopia that would engage high levels of compliance but that would also allow us to assess the role of suppression in children's response to binocular treatment. Balanced binocular viewing therapy (BBV) involves daily viewing of dichoptic movies (with "visibility" matched across the two eyes) and gameplay (to monitor compliance and suppression). Twenty-two children (3-11 years) with anisometropic (n = 7; group 1) and strabismic or combined mechanism amblyopia (group 2; n = 6 and 9, respectively) completed the study. Groups 1 and 2 were treated for a maximum of 8 or 24 weeks, respectively. The treatment elicited high levels of compliance (on average, 89.4% ± 24.2% of daily dose in 68.23% ± 12.2% of days on treatment) and led to a mean improvement in acuity of 0.27 logMAR (SD 0.22) for the amblyopic eye. Importantly, acuity gains were not correlated with a reduction in suppression. BBV is a binocular treatment for amblyopia that can be self-administered at home (with remote monitoring), producing rapid and substantial benefits that cannot be solely mediated by a reduction in interocular suppression.

  6. Linoleic acid suppresses cholesterol efflux and ATP-binding cassette transporters in murine bone marrow-derived macrophages

    USDA-ARS?s Scientific Manuscript database

    Individuals with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease (CVD), possibly associated with elevated plasma free fatty acid concentrations. Paradoxically, evidence suggests that unsaturated, compared to saturated fatty acids, suppress macrophage chole...

  7. Science review: The use of proton pump inhibitors for gastric acid suppression in critical illness

    PubMed Central

    Brett, Stephen

    2005-01-01

    Prophylaxis is routinely provided for critically ill patients admitted to intensive care units (ICUs) who are at high risk for stress-related mucosal damage (SRMD), an erosive process of the gastroduodenum associated with abnormally high physiological demands. Traditionally, treatment options have included sucralfate, antacids and histamine H2 receptor antagonists (H2RAs). The H2RAs are currently the most widely used agents in prophylactic acid suppression; however, proton pump inhibitors (PPIs) have recently replaced H2RAs in the treatment of many acid-related conditions. PPIs achieve a more rapid and sustained increase in gastric pH and are not associated with the rapid tachyphylaxis seen with H2RAs. As a result, and after the introduction of intravenous formulations, PPIs are beginning to be used for the prophylaxis of SRMD in critically ill adults. The high prevalence of renal and hepatic impairment among the ICU population, as well as the need for multiple drug therapy in many patients, means that pharmacokinetic characteristics and the potential for drug interactions may be important considerations in the choice of prophylactic agent. This review seeks to present the pharmacological evidence that may inform decision-making about the prescription of drugs for prophylaxis of SRMD. PMID:15693983

  8. Gene therapy mediated seizure suppression in Genetic Generalised Epilepsy: Neuropeptide Y overexpression in a rat model.

    PubMed

    Powell, Kim L; Fitzgerald, Xavier; Shallue, Claire; Jovanovska, Valentina; Klugmann, Matthias; Von Jonquieres, Georg; O'Brien, Terence J; Morris, Margaret J

    2018-05-01

    Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippocampus can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures. Three cohorts of GAERS were injected bilaterally into the thalamus (short term n = 14 and long term n = 8) or the somatosensory cortex (n = 26) with rAAV-NPY or rAAV-empty. EEG recordings were acquired weekly post-treatment and seizure expression was quantified. Anxiety levels were tested using elevated plus maze and open field test. NPY and NPY receptor mRNA and protein expression were evaluated using quantitative PCR, immunohistochemistry and immunofluorescence. Viral overexpression of human NPY in the thalamus and somatosensory cortex in GAERS significantly reduced the time spent in seizure activity and number of seizures, whereas seizure duration was only reduced after thalamic NPY overexpression. Human and rat NPY and rat Y2 receptor mRNA expression was significantly increased in the somatosensory cortex. NPY overexpression in the thalamus was observed in rAAV-NPY treated rats compared to controls in the long term cohort. No effect was observed on anxiety behaviour. We conclude that virally-mediated human NPY overexpression in the thalamus or somatosensory cortex produces sustained anti-epileptic effects in GAERS. NPY gene therapy may represent a novel approach for the treatment of patients with genetic generalised epilepsies. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas

    PubMed Central

    Long, Adrienne H.; Highfill, Steven L.; Cui, Yongzhi; Smith, Jillian P.; Walker, Alec J.; Ramakrishna, Sneha; El-Etriby, Rana; Galli, Susana; Tsokos, Maria G.; Orentas, Rimas J.; Mackall, Crystal L.

    2016-01-01

    Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CARs) have shown impressive activity against B cell malignancies, and preliminary results suggest that T cells expressing a first generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18/18 (100%) of osteosarcomas, 2/15 (13%) of rhabdomyosarcomas, and 7/35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro. However in xenograft models, GD2-CAR T cells had no antitumor effect against GD2+ sarcoma, despite effectively controlling GD2+ neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSCs) that inhibited human CAR T-cell responses in vitro. Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. PMID:27549124

  10. Interactions between cranberries and fungi: the proposed function of organic acids in virulence suppression of fruit rot fungi

    PubMed Central

    Tadych, Mariusz; Vorsa, Nicholi; Wang, Yifei; Bergen, Marshall S.; Johnson-Cicalese, Jennifer; Polashock, James J.; White, James F.

    2015-01-01

    Cranberry fruit are a rich source of bioactive compounds that may function as constitutive or inducible barriers against rot-inducing fungi. The content and composition of these compounds change as the season progresses. Several necrotrophic fungi cause cranberry fruit rot disease complex. These fungi remain mostly asymptomatic until the fruit begins to mature in late August. Temporal fluctuations and quantitative differences in selected organic acid profiles between fruit of six cranberry genotypes during the growing season were observed. The concentration of benzoic acid in fruit increased while quinic acid decreased throughout fruit development. In general, more rot-resistant genotypes (RR) showed higher levels of benzoic acid early in fruit development and more gradual decline in quinic acid levels than that observed in the more rot-susceptible genotypes. We evaluated antifungal activities of selected cranberry constituents and found that most bioactive compounds either had no effects or stimulated growth or reactive oxygen species (ROS) secretion of four tested cranberry fruit rot fungi, while benzoic acid and quinic acid reduced growth and suppressed secretion of ROS by these fungi. We propose that variation in the levels of ROS suppressive compounds, such as benzoic and quinic acids, may influence virulence by the fruit rot fungi. Selection for crops that maintain high levels of virulence suppressive compounds could yield new disease resistant varieties. This could represent a new strategy for control of disease caused by necrotrophic pathogens that exhibit a latent or endophytic phase. PMID:26322038

  11. Omega-3 Free Fatty Acids Suppress Macrophage Inflammasome Activation by Inhibiting NF-κB Activation and Enhancing Autophagy

    PubMed Central

    Williams-Bey, Yolanda; Boularan, Cedric; Vural, Ali; Huang, Ning-Na; Hwang, Il-Young; Shan-Shi, Chong; Kehrl, John H.

    2014-01-01

    The omega-3 (ω3) fatty acid docosahexaenoic acid (DHA) can suppress inflammation, specifically IL-1β production through poorly understood molecular mechanisms. Here, we show that DHA reduces macrophage IL-1β production by limiting inflammasome activation. Exposure to DHA reduced IL-1β production by ligands that stimulate the NLRP3, AIM2, and NAIP5/NLRC4 inflammasomes. The inhibition required Free Fatty Acid Receptor (FFAR) 4 (also known as GPR120), a G-protein coupled receptor (GPR) known to bind DHA. The exposure of cells to DHA recruited the adapter protein β-arrestin1/2 to FFAR4, but not to a related lipid receptor. DHA treatment reduced the initial inflammasome priming step by suppressing the nuclear translocation of NF-κB. DHA also reduced IL-1β levels by enhancing autophagy in the cells. As a consequence macrophages derived from mice lacking the essential autophagy protein ATG7 were partially resistant to suppressive effects of DHA. Thus, DHA suppresses inflammasome activation by two distinct mechanisms, inhibiting the initial priming step and by augmenting autophagy, which limits inflammasome activity. PMID:24911523

  12. Thyroid stimulating hormone suppression post-therapy in patients with Graves' disease: a systematic review of pathophysiology and clinical data.

    PubMed

    Yu, Huan; Farahani, Pendar

    2015-04-08

    Post-treatment hypothyroidism is common in Graves' disease, and clinical guidelines recommend monitoring for it; however, thyroid stimulating hormone (TSH) can remain suppressed in these patients following treatment. The objectives of this study were to explore the proposed pathophysiology behind the phenomenon of post-therapy TSH suppression and to systematically review existing clinical data on post-therapy TSH suppression in patients with Graves' disease. A systematic literature search was performed using EMBASE and PubMed databases, with several combinations of MeSH terms. Bibliography mining was also done on relevant articles to be as inclusive as possible. A total of 18 articles described possible mechanisms for post-therapy TSH suppression. Several of the studies demonstrate evidence of thyrotroph atrophy and hypothesize that this contributes to the ongoing suppression. TSH receptors have been identified in folliculo-stellate cells of the pituitary as well as astroglial cells of the hypothalamus, mediating paracrine feedback. A few studies have demonstrated inverse correlation between autoantibody titres and TSH levels, suggestive of their role in mediating ongoing TSH suppression in patients with Graves' disease. In addition, five studies were identified that provided clinical data on the duration of TSH suppression. Combined data show that 45.5% of patients recover TSH by 3 months after treatment, increasing to 69.3% by 6 months, and plateauing to 73.8% by 12 months (p>0.0001). Sub-analysis also shows that for patients who are TBII negative, 80.7% recover their TSH by 6 months compared with only 58.7% in those who are TBII positive (p= 0.003). Clinical data suggests that TSH recovery is most likely to occur within the first 6 months after treatment, with recovery plateauing at approximately 70% of patients, suggesting that reliance on this assay for monitoring can be very misleading. Furthermore, TBII positivity is associated with lower likelihood of TSH

  13. Correlates of HIV-1 viral suppression in a cohort of HIV-positive drug users receiving antiretroviral therapy in Hanoi, Vietnam

    PubMed Central

    Jordan, Michael R; La, Hanh; Nguyen, Hien Duc; Sheehan, Heidi; Lien, Trinh Thi Minh; Van Dang, Duong; Hellinger, James; Wanke, Christine; Tang, Alice M

    2009-01-01

    Summary Injection drug users bear the burden of HIV in Vietnam and are a focus of national treatment programs. To date, determinants of successful therapy in this population are unknown. Substance use and clinical correlates of viral suppression were studied in 100 HIV-1 infected drug users receiving antiretroviral therapy (ART) for at least 6 months in Hanoi, Vietnam. Mean age of the cohort was 29.9 + 4.9 years; all were men. A majority of patients (73%) achieved viral suppression (HIV-RNA < 1000 copies/ml). Correlates of viral suppression include self-reported >95% adherence (p<0.01) and current use of trimethoprim/sulfamethoxazole (p<0.01); current or ever diagnosed with tuberculosis was associated with viral non-suppression (p=0.006). Tobacco use was prevalent (84%), and surprisingly 48% of patients reported active drug use; neither was associated with viral non-suppression. This is the first study to document successful ART treatment in a population of Vietnamese drug users; rates of viral suppression are comparable to other international populations. The 28% of patients without HIV-1 suppression highlights the need for adherence promotion, risk reduction programs, and population based surveillance strategies for assessing the emergence of HIV drug resistance in settings where access to viral load and drug resistance testing is limited. PMID:19451329

  14. Correlates of HIV-1 viral suppression in a cohort of HIV-positive drug users receiving antiretroviral therapy in Hanoi, Vietnam.

    PubMed

    Jordan, M R; La, H; Nguyen, H D; Sheehan, H; Lien, T T M; Duong, D V; Hellinger, J; Wanke, C; Tang, A M

    2009-06-01

    Injection drug users bear the burden of HIV in Vietnam and are a focus of national treatment programmes. To date, determinants of successful therapy in this population are unknown. Substance use and clinical correlates of viral suppression were studied in 100 HIV-1-infected drug users receiving antiretroviral therapy (ART) for at least six months in Hanoi, Vietnam. The mean age of the cohort was 29.9 + 4.9 years; all were men. A majority of patients (73%) achieved viral suppression (HIV-RNA <1000 copies/mL). Correlates of viral suppression include self-reported > or = 95% adherence (P < 0.01) and current use of trimethoprim/sulphamethoxazole (P < 0.01); current or ever diagnosed with tuberculosis was associated with viral non-suppression (P = 0.006). Tobacco use was prevalent (84%), and surprisingly 48% of patients reported active drug use; neither was associated with viral non-suppression. This is the first study to document successful ART treatment in a population of Vietnamese drug users; rates of viral suppression are comparable to other international populations. The 28% of patients without HIV-1 suppression highlight the need for adherence promotion, risk reduction programmes, and population-based surveillance strategies for assessing the emergence of HIV drug resistance in settings where access to viral load and drug resistance testing is limited.

  15. Ferulic Acid Suppresses Glutamate Release Through Inhibition of Voltage-Dependent Calcium Entry in Rat Cerebrocortical Nerve Terminals

    PubMed Central

    Lin, Tzu Yu; Lu, Cheng Wei; Huang, Shu-Kuei

    2013-01-01

    Abstract This study investigated the effects and possible mechanism of ferulic acid, a naturally occurring phenolic compound, on endogenous glutamate release in the nerve terminals of the cerebral cortex in rats. Results show that ferulic acid inhibited the release of glutamate evoked by the K+ channel blocker 4-aminopyridine (4-AP). The effect of ferulic acid on the evoked glutamate release was prevented by chelating the extracellular Ca2+ ions, but was insensitive to the glutamate transporter inhibitor DL-threo-beta-benzyl-oxyaspartate. Ferulic acid suppressed the depolarization-induced increase in a cytosolic-free Ca2+ concentration, but did not alter 4-AP–mediated depolarization. Furthermore, the effect of ferulic acid on evoked glutamate release was abolished by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but not by blocking ryanodine receptors or mitochondrial Na+/Ca2+ exchange. These results show that ferulic acid inhibits glutamate release from cortical synaptosomes in rats through the suppression of presynaptic voltage-dependent Ca2+ entry. PMID:23342970

  16. α-Lipoic acid suppresses the development of DNFB-induced atopic dermatitis-like symptoms in NC/Nga mice.

    PubMed

    Kim, Gun-Dong; Kim, Tae-Ho; Jang, An-Hee; Ahn, Hyun-Jong; Park, Yong Seek; Park, Cheung-Seog

    2011-02-01

    Atopic dermatitis (AD) is a common skin disease that has complex pathogenic mechanisms. Under specific pathogen-free conditions, repeated epicutaneous treatment of 2-4-dinitrofluorobenzene (DNFB) evokes AD-like clinical symptoms in NC/Nga mice. α-Lipoic acid (α-LA; 1, 2-dithiolane-3-pentanoic acid) is a dietary component that is synthesized in bacteria, yeast, plants, and mammals. α-LA and its reduced form, dihydrolipoic acid, are powerful antioxidants that have many physiological functions, including free radical scavenging of reactive oxygen species, generation of cellular antioxidants, chelation of metal ions, and inflammatory suppression. In this study, we investigated whether α-LA suppresses AD-like skin lesions induced by repeated DNFB application in NC/Nga mice. α-LA significantly suppressed production of interferon (IFN)-γ and interleukin (IL)-4 by activated CD4(+) T cells. We found that the oral administration of α-LA reduced AD-like clinical symptoms and inhibited increases of epidermal thickness in DNFB-induced AD-like skin lesions of NC/Nga mice. Furthermore, total serum IgE levels were dramatically reduced by topical α-LA treatment. Our findings suggest that oral administration of α-LA suppresses the development of AD in DNFB-treated NC/Nga mice and reduces IFN-γ and IL-4 production from activated CD4(+) T cells as well as total serum IgE levels. © 2011 John Wiley & Sons A/S.

  17. Tranexamic acid suppresses ultraviolet B eye irradiation-induced melanocyte activation by decreasing the levels of prohormone convertase 2 and alpha-melanocyte-stimulating hormone.

    PubMed

    Hiramoto, Keiichi; Yamate, Yurika; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2014-12-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medicinal amino acid used in skin whitening care. This study examined the effects of tranexamic acid on the melanocyte activation of the skin induced by an ultraviolet (UV) B eye irradiation. The eye or ear was locally exposed to UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp after covering the remaining body surface with aluminum foil. UVB eye irradiation induced melanocyte activation of the skin, similar to that observed following UVB ear irradiation, which was suppressed by the administration of tranexamic acid treatment. The plasma α-melanocyte-stimulating hormone (α-MSH) content was increased by UVB irradiation of the eye; however, the increase in α-MSH was suppressed by tranexamic acid treatment. In addition, UVB eye irradiation induced the up-regulation of prohormone convertase (PC) 2 in the pituitary gland. Meanwhile, the increase in PC2 induced by UVB eye irradiation was suppressed by tranexamic acid treatment. These results clearly indicate that tranexamic acid decreases the expression of PC2, which cleavages from proopiomelanocortin to α-MSH in the pituitary gland, thereby suppressing melanocyte activation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study.

    PubMed

    Han, Hye Sook; Park, Ji Chan; Park, Suk Young; Lee, Kyu Taek; Bae, Sang Byung; Kim, Han Jo; Kim, Samyoung; Yun, Hwan Jung; Bae, Woo Kyun; Shim, Hyun-Jeong; Hwang, Jun-Eul; Cho, Sang-Hee; Park, Moo-Rim; Shim, Hyeok; Kwon, Jihyun; Choi, Moon Ki; Kim, Seung Taik; Lee, Ki Hyeong

    2015-12-01

    In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded. Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001). This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate. ©AlphaMed Press.

  19. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells.

    PubMed

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy.

  20. Animal model of acid-reflux esophagitis: pathogenic roles of acid/pepsin, prostaglandins, and amino acids.

    PubMed

    Takeuchi, Koji; Nagahama, Kenji

    2014-01-01

    Esophagitis was induced in rats within 3 h by ligating both the pylorus and transitional region between the forestomach and glandular portion under ether anesthesia. This esophageal injury was prevented by the administration of acid suppressants and antipepsin drug and aggravated by exogenous pepsin. Damage was also aggravated by pretreatment with indomethacin and the selective COX-1 but not COX-2 inhibitor, whereas PGE2 showed a biphasic effect depending on the dose; a protection at low doses, and an aggravation at high doses, with both being mediated by EP1 receptors. Various amino acids also affected this esophagitis in different ways; L-alanine and L-glutamine had a deleterious effect, while L-arginine and glycine were highly protective, both due to yet unidentified mechanisms. It is assumed that acid/pepsin plays a major pathogenic role in this model of esophagitis; PGs derived from COX-1 are involved in mucosal defense of the esophagus; and some amino acids are protective against esophagitis. These findings also suggest a novel therapeutic approach in the treatment of esophagitis, in addition to acid suppressant therapy. The model introduced may be useful to test the protective effects of drugs on esophagitis and investigate the mucosal defense mechanism in the esophagus.

  1. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

    PubMed

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-06-01

    The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

  2. Nonlinear system identification for prostate cancer and optimality of intermittent androgen suppression therapy.

    PubMed

    Suzuki, Taiji; Aihara, Kazuyuki

    2013-09-01

    These days prostate cancer is one of the most common types of malignant neoplasm in men. Androgen ablation therapy (hormone therapy) has been shown to be effective for advanced prostate cancer. However, continuous hormone therapy often causes recurrence. This results from the progression of androgen-dependent cancer cells to androgen-independent cancer cells during the continuous hormone therapy. One possible method to prevent the progression to the androgen-independent state is intermittent androgen suppression (IAS) therapy, which ceases dosing intermittently. In this paper, we propose two methods to estimate the dynamics of prostate cancer, and investigate the IAS therapy from the viewpoint of optimality. The two methods that we propose for dynamics estimation are a variational Bayesian method for a piecewise affine (PWA) system and a Gaussian process regression method. We apply the proposed methods to real clinical data and compare their predictive performances. Then, using the estimated dynamics of prostate cancer, we observe how prostate cancer behaves for various dosing schedules. It can be seen that the conventional IAS therapy is a way of imposing high cost for dosing while keeping the prostate cancer in a safe state. We would like to dedicate this paper to the memory of Professor Luigi M. Ricciardi. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice.

    PubMed

    Mathers, A R; Carey, C D; Killeen, M E; Diaz-Perez, J A; Salvatore, S R; Schopfer, F J; Freeman, B A; Falo, L D

    2017-04-01

    Reactions between nitric oxide (NO), nitrite (NO2-), and unsaturated fatty acids give rise to electrophilic nitro-fatty acids (NO 2 -FAs), such as nitro oleic acid (OA-NO 2 ) and nitro linoleic acid (LNO 2 ). Endogenous electrophilic fatty acids (EFAs) mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction reactions. Hence, there is considerable interest in employing NO 2 -FAs and other EFAs for the prevention and treatment of inflammatory disorders. Thus, we sought to determine whether OA-NO 2 , an exemplary nitro-fatty acid, has the capacity to inhibit cutaneous inflammation. We evaluated the effect of OA-NO 2 on allergic contact dermatitis (ACD) using an established model of contact hypersensitivity in C57Bl/6 mice utilizing 2,4-dinitrofluorobenzene as the hapten. We found that subcutaneous (SC) OA-NO 2 injections administered 18 h prior to sensitization and elicitation suppresses ACD in both preventative and therapeutic models. In vivo SC OA-NO 2 significantly inhibits pathways that lead to inflammatory cell infiltration and the production of inflammatory cytokines in the skin. Moreover, OA-NO 2 is capable of enhancing regulatory T-cell activity. Thus, OA-NO 2 treatment results in anti-inflammatory effects capable of inhibiting ACD by inducing immunosuppressive responses. Overall, these results support the development of OA-NO 2 as a promising therapeutic for ACD and provides new insights into the role of electrophilic fatty acids in the control of cutaneous immune responses potentially relevant to a broad range of allergic and inflammatory skin diseases. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    PubMed Central

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  5. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells

    PubMed Central

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy. PMID:27073325

  6. Chromatographic retention prediction and octanol-water partition coefficient determination of monobasic weak acidic compounds in ion-suppression reversed-phase liquid chromatography using acids as ion-suppressors.

    PubMed

    Ming, Xin; Han, Shu-ying; Qi, Zheng-chun; Sheng, Dong; Lian, Hong-zhen

    2009-08-15

    Although simple acids, replacing buffers, have been widely applied to suppress the ionization of weakly ionizable acidic analytes in reversed-phase liquid chromatography (RPLC), none of the previously reported works focused on the systematic studies about the retention behavior of the acidic solutes in this ion-suppression RPLC mode. The subject of this paper was therefore to investigate the retention behavior of monobasic weak acidic compounds using acetic, perchloric and phosphoric acids as the ion-suppressors. The apparent octanol-water partition coefficient (K" ow) was proposed to calibrate the octanol-water partition coefficient (K(ow)) of these weak acidic compounds, which resulted in a better linear correlation with log k(w), the logarithm of the hypothetical retention factor corresponding to neat aqueous fraction of hydroorganic mobile phase. This log K" ow-log k w linear correlation was successfully validated by the results of monocarboxylic acids and monohydrating phenols, and moreover by the results under diverse experimental conditions for the same solutes. This straightforward relationship not only can be used to effectively predict the retention values of weak acidic solutes combined with Snyder-Soczewinski equation, but also can offer a promising medium for directly measuring K(ow) data of these compounds via Collander equation. In addition, the influence of the different ion-suppressors on the retention of weak acidic compounds was also compared in this RPLC mode.

  7. Breast-cancer adjuvant therapy with zoledronic acid.

    PubMed

    Coleman, Robert E; Marshall, Helen; Cameron, David; Dodwell, David; Burkinshaw, Roger; Keane, Maccon; Gil, Miguel; Houston, Stephen J; Grieve, Robert J; Barrett-Lee, Peter J; Ritchie, Diana; Pugh, Julia; Gaunt, Claire; Rea, Una; Peterson, Jennifer; Davies, Claire; Hiley, Victoria; Gregory, Walter; Bell, Richard

    2011-10-13

    Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients. In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed. At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups. These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

  8. Cancer risk in HIV patients with incomplete viral suppression after initiation of antiretroviral therapy.

    PubMed

    Lee, Jennifer S; Cole, Stephen R; Achenbach, Chad J; Dittmer, Dirk P; Richardson, David B; Miller, William C; Mathews, Christopher; Althoff, Keri N; Moore, Richard D; Eron, Joseph J

    2018-01-01

    Cancer causes significant morbidity and mortality among HIV patients in the US due to extended life expectancy with access to effective antiretroviral therapy. Low, detectable HIV RNA has been studied as a risk factor for adverse health outcomes, but its clinical impact on cancer risk remains unclear. The objective of this study was to determine whether HIV RNA <1,000 copies/mL six months after starting therapy was associated with 10-year first cancer risk. We followed 7,515 HIV therapy initiators from a US-based multicenter clinical cohort from 1998 to 2014. We used nonparametric multiple imputation to account for viral loads that fell below assay detection limits, and categorized viral loads six months after therapy initiation into four groups: <20, 20-199, 200-999, and >999 copies/mL. We calculated estimates of the cumulative incidence of cancer diagnosis, accounting for death as a competing event. Inverse probability of exposure and censoring weights were used to control for confounding and differential loss to follow up, respectively. Crude 10-year first cancer risk in the study sample was 7.03% (95% CI: 6.08%, 7.98%), with the highest risk observed among patients with viral loads between 200 and 999 copies/mL six months after ART initiation (10.7%). After controlling for baseline confounders, 10-year first cancer risk was 6.90% (95% CI: 5.69%, 8.12%), and was similar across viral load categories. Overall risk of first cancer was not associated with incomplete viral suppression; however, cancer remains a significant threat to HIV patients after treatment initiation. As more HIV patients gain access to treatment in the current "treat all" era, occurrences of incomplete viral suppression will be observed more frequently in clinical practice, which supports continued study of the role of low-level HIV RNA on cancer development.

  9. Comparative study of trichloroacetic acid vs. photodynamic therapy with topical 5-aminolevulinic acid for actinic keratosis of the scalp.

    PubMed

    Di Nuzzo, Sergio; Cortelazzi, Chiara; Boccaletti, Valeria; Zucchi, Alfredo; Conti, Maria Luisa; Montanari, Paola; Feliciani, Claudio; Fabrizi, Giuseppe; Pagliarello, Calogero

    2015-09-01

    Photodynamic therapy with 5-methyl-aminolevulinate and photodynamic therapy with trichloroacetic acid 50% are the two techniques utilized in the management of actinic keratosis. This study was planned to compare the efficacy, adverse effects, recurrence and cosmetic outcome of these option therapies in patients with multiple actinic keratosis of the scalp. Thirteen patients with multiple actinic keratosis were treated with one of the two treatments on half of the scalp at baseline, while the other treatment was performed on the other half 15 days apart, randomly. Efficacy, adverse effects, cosmetic outcome and recurrence were recorded at follow-up visit at 1, 3, 6 and 12 months. Photodynamic therapy with 5 methyl-aminolevulinate was more effective than trichloroacetic acid although less tolerated by patients as it was more painful. Early adverse effects were almost the same even if trichloroacetic acid leads also to crust formation and to a worse cosmetic outcome characterized by hypopigmentation. Recurrence was lower in the area treated with photodynamic therapy. Trichloroacetic acid 50% is less effective than photodynamic therapy with 5 methyl-aminolevulinate in the treatment of multiple actinic keratosis of the scalp although better tolerated by patients. As this technique is less painful and less expensive than photodynamic therapy, we hypothesize and suggest that more sequential treatments could lead to better results. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Assessing the Role of ETHYLENE RESPONSE FACTOR Transcriptional Repressors in Salicylic Acid-Mediated Suppression of Jasmonic Acid-Responsive Genes.

    PubMed

    Caarls, Lotte; Van der Does, Dieuwertje; Hickman, Richard; Jansen, Wouter; Verk, Marcel C Van; Proietti, Silvia; Lorenzo, Oscar; Solano, Roberto; Pieterse, Corné M J; Van Wees, Saskia C M

    2017-02-01

    Salicylic acid (SA) and jasmonic acid (JA) cross-communicate in the plant immune signaling network to finely regulate induced defenses. In Arabidopsis, SA antagonizes many JA-responsive genes, partly by targeting the ETHYLENE RESPONSE FACTOR (ERF)-type transcriptional activator ORA59. Members of the ERF transcription factor family typically bind to GCC-box motifs in the promoters of JA- and ethylene-responsive genes, thereby positively or negatively regulating their expression. The GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Here, we investigated whether SA-induced ERF-type transcriptional repressors, which may compete with JA-induced ERF-type activators for binding at the GCC-box, play a role in SA/JA antagonism. We selected ERFs that are transcriptionally induced by SA and/or possess an EAR transcriptional repressor motif. Several of the 16 ERFs tested suppressed JA-dependent gene expression, as revealed by enhanced JA-induced PDF1.2 or VSP2 expression levels in the corresponding erf mutants, while others were involved in activation of these genes. However, SA could antagonize JA-induced PDF1.2 or VSP2 in all erf mutants, suggesting that the tested ERF transcriptional repressors are not required for SA/JA cross-talk. Moreover, a mutant in the co-repressor TOPLESS, that showed reduction in repression of JA signaling, still displayed SA-mediated antagonism of PDF1.2 and VSP2. Collectively, these results suggest that SA-regulated ERF transcriptional repressors are not essential for antagonism of JA-responsive gene expression by SA. We further show that de novo SA-induced protein synthesis is required for suppression of JA-induced PDF1.2, pointing to SA-stimulated production of an as yet unknown protein that suppresses JA-induced transcription. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  11. Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India.

    PubMed

    Dravid, Ameet N; Natrajan, Kartik; Kulkarni, Milind M; Saraf, Chinmay K; Mahajan, Uma S; Kore, Sachin D; Rathod, Niranjan M; Mahajan, Umakant S; Wadia, Rustom S

    2018-02-01

    Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) <1000 copies/mL (virologically suppressed) were included. Among these, individuals presenting with neurologic symptoms during follow-up were assessed for CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): <20 to 332.5] and 4250 (IQR: 2550.0- 9615.0) copies/mL, respectively. All 9 individuals in which CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P < .001). The risk of discordance was also greater in patients who received protease inhibitor (PI) containing ART (P < .001) and those on ART regimens with central nervous system (CNS) penetration effectiveness (CPE) value <6 (P = .006).CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has

  12. Nucleic acid aptamers: an emerging frontier in cancer therapy.

    PubMed

    Zhu, Guizhi; Ye, Mao; Donovan, Michael J; Song, Erqun; Zhao, Zilong; Tan, Weihong

    2012-11-04

    The last two decades have witnessed the development and application of nucleic acid aptamers in a variety of fields, including target analysis, disease therapy, and molecular and cellular engineering. The efficient and widely applicable aptamer selection, reproducible chemical synthesis and modification, generally impressive target binding selectivity and affinity, relatively rapid tissue penetration, low immunogenicity, and rapid systemic clearance make aptamers ideal recognition elements for use as therapeutics or for in vivo delivery of therapeutics. In this feature article, we discuss the development and biomedical application of nucleic acid aptamers, with emphasis on cancer cell aptamer isolation, targeted cancer therapy, oncology biomarker identification and drug discovery.

  13. Methods for suppressing isomerization of olefin metathesis products

    DOEpatents

    Firth, Bruce E.; Kirk, Sharon E.; Gavaskar, Vasudeo S.

    2015-09-22

    A method for suppressing isomerization of an olefin metathesis product produced in a metathesis reaction includes adding an isomerization suppression agent to a mixture that includes the olefin metathesis product and residual metathesis catalyst from the metathesis reaction under conditions that are sufficient to passivate at least a portion of the residual metathesis catalyst. The isomerization suppression agent is phosphorous acid, a phosphorous acid ester, phosphinic acid, a phosphinic acid ester or combinations thereof. Methods of refining natural oils are described.

  14. Extracellular acidification by lactic acid suppresses glucose deprivation-induced cell death and autophagy in B16 melanoma cells.

    PubMed

    Matsuo, Taisuke; Sadzuka, Yasuyuki

    2018-02-19

    In solid tumors, cancer cells survive and proliferate under conditions of microenvironment stress such as poor nutrients and hypoxia due to inadequate vascularization. These stress conditions in turn activate autophagy, which is important for cancer cell survival. However, autophagy has a contrary effect of inducing cell death in cancer cells cultured in vitro under conditions of glucose deprivation. In this study, we hypothesized that supplementation of lactic acid serves as a means of cell survival under glucose-deprived conditions. At neutral pH, cell death of B16 murine melanoma cells by autophagy under glucose-deprived conditions was observed. However, supplementation of lactic acid suppressed cell death and autophagy in B16 melanoma cells when cultured in glucose-deprived conditions. Sodium lactate, which does not change extracellular pH, did not inhibit cell death, while HCl-adjusted acidic pH suppressed cell death under glucose-deprived conditions. These results suggested that an acidic pH is crucial for cell survival under glucose-deprived conditions. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Molecular mechanisms in therapy of acid-related diseases

    PubMed Central

    Shin, J. M.; Vagin, O.; Munson, K.; Kidd, M.; Modlin, I. M.; Sachs, G.

    2011-01-01

    Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists. PMID:17928953

  16. In vivo Therapy with Monoclonal Anti-I-A Antibody Suppresses Immune Responses to Acetylcholine Receptor

    NASA Astrophysics Data System (ADS)

    Waldor, Matthew K.; Sriram, Subramaniam; McDevitt, Hugh O.; Steinman, Lawrence

    1983-05-01

    A monoclonal antibody to I-A gene products of the immune response gene complex attenuates both humoral and cellular responses to acetylcholine receptor and appears to suppress clinical manifestations of experimental autoimmune myasthenia gravis. This demonstrates that use of antibodies against immune response gene products that are associated with susceptibility to disease may be feasible for therapy in autoimmune conditions such as myasthenia gravis.

  17. Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy.

    PubMed

    Tsai, Angela; Irrinki, Alivelu; Kaur, Jasmine; Cihlar, Tomas; Kukolj, George; Sloan, Derek D; Murry, Jeffrey P

    2017-04-15

    Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs. IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is persistently

  18. Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy

    PubMed Central

    Tsai, Angela; Irrinki, Alivelu; Kaur, Jasmine; Cihlar, Tomas; Kukolj, George

    2017-01-01

    ABSTRACT Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs. IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is

  19. Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases.

    PubMed

    Keeling, Kim M; Bedwell, David M

    2011-01-01

    Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in-frame premature termination codons (PTCs) to restore translation of a full-length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense-mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy. Copyright © 2011 John Wiley & Sons, Ltd.

  20. Antiretroviral Therapy Use, Medication Adherence, and Viral Suppression Among PLWHA with Panic Symptoms.

    PubMed

    Sam, Tanyka Suzanne; Hutton, Heidi E; Lau, Bryan; McCaul, Mary E; Keruly, Jeanne; Moore, Richard; Chander, Geetanjali

    2015-11-01

    Panic symptoms are prevalent among PLWHAs, yet few studies have examined their relationship with HIV outcomes. Using data from an observational cohort study in Baltimore, MD, we examined the association between panic symptoms and antiretroviral therapy (ART) use, medication adherence, and viral suppression. Data were analyzed using generalized estimating equations and adjusted for age, sex, race/ethnicity, cocaine and/or heroin use, clinic enrollment time, alcohol use, and depressive symptoms. Between June 2010 and September 2012, 1195 individuals participated in 2080 audio computer assisted interviews; 9.9 % (n = 118) of individuals endorsed current panic symptoms. In multivariate analysis, panic symptoms were associated with decreased ART use (IRR 0.94; p = 0.05). Panic symptoms were neither associated with medication adherence nor viral suppression. These findings were independent of depressive symptoms and substance use. Panic symptoms are under-recognized in primary care settings and present an important barrier to ART use. Further studies investigating the reasons for this association are needed.

  1. Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59.

    PubMed

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C M; Pieterse, Corné M J

    2013-02-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCF(COI1), which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCF(COI1)-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59.

  2. Acidic conditions induce the suppression of CD86 and CD54 expression in THP-1 cells.

    PubMed

    Mitachi, Takafumi; Mezaki, Minori; Yamashita, Kunihiko; Itagaki, Hiroshi

    2018-01-01

    To evaluate the sensitization potential of chemicals in cosmetics, using non-animal methods, a number of in vitro safety tests have been designed. Current assays are based on the expression of cell surface markers, such as CD86 and CD54, which are associated with the activation of dendritic cells, in skin sensitization tests. However, these markers are influenced by culture conditions through activating danger signals. In this study, we investigated the relationship between extracellular pH and the expression of the skin sensitization test human cell line activation test (h-CLAT) markers CD86 and CD54. We measured expression levels after THP-1 cells were exposed to representative contact allergens, i.e., 2,4-dinitrochlorobenzene and imidazolidinyl urea, under acidic conditions. These conditions were set by exposure to hydrochloric acid, lactic acid, and citric acid. An acidic extracellular pH (6-7) suppressed the augmentation of CD86 and CD54 levels by the sensitizer. Additionally, when the CD86/CD54 expression levels were suppressed, a reduction in the intracellular pH was confirmed. Furthermore, we observed that Na + /H + exchanger 1 (NHE-1), a protein that contributes to the regulation of extracellular/intracellular pH, is involved in CD86 and CD54 expression. These findings suggest that the extracellular/intracellular pH has substantial effects on in vitro skin sensitization markers and should be considered in evaluations of the safety of mixtures and commercial products in the future.

  3. The current use of estrogens for growth-suppressant therapy in adolescent girls.

    PubMed

    Barnard, Neal D; Scialli, Anthony R; Bobela, Suzanne

    2002-02-01

    To assess the current prevalence of growth-suppressant therapy using oral estrogens for tall adolescent girls among U.S. pediatric endocrinologists. A questionnaire was mailed to pediatric endocrinologists practicing in the United States, asking how many patients each clinician had recently treated for tall stature using oral estrogens, whether he/she continued to offer such treatment, reasons for offering or declining to offer it, criteria for initiating and terminating treatment, choice of estrogen, and typical doses, durations, and effects. Of 411 respondents, 92 (22%) reported having treated 1-5 girls for tall stature during the preceding five years. Only 4 (1%) had treated more than 5 cases during this period. Growth-suppression treatment was currently offered by 137 respondents (33.3%). Reasons for doing so included parents' and patients' concerns about stature and the adverse social effects of unusually tall stature. Reasons for not offering such treatments were that its long-term risks are unknown, that tall stature is not a disease, and a lack of referrals. Few clinicians initiated treatment if predicted mature height was below 183 cm. Treatment was typically terminated based on evidence of epiphyseal fusion, usually within less than two years, although extended treatments were common. Frequently reported adverse effects included weight gain, nausea/vomiting, areolar or nipple pigmentation, headache, and irregular menses. Although treatment is less commonly initiated than in the past, many pediatric endocrinologists continue to offer oral estrogens to suppress growth for tall adolescent girls.

  4. Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.

    PubMed

    Yang, Guang-Wei; Jiang, Jin-Song; Lu, Wei-Qin

    2015-10-12

    Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.

  5. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting

    EPA Science Inventory

    T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARa)-dependent and...

  6. Carbon dioxide therapy and hyaluronic acid for cosmetic correction of the nasolabial folds.

    PubMed

    Nisi, Giuseppe; Cuomo, Roberto; Brandi, Cesare; Grimaldi, Luca; Sisti, Andrea; D'Aniello, Carlo

    2016-06-01

    The main application of hyaluronic acid filling, in esthetic medicine, is the augmentation of soft tissues. The carbon dioxide therapy, instead, improves quality and elasticity of the dermis and increases the oxygen release to the tissue through an enhancing of the Bohr's effect. The aim of the study was to compare the efficacy, tolerability, and effect duration of hyaluronic acid fillers and the use of carbon dioxide therapy plus hyaluronic acid in the cosmetic correction of nasolabial folds. Forty healthy female patients received a blinded and randomized treatment on nasolabial folds (hyaluronic acid in group A and hyaluronic acid plus subcutaneous injections of carbon dioxide in group B) for cosmetic correction of the nasolabial folds. The results were evaluated by two blinded plastic surgeons after the implant (1 week, 4 and 6 months) using a 1-5 graduated scale (GAIS), and at the same time, each patient was asked to express her opinion about the cosmetic result. Any long-term adverse reaction was reported. The blinded evaluation at 4 and 6 months from the implant shows in all patients a maintenance of a good cosmetic result higher for the side treated with carbon dioxide therapy plus hyaluronic acid. At the control visit, 6 months after the treatment, the patients treated with hyaluronic acid plus carbon dioxide therapy maintain a satisfactory esthetic result while the nasolabial fold treated only with hyaluronic acid shows, in almost all patients, a come back to pretreatment appearance. © 2016 Wiley Periodicals, Inc.

  7. Indole-3-acetic acid: a potential new photosensitizer for photodynamic therapy of acne vulgaris.

    PubMed

    Na, Jung-Im; Kim, So-Young; Kim, Jeong-Hye; Youn, Sang-Woong; Huh, Chang-Hun; Park, Kyoung-Chan

    2011-03-01

    ALA (5-aminolevulinic acid) photodynamic therapy (PDT) is a new treatment option for acne. However, it needs a relatively long incubation period and adverse effects are common. Indole-3-acetic acid (IAA) is not toxic by itself but produces free radicals with ultraviolet B. In this study we examined the potential of IAA as a photosensitizer for acne treatment. Free radical formation was measured after visible light irradiation of IAA. Antimicrobial effect was evaluated by assessing growth suppression of Propionibacterium acnes and Staphylococcus aureus after IAA PDT. To evaluate the histological changes, skin biopsies were performed on nude mice skin after IAA PDT. To evaluate the clinical efficacy of IAA PDT, 14 acne patients were treated with the following IAA PDT regimen: three times each with a 15 minutes incubation period and a 2-week interval. The number of inflammatory lesions and the amount of sebum secretion were then assessed. IAA produced free radicals with green light irradiation. Importantly, IAA lost its photosensitizing ability after exposure to certain amount of light. This implies IAA PDT would not require post-procedure photo-protection. The growth of P. acnes and S. aureus were significantly suppressed with IAA PDT. In addition, IAA PDT treated skin showed destruction of follicular ostia epithelium. Interestingly, there was no significant difference between a 4 hours and a 30 minutes incubation, which means that longer absorption time is not necessary for IAA PDT. In the clinical study, inflammatory lesions and sebum secretion were significantly reduced. The procedure was painless and no adverse effect was observed. Photo-protection was not performed and there were no further phototoxic responses. IAA PDT has therapeutic effects on acne via its antimicrobial activities, its sebum-reducing effect and through relieving follicular occlusion. It is a very simple and safe treatment option for acne. Copyright © 2011 Wiley-Liss, Inc.

  8. Mature Results of the Ottawa Phase II Study of Intermittent Androgen-Suppression Therapy in Prostate Cancer: Clinical Predictors of Outcome

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Malone, Shawn; Perry, Gad; Eapen, Libni

    2007-07-01

    Purpose: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). Methods and Materials: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. Results: Ninety-five patients completed 187more » cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. Conclusions: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs.« less

  9. [The importance of bisoprolol in prevention of heart left ventricular hypertrophy in patients with long term L-thyroxin suppressive therapy, after the operation of differentiated thyroid carcinoma].

    PubMed

    Matuszewska, Gabriela; Marek, Bogdan; Kajdaniuk, Dariusz; Przywara-Chowaniec, Brygida; Jarzab, Jerzy; Jarzab, Barbara

    2007-01-01

    Patients with differentiated thyroid carcinoma have to undergo radical surgical treatment, which includes total thyreoidectomy, radioiodine therapy and a life-time suppressive therapy with L-thyroxine. The aim of this study was a prospective evaluation of left ventricular hypertrophy during L suppressive-thyroxine treatment in patients treated for differentiated thyroid carcinoma. The examined group comprised 50 patients with differentiated thyroid carcinoma, treated by total thyroidectomy and 131I therapy. Echocardiographic measurements were needed for estimation of left ventricular mass and its index, according to recommendations of American Echocardiography Society. During two-years long suppressive therapy we observed a significant rise in left ventricular mass. In woman group left ventricular mass was increased from 168+/-39 g to 204+/-45 g (p<0.001) and in men from 205+/-60 to 320+/-21 g. Likewise, left ventricular mass index was increased in women group from 96+/-18 g/m(2) to 116+/-25 g/m(2) (p<0.001) and in men group from 107+/-37 g/m(2) to 158+/-28 g/m(2). Simultaneous treatment with bisoprolol caused a regression of left myocardial hypertrophy. Already after 6 months of simultaneous treatment with L-thyroxin and bisoprolol, for left ventricular mass was reduced to normal: in woman 165+/-35 g, and in men to 178+/-38 g. Analogous results were obtained left ventricular mass index. After 6 months it was reduced to 94+/-12 g/m(2) in woman and in men to 132+/-32 g/m(2). 1. In differentiated thyroid cancer patients, treated postoperatively with L-thyroxine suppressive therapy, left ventricular hypertrophy is observed already during the first year of suppressive therapy and progresses during the next year of treatment. 2 Addition of a beta-adrenergic antagonist to suppressive doses of L-thyroxine causes a regression of left ventricular hypertrophy, thus, beta-adrenergic antagonists should be administered in this group of patients.

  10. Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhai, Yingying; Chen, Xi; Yu, Dehai

    2015-09-10

    Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phasemore » blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.« less

  11. Comparison of clinical characteristics of chronic cough due to non-acid and acid gastroesophageal reflux.

    PubMed

    Xu, Xianghuai; Yang, Zhongmin; Chen, Qiang; Yu, Li; Liang, Siwei; Lü, Hanjing; Qiu, Zhongmin

    2015-04-01

    Little is known about non-acid gastroesophageal reflux-induced chronic cough (GERC). The purpose of the study is to explore the clinical characteristics of non-acid GERC. Clinical symptoms, cough symptom score, capsaicin cough sensitivity, gastroesophageal reflux diagnostic questionnaire (GerdQ) score, findings of multichannel intraluminal impedance-pH monitoring (MII-pH) and response to pharmacological anti-reflux therapy were retrospectively reviewed in 38 patients with non-acid GERC and compared with those of 49 patients with acid GERC. Non-acid GERC had the similar cough character, cough symptom score, and capsaicin cough sensitivity to acid GERC. However, non-acid GERC had less frequent regurgitation (15.8% vs 57.1%, χ(2)  = 13.346, P = 0.000) and heartburn (7.9% vs 32.7%, χ(2)  = 7.686, P  = 0.006), and lower GerdQ score (7.4 ± 1.4 vs 10.6 ± 2.1, t = -6.700, P = 0.003) than acid GERC. Moreover, MII-pH revealed more weakly acidic reflux episodes, gas reflux episodes and a higher symptom association probability (SAP) for non-acid reflux but lower DeMeester score, acidic reflux episodes and SAP for acid reflux in non-acid GERC than in acid GERC. Non-acid GERC usually responded to the standard anti-reflux therapy but with delayed cough resolution or attenuation when compared with acid GERC. Fewer patients with non-acid GERC needed an augmented acid suppressive therapy or treatment with baclofen. There are some differences in the clinical manifestations between non-acid and acid GERC, but MII-pH is essential to diagnose non-acid GERC. © 2014 John Wiley & Sons Ltd.

  12. Ursolic acid and oleanolic acid suppress preneoplastic lesions induced by 1,2-dimethylhydrazine in rat colon.

    PubMed

    Furtado, Ricardo A; Rodrigues, Erlon P; Araújo, Felipe R R; Oliveira, Wendel L; Furtado, Michelle A; Castro, Márcio B; Cunha, Wilson R; Tavares, Denise C

    2008-06-01

    Ursolic acid (UA) and oleanolic acid (OA) are pentacyclic triterpenoid compounds found in plants used in the human diet and in medicinal herbs, in the form of aglycones or as the free acid. These compounds are known for their hepatoprotective, anti-inflammatory, antimicrobial, hypoglycemic, antimutagenic, antioxidant, and antifertility activities. In the present study, we evaluated the effects of UA and OA on the formation of 1,2-dimethyl-hydrazine (DMH)-induced aberrant crypt foci (ACF) in the colon of the male Wistar rat. The animals received subcutaneous (sc) injections of DMH (40 mg/kg body weight) twice a week for two weeks to induce ACF. UA, OA and a mixture of UA and OA were administered to the rats five times a week for four weeks by gavage at doses of 25 mg/kg body weight/day each, during and after DMH treatment. All animals were sacrificed in week 5 for the evaluation of ACF. The results showed a significant reduction in the frequency of ACF in the group treated with the triterpenoid compounds plus DMH when compared to those treated with DMH alone, suggesting that UA and OA suppress the formation of ACF and have a protective effect against colon carcinogenesis.

  13. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer.

    PubMed

    Martey, Orleans; Nimick, Mhairi; Taurin, Sebastien; Sundararajan, Vignesh; Greish, Khaled; Rosengren, Rhonda J

    2017-01-01

    Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks) also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg) for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles.

  14. The suppression of enhanced bitterness intensity of macrolide dry syrup mixed with an acidic powder.

    PubMed

    Ishizaka, Toshihiko; Okada, Sachie; Takemoto, Eri; Tokuyama, Emi; Tsuji, Eriko; Mukai, Junji; Uchida, Takahiro

    2007-10-01

    The aim of the present study was to identify a medicine which strongly enhanced the bitterness of clarithromycin dry syrup (CAMD) when administered concomitantly and to develop a method to suppress this enhanced bitterness. The bitterness enhancement was evaluated not only by gustatory sensation tests but also using pH and taste sensor measurements of the mixed sample. A remarkable bitterness enhancement was found when CAMD was mixed with the acidic powder L-carbocysteine. The acidic pH (pH 3.40) of the suspension made from these two preparations, seemed to be due to enhanced release of clarithromycin caused by the dissolution of the alkaline polymer film-coating. Several methods for preventing this bitterness enhancement were investigated. Neither increasing the volume of water taken with the mixture, nor changing the ratio of CAMD:L-carbocysteine in the mixture, were effective in reducing the bitterness intensity of the CAMD/L-carbocysteine mixture. The best way to achieve taste masking was to first administer CAMD mixed with chocolate jelly, which has a neutral pH, followed by the L-carbocysteine suspension. Similar results were obtained for the bitterness suppression of azithromycin fine granules with L-carbocysteine. The chocolate jelly will be useful for taste masking of bitter macrolide drug formulations, when they need to be administered together with acidic drug formulations.

  15. Role of Acid and Weakly Acidic Reflux in Gastroesophageal Reflux Disease Off Proton Pump Inhibitor Therapy

    PubMed Central

    Sung, Hea Jung; Moon, Sung Jin; Kim, Jin Su; Lim, Chul Hyun; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Myung-Gye

    2012-01-01

    Background/Aims Available data about reflux patterns and symptom determinants in the gastroesophageal reflux disease (GERD) subtypes off proton pump inhibitor (PPI) therapy are lacking. We aimed to evaluate reflux patterns and determinants of symptom perception in patients with GERD off PPI therapy by impedance-pH monitoring. Methods We retrospectively reviewed the impedance-pH data in patients diagnosed as GERD based on results of impedance-pH monitoring, endoscopy and/or typical symptoms. The characteristics of acid and weakly acidic reflux were evaluated. Symptomatic and asymptomatic reflux were compared according to GERD subtypes and individual symptoms. Results Forty-two patients (22 males, mean age 46 years) were diagnosed as GERD (17 erosive reflux disease, 9 pH(+) non-erosive reflux disease [NERD], 9 hypersensitive esophagus and 7 symptomatic NERD). A total of 1,725 reflux episodes were detected (855 acid [50%], 857 weakly acidic [50%] and 13 weakly alkaline reflux [< 1%]). Acid reflux was more frequently symptomatic and bolus clearance was longer compared with weakly acidic reflux. In terms of globus, weakly acidic reflux was more symptomatic. Symptomatic reflux was more frequently acid and mixed reflux; these associations were more pronounced in erosive reflux disease and symptomatic NERD. The perception of regurgitation was related to acid reflux, while that of globus was more related to weakly acidic reflux. Conclusions In patients not taking PPI, acid reflux was more frequently symptomatic and had longer bolus clearance. Symptomatic reflux was more frequently acid and mixed type; however, weakly acidic reflux was associated more with globus. These data suggest a role for impedance-pH data in the evaluation of globus. PMID:22837877

  16. Role of Acid and weakly acidic reflux in gastroesophageal reflux disease off proton pump inhibitor therapy.

    PubMed

    Sung, Hea Jung; Cho, Yu Kyung; Moon, Sung Jin; Kim, Jin Su; Lim, Chul Hyun; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Myung-Gye

    2012-07-01

    Available data about reflux patterns and symptom determinants in the gastroesophageal reflux disease (GERD) subtypes off proton pump inhibitor (PPI) therapy are lacking. We aimed to evaluate reflux patterns and determinants of symptom perception in patients with GERD off PPI therapy by impedance-pH monitoring. We retrospectively reviewed the impedance-pH data in patients diagnosed as GERD based on results of impedance-pH monitoring, endoscopy and/or typical symptoms. The characteristics of acid and weakly acidic reflux were evaluated. Symptomatic and asymptomatic reflux were compared according to GERD subtypes and individual symptoms. Forty-two patients (22 males, mean age 46 years) were diagnosed as GERD (17 erosive reflux disease, 9 pH(+) non-erosive reflux disease [NERD], 9 hypersensitive esophagus and 7 symptomatic NERD). A total of 1,725 reflux episodes were detected (855 acid [50%], 857 weakly acidic [50%] and 13 weakly alkaline reflux [< 1%]). Acid reflux was more frequently symptomatic and bolus clearance was longer compared with weakly acidic reflux. In terms of globus, weakly acidic reflux was more symptomatic. Symptomatic reflux was more frequently acid and mixed reflux; these associations were more pronounced in erosive reflux disease and symptomatic NERD. The perception of regurgitation was related to acid reflux, while that of globus was more related to weakly acidic reflux. In patients not taking PPI, acid reflux was more frequently symptomatic and had longer bolus clearance. Symptomatic reflux was more frequently acid and mixed type; however, weakly acidic reflux was associated more with globus. These data suggest a role for impedance-pH data in the evaluation of globus.

  17. Impact of persistent, frequent regurgitation on quality of life in heartburn responders treated with acid suppression: a multinational primary care study.

    PubMed

    Kahrilas, P J; Howden, C W; Wernersson, B; Denison, H; Nuevo, J; Gisbert, J P

    2013-05-01

    In gastro-oesophageal reflux disease (GERD), heartburn responds well to acid suppression, but regurgitation is a common cause of incomplete treatment response. To assess the prevalence and burden of persistent, frequent regurgitation in primary care patients with GERD treated with acid suppression. We analysed observational data from 134 sites across six European countries in patients diagnosed with GERD. Within 3 months of the index visit, symptoms were assessed using the Reflux Disease Questionnaire, and their impact on sleep and work productivity with the Quality of Life in Reflux and Dyspepsia questionnaire and the Work Productivity and Activity Impairment Questionnaire, respectively. Patients provided information on concomitant over-the-counter (OTC) GERD medication use. Persistent, frequent (3-7 days/week) regurgitation was reported by 13.2% (153/1156) of GERD patients with no heartburn on acid suppression; the prevalence was very similar for patients with up to 2 days/week of ongoing mild heartburn. Among patients without heartburn, sleep disturbance of any type was reported by 50.7-60.1% with persistent, frequent regurgitation, compared with 38.1-51.1% and 14.4-19.2% of those with less frequent or no regurgitation respectively. Persistent, frequent regurgitation was associated with increased use of OTC medication and more hours of work missed, whether mild, infrequent heartburn was present or not. Frequent regurgitation, which persisted in 12-13% of patients with no or infrequent, mild heartburn on acid suppression, negatively affected sleep and work productivity, and increased use of OTC medication. Persistent, frequent regurgitation is problematic for primary care patients with GERD. © 2013 Blackwell Publishing Ltd.

  18. Ethylene signaling renders the jasmonate response of Arabidopsis insensitive to future suppression by salicylic Acid.

    PubMed

    Leon-Reyes, Antonio; Du, Yujuan; Koornneef, Annemart; Proietti, Silvia; Körbes, Ana P; Memelink, Johan; Pieterse, Corné M J; Ritsema, Tita

    2010-02-01

    Cross-talk between jasmonate (JA), ethylene (ET), and Salicylic acid (SA) signaling is thought to operate as a mechanism to fine-tune induced defenses that are activated in response to multiple attackers. Here, 43 Arabidopsis genotypes impaired in hormone signaling or defense-related processes were screened for their ability to express SA-mediated suppression of JA-responsive gene expression. Mutant cev1, which displays constitutive expression of JA and ET responses, appeared to be insensitive to SA-mediated suppression of the JA-responsive marker genes PDF1.2 and VSP2. Accordingly, strong activation of JA and ET responses by the necrotrophic pathogens Botrytis cinerea and Alternaria brassicicola prior to SA treatment counteracted the ability of SA to suppress the JA response. Pharmacological assays, mutant analysis, and studies with the ET-signaling inhibitor 1-methylcyclopropene revealed that ET signaling renders the JA response insensitive to subsequent suppression by SA. The APETALA2/ETHYLENE RESPONSE FACTOR transcription factor ORA59, which regulates JA/ET-responsive genes such as PDF1.2, emerged as a potential mediator in this process. Collectively, our results point to a model in which simultaneous induction of the JA and ET pathway renders the plant insensitive to future SA-mediated suppression of JA-dependent defenses, which may prioritize the JA/ET pathway over the SA pathway during multi-attacker interactions.

  19. Improved accuracy of markerless motion tracking on bone suppression images: preliminary study for image-guided radiation therapy (IGRT)

    NASA Astrophysics Data System (ADS)

    Tanaka, Rie; Sanada, Shigeru; Sakuta, Keita; Kawashima, Hiroki

    2015-05-01

    The bone suppression technique based on advanced image processing can suppress the conspicuity of bones on chest radiographs, creating soft tissue images obtained by the dual-energy subtraction technique. This study was performed to evaluate the usefulness of bone suppression image processing in image-guided radiation therapy. We demonstrated the improved accuracy of markerless motion tracking on bone suppression images. Chest fluoroscopic images of nine patients with lung nodules during respiration were obtained using a flat-panel detector system (120 kV, 0.1 mAs/pulse, 5 fps). Commercial bone suppression image processing software was applied to the fluoroscopic images to create corresponding bone suppression images. Regions of interest were manually located on lung nodules and automatic target tracking was conducted based on the template matching technique. To evaluate the accuracy of target tracking, the maximum tracking error in the resulting images was compared with that of conventional fluoroscopic images. The tracking errors were decreased by half in eight of nine cases. The average maximum tracking errors in bone suppression and conventional fluoroscopic images were 1.3   ±   1.0 and 3.3   ±   3.3 mm, respectively. The bone suppression technique was especially effective in the lower lung area where pulmonary vessels, bronchi, and ribs showed complex movements. The bone suppression technique improved tracking accuracy without special equipment and implantation of fiducial markers, and with only additional small dose to the patient. Bone suppression fluoroscopy is a potential measure for respiratory displacement of the target. This paper was presented at RSNA 2013 and was carried out at Kanazawa University, JAPAN.

  20. Curcumin improves alcoholic fatty liver by inhibiting fatty acid biosynthesis.

    PubMed

    Guo, Chang; Ma, Jingfan; Zhong, Qionghong; Zhao, Mengyuan; Hu, Tianxing; Chen, Tong; Qiu, Longxin; Wen, Longping

    2017-08-01

    Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy. Copyright © 2017. Published by Elsevier Inc.

  1. [Suppression of tinnitus by band noise masker--a study of 600 cases].

    PubMed

    Watanabe, K; Kamio, T; Ohkawara, D; Aoki, H; Baba, S; Yagi, T

    1997-09-01

    We performed Band Noise Masker (BNM) therapy for the suppression of tinnitus in 600 patients and measured the pitch, loudness and masking level of tinnitus and residual inhibition (RI). We examined the efficiency of BNM therapy. The purpose of this study was to investigate the mechanism of suppression of tinnitus by BNM. Tinnitus was suppressed in 394 patients (66%) after BNM therapy. In the group of patients in whom we suppressed tinnitus, the loudness of tinnitus was reduced from 7.7 +/- 5.7dBSL to 7.5 +/- 5.5dBSL (p < 0.05) and the pitch of tinnitus did not exhibit a marked change. In the group of patients in whom we did not suppress tinnitus, the loudness and pitch of tinnitus did not exhibit a marked change. The efficiency of BNM therapy was high in the cases of presbyacusis and low in the cases of sudden deafness. There was no significant relationship between RI and the efficiency of BNM therapy. We examined these data and discussed the mechanism of suppression of tinnitus by BNM therapy. In all cases, after BNM therapy, the auditory threshold did not become worse. In 4 cases tinnitus became worse temporarily. In conclusion, BNM therapy is an effective mode for tinnitus control, is easily performed in our outpatient clinic or at home, and has no serious complications.

  2. Risk of spontaneous bacterial peritonitis associated with gastric Acid suppression.

    PubMed

    Chang, Shy-Shin; Lai, Chih-Cheng; Lee, Meng-tse Gabriel; Lee, Yu-Chien; Tsai, Yi-Wen; Hsu, Wan-Ting; Lee, Chien-Chang

    2015-06-01

    The primary objective of this study was to determine the association between the use of gastric acid suppressants (GAS) and the risk of developing spontaneous bacterial peritonitis (SBP) in patients with advanced liver cirrhosis (LC). A case-control study nested within a cohort of 480,000 representatives of Taiwan National Health Insurance beneficiaries was carried out. A case was matched with 100 controls on age, gender, and index date of SBP diagnosis. GAS use was identified from the 1-year period before the index date. Conditional logistic regression analysis was used to adjust for various unbalanced covariates between users and nonusers of GAS. A total of 947 cases of SBP were identified among the 86,418 patients with advanced LC. A significant increased risk of developing SBP was found to be associated with current (within 30 days), and recent (within 30-90 day) use of 2 different classes of GAS: proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). The confounder adjusted rate ratio (aRR) for the current use of PPIs was 2.77 (95% CI: 1.90-4.04) and H2RAs was 2.62 (95% CI: 2.00-3.42). The risk of SBP attenuated for the recent use of PPIs (aRR: 2.20, 95%CI: 1.60-3.02) or H2RAs (aRR: 1.72, 95% CI: 1.25-2.37). In addition, sensitivity analysis using hospitalized SBP as the primary outcome showed a similar risk for the current use of PPIs (aRR, 3.24; 95% CI: 2.08-5.05) and H2RAs (aRR 2.43; 95% CI 1.71-3.46). Furthermore, higher cumulative days of gastric acid suppression were associated with a higher risk of SBP (trend P < 0.0001). To conclude, exposure to GAS was associated with an increased risk of SBP in patients with advanced LC. The association was more pronounced in current PPI users compared with nonusers.

  3. Drug therapies for reducing gastric acidity in people with cystic fibrosis.

    PubMed

    Ng, Sze May; Francini, Angelo J

    2012-04-18

    Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 15 February 2012. All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. Both authors independently selected trials, assessed trial quality and extracted data. Thirty-eight trials were identified from the searches. Sixteen trials, with 256 participants, were suitable for inclusion. Seven trials were limited to children and three trials enrolled only adults. Meta-analysis was not performed. However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures

  4. Suppression of DS1 Phosphatidic Acid Phosphatase Confirms Resistance to Ralstonia solanacearum in Nicotiana benthamiana

    PubMed Central

    Nakano, Masahito; Nishihara, Masahiro; Yoshioka, Hirofumi; Takahashi, Hirotaka; Sawasaki, Tatsuya; Ohnishi, Kouhei; Hikichi, Yasufumi; Kiba, Akinori

    2013-01-01

    Nicotiana benthamiana is susceptible to Ralstonia solanacearum. To analyze molecular mechanisms for disease susceptibility, we screened a gene-silenced plant showing resistance to R. solanacearum, designated as DS1 (Disease suppression 1). The deduced amino acid sequence of DS1 cDNA encoded a phosphatidic acid phosphatase (PAP) 2. DS1 expression was induced by infection with a virulent strain of R. solanacearum in an hrp-gene-dependent manner. DS1 rescued growth defects of the temperature-sensitive ∆lpp1∆dpp1∆pah1 mutant yeast. Recombinant DS1 protein showed Mg2+-independent PAP activity. DS1 plants showed reduced PAP activity and increased phosphatidic acid (PA) content. After inoculation with R. solanacearum, DS1 plants showed accelerated cell death, over-accumulation of reactive oxygen species (ROS), and hyper-induction of PR-4 expression. In contrast, DS1-overexpressing tobacco plants showed reduced PA content, greater susceptibility to R. solanacearum, and reduced ROS production and PR-4 expression. The DS1 phenotype was partially compromised in the plants in which both DS1 and NbCoi1 or DS1 and NbrbohB were silenced. These results show that DS1 PAP may affect plant immune responses related to ROS and JA cascades via regulation of PA levels. Suppression of DS1 function or DS1 expression could rapidly activate plant defenses to achieve effective resistance against Ralstonia solanacearum. PMID:24073238

  5. Higher Anti-CMV IgG Concentrations are Associated with Worse Neurocognitive Performance During Suppressive Antiretroviral Therapy.

    PubMed

    Letendre, Scott; Bharti, Ajay; Perez-Valero, Ignacio; Hanson, Barbara; Franklin, Donald; Woods, Steven Paul; Gianella, Sara; de Oliveira, Michelli Faria; Heaton, Robert K; Grant, Igor; Landay, Alan L; Lurain, Nell

    2018-03-01

    To determine the association of CMV infection with neurocognitive performance in HIV+ adults. Cross-sectional, observational, exploratory study. Anti-CMV IgG concentrations in blood and CMV DNA copies in blood and cerebrospinal fluid (CSF) were measured in stored specimens of 80 HIV+ adults who were previously assessed with a standardized, comprehensive neurocognitive test battery. Thirty-eight were taking suppressive antiretroviral therapy (ART, HIV RNA ≤ 50 copies/mL) and 42 were not taking ART. A panel of 7 soluble biomarkers were also measured by immunoassay in CSF. Anti-CMV IgG concentrations ranged from 5.2 to 46.1 U/mL. CMV DNA was detected in 7 (8.8%) blood plasma but in none of the CSF specimens. Higher anti-CMV IgG levels were associated with older age (p=0.0017), lower nadir CD4+ T-cell count (p<0.001), AIDS (p<0.001), and higher soluble CD163 (p=0.009). Higher anti-CMV IgG levels trended toward an association with worse neurocognitive performance overall (p=0.059). This correlation was present in those taking suppressive ART (p=0.0049) but not in those who were not taking ART (p=0.92). Worse neurocognitive performance remained associated with higher anti-CMV IgG levels after accounting for other covariates in multivariate models (Model p=0.0038). Detectable plasma CMV DNA was associated with AIDS (p=0.05) but not with neurocognitive performance. CMV may influence neurocognitive performance in HIV+ adults taking suppressive ART. Future clinical trials of anti-CMV therapy should help determine whether the observed relationships are causal.

  6. Tumor acidity-activatable manganese phosphate nanoplatform for amplification of photodynamic cancer therapy and magnetic resonance imaging.

    PubMed

    Hao, Yongwei; Zheng, Cuixia; Wang, Lei; Zhang, Jinjie; Niu, Xiuxiu; Song, Qingling; Feng, Qianhua; Zhao, Hongjuan; Li, Li; Zhang, Hongling; Zhang, Zhenzhong; Zhang, Yun

    2017-10-15

    Amorphous biodegradable metal phosphate nanomaterials are considered to possess great potential in cancer theranostic application due to their promise in providing ultra-sensitive pH-responsive therapeutic benefits and diagnostic functions simultaneously. Here we report the synthesis of photosensitising and acriflavine-carrying amorphous porous manganese phosphate (PMP) nanoparticles with ultra-sensitive pH-responsive degradability and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF1α/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Carboxymethyl dextran (CMD) is chemically anchored on the surface of porous manganese phosphate theranostic system through the pH-responsive boronate esters. Upon the stimulus of the tumor acid microenvironment, manganese phosphate disintegrates and releases Mn 2+ ions rapidly, which are responsible for the magnetic resonance imaging (MRI) effect. Meanwhile, the released photosensitizer chlorin e6 (Ce6) produces ROS under irradiation while acriflavine (ACF) inhibits the HIF-1α/VEGF pathway during the burst release of VEGF in tumour induced by photodynamic therapy (PDT), resulting in increased therapeutic efficacy. Considering the strong pH responsivity, MRI signal amplification and drug release profile, the PMP nanoparticles offer new prospects for tumor acidity-activatable theranostic application by amplifying the PDT through inhibiting the HIF-1α /VEGF pathway timely while enhancing the MRI effect. In this study, we report the synthesis of the tumor acidity-activatable amorphous porous manganese phosphate nanoparticles and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF-1

  7. Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

    PubMed Central

    Van den Bossche, Lien; Hindryckx, Pieter; Devisscher, Lindsey; Devriese, Sarah; Van Welden, Sophie; Holvoet, Tom; Vilchez-Vargas, Ramiro; Vital, Marius; Pieper, Dietmar H.; Vanden Bussche, Julie; Vanhaecke, Lynn; Van de Wiele, Tom; De Vos, Martine

    2017-01-01

    ABSTRACT The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes. Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD. IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered

  8. Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice.

    PubMed

    Van den Bossche, Lien; Hindryckx, Pieter; Devisscher, Lindsey; Devriese, Sarah; Van Welden, Sophie; Holvoet, Tom; Vilchez-Vargas, Ramiro; Vital, Marius; Pieper, Dietmar H; Vanden Bussche, Julie; Vanhaecke, Lynn; Van de Wiele, Tom; De Vos, Martine; Laukens, Debby

    2017-04-01

    The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila , bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD. IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we

  9. Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine

    PubMed Central

    Zylka, Mark J.; Sowa, Nathaniel A.; Taylor-Blake, Bonnie; Twomey, Margaret A.; Herrala, Annakaisa; Voikar, Vootele; Vihko, Pirkko

    2008-01-01

    SUMMARY Thiamine monophosphatase (TMPase, also known as Fluoride-Resistant Acid Phosphatase) is a classic histochemical marker of small-diameter dorsal root ganglia neurons. The molecular identity of TMPase is currently unknown. We found that TMPase is identical to the transmembrane isoform of Prostatic Acid Phosphatase (PAP), an enzyme with unknown molecular and physiological functions. We then found that PAP knockout mice have normal acute pain sensitivity but enhanced sensitivity in chronic inflammatory and neuropathic pain models. In gain-of-function studies, intraspinal injection of PAP protein has potent anti-nociceptive, anti-hyperalgesic and anti-allodynic effects that last longer than the opioid analgesic morphine. PAP suppresses pain by functioning as an ecto-5’-nucleotidase. Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. Our studies reveal molecular and physiological functions for PAP in purine nucleotide metabolism and nociception and suggest a novel use for PAP in the treatment of chronic pain. PMID:18940592

  10. New therapy with ASC-J9® to suppress the prostatitis via altering the cytokine CCL2 signals

    PubMed Central

    Lin, Shin-Jen; Chou, Fu-Ju; Lin, Chang-Yi; Chang, Hong-Chiang; Yeh, Shuyuan; Chang, Chawnshang

    2016-01-01

    Prostatitis is a common disease contributing to 8% of all urologist visits. Yet the etiology and effective treatment remain to be further elucidated. Using a non-obese diabetes mouse model that can be induced by autoimmune response for the spontaneous development of prostatitis, we found that injection of the ASC-J9® at 75 mg/Kg body weight/48 hours led to significantly suppressed prostatitis that was accompanied with reduction of lymphocyte infiltration with reduced CD4+ T cells in prostate. In vitro studies with a co-culture system also confirmed that ASC-J9® treatment could suppress the CD4+ T cell migration to prostate stromal cells. Mechanisms dissection indicated that ASC-J9® can suppress CD4+ T cell migration via decreasing the cytokine CCL2 in vitro and in vivo, and restoring CCL2 could interrupt the ASC-J9® suppressed CD4+ T cell migration. Together, results from in vivo and in vitro studies suggest that ASC-J9® can suppress prostatitis by altering the autoimmune response induced by CD4+ T cell recruitment, and using ASC-J9® may help us to develop a potential new therapy to battle the prostatitis with little side effects. PMID:27564257

  11. New therapy with ASC-J9® to suppress the prostatitis via altering the cytokine CCL2 signals.

    PubMed

    Lin, Shin-Jen; Chou, Fu-Ju; Lin, Chang-Yi; Chang, Hong-Chiang; Yeh, Shuyuan; Chang, Chawnshang

    2016-10-11

    Prostatitis is a common disease contributing to 8% of all urologist visits. Yet the etiology and effective treatment remain to be further elucidated. Using a non-obese diabetes mouse model that can be induced by autoimmune response for the spontaneous development of prostatitis, we found that injection of the ASC-J9® at 75 mg/Kg body weight/48 hours led to significantly suppressed prostatitis that was accompanied with reduction of lymphocyte infiltration with reduced CD4+ T cells in prostate. In vitro studies with a co-culture system also confirmed that ASC-J9® treatment could suppress the CD4+ T cell migration to prostate stromal cells. Mechanisms dissection indicated that ASC-J9® can suppress CD4+ T cell migration via decreasing the cytokine CCL2 in vitro and in vivo, and restoring CCL2 could interrupt the ASC-J9® suppressed CD4+ T cell migration. Together, results from in vivo and in vitro studies suggest that ASC-J9® can suppress prostatitis by altering the autoimmune response induced by CD4+ T cell recruitment, and using ASC-J9® may help us to develop a potential new therapy to battle the prostatitis with little side effects.

  12. Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in Apc(Min/+) mice.

    PubMed

    Fini, Lucia; Piazzi, Giulia; Ceccarelli, Claudio; Daoud, Yahya; Belluzzi, Andrea; Munarini, Alessandra; Graziani, Giulia; Fogliano, Vincenzo; Selgrad, Michael; Garcia, Melissa; Gasbarrini, Antonio; Genta, Robert M; Boland, C Richard; Ricciardiello, Luigi

    2010-12-01

    Although cyclooxygenase (COX)-2 inhibitors could represent the most effective chemopreventive tool against colorectal cancer (CRC), their use in clinical practice is hampered by cardiovascular side effects. Consumption of ω-3-polyunsaturated fatty acids (ω-3-PUFAs) is associated with a reduced risk of CRC. Therefore, in this study, we assessed the efficacy of a novel 99% pure preparation of ω-3-PUFA eicosapentaenoic acid as free fatty acids (EPA-FFA) on polyps in Apc(Min/+) mice. Apc(Min/+) and corresponding wild-type mice were fed control diet (Ctrl) or diets containing either EPA-FFA 2.5% or 5%, for 12 weeks while monitoring food intake and body weight. We found that both EPA-FFA diets protected from the cachexia observed among Apc(Min/+) animals fed Ctrl diet (P < 0.0054), without toxic effect, in conjunction with a significant decrease in lipid peroxidation in the treated arms. Moreover, both EPA-FFA diets dramatically suppressed polyp number (by 71.5% and 78.6%, respectively; P < 0.0001) and load (by 82.5% and 93.4%, respectively; P < 0.0001) in both small intestine and colon. In addition, polyps less than 1 mm in size were predominantly found in the EPA-FFA 5% arm whereas those 1 to 3 mm in size were more frequent in the Ctrl arm (P < 0.0001). Interestingly, in the EPA-FFA groups, mucosal arachidonic acid was replaced by EPA (P < 0.0001), leading to a significant reduction in COX-2 expression and β-catenin nuclear translocation. Moreover, in the EPA-FFA arms, we found a significant decrease in proliferation throughout the intestine together with an increase in apoptosis. Our data make 99% pure EPA-FFA an excellent candidate for CRC chemoprevention. ©2010 AACR.

  13. HIV-infected patients receiving lopinavir/ritonavir-based antiretroviral therapy achieve high rates of virologic suppression despite adherence rates less than 95%.

    PubMed

    Shuter, Jonathan; Sarlo, Julie A; Kanmaz, Tina J; Rode, Richard A; Zingman, Barry S

    2007-05-01

    The observation that extremely high levels of medication adherence are required to achieve complete virologic suppression is based largely on studies of treatment-experienced patients receiving HIV protease inhibitor (PI)-based therapy without ritonavir boosting. This study aims to define the level of adherence needed to achieve virologic suppression in patients receiving boosted PI-based highly active antiretroviral therapy (HAART) with lopinavir/ritonavir. HIV-infected adults receiving a regimen containing lopinavir/ritonavir were recruited into a prospective, observational study of the relation between adherence to lopinavir/ritonavir and virologic outcomes. Adherence was measured using the Medication Event Monitoring System (MEMS; Aardex, Union City, CA). HIV-1 viral load (VL) was measured at week 24. The final study population contained 64 subjects. Eighty percent had AIDS, 97% received lopinavir/ritonavir before enrollment, and most had more than 7 years of HAART experience. Mean adherence overall was 73%. Eighty percent and 59% achieved a VL <400 copies/mL and a VL <75 copies/mL, respectively. Mean adherence was 75% in those achieving a VL <75 copies/mL. High rates of virologic suppression were observed in all adherence quartiles, including the lowest quartile (range of adherence: 23.5%-53.3%). Moderate levels of adherence can lead to virologic suppression in most patients taking lopinavir/ritonavir-based HAART.

  14. Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways.

    PubMed

    Pandey, Manoj K; Kale, Vijay P; Song, Chunhua; Sung, Shen-shu; Sharma, Arun K; Talamo, Giampaolo; Dovat, Sinisa; Amin, Shantu G

    2014-10-01

    Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-κB) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1α-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. Published by Elsevier Inc.

  15. ω-3 Polyunsaturated fatty acids and their cytochrome P450-derived metabolites suppress colorectal tumor development in mice.

    PubMed

    Wang, Weicang; Yang, Jun; Nimiya, Yoshiki; Lee, Kin Sing Stephen; Sanidad, Katherine; Qi, Weipeng; Sukamtoh, Elvira; Park, Yeonhwa; Liu, Zhenhua; Zhang, Guodong

    2017-10-01

    Many studies have shown that dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) reduces the risks of colorectal cancer; however, the underlying mechanisms are not well understood. Here we used a LC-MS/MS-based lipidomics to explore the role of eicosanoid signaling in the anti-colorectal cancer effects of ω-3 PUFAs. Our results showed that dietary feeding of ω-3 PUFAs-rich diets suppressed growth of MC38 colorectal tumor, and modulated profiles of fatty acids and eicosanoid metabolites in C57BL/6 mice. Notably, we found that dietary feeding of ω-3 PUFAs significantly increased levels of epoxydocosapentaenoic acids (EDPs, metabolites of ω-3 PUFA produced by cytochrome P450 enzymes) in plasma and tumor tissue of the treated mice. We further showed that systematic treatment with EDPs (dose=0.5 mg/kg per day) suppressed MC38 tumor growth in mice, with reduced expressions of pro-oncogenic genes such as C-myc, Axin2, and C-jun in tumor tissues. Together, these results support that formation of EDPs might contribute to the anti-colorectal cancer effects of ω-3 PUFAs. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Review article: pH, healing and symptom relief with rabeprazole treatment in acid-related disorders.

    PubMed

    Robinson, M

    2004-11-01

    Control of gastric acid secretion by antisecretory agents has been the cornerstone of therapy in the successful management of all acid-related disorders, including gastro-oesophageal reflux disease (GERD), and duodenal and gastric ulcer. Treatment efficacy has been strongly correlated with degree and duration of acid suppression within the 24-h period and with total duration of therapy. All proton pump inhibitors are highly effective for the healing of ulcers and erosive oesophagitis. All have closely similar mechanisms of action, yet important pharmacological differences exist, which can significantly impact certain aspects of their clinical efficacy. Rabeprazole's rapid activation over a wide pH range may be the explanation for its early onset of effective acid inhibition compared with other proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole. Like rabeprazole, esomeprazole is also a potent inhibitor of gastric acid at steady state, although it is thought that rabeprazole may provide enhanced first-day acid suppression compared with esomeprazole. First-day antisecretory efficacy should produce faster symptom relief, a hypothesis supported by clinical data. Moreover, drugs with pharmacological profiles that include both rapid onset and potent antisecretory effects should help control healthcare costs by reducing the need for otherwise commonly used twice-daily proton pump inhibitor administration.

  17. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.

    PubMed

    Rensen, Niki; Gemke, Reinoud Jbj; van Dalen, Elvira C; Rotteveel, Joost; Kaspers, Gertjan Jl

    2017-11-06

    Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. We identified 10 studies (total of 298 children; we identified two studies

  18. Salicylic Acid Suppresses Jasmonic Acid Signaling Downstream of SCFCOI1-JAZ by Targeting GCC Promoter Motifs via Transcription Factor ORA59[C][W][OA

    PubMed Central

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C.; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P.; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C.M.; Pieterse, Corné M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCFCOI1, which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCFCOI1-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59. PMID:23435661

  19. Ellagic acid, sulforaphane, and ursolic acid in the prevention and therapy of breast cancer: current evidence and future perspectives.

    PubMed

    Jaman, Md Sadikuj; Sayeed, Md Abu

    2018-05-03

    Globally, breast cancer is the most common cancer and the second leading cause of cancer-related death among women. Surgery, chemotherapy, hormonal therapy, and radiotherapy are currently available treatment options for breast cancer therapy. However, chemotherapy, hormonal therapy, and radiotherapy are often associated with side effects and multidrug resistance, recurrence, and lack of treatment in metastasis are the major problems in the treatment of breast cancer. Recently, dietary phytochemicals have emerged as advantageous agents for the prevention and therapy of cancer due to their safe nature. Ellagic acid (EA), sulforaphane (SF), and ursolic acid (UA), which are found in widely consumed fruits and vegetables, have been shown to inhibit breast cancer cell proliferation and to induce apoptosis. This review encompasses the role of EA, SF, and UA in the fight against breast cancer. Both in vitro and in vivo effects of these agents are presented.

  20. Thyrotropin Suppressive Therapy for Low-Risk Small Thyroid Cancer: A Propensity Score-Matched Cohort Study.

    PubMed

    Park, Suyeon; Kim, Won Gu; Han, Minkyu; Jeon, Min Ji; Kwon, Hyemi; Kim, Mijin; Sung, Tae-Yon; Kim, Tae Yong; Kim, Won Bae; Hong, Suck Joon; Shong, Young Kee

    2017-09-01

    Thyrotropin (TSH) suppression has improved the clinical outcomes of patients with differentiated thyroid cancer (DTC). However, the efficacy of TSH suppressive therapy (TST) is unclear in patients with low-risk DTC. This study aimed to evaluate the efficacy of TST and optimal TSH levels of patients with low-risk DTC. This retrospective propensity score-matched cohort study included DTC patients (n = 446) who underwent lobectomy from 2002 to 2008 with or without TST (TST group and No-TST group). Disease-free survival (DFS) and dynamic risk stratification were compared between both groups using serum TSH levels. Approximately 74% of TST patients and 11% of No-TST patients had suppressed serum TSH levels (<2 mIU/L). The median follow-up period was 8.6 years. During follow-up, the disease recurred in 10 (2.7%) patients, with no significant difference in DFS between the groups (p = 0.63). The proportion of patients with excellent treatment response was similar between the TST (65.2%) and No-TST (64.4%) groups. Incomplete biochemical response was noted in 17.2% of the TST group patients and 9.4% of the No-TST group patients. No significant difference was observed in the DFS between both groups by comparing serum TSH level (p = 0.57). TST did not improve clinical outcomes, and serum TSH levels were not associated with recurrence in patients with low-risk small DTC. No clinical benefits were shown for TSH suppression in low-risk patients who underwent lobectomy. Thus, levothyroxine is not necessary for patients without evidence of hypothyroidism.

  1. Hyperhomocysteinemia induced by guanidinoacetic acid is effectively suppressed by choline and betaine in rats.

    PubMed

    Setoue, Minoru; Ohuchi, Seiya; Morita, Tatsuya; Sugiyama, Kimio

    2008-07-01

    Rats were fed 25% casein (25C) diets differing in choline levels (0-0.5%) with and without 0.5% guanidinoacetic acid (GAA) or 0.75% L-methionine for 7 d to determine the effects of dietary choline level on experimental hyperhomocysteinemia. The effects of dietary choline (0.30%) and betaine (0.34%) on GAA- and methionine-induced hyperhomocysteinemia were also compared. Dietary choline suppressed hyperhomocysteinemia induced by GAA, but not by methionine, in a dose-dependent manner. GAA-induced enhancement of the plasma homocysteine concentration was suppressed by choline and betaine to the same degree, but the effects of these compounds were relatively small on methionine-induced hyperhomocysteinemia. Dietary supplementation with choline and betaine significantly increased the hepatic betaine concentration in rats fed a GAA diet, but not in rats fed a methionine diet. These results indicate that choline and betaine are effective at relatively low levels in reducing plasma homocysteine, especially under the condition of betaine deficiency without a loading of homocysteine precursor.

  2. Severe Bone Marrow Suppression Accompanying Pulmonary Infection and Hemorrhage of the Digestive Tract Associated with Leflunomide and Low-dose Methotrexate Combination Therapy

    PubMed Central

    Qu, Caihong; Lu, Ying; Liu, Weimin

    2017-01-01

    A 60-year-old male patient developed hyperpyrexia, cough, expectoration with blood-stained sputum, mouth ulcers, and suppurative tonsillitis after receiving 35 days of combination treatment with leflunomide (LEF) and low-dose methotrexate (MTX) for active rheumatoid arthritis. On admission, routine blood tests showed severe thrombocytopenia, agranulocytosis, and decreased hemoglobin concentration compared with the relatively normal results of 1 month previously during the first hospitalization. Chest radiography revealed inflammation in both lungs, and a fecal occult blood test was positive. Given this presentation, severe bone marrow suppression accompanying pulmonary infection and hemorrhage of the digestive tract associated with LEF and MTX combination therapy was diagnosed. After 28 days of symptomatic treatment, the patient's complications subsided gradually. This case highlighted that bone marrow suppression associated with MTX and LEF combination therapy could be very serious, even at a normal dose or especially at the beginning of treatment. MTX and LEF combination therapy should be used with caution or be limited in those with a history of pulmonary disease, hemorrhage of the digestive tract, or other relevant diseases. PMID:28405135

  3. Azadirachtin Interacts with Retinoic Acid Receptors and Inhibits Retinoic Acid-mediated Biological Responses*

    PubMed Central

    Thoh, Maikho; Babajan, Banaganapalli; Raghavendra, Pongali B.; Sureshkumar, Chitta; Manna, Sunil K.

    2011-01-01

    Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor κB (NF-κB) activation, not the DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-κB, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies. PMID:21127062

  4. Azadirachtin interacts with retinoic acid receptors and inhibits retinoic acid-mediated biological responses.

    PubMed

    Thoh, Maikho; Babajan, Banaganapalli; Raghavendra, Pongali B; Sureshkumar, Chitta; Manna, Sunil K

    2011-02-11

    Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor κB (NF-κB) activation, not the DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-κB, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies.

  5. Drug therapies for reducing gastric acidity in people with cystic fibrosis.

    PubMed

    Ng, Sze May; Franchini, Angelo J

    2014-07-13

    Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 17 March 2014. All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. Both authors independently selected trials, assessed trial quality and extracted data. The searches identified 39 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. The included trials were generally not reported adequately enough to allow judgements on risk of bias.However, one trial found that drug therapies

  6. Acid ceramidase in prostate cancer radiation therapy resistance and relapse

    NASA Astrophysics Data System (ADS)

    Cheng, Joseph C.

    Prostate tumor cell escape from ionizing radiation (IR)-induced killing can lead to disease progression and relapse. Sphingolipids such as ceramide and sphingosine 1-phosphate influence signal transduction pathways that regulate stress response in cancer cells. In particular, metabolism of apoptotic ceramide constitutes an important survival adaptation. Assessments of enzyme activity, mRNA, and protein demonstrated preferential upregulation of the ceramide deacylating enzyme acid ceramidase (AC) in irradiated cancer cells. Promoter-reporter and ChIP-qPCR assays revealed AC transcription by activator protein 1 (AP-1) is sensitive to pharmacological inhibition of de novo ceramide biosynthesis, identifying a protective feedback mechanism that mitigates the effects of IR-induced ceramide. Deregulation of c-Jun, in particular, induced marked radiosensitization in vitro and in vivo, which was rescued by ectopic AC over-expression. AC over-expression in prostate cancer clonogens surviving 80 Gray fractionated irradiation was associated with increased radioresistance and proliferation, suggesting a role in radiotherapy failure and relapse. Indeed, immunohistochemical analysis of human prostate cancer tissues revealed higher levels of AC after radiotherapy failure than therapy-naive adenocarcinoma, PIN, or benign tissues. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Finally, treatment with lysosomotropic small molecule inhibitors of AC, LCL385 or LCL521, induced prostate cancer xenograft radiosensitization and long-term suppression, suggesting AC is a tractable target for adjuvant radiotherapy.

  7. Climate dependency of tree growth suppressed by acid deposition effects on soils in Northwest Russia

    USGS Publications Warehouse

    Lawrence, G.B.; Lapenis, A.G.; Berggren, D.; Aparin, B.F.; Smith, K.T.; Shortle, W.C.; Bailey, S.W.; Varlyguin, D.L.; Babikov, B.

    2005-01-01

    Increased tree growth in temperate and boreal forests has been proposed as a direct consequence of a warming climate. Acid deposition effects on nutrient availability may influence the climate dependency of tree growth, however. This study presents an analysis of archived soil samples that has enabled changes in soil chemistry to be tracked with patterns of tree growth through the 20th century. Soil samples collected in 1926, 1964, and 2001, near St. Petersburg, Russia, showed that acid deposition was likely to have decreased root-available concentrations of Ca (an essential element) and increased root-available concentrations of Al (an inhibitor of Ca uptake). These soil changes coincided with decreased diameter growth and a suppression of climate-tree growth relationships in Norway spruce. Expected increases in tree growth from climate warming may be limited by decreased soil fertility in regions of northern and eastern Europe, and eastern North America, where Ca availability has been reduced by acidic deposition. ?? 2005 American Chemical Society.

  8. Climate dependency of tree growth suppressed by acid deposition effects on soils in northwest Russia.

    PubMed

    Lawrence, Gregory B; Lapenis, Andrei G; Berggren, Dan; Aparin, Boris F; Smith, Kevin T; Shortle, Walter C; Bailey, Scott W; Varlyguin, Dmitry L; Babikov, Boris

    2005-04-01

    Increased tree growth in temperate and boreal forests has been proposed as a direct consequence of a warming climate. Acid deposition effects on nutrient availability may influence the climate dependency of tree growth, however. This study presents an analysis of archived soil samples that has enabled changes in soil chemistry to be tracked with patterns of tree growth through the 20th century. Soil samples collected in 1926, 1964, and 2001, near St. Petersburg, Russia, showed that acid deposition was likely to have decreased root-available concentrations of Ca (an essential element) and increased root-available concentrations of Al (an inhibitor of Ca uptake). These soil changes coincided with decreased diameter growth and a suppression of climate-tree growth relationships in Norway spruce. Expected increases in tree growth from climate warming may be limited by decreased soil fertility in regions of northern and eastern Europe, and eastern North America, where Ca availability has been reduced by acidic deposition.

  9. Early age at start of antiretroviral therapy associated with better virologic control after initial suppression in HIV-infected infants.

    PubMed

    Shiau, Stephanie; Strehlau, Renate; Technau, Karl-Günter; Patel, Faeezah; Arpadi, Stephen M; Coovadia, Ashraf; Abrams, Elaine J; Kuhn, Louise

    2017-01-28

    The report of the 'Mississippi baby' who was initiated on antiretroviral therapy (ART) within 30 h of birth and maintained viral suppression off ART for 27 months has increased interest in the timing of ART initiation early in life. We examined associations between age at ART initiation and virologic outcomes in five cohorts of HIV-infected infants and young children who initiated ART before 2 years of age in Johannesburg, South Africa. We compared those who initiated ART early (<6 months of age) and those who started ART late (6-24 months of age). Two primary outcomes were examined: initial response to ART in three cohorts and later sustained virologic control after achieving suppression on ART in two cohorts. We did not observe consistent differences in initial viral suppression rates by age at ART initiation. Overall, initial viral suppression rates were low. Only 31, 40.1, and 26.5% of early-treated infants (<6 months of age) in the three cohorts, respectively, were suppressed less than 50 copies/ml of HIV RNA 6 months after starting ART. We did observe better sustained virologic control after achieving suppression on ART among infants starting ART early compared with late. Children who started ART early were less likely to experience viral rebound (>50 copies/ml or >1000 copies/ml) than children who started late in both cohorts. These findings provide additional support for early initiation of ART in HIV-infected infants.

  10. Suppression of fat deposition in broiler chickens by (-)-hydroxycitric acid supplementation: A proteomics perspective

    PubMed Central

    Peng, Mengling; Han, Jing; Li, Longlong; Ma, Haitian

    2016-01-01

    (-)-Hydroxycitric acid (HCA) suppresses fatty acid synthesis in animals, but its biochemical mechanism in poultry is unclear. This study identified the key proteins associated with fat metabolism and elucidated the biochemical mechanism of (-)-HCA in broiler chickens. Four groups (n = 30 each) received a diet supplemented with 0, 1000, 2000 or 3000 mg/kg (-)-HCA for 4 weeks. Of the differentially expressed liver proteins, 40 and 26 were identified in the mitochondrial and cytoplasm respectively. Pyruvate dehydrogenase E1 components (PDHA1 and PDHB), dihydrolipoyl dehydrogenase (DLD), aconitase (ACO2), a-ketoglutarate dehydrogenase complex (DLST), enoyl-CoA hydratase (ECHS1) and phosphoglycerate kinase (PGK) were upregulated, while NADP-dependent malic enzyme (ME1) was downregulated. Biological network analysis showed that the identified proteins were involved in glycometabolism and lipid metabolism, whereas PDHA1, PDHB, ECHS1, and ME1 were identified in the canonical pathway by Ingenuity Pathway Analysis. The data indicated that (-)-HCA inhibited fatty acid synthesis by reducing the acetyl-CoA supply, via promotion of the tricarboxylic acid cycle (upregulation of PDHA1, PDHB, ACO2, and DLST expression) and inhibition of ME1 expression. Moreover, (-)-HCA promoted fatty acid beta-oxidation by upregulating ECHS1 expression. These results reflect a biochemically relevant mechanism of fat reduction by (-)-HCA in broiler chickens. PMID:27586962

  11. Epsilon-aminocaproic acid therapy in ulcerative colitis

    PubMed Central

    Salter, R. H.; Read, A. E.

    1970-01-01

    On the supposition that excessive fibrinolysis at the rectal mucosal level may contribute to the pathogenesis of ulcerative colitis, 11 patients with this condition, in whom rectal bleeding was the predominant feature, were given a course of epsilon-aminocaproic acid therapy. Six patients responded dramatically to this treatment, there was a partial response in two, no effect in two others, and one patient found it necessary to discontinue the treatment after 48 hours because of the severity of side effects. PMID:5311202

  12. Suppression of muscle wasting by the plant‐derived compound ursolic acid in a model of chronic kidney disease

    PubMed Central

    Yu, Rizhen; Chen, Ji‐an; Xu, Jing; Cao, Jin; Wang, Yanlin; Thomas, Sandhya S.

    2016-01-01

    Abstract Background Muscle wasting in chronic kidney disease (CKD) and other catabolic disorders contributes to morbidity and mortality, and there are no therapeutic interventions that regularly and safely block losses of muscle mass. We have obtained evidence that impaired IGF‐1/insulin signalling and increases in glucocorticoids, myostatin and/or inflammatory cytokines that contribute to the development of muscle wasting in catabolic disorders by activating protein degradation. Methods Using in vitro and in vivo models of muscle wasting associated with CKD or dexamethasone administration, we measured protein synthesis and degradation and examined mechanisms by which ursolic acid, derived from plants, could block the loss of muscle mass stimulated by CKD or excessive levels of dexamethasone. Results Using cultured C2C12 myotubes to study muscle wasting, we found that exposure to glucocorticoids cause loss of cell proteins plus an increase in myostatin; both responses are significantly suppressed by ursolic acid. Results from promoter and ChIP assays demonstrated a mechanism involving ursolic acid blockade of myostatin promoter activity that is related to CEBP/δ expression. In mouse models of CKD‐induced or dexamethasone‐induced muscle wasting, we found that ursolic acid blocked the loss of muscle mass by stimulating protein synthesis and decreasing protein degradation. These beneficial responses included decreased expression of myostatin and inflammatory cytokines (e.g. TGF‐β, IL‐6 and TNFα), which are initiators of muscle‐specific ubiquitin‐E3 ligases (e.g. Atrogin‐1, MuRF‐1 and MUSA1). Conclusions Ursolic acid improves CKD‐induced muscle mass by suppressing the expression of myostatin and inflammatory cytokines via increasing protein synthesis and reducing proteolysis. PMID:27897418

  13. Predator evasion in zooplankton is suppressed by polyunsaturated fatty acid limitation.

    PubMed

    Brzeziński, Tomasz; von Elert, Eric

    2015-11-01

    Herbivorous zooplankton avoid size-selective predation by vertical migration to a deep, cold water refuge. Adaptation to low temperatures in planktonic poikilotherms depends on essential dietary lipids; the availability of these lipids often limits growth and reproduction of zooplankton. We hypothesized that limitation by essential lipids may affect habitat preferences and predator avoidance behavior in planktonic poikilotherms. We used a liposome supplementation technique to enrich the green alga Scenedesmus obliquus and the cyanobacterium Synecchococcus elongatus with the essential lipids, cholesterol and eicosapentaenoic acid (EPA), and an indoor system with a stratified water-column (plankton organ) to test whether the absence of these selected dietary lipids constrains predator avoidance (habitat preferences) in four species of the key-stone pelagic freshwater grazer Daphnia. We found that the capability of avoiding fish predation through habitat shift to the deeper and colder environment was suppressed in Daphnia unless the diet was supplemented with EPA; however, the availability of cholesterol did not affect habitat preferences of the tested taxa. Thus, their ability to access a predator-free refuge and the outcome of predator-prey interactions depends upon food quality (i.e. the availability of an essential fatty acid). Our results suggest that biochemical food quality limitation, a bottom-up factor, may affect the top-down control of herbivorous zooplankton.

  14. Retinoic acid as a novel medical therapy for Cushing's disease in dogs.

    PubMed

    Castillo, Victor; Giacomini, Damiana; Páez-Pereda, Marcelo; Stalla, Johanna; Labeur, Marta; Theodoropoulou, Marily; Holsboer, Florian; Grossman, Ashley B; Stalla, Günter K; Arzt, Eduardo

    2006-09-01

    Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.

  15. Asiatic acid ameliorates pulmonary fibrosis induced by bleomycin (BLM) via suppressing pro-fibrotic and inflammatory signaling pathways.

    PubMed

    Dong, Shu-Hong; Liu, Yan-Wei; Wei, Feng; Tan, Hui-Zhen; Han, Zhi-Dong

    2017-05-01

    Idiopathic pulmonary fibrosis is known as a life-threatening disease with high mortality and limited therapeutic strategies. In addition, the molecular mechanism by which pulmonary fibrosis developed is not fully understood. Asiatic acid (AA) is a triterpenoid, isolated from Centella asiatica, exhibiting efficient anti-inflammatory and anti-oxidative activities. In our study, we attempted to explore the effect of Asiatic acid on bleomycin (BLM)-induced pulmonary fibrosis in mice. The findings indicated that pre-treatment with Asiatic acid inhibited BLM-induced lung injury and fibrosis progression in mice. Further, Asiatic acid down-regulates inflammatory cells infiltration in bronchoalveolar lavage fluid (BALF) and pro-inflammatory cytokines expression in lung tissue specimens induced by BLM. Also, Asiatic acid apparently suppressed transforming growth factor-beta 1 (TGF-β1) expression in tissues of lung, accompanied with Collagen I, Collagen III, α-SMA and matrix metalloproteinase (TIMP)-1 decreasing, as well as Smads and ERK1/2 inactivation. Of note, Asiatic acid reduces NOD-like receptor, pyrin domain containing-3 (NLRP3) inflammasome. The findings indicated that Asiatic acid might be an effective candidate for pulmonary fibrosis and inflammation treatment. Copyright © 2017. Published by Elsevier Masson SAS.

  16. Clozapine and gastro-oesophageal reflux disease (GORD) - an investigation of temporal association.

    PubMed

    van Veggel, M; Olofinjana, O; Davies, G; Taylor, D

    2013-01-01

    To establish the temporal relationship between prescription of acid-suppressant therapy, GORD and clozapine prescribing. In this retrospective cohort study, we identified out-patients prescribed clozapine and other atypical antipsychotics (AAP) and compared times and rates of prescribing of acid-suppressant therapy. Odds ratios were calculated. Of 352 patients on clozapine and 358 patients on other AAP, there were 74 (21.0%) and 23 (6.7%) patients prescribed acid-suppressant therapy respectively [OR = 3.9 (95% CI: 2.4-6.4) P ≤ 0.0001]. In 67 of 74 cases (90.5%) vs. 18 of 23 cases (81.8%), acid-suppressant therapy began after the start of the antipsychotic. Clozapine patients were more likely to be prescribed acid-suppressant therapy within the first 5 years of initiation than those on other AAP (P = 0.039). Where indication for acid-suppressant therapy was known, it was prescribed for GORD in 44 of 62 (71.0%) of the clozapine patients and 6 of 13 (46.2%) of those on other AAP (P = 0.109). Rate of known GORD was 44 of 352 (12.5%) for clozapine and 6 of 358 (1.7%) for other atypicals [OR = 8.4 (95% CI: 3.5-19.9) P ≤ 0.0001]. Clozapine was associated with higher rates of GORD and acid-suppressant therapy prescribing than other AAP. There was a clear temporal relationship between the prescribing of clozapine and the later use of acid-suppressant therapy. These observations strongly suggest that prescription of clozapine was associated with the onset of GORD. © 2012 John Wiley & Sons A/S.

  17. Suppression Effects of Betaine-Enriched Spinach on Hyperhomocysteinemia Induced by Guanidinoacetic Acid and Choline Deficiency in Rats

    PubMed Central

    Liu, Yi-Qun; Jia, Zheng; Han, Feng; Inakuma, Takahiro; Miyashita, Tatsuya; Sugiyama, Kimio; Sun, Li-Cui; Xiang, Xue-Song; Huang, Zhen-Wu

    2014-01-01

    Betaine is an important natural component of rich food sources, especially spinach. Rats were fed diets with betaine or spinach powder at the same level of betaine for 10 days to investigate the dose-dependent effects of spinach powder supplementation on hyperhomocysteinemia induced by guanidinoacetic acid (GAA) addition and choline deprivation. The GAA-induced hyperhomocysteinemia in rats fed 25% casein diet (25C) was significantly suppressed by supplementation with betaine or spinach, and it was completely suppressed by taking 11.0% spinach supplementation. The choline deprivation-induced enhancement of plasma homocysteine concentration in rats fed 25% soybean protein diet (25S) was markedly suppressed by 3.82% spinach. Supplementation with betaine or spinach partially prevented the effects of GAA on hepatic concentrations of methionine metabolites. The decrease in activity of betaine-homocysteine S-methyltransferase (BHMT) and cystathionine β-synthase (CBS) in GAA-induced hyperhomocysteinemia was recovered by supplementation with betaine or spinach. Supplementation with betaine or spinach did not affect BHMT activity, whereas it partially restored CBS activity in choline-deprived 25S. The results indicated that betaine or spinach could completely suppress the hyperhomocysteinemia induced by choline deficiency resulting from stimulating the homocysteine removal by both remethylation and cystathionine formation. PMID:25250392

  18. Suppression effects of betaine-enriched spinach on hyperhomocysteinemia induced by guanidinoacetic acid and choline deficiency in rats.

    PubMed

    Liu, Yi-Qun; Jia, Zheng; Han, Feng; Inakuma, Takahiro; Miyashita, Tatsuya; Sugiyama, Kimio; Sun, Li-Cui; Xiang, Xue-Song; Huang, Zhen-Wu

    2014-01-01

    Betaine is an important natural component of rich food sources, especially spinach. Rats were fed diets with betaine or spinach powder at the same level of betaine for 10 days to investigate the dose-dependent effects of spinach powder supplementation on hyperhomocysteinemia induced by guanidinoacetic acid (GAA) addition and choline deprivation. The GAA-induced hyperhomocysteinemia in rats fed 25% casein diet (25 C) was significantly suppressed by supplementation with betaine or spinach, and it was completely suppressed by taking 11.0% spinach supplementation. The choline deprivation-induced enhancement of plasma homocysteine concentration in rats fed 25% soybean protein diet (25S) was markedly suppressed by 3.82% spinach. Supplementation with betaine or spinach partially prevented the effects of GAA on hepatic concentrations of methionine metabolites. The decrease in activity of betaine-homocysteine S-methyltransferase (BHMT) and cystathionine β-synthase (CBS) in GAA-induced hyperhomocysteinemia was recovered by supplementation with betaine or spinach. Supplementation with betaine or spinach did not affect BHMT activity, whereas it partially restored CBS activity in choline-deprived 25S. The results indicated that betaine or spinach could completely suppress the hyperhomocysteinemia induced by choline deficiency resulting from stimulating the homocysteine removal by both remethylation and cystathionine formation.

  19. Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase.

    PubMed

    Pandey, Puspa R; Okuda, Hiroshi; Watabe, Misako; Pai, Sudha K; Liu, Wen; Kobayashi, Aya; Xing, Fei; Fukuda, Koji; Hirota, Shigeru; Sugai, Tamotsu; Wakabayashi, Go; Koeda, Keisuke; Kashiwaba, Masahiro; Suzuki, Kazuyuki; Chiba, Toshimi; Endo, Masaki; Fujioka, Tomoaki; Tanji, Susumu; Mo, Yin-Yuan; Cao, Deliang; Wilber, Andrew C; Watabe, Kounosuke

    2011-11-01

    Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. Resveratrol has been shown to have strong hypolipidemic effect on normal adipocytes and as hyper-lipogenesis is a hallmark of cancer cell physiology, the effect of resveratrol on lipid synthesis in cancer stem-like cells (CD24(-)/CD44(+)/ESA(+)) that were isolated from both ER+ and ER- breast cancer cell lines was examined. The authors found that resveratrol significantly reduced the cell viability and mammosphere formation followed by inducing apoptosis in cancer stem-like cells. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the fatty acid synthase (FAS) gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by TOFA and by Fumonisin B1, suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of cancer stem-like cells in an animal model of xenograft without showing apparental toxicity. Taken together, the results of this study indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol.

  20. Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase

    PubMed Central

    Pandey, Puspa R.; Okuda, Hiroshi; Watabe, Misako; Pai, Sudha K.; Liu, Wen; Kobayashi, Aya; Xing, Fei; Fukuda, Koji; Hirota, Shigeru; Sugai, Tamotsu; Wakabayashi, Go; Koeda, Keisuke; Kashiwaba, Masahiro; Suzuki, Kazuyuki; Chiba, Toshimi; Endo, Masaki; Fujioka, Tomoaki; Tanji, Susumu; Mo, Yin-Yuan; Cao, Deliang; Wilber, Andrew C.; Watabe, Kounosuke

    2012-01-01

    Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. Resveratrol has been shown to have strong hypolipidemic effect on normal adipocytes and as hyper-lipogenesis is a hallmark of cancer cell physiology, we examined the effect of resveratrol on lipid synthesis in cancer stem-like cells (CD24−/CD44+/ESA+) that were isolated from both ER+ and ER− breast cancer cell lines. We found that resveratrol significantly reduced the cell viability and mammosphere formation followed by inducing apoptosis in cancer stem-like cells. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the fatty acid synthase (FAS) gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by TOFA and by Fumonisin B1, suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of cancer stem-like cells in an animal model of xenograft without showing apparental toxicity. Taken together, our results indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol. PMID:21188630

  1. Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real world.

    PubMed

    Truong, J; Shadbolt, B; Ooi, M; Chitturi, S; Kaye, G; Farrell, G C; Teoh, N C

    2017-01-01

    Entecavir and tenofovir potently suppress hepatitis B virus (HBV) replication so that serum HBV DNA levels <20 IU/mL can be achieved after 2 years. Despite this, inadequate suppression is reported in >20% of cases for unclear reasons. We tested whether 4-week viral load (VL) assessment could improve 96-week treatment outcome. Data on all chronic hepatitis B patients treated with entecavir or tenofovir between 2005 and 2014 were entered prospectively. Full data capture included pre-treatment, weeks 4, 24, 48 and 96 HBV DNA titre, HBeAg, age, gender, antiviral agent and dose escalation. Compliance data were compiled from pharmacy records, doctors' letters and clinic bookings/attendance. Time to achieve complete viral suppression (HBV DNA < 20 IU/mL) was graphed using Kaplan-Meier curves. Factors affecting this were examined using a multivariate Cox Proportional Hazard model. Among 156 patients treated, 72 received entecavir and 84 tenofovir. Pre-treatment HBV DNA titre, 4-week assessment and compliance impacted significantly on time to complete viral suppression. At 96 weeks, 90% of those assessed as compliant by 4-week HBV DNA had complete viral suppression versus 50% followed by 6-month VL estimation. Continuing care by the same physician was related to 4-week VL testing and optimal compliance. Medium-term outcomes of HBV antiviral therapy are improved by early on-treatment VL testing, facilitating patient engagement and improved compliance. The observation that 90% complete viral suppression after 2 years monotherapy is achievable in a routine clinic setting questions the need for combination therapy in HBV cases with suboptimal response. © 2016 Royal Australasian College of Physicians.

  2. Gastroesophageal Acid Reflux Control 5 Years After Antireflux Surgery, Compared With Long-term Esomeprazole Therapy.

    PubMed

    Hatlebakk, Jan G; Zerbib, Frank; Bruley des Varannes, Stanislas; Attwood, Stephen E; Ell, Christian; Fiocca, Roberto; Galmiche, Jean-Paul; Eklund, Stefan; Långström, Göran; Lind, Tore; Lundell, Lars R

    2016-05-01

    We compared the ability of laparoscopic antireflux surgery (LARS) and esomeprazole to control esophageal acid exposure, over a 5-year period, in patients with chronic gastroesophageal reflux disease (GERD). We also studied whether intraesophageal and intragastric pH parameters off and on therapy were associated with long-term outcomes. We analyzed data from a prospective, randomized, open-label trial comparing the efficacy and safety of LARS vs esomeprazole (20 or 40 mg/d) over 5 years in patients with chronic GERD. Ambulatory intraesophageal and intragastric 24-hour pH monitoring data were compared between groups before LARS or the start of esomeprazole treatment, and 6 months and 5 years afterward. A secondary aim was to evaluate the association between baseline and 6-month pH parameters and esomeprazole dose escalation, reappearance of GERD symptoms, and treatment failure over 5 years in patients receiving LARS or esomeprazole. In the LARS group (n = 116), the median 24-hour esophageal acid exposure was 8.6% at baseline and 0.7% after 6 months and 5 years (P < .001 vs baseline). In the esomeprazole group (n = 151), the median 24-hour esophageal acid exposure was 8.8% at baseline, 2.1% after 6 months, and 1.9% after 5 years (P < .001, therapy vs baseline, and LARS vs esomeprazole). Gastric acidity was stable in both groups. Patients who required a dose increase to 40 mg/d had more severe supine reflux at baseline, and decreased esophageal acid exposure (P < .02) and gastric acidity after dose escalation. Esophageal and intragastric pH parameters, off and on therapy, did not predict long-term symptom breakthrough. In a prospective study of patients with chronic GERD, esophageal acid reflux was reduced greatly by LARS or esomeprazole therapy. However, patients receiving LARS had significantly greater reductions in 24-hour esophageal acid exposure after 6 months and 5 years. Esophageal and gastric pH, off and on therapy, did not predict long-term outcomes of

  3. Ursolic acid inhibits breast cancer growth by inhibiting proliferation, inducing autophagy and apoptosis, and suppressing inflammatory responses via the PI3K/AKT and NF-κB signaling pathways in vitro

    PubMed Central

    Luo, Juan; Hu, Yan-Ling; Wang, Hong

    2017-01-01

    Breast cancer, which is the second leading cause of cancer-associated mortality in women worldwide, develops from breast tissue. Chemotherapy is the most commonly used therapy to treat breast cancer. However, a number of natural plant-derived products have been suggested as alternative therapies to treat different types of cancer, such as breast cancer. The aim of the present study was to determine the anti-tumor effects of ursolic acid and its effect on apoptosis and inflammation in breast cancer cells. The anti-cancer effects of ursolic acid were evaluated in vitro using flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results suggest that ursolic acid inhibits the viability of breast cancer cells by inducing autophagy and apoptosis without inducing cell death. Cellular migration assays demonstrated that ursolic acid was able to suppress the invasive ability of breast cancer cells (P<0.05). In addition, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was downregulated following ursolic acid administration (P<0.05), leading to an upregulation of glycogen synthase kinase activity (P<0.05) and downregulation of B-cell lymphoma 2 (P<0.05), subsequently causing autophagy and apoptosis via cyclin-D1 inhibition and caspase-3 stimulation (P<0.05). Furthermore, the inflammatory response of breast cancer cells was assessed by measuring levels of nuclear factor (NF)-κB. Ursolic acid was found to downregulate NF-κB in breast cancer cells, thus inhibiting inflammation and preventing the progression of breast cancer (P<0.05). To the best of our knowledge, the present study is the first to assess the effect of ursolic acid on breast cancer cells through PI3K/AKT-regulated GSK and caspase-3 accompanied by NF-κB signaling pathways. The results of the present study regarding the potential underlying molecular mechanisms of ursolic acid may be used to develop novel therapeutic strategies for breast cancer

  4. Drug therapies for reducing gastric acidity in people with cystic fibrosis.

    PubMed

    Ng, Sze May; Moore, Helen S

    2016-08-22

    Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. This is an update of a previously published review. To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 12 May 2016. All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. Both authors independently selected trials, assessed trial quality and extracted data. The searches identified 39 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. All the trials were run in single centres and duration ranged from five days to six months. The

  5. Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors.

    PubMed

    Kang, Jaeseung; Kim, Eunjoon

    2015-01-01

    Animals prenatally exposed to valproic acid (VPA), an antiepileptic agent, have been used as a model for autism spectrum disorders (ASDs). Previous studies have identified enhanced NMDA receptor (NMDAR) function in the brain of VPA rats, and demonstrated that pharmacological suppression of NMDAR function normalizes social deficits in these animals. However, whether repetitive behavior, another key feature of ASDs, can be rescued by NMDAR inhibition remains unknown. We report here that memantine, an NMDAR antagonist, administered to VPA mice rescues both social deficits and repetitive behaviors such as self-grooming and jumping. These results suggest that suppression of elevated NMDAR function in VPA animals normalizes repetitive behaviors in addition to social deficits.

  6. Improved amber and opal suppressor tRNAs for incorporation of unnatural amino acids in vivo. Part 2: Evaluating suppression efficiency

    PubMed Central

    Rodriguez, Erik A.; Lester, Henry A.; Dougherty, Dennis A.

    2007-01-01

    The incorporation of unnatural amino acids into proteins is a valuable tool for addition of biophysical probes, bio-orthogonal functionalities, and photoreactive cross-linking agents, although these approaches often require quantities of protein that are difficult to access with chemically aminoacylated tRNAs. THG73 is an amber suppressor tRNA that has been used extensively, incorporating over 100 residues in 20 proteins. In vitro studies have shown that the Escherichia coli Asn amber suppressor (ENAS) suppresses better than THG73. However, we report here that ENAS suppresses with <26% of the efficiency of THG73 in Xenopus oocytes. We then tested the newly developed Tetrahymena thermophila Gln amber suppressor (TQAS) tRNA library, which contains mutations in the second to fourth positions of the acceptor stem. The acceptor stem mutations have no adverse effect on suppression efficiency and, in fact, can increase the suppression efficiency. Combining mutations causes an averaging of suppression efficiency, and increased suppression efficiency does not correlate with increased ΔG of the acceptor stem. We created a T. thermophila opal suppressor, TQOpS′, which shows ∼50% suppression efficiency relative to THG73. The TQAS tRNA library, composed of functional suppressor tRNAs, has been created and will allow for screening in eukaryotic cells, where rapid analysis of large libraries is not feasible. PMID:17698637

  7. Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy.

    PubMed

    Pittschieler, Sabine; Brezinka, Christoph; Jahn, Beate; Trinka, Eugen; Unterberger, Iris; Dobesberger, Judith; Walser, Gerald; Auckenthaler, Andrea; Embacher, Norbert; Bauer, Gerhard; Luef, Gerhard

    2008-12-01

    Antiepileptic drugs (AEDs) like phenytoin (PHE), carbamazepine (CBZ), barbiturates and valproic acid (VPA) interfere with folic acid absorption and metabolism, which in turn can be the cause of adverse pregnancy outcome. To study the prophylactic effect of folic acid supplementation with regard to spontaneous abortion and preterm delivery (fetal demise after week 20 of gestational age) in pregnant women receiving AED therapy, as well as benefits of most common dosage and preconceptional commencement. Prospective examination of 104 patients, registered in EURAP from 1999-2004 at a single center and a retrospective analysis of data from our epilepsy databank completed with medical records and patients interviews of the Department of Neurology of Innsbruck University Hospital from 1971 to 1999. 388 pregnancies in 244 patients were analyzed. Pregnancies with folic acid supplementation showed significant reduction of spontaneous abortion. With regard to monotherapies, in the group of women taking VPA, supplementation of folic acid had significant benefit. Other examined monotherapies (CBZ, PHE, and PB) known to interfere with folic acid showed no significant results. This study confirms the prophylactic effect of folic acid supplementation on spontaneous abortion. For AED therapy, folic acid supplementation should be part of the therapy of every pregnant epileptic woman, especially for those treated with VPA.

  8. Lipoic acid prevents suppression of connective tissue proliferation in the rat liver induced by n-3 PUFAs. A pilot study.

    PubMed

    Arend, A; Zilmer, M; Vihalemm, T; Selstam, G; Sepp, E

    2000-01-01

    As previously shown, dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) suppress connective tissue proliferation in the rat liver wound concurrent with an elevated level of lipid peroxidation. The present study was undertaken to investigate the influence of alpha-lipoic acid (LA), a natural anti-oxidant, on these effects of n-3 PUFAs. Rats were fed with a commercial pellet diet (control group) or with diets enriched with 10% of sunflower oil (n-6 group) or 10% of fish oil (n-3 group) for 8 weeks followed by addition of LA to the same diets for 10 days. Then a liver thermic wound was induced and the administration of LA was continued for 6 days. The proliferation of the connective tissue, the level of lipid peroxidation and their peroxidizability and the content of prostaglandins E2 and F2alpha were measured in the liver wounds. LA prevented the suppression of connective tissue proliferation in the healing wound induced by n-3 PUFAs, avoided the increase in peroxidation of lipids, reduced peroxidizability of lipids and modulated the decrease in PGE2 and PGF2alpha. The results indicate that dietary LA may prevent the suppression of liver wound healing induced by n-3 PUFAs.

  9. [The advances of suppression in research of amblyopia].

    PubMed

    Liu, S; Liu, H

    2016-04-11

    Suppression that is the result of interocular competition is an important machanism of amblyopia. The imbalance of suppression may lead the consequence to amblyopia. In the early study, researchers had raised the theory of II. Quadratic Summation which had revealed the relationship of interocular interaction and suppression. In some basic researches, other studies had showed the most possible anatomic location of suppression. Recently, researchers found a new method to quantify the interocular suppression named the noise model. Further studies found a novel disinhibition therapy to treat amblyopia. We summarized the research advances in suppression and disinhibition treatment in amblyopia. (Chin J Ophthalmol, 2016, 52: 305-308).

  10. DISRUPTION IN RAT ESTROUS CYCLICITY BY THE DRINKING WATER DISINFECTANT BY-PRODUCT DIBROMOACETIC ACID: RELATIONSHIP TO A SUPPRESSION ON ESTRADIOL METABOLISM?

    EPA Science Inventory

    Disruption in Rat Estrous Cyclicity by the Drinking Water Disinfectant By-Product Dibromoacetic Acid: Relationship to A Suppression on Estradiol Metabolism?

    Ashley S. Murr and Jerome M. Goldman, Endocrinology Branch, Reproductive Toxicology Division National Health and En...

  11. Epigenetic therapy potential of suberoylanilide hydroxamic acid on invasive human non-small cell lung cancer cells.

    PubMed

    Zhang, Shirong; Wu, Kan; Feng, Jianguo; Wu, Zhibing; Deng, Qinghua; Guo, Chao; Xia, Bing; Zhang, Jing; Huang, Haixiu; Zhu, Lucheng; Zhang, Ke; Shen, Binghui; Chen, Xufeng; Ma, Shenglin

    2016-10-18

    Metastasis is the reason for most cancer death, and a crucial primary step for cancer metastasis is invasion of the surrounding tissue, which may be initiated by some rare tumor cells that escape the heterogeneous primary tumor. In this study, we isolated invasive subpopulations of cancer cells from human non-small cell lung cancer (NSCLC) H460 and H1299 cell lines, and determined the gene expression profiles and the responses of these invasive cancer cells to treatments of ionizing radiation and chemotherapeutic agents. The subpopulation of highly invasive NSCLC cells showed epigenetic signatures of epithelial-mesenchymal transition, cancer cell stemness, increased DNA damage repair and cell survival signaling. We also investigated the epigenetic therapy potential of suberoylanilide hydroxamic acid (SAHA) on invasive cancer cells, and found that SAHA suppresses cancer cell invasiveness and sensitizes cancer cells to treatments of IR and chemotherapeutic agents. Our results provide guidelines for identification of metastatic predictors and for clinical management of NSCLC. This study also suggests a beneficial clinical potential of SAHA as a chemotherapeutic agent for NSCLC patients.

  12. Enhancement of renal excretion of uric acid during long-term thiazide therapy.

    PubMed

    Pak, C Y; Tolentino, R; Stewart, A; Galosy, R A

    1978-11-01

    The effect of thiazide (hydrochlorothiazide 100 mg per day orally in two divided doses for up to 3 years) on uric acid metabolism was examined in 21 patients with renal stones suffering from renal hypercalciuria or absorptive hypercalciuria. Serum concentration of uric acid increased during thiazide therapy in every patient. In 12 of 21 patients, there was a transient or persistent rise in urinary uric acid of more than 50 mg per day during treatment. The mean urinary uric acid produced by thiazide was positively correlated with the change in the renal clearance of uric acid. Thus, an increase in urinary uric acid was often associated with a rise in uric acid clearance. The results suggest that thiazide may either increase the production of uric acid or decrease the extrarenal disposal of uric acid, in some patients.

  13. Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed HIV-infected patients: 96 week outcomes of a randomized trial.

    PubMed

    Fabbiani, Massimiliano; Gagliardini, Roberta; Ciccarelli, Nicoletta; Quiros Roldan, Eugenia; Latini, Alessandra; d'Ettorre, Gabriella; Antinori, Andrea; Castagna, Antonella; Orofino, Giancarlo; Francisci, Daniela; Chinello, Pierangelo; Madeddu, Giordano; Grima, Pierfrancesco; Rusconi, Stefano; Del Pin, Barbara; Lombardi, Francesca; D'Avino, Alessandro; Focà, Emanuele; Colafigli, Manuela; Cauda, Roberto; Di Giambenedetto, Simona; De Luca, Andrea

    2018-04-12

    To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with atazanavir/ritonavir + 2NRTI in virologically suppressed patients. ATLAS-M is a 96 week open-label, randomized, non-inferiority (margin -12%) trial enrolling HIV-infected adults on atazanavir/ritonavir + 2NRTI, with stable HIV-RNA <50 copies/mL and CD4 counts >200 cells/mm3. At baseline, patients were randomized 1:1 to switch to atazanavir/ritonavir + lamivudine or to continue the previous regimen. Here, we report the 96 week efficacy and safety data. The study was registered with ClinicalTrials.gov, number NCT01599364. Overall, 266 subjects were enrolled (133 in each arm). At 96 weeks, in the ITT population, patients free of treatment failure totalled 103 (77.4%) with atazanavir/ritonavir + lamivudine and 87 (65.4%) with triple therapy (difference +12.0%, 95% CI +1.2/+22.8, P = 0.030), demonstrating the superiority of dual therapy. Two (1.5%) and 9 (6.8%) virological failures occurred in the dual-therapy arm and the triple-therapy arm, respectively, without development of resistance to any study drug. Clinical adverse events occurred at similar rates in both arms. A higher frequency of grade 3-4 hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) occurred with dual therapy, although this never led to treatment discontinuation. A significant improvement in renal function and lumbar spine bone mineral density occurred in the dual-therapy arm. The evolution of CD4, HIV-DNA levels and neurocognitive performance was similar in both arms. In this randomized study, a treatment switch to atazanavir/ritonavir + lamivudine was superior over the continuation of atazanavir/ritonavir + 2NRTI in virologically suppressed patients, with a sustained benefit in terms of improved renal function and bone mineral density.

  14. Detection of high concentrations of organic acids in fish emulsion and their role in pathogen or disease suppression.

    PubMed

    Abbasi, Pervaiz A; Lazarovits, George; Jabaji-Hare, Suha

    2009-03-01

    Fish emulsion (FE) added to a sandy-loam soil at 1 and 2% rates reduced the viability of Verticillium dahliae microsclerotia by 39 and 74% in 1 day, 87 and 98% in 3 days, and 95 and 99% in 6 days, respectively. The immediate kill of microsclerotia indicated that FE contains toxic substances. We found in FE high concentrations (400 mmol/liter) of organic acids, including some known toxicants. Glycolic, acetic, formic, n-butyric, and propionic acids were the major organic acids detected in FE at the proportions of 52.5, 26.9, 7.9, 7.2, and 4.7%, respectively. In solution assays, the viability of V. dahliae microsclerotia treated for 24 h in 1, 2, 5, and 10% FE (pH 3.6 to 3.0) or a mixture of organic acids (pH 4.1 to 3.9) equivalent to the proportions in FE was reduced by 74, 94, 97, and 99% or 81, 91, 98, and 99%, respectively. The viability of microsclerotia was increased when the treatment solutions were buffered to pH 6.0. The organic acids mixtures and formic (0.025%) and acetic (0.1%) acids were toxic to Pythium ultimum. A mixture of organic acids (1, 2, and 4%) provided immediate protection of cucumber seedlings from damping-off in P. ultimum-infested muck and sandy-loam soils but not in peat-based mix. FE (1 and 2%) provided immediate protection of cucumber seedlings from damping-off in an infested muck soil, and disease protection was consistent when planting was delayed for 7, 14, and 28 days after adding FE. FE (1, 2, and 4%) did not provide immediate protection of cucumber seedlings from damping-off in a P. ultimum-infested peat-based mix; however, disease suppression was evident when planting was delayed for 7, 14, and 21 days after adding FE. Real-time polymerase chain reaction analyses of the peat-based mix indicated that the P. ultimum populations in the FE-amended mix declined over time. This study suggests that these organic acids in FE played a major role in pathogen or disease suppression, depending on the soil and substrate.

  15. Interest of proviral HIV-1 DNA genotypic resistance testing in virologically suppressed patients candidate for maintenance therapy.

    PubMed

    Allavena, C; Rodallec, A; Leplat, A; Hall, N; Luco, C; Le Guen, L; Bernaud, C; Bouchez, S; André-Garnier, E; Boutoille, D; Ferré, V; Raffi, F

    2018-01-01

    Switch of antiretroviral therapy in virologically suppressed HIV-infected patients is frequent, to prevent toxicities, for simplification or convenience reasons. Pretherapeutic genotypic resistance testing on RNA can be lacking in some patients, which could enhance the risk of virologic failure, if resistance-associated mutations of the new regimen are not taken into account. Proviral DNA resistance testing in 69 virologically suppressed patients on antiretroviral treatment with no history of virological failure were pair-wised compared with pre-ART plasma RNA resistance testing. The median time between plasma (RNA testing) and whole blood (proviral DNA testing) was 47 months (IQR 29-63). A stop codon was evidenced in 23% (16/69) of proviral DNA sequences; these strains were considered as defective, non-replicative, and not taken into consideration. Within the non defective strains, concordance rate between plasma RNA and non-defective proviral DNA was high both on protease (194/220 concordant resistance-associated mutations=88%) and reverse transcriptase (28/37 concordant resistance-associated mutations=76%) genes. This study supports that proviral DNA testing might be an informative tool before switching antiretrovirals in virologically suppressed patients with no history of virological failure, but the interpretation should be restricted to non-defective viruses. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

    PubMed Central

    Josefsson, Lina; von Stockenstrom, Susanne; Faria, Nuno R.; Sinclair, Elizabeth; Bacchetti, Peter; Killian, Maudi; Epling, Lorrie; Tan, Alice; Ho, Terence; Lemey, Philippe; Shao, Wei; Hunt, Peter W.; Somsouk, Ma; Wylie, Will; Douek, Daniel C.; Loeb, Lisa; Custer, Jeff; Hoh, Rebecca; Poole, Lauren; Deeks, Steven G.; Hecht, Frederick; Palmer, Sarah

    2013-01-01

    The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4–12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4+ T cells [CD45RO+/CD27(+/−)]. The HIV-1 infection frequency of CD4+ T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4–12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4–12 y of suppressive therapy. We also identified a clearly replication-incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes. PMID:24277811

  17. Clinical Trial: High-Dose Acid Suppression for Chronic Cough: A Randomized, Double-Blind, Placebo-Controlled Trial

    PubMed Central

    Shaheen, Nicholas J.; Crockett, Seth D.; Bright, Stephanie D.; Madanick, Ryan D.; Buckmire, Robert; Couch, Marion; Dellon, Evan S.; Galanko, Joseph A.; Sharpless, Ginny; Morgan, Douglas R.; Spacek, Melissa B.; Heidt-Davis, Paris; Henke, David

    2011-01-01

    Summary Background Cough may be a manifestation of gastro-esophageal reflux disease (GERD). The utility of acid suppression in GERD-related cough is uncertain. Aim To assess the impact of high-dose acid suppression with proton pump inhibitors (PPI) on chronic cough in subjects with rare or no heartburn. Methods Subjects were non-smokers without history of asthma, with chronic cough for > 8 weeks. All subjects underwent a baseline 24 hr pH/impedance study, methacholine challenge test (MCT), and laryngoscopy. Subjects were randomized to either 40 mg of esomeprazole twice daily or placebo for 12 weeks. The primary outcome measure was the Cough-Specific Quality of Life Questionnaire (CQLQ). Secondary outcomes were response on Fisman Cough Severity/Frequency scores, and change in laryngeal findings. Results 40 subjects were randomized (22 PPI, 18 placebo) and completed the study. There was no difference between PPI and placebo in CQLQ (mean improvement 9.8, vs. 5.9 in placebo, p = 0.3), or Fisman Cough Severity/Frequency scores. The proportion of patients who improved by >1 standard deviation on the CQLQ was 27.8% (5/18) and 31.8% (7/22) in the placebo and PPI groups respectively. Conclusions In subjects with chronic cough and rare or no heartburn, high-dose PPI did not improve cough-related quality of life or symptoms in this randomized controlled trial. PMID:21083673

  18. Improvement of Liver Cell Therapy in Rats by Dietary Stearic Acid

    PubMed Central

    Goradel, Nasser Hashemi; Eghbal, Mohammad Ali; Darabi, Masoud; Roshangar, Leila; Asadi, Maryam; Zarghami, Nosratollah; Nouri, Mohammad

    2016-01-01

    Background: Stearic acid is known as a potent anti-inflammatory lipid. This fatty acid has profound and diverse effects on liver metabolism. The aim of this study was to investigate the effect of stearic acid on markers of hepatocyte transplantation in rats with acetaminophen (APAP)-induced liver damage. Methods: Wistar rats were randomly assigned to 10-day treatment. Stearic acid was administered to the rats with APAP-induced liver damage. The isolated liver cells were infused intraperitoneally into rats. Blood samples were obtained to evaluate the changes in the serum liver enzymes, including activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and the level of serum albumin. To assess the engraftment of infused hepatocytes, rats were euthanized, and the liver DNA was used for PCR using sex-determining region Y (SRY) primers. Results: The levels of AST, ALT and ALP in the serum of rats with APAP-induced liver injury were significantly increased and returned to the levels in control group by day six. The APAP-induced decrease in albumin was significantly improved in rats through cell therapy, when compared with that in the APAP-alone treated rats. SRY PCR analysis showed the presence of the transplanted cells in the liver of transplanted rats. Conclusion: Stearic acid-rich diet in combination with cell therapy accelerates the recovering of hepatic dysfunction in a rat model of liver injury. PMID:27090202

  19. Experimental lead intoxication in dogs: a comparison of blood lead and urinary delta-aminolevulinic acid following intoxication and chelation therapy.

    PubMed Central

    Green, R A; Selby, L A; Zumwalt, R W

    1978-01-01

    Intravenous lead administration to dogs produced an acute syndrome of lead intoxication charcterized by depression, vomiting, anorexia and weight loss. The effect of chelation therapy with calcium disodium ethylene diamine tetraacetate, penicillamine or both was determined by serially monitoring changes in blood lead and urine delta-aminolevulinic acid. Following therapy, blood lead values were significantly lower in chelated dogs than non-treated lead exposed dogs on days 7 and 10. Urine delta-aminolevulinic acid at day 7 was significantly higher in untreated lead exposed dogs than in other groups. There was no significant difference in blood lead or urine delta-aminolevulinic acid between lead intoxicated dogs which underwent the indicated chelation therapy protocols. There was, however, a trend for higher urinary delta-aminolevulinic acid excretion in those intoxicated dogs undergoing calcium disodium ethylene diamine tetraacetate therapy as opposed to those undergoing penicilamine therapy. There was no significant correlation between blood lead and urinary delta-aminolevulinic acid previous to lead exposure. However, after lead exposure significant correlation was present at days 4, 7, 10 and 14. Certain lead exposed dogs following chelation therapy were noted to have normal blood lead levels but elevated urinary delta-aminolevulinic acid suggesting that blood lead does not always correlate with metabolic effects of lead in the body. Urinary delta-aminolevulinic acid was therefore recommended as an additional laboratory parameter which improved assessment of lead exposure in dogs, particularly in determining adequacy of chelation therapy. PMID:667707

  20. Agent-based model of fecal microbial transplant effect on bile acid metabolism on suppressing Clostridium difficile infection: an example of agent-based modeling of intestinal bacterial infection.

    PubMed

    Peer, Xavier; An, Gary

    2014-10-01

    Agent-based modeling is a computational modeling method that represents system-level behavior as arising from multiple interactions between the multiple components that make up a system. Biological systems are thus readily described using agent-based models (ABMs), as multi-cellular organisms can be viewed as populations of interacting cells, and microbial systems manifest as colonies of individual microbes. Intersections between these two domains underlie an increasing number of pathophysiological processes, and the intestinal tract represents one of the most significant locations for these inter-domain interactions, so much so that it can be considered an internal ecology of varying robustness and function. Intestinal infections represent significant disturbances of this internal ecology, and one of the most clinically relevant intestinal infections is Clostridium difficile infection (CDI). CDI is precipitated by the use of broad-spectrum antibiotics, involves the depletion of commensal microbiota, and alterations in bile acid composition in the intestinal lumen. We present an example ABM of CDI (the C. difficile Infection ABM, or CDIABM) to examine fundamental dynamics of the pathogenesis of CDI and its response to treatment with anti-CDI antibiotics and a newer treatment therapy, fecal microbial transplant. The CDIABM focuses on one specific mechanism of potential CDI suppression: commensal modulation of bile acid composition. Even given its abstraction, the CDIABM reproduces essential dynamics of CDI and its response to therapy, and identifies a paradoxical zone of behavior that provides insight into the role of intestinal nutritional status and the efficacy of anti-CDI therapies. It is hoped that this use case example of the CDIABM can demonstrate the usefulness of both agent-based modeling and the application of abstract functional representation as the biomedical community seeks to address the challenges of increasingly complex diseases with the goal of

  1. Agent-based model of Fecal Microbial Transplant effect on Bile Acid Metabolism on suppressing Clostridium difficile infection: an example of agent-based modeling of intestinal bacterial infection

    PubMed Central

    Peer, Xavier; An, Gary

    2014-01-01

    Agent-based modeling is a computational modeling method that represents system-level behavior as arising from multiple interactions between the multiple components that make up a system. Biological systems are thus readily described using agent-based models (ABMs), as multi-cellular organisms can be viewed as populations of interacting cells, and microbial systems manifest as colonies of individual microbes. Intersections between these two domains underlie an increasing number of pathophysiological processes, and the intestinal tract represents one of the most significant locations for these inter-domain interactions, so much so that it can be considered an internal ecology of varying robustness and function. Intestinal infections represent significant disturbances of this internal ecology, and one of the most clinically relevant intestinal infections is Clostridium difficile infection (CDI). CDI is precipitated by the use of broad-spectrum antibiotics, involves the depletion of commensal microbiota, and alterations in bile acid composition in the intestinal lumen. We present an example ABM of CDI (the Clostridium difficile Infection ABM, or CDIABM) to examine fundamental dynamics of the pathogenesis of CDI and its response to treatment with anti-CDI antibiotics and a newer treatment therapy, Fecal Microbial Transplant (FMT). The CDIABM focuses on one specific mechanism of potential CDI suppression: commensal modulation of bile acid composition. Even given its abstraction, the CDIABM reproduces essential dynamics of CDI and its response to therapy, and identifies a paradoxical zone of behavior that provides insight into the role of intestinal nutritional status and the efficacy of anti-CDI therapies. It is hoped that this use case example of the CDIABM can demonstrate the usefulness of both agent-based modeling and the application of abstract functional representation as the biomedical community seeks to address the challenges of increasingly complex diseases with

  2. Management of osteoporosis in the aging male: Focus on zoledronic acid

    PubMed Central

    Piper, Paul K; Gruntmanis, Ugis

    2009-01-01

    Osteoporosis in the aging male remains an important yet under-recognized and undertreated disease. Current US estimates indicate that over 14 million men have osteoporosis or low bone mass, and men suffer approximately 500,000 osteoporotic fractures each year. Men experience fewer osteoporotic fractures than women but have higher mortality after fracture. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and improve survival in men with osteoporosis. Intravenous zoledronic acid may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, or significant gastrointestinal pathology. Zoledronic acid (Reclast) is approved in the US as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid (Zometa) 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy. PMID:19750231

  3. Management of osteoporosis in the aging male: focus on zoledronic acid.

    PubMed

    Piper, Paul K; Gruntmanis, Ugis

    2009-01-01

    Osteoporosis in the aging male remains an important yet under-recognized and undertreated disease. Current US estimates indicate that over 14 million men have osteoporosis or low bone mass, and men suffer approximately 500,000 osteoporotic fractures each year. Men experience fewer osteoporotic fractures than women but have higher mortality after fracture. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and improve survival in men with osteoporosis. Intravenous zoledronic acid may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, or significant gastrointestinal pathology. Zoledronic acid (Reclast) is approved in the US as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid (Zometa) 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy.

  4. Antisense suppression of phospholipase D alpha retards abscisic acid- and ethylene-promoted senescence of postharvest Arabidopsis leaves.

    PubMed Central

    Fan, L; Zheng, S; Wang, X

    1997-01-01

    Membrane disruption has been proposed to be a key event in plant senescence, and phospholipase D (PLD; EC 3.1.4.4) has been thought to play an important role in membrane deterioration. We recently cloned and biochemically characterized three different PLDs from Arabidopsis. In this study, we investigated the role of the most prevalent phospholipid-hydrolyzing enzyme, PLD alpha, in membrane degradation and senescence in Arabidopsis. The expression of PLD alpha was suppressed by introducing a PLD alpha antisense cDNA fragment into Arabidopsis. When incubated with abscisic acid and ethylene, leaves detached from the PLD alpha-deficient transgenic plants showed a slower rate of senescence than did those from wild-type and transgenic control plants. The retardation of senescence was demonstrated by delayed leaf yellowing, lower ion leakage, greater photosynthetic activity, and higher content of chlorophyll and phospholipids in the PLD alpha antisense leaves than in those of the wild type. Treatment of detached leaves with abscisic acid and ethylene stimulated PLD alpha expression, as indicated by increases in PLD alpha mRNA, protein, and activity. In the absence of abscisic acid and ethylene, however, detached leaves from the PLD alpha-deficient and wild-type plants showed a similar rate of senescence. In addition, the suppression of PLD alpha did not alter natural plant growth and development. These data suggest that PLD alpha is an important mediator in phytohormone-promoted senescence in detached leaves but is not a direct promoter of natural senescence. The physiological relevance of these findings is discussed. PMID:9437863

  5. Difference in the action mechanism of radon inhalation and radon hot spring water drinking in suppression of hyperuricemia in mice

    PubMed Central

    Etani, Reo; Kataoka, Takahiro; Kanzaki, Norie; Sakoda, Akihiro; Tanaka, Hiroshi; Ishimori, Yuu; Mitsunobu, Fumihiro; Yamaoka, Kiyonori

    2016-01-01

    Although radon therapy is indicated for hyperuricemia, the underlying mechanisms of action have not yet been elucidated in detail. Therefore, we herein examined the inhibitory effects of radon inhalation and hot spring water drinking on potassium oxonate (PO)–induced hyperuricemia in mice. Mice inhaled radon at a concentration of 2000 Bq/m3 for 24 h or were given hot spring water for 2 weeks. Mice were then administrated PO at a dose of 500 mg/kg. The results obtained showed that serum uric acid levels were significantly increased by the administration of PO. Radon inhalation or hot spring water drinking significantly inhibited elevations in serum uric acid levels through the suppression of xanthine oxidase activity in the liver. Radon inhalation activated anti-oxidative functions in the liver and kidney. These results suggest that radon inhalation inhibits PO-induced hyperuricemia by activating anti-oxidative functions, while hot spring water drinking may suppress PO-induced elevations in serum uric acid levels through the pharmacological effects of the chemical compositions dissolved in it. PMID:27021217

  6. Combination photodynamic therapy of human breast cancer using salicylic acid and methylene blue

    NASA Astrophysics Data System (ADS)

    Hosseinzadeh, Reza; Khorsandi, Khatereh; Jahanshiri, Maryam

    2017-09-01

    The objective of this study was to evaluate the effects of combination therapy with methylene blue (MB) assisted photodynamic therapy (PDT) and salicylic acid (SA) as chemo-therapy anticancer agent. The binding of salicylic acid to methylene blue was studied using spectrophotometric method. The results show the 1:2 complex formation between SA and MB. The binding constants and related Gibbs free energies o are obtained (Kb1 = 183.74, Kb2 = 38.13 and ∆ Gb1° = 12.92 kJ·mol- 1, ∆ Gb2° =9.02 kJ·mol- 1). The spectrophotometric results show the improvement in solubilization and reduction prevention for SA and MB in the complex form. These results are in agreements with cellular experiments. The dark toxicity measurements represent the improve efficacy of chemotherapy using combination of SA and MB. The photodynamic therapy results (using red LED as light source (630 nm; power density: 30 mW cm- 2)) show that the cancer cell killing efficiency of MB increases in the combination with SA due to reduction prevention and stabilization of monomeric form of MB.

  7. Optimising antiresorptive therapies in postmenopausal women: why do we need to give due consideration to the degree of suppression?

    PubMed

    Karsdal, Morten A; Qvist, Per; Christiansen, Claus; Tankó, László B

    2006-01-01

    Accelerated bone turnover with bone resorption exceeding bone formation is a major mechanism underlying postmenopausal bone loss and hence the development of osteoporosis. Accordingly, inhibition of bone resorption is a rational approach for the prevention of osteoporosis. In this context, the most logical option, hormone replacement therapy, reverses the rate of bone turnover to premenopausal levels, whereas the magnitude of inhibition by amino-bisphosphonates and the recently introduced anti-receptor activator of NFkappaB ligand (RANKL) antibody often exceeds this. As bone turnover has crucial implications for the continuous renewal of bone tissue, the over-suppression of bone turnover has potential consequences for bone quality and strength. Long-term treatment with potent bisphosphonates has recently been associated with osteonecrosis of the jaw and dose-dependent increases in micro-crack accumulation in animals. Although these observations are the subject of ongoing discussions, it is timely to discuss whether the over-suppression of bone turnover below premenopausal levels is really our ultimate goal when defining the success criteria for antiresorptive agents. In this review, the implications of high and excessively low bone turnover of endogenous origin for bone quality, fracture risk and integrity of the jaw are discussed. In addition, animal and clinical research revealing initial findings regarding the potential adverse effects of drug-induced suppression of bone remodeling are summarised. The inhibition of bone resorption, which is either transient between doses (e.g. with calcitonin) or does not exceed premenopausal levels (with hormone replacement therapy or selective estrogen receptor modulators), is preferable because it not only provides similar antifracture efficacy but can also assist in the maintenance of the dynamic repair of micro-cracks/micro-fractures.

  8. Raltegravir Treatment Intensification Does Not Alter Cerebrospinal Fluid HIV-1 Infection or Immunoactivation in Subjects on Suppressive Therapy

    PubMed Central

    Dahl, Viktor; Lee, Evelyn; Peterson, Julia; Spudich, Serena S.; Leppla, Idris; Sinclair, Elizabeth; Fuchs, Dietmar; Palmer, Sarah

    2011-01-01

    Background. Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation. Methods. This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4+ and CD8+ T-cell surface antigen expression. Results. Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4+ and CD8+ T-cell activation. Conclusions. Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. Clinical Trials Registration. NCT00672932. PMID:22021620

  9. Caffeic acid phenethyl ester suppresses monocyte adhesion to the endothelium by inhibiting NF-κB/NOX2-derived ROS signaling

    PubMed Central

    Nakahara, Risa; Makino, Junya; Kamiya, Tetsuro; Hara, Hirokazu; Adachi, Tetsuo

    2016-01-01

    Caffeic acid phenethyl ester (CAPE), one of the major polyphenols, exhibits anti-oxidative, anti-bacterial, and anti-cancer properties. Atherosclerosis is a chronic inflammatory disease, the progression of which is closely related to the accumulated adhesion of inflammatory monocytes/macrophages to the endothelium. We herein determined whether CAPE and its derivatives suppressed THP-1 cell adhesion to human umbilical vein endothelial cells (HUVEC). Of the four polyphenols tested, CAPE significantly suppressed the 12-O-tetradecanoylphorbol 13-acetate (TPA)-elicited expression of cluster for differentiation (CD) 11b, 14, and 36, and this was accompanied by the inhibition of THP-1 cell adhesion to HUVEC. CAPE also suppressed the activation of TPA-elicited nuclear factor-κB (NF-κB) and accumulation of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS), but did not affect extracellular signal-regulated kinase (ERK) phosphorylation. Taken together, these results demonstrated that CAPE suppressed THP-1 cell adhesion to HUVEC through, at least in part, the NF-κB, NOX2, and ROS-derived signaling axis. PMID:27257341

  10. Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells.

    PubMed

    Shin, Hee Soon; Satsu, Hideo; Bae, Min-Jung; Totsuka, Mamoru; Shimizu, Makoto

    2017-02-20

    Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H₂O₂)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-κB ) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H₂O₂-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H₂O₂-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells.

  11. Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells

    PubMed Central

    Shin, Hee Soon; Satsu, Hideo; Bae, Min-Jung; Totsuka, Mamoru; Shimizu, Makoto

    2017-01-01

    Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H2O2)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H2O2-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H2O2-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells. PMID:28230729

  12. Methionine and serine synergistically suppress hyperhomocysteinemia induced by choline deficiency, but not by guanidinoacetic acid, in rats fed a low casein diet.

    PubMed

    Liu, Yi-qun; Liu, Ying; Morita, Tatsuya; Sugiyama, Kimio

    2011-01-01

    The effects of dietary supplementation with 0.5% methionine, 2.5% serine, or both on hyperhomocysteinemia induced by deprivation of dietary choline or by dietary addition of 0.5% guanidinoacetic acid (GAA) were investigated in rats fed a 10% casein diet. Hyperhomocysteinemia induced by choline deprivation was not suppressed by methionine alone and was only partially suppressed by serine alone, whereas it was completely suppressed by a combination of methionine and serine, suggesting a synergistic effect of methionine and serine. Fatty liver was also completely prevented by the combination of methionine and serine. Compared with methionine alone, the combination of methionine and serine decreased hepatic S-adenosylhomocysteine and homocysteine concentrations and increased hepatic betaine and serine concentrations and betaine-homocysteine S-methyltransferase activity. GAA-induced hyperhomocysteinemia was partially suppressed by methionine alone, but no interacting effect of methionine and serine was detected. In contrast, GAA-induced fatty liver was completely prevented by the combination of methionine and serine. These results indicate that a combination of methionine and serine is effective in suppressing both hyperhomocysteinemia and fatty liver induced by choline deprivation, and that methionine alone is effective in suppressing GAA-induced hyperhomocysteinemia partially.

  13. Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy.

    PubMed

    Ticona, Eduardo; Bull, Marta E; Soria, Jaime; Tapia, Kenneth; Legard, Jillian; Styrchak, Sheila M; Williams, Corey; Mitchell, Caroline; La Rosa, Alberto; Rosa, Alberto L A; Coombs, Robert W; Frenkel, Lisa M

    2015-08-24

    Inflammatory biomarkers associated with cardiovascular disease are elevated in HIV-infected persons. These biomarkers improve with antiretroviral therapy (ART) but do not normalize to values observed in HIV-uninfected adults. Little is known regarding biomarkers of inflammation in HIV-infected Peruvians, in whom an increased burden of infectious diseases may exacerbate inflammation, and women, in whom sex difference may alter inflammation compared with men. Peruvians initiating first-line ART were enrolled in a prospective observational study. Individuals with suppression of HIV RNA plasma loads to less than 30 copies/ml when determined quarterly over 24 months of ART, had biomarkers of inflammation and cellular activation measured pre-ART and at 24-months of ART, and evaluated for associations with sex and clinical parameters. Pre-ART high-sensitivity C-reactive protein (hsCRP) values of men were in the high-risk cardiovascular disease category (>3.0 mg/l) more frequently compared with women (P = 0.02); most women's values were in the low/average-risk categories. At 24 months of suppressive ART, hsCRP concentrations decreased in men (P = 0.03), but tended to increase in women, such that the proportion with high-risk hsCRP did not differ by sex. Pre-ART, soluble CD163 concentrations were higher in women compared with men (P = 0.02), and remained higher after 24 months of suppressive ART (P = 0.02). All other inflammatory biomarkers (P < 0.03) decreased across sexes. Biomarker concentrations were not associated with BMI or coinfections. Elevated inflammatory biomarkers persisted despite 24 months of suppressive ART in a subset of Peruvians, and to a greater extent in women compared with men. These findings suggest that lifestyle or pharmacologic interventions may be required to optimize the health of HIV-infected Peruvians, particularly women.

  14. Insulin activation of plasma non-esterified fatty acid uptake in metabolic syndrome

    PubMed Central

    Ramos-Roman, Maria A.; Lapidot, Smadar A.; Phair, Robert D.; Parks, Elizabeth J.

    2012-01-01

    Objectives Insulin control of fatty acid metabolism has long been deemed dominated by suppression of adipose lipolysis. This study’s goal was to test the hypothesis that this single role of insulin is insufficient to explain observed fatty acid dynamics. Methods and Results Fatty acid kinetics were measured during a meal-tolerance test and insulin sensitivity assessed by IVGTT in overweight human subjects (n=15, BMI 35.8 ± 7.1 kg/m2). Non-steady state tracer kinetic models were formulated and tested using ProcessDB© software. Suppression of adipose release alone could not account for NEFA concentration changes postprandially, but when combined with insulin activation of fatty acid uptake was consistent with the NEFA data. The observed insulin Km for NEFA uptake was inversely correlated with both insulin sensitivity of glucose uptake (IVGTT Si) (r=−0.626, P=0.01), and whole body fat oxidation after the meal (r=−0.538, P=0.05). Conclusions These results support insulin regulation of fatty acid turnover by both release and uptake mechanisms. Activation of fatty acid uptake is consistent with the human data, has mechanistic precedent in cell culture, and highlights a new potential target for therapies aimed at improving the control of fatty acid metabolism in insulin-resistant disease states. PMID:22723441

  15. Comparison of acoustic therapies for tinnitus suppression: a preliminary trial.

    PubMed

    Schad, Maggie L; McMillan, Garnett P; Thielman, Emily J; Groon, Katherine; Morse-Fortier, Charlotte; Martin, Jennifer L; Henry, James A

    2018-02-01

    This study obtained preliminary data using two types of sound therapy to suppress tinnitus and/or reduce its functional effects: (1) Notched noise (1000-12,000 Hz notched within a 1-octave range centred around the tinnitus pitch match [PM] frequency); and (2) Matched noise (1-octave wide band of noise centred around the PM frequency). A third (Placebo) group listened to low frequency noise (250-700 Hz). Participants with bothersome tinnitus were randomised into one of the three groups and instructed to listen to the acoustic stimulus for 6 hours a day for 2 weeks. Stimuli were delivered using an iPod Nano, and tinnitus counselling was not performed. Outcome measures were recorded at the 0, 2 and 4 week study visits. Thirty participants with constant and bothersome tinnitus were recruited and randomised. All groups showed, on average, overall improvement, both immediately post-treatment and 2 weeks following treatment. Outcomes varied between groups on the different measures and at the two outcome points. This study showed improvement for all of the groups, lending support to the premise that any type of sound stimulation is beneficial for relieving effects of tinnitus. These results may serve as a preliminary evidence for a larger study.

  16. Gonadal suppressive and cross-sex hormone therapy for gender dysphoria in adolescents and adults.

    PubMed

    Smith, Katherine P; Madison, Christina M; Milne, Nikki M

    2014-12-01

    Individuals with gender dysphoria experience distress associated with incongruence between their biologic sex and their identified gender. Gender dysphoric natal males receive treatment with antiandrogens and estrogens to become feminized (transsexual females), whereas natal females with gender dysphoria receive treatment with androgens to become masculinized (transsexual males). Because of the permanence associated with cross-sex hormone therapy (CSHT), adolescents diagnosed with gender dysphoria receive gonadotropin-releasing hormone analogs to suppress puberty. High rates of depression and suicide are linked to social marginalization and barriers to care. Behavior, emotional problems, depressive symptoms, and global functioning improve in adolescents receiving puberty suppression therapy. Gender dysphoria, psychological symptoms, quality of life, and sexual function improve in adults who receive CSHT. Within the first 6 months of CSHT, changes in transsexual females include breast growth, decreased testicular volume, and decreased spontaneous erections, and changes in transsexual males include cessation of menses, breast atrophy, clitoral enlargement, and voice deepening. Both transsexual females and males experience changes in body fat redistribution, muscle mass, and hair growth. Desired effects from CSHT can take between 3 and 5 years; however, effects that occur during puberty, such as voice deepening and skeletal structure changes, cannot be reversed with CSHT. Decreased sexual desire is a greater concern in transsexual females than in transsexual males, with testosterone concentrations linked to sexual desire in both. Regarding CSHT safety, bone mineral density is preserved with adequate hormone supplementation, but long-term fracture risk has not been studied. The transition away from high-dose traditional regimens is tied to a lower risk of venous thromboembolism and cardiovascular disease, but data quality is poor. Breast cancer has been reported in

  17. Suppression of skin inflammation in keratinocytes and acute/chronic disease models by caffeic acid phenethyl ester.

    PubMed

    Lim, Kyung-Min; Bae, SeungJin; Koo, Jung Eun; Kim, Eun-Sun; Bae, Ok-Nam; Lee, Joo Young

    2015-04-01

    Skin inflammation plays a central role in the pathophysiology and symptoms of diverse chronic skin diseases including atopic dermatitis (AD). In this study, we examined if caffeic acid phenethyl ester (CAPE), a skin-permeable bioactive compound from propolis, was protective against skin inflammation using in vitro cell system and in vivo animal disease models. CAPE suppressed TNF-α-induced NF-κB activation and expression of inflammatory cytokines in human keratinocytes (HaCaT). The potency and efficacy of CAPE were superior to those of a non-phenethyl derivative, caffeic acid. Consistently, topical treatment of CAPE (0.5 %) attenuated 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced skin inflammation on mouse ear as CAPE reduced ear swelling and histologic inflammation scores. CAPE suppressed increased expression of pro-inflammatory molecules such as TNF-α, cyclooxygenase-2 and inducible NO synthase in TPA-stimulated skin. TPA-induced phosphorylation of IκB and ERK was blocked by CAPE suggesting that protective effects of CAPE on skin inflammation is attributed to inhibition of NF-κB activation. Most importantly, in an oxazolone-induced chronic dermatitis model, topical application of CAPE (0.5 and 1 %) was effective in alleviating AD-like symptoms such as increases of trans-epidermal water loss, skin thickening and serum IgE as well as histologic inflammation assessment. Collectively, our results propose CAPE as a promising candidate for a novel topical drug for skin inflammatory diseases.

  18. Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis

    PubMed Central

    Yamada, Yuko; Takanashi, Masakatsu; Sudo, Katsuko; Ueda, Shinobu; Ohno, Shin-ichiro; Kuroda, Masahiko

    2017-01-01

    MicroRNA 29b (miR-29b) replacement therapy is effective for suppressing fibrosis in a mouse model. However, to develop clinical applications for miRNA mimics, the side effects of nucleic acid drugs have to be addressed. In this study, we focused on miRNA mimics in order to develop therapies for idiopathic pulmonary fibrosis. We developed a single-stranded RNA, termed “miR-29b Psh-match,” that has a unique structure to avoid problems associated with the therapeutic uses of miRNAs. A comparison of miR-29b Psh-match and double-stranded one, termed “miR-29b mimic” indicated that the single-stranded form was significantly effective towards fibrosis according to both in vivo and in vitro experiments. This novel form of miR-29b may become the foundation for developing an effective therapeutic drug for pulmonary fibrosis. PMID:28234907

  19. Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression.

    PubMed

    Kim, Yoon Jae; Lee, Jeong Sang; Hong, Kyung Sook; Chung, Jun Won; Kim, Ju Hyun; Hahm, Ki Baik

    2010-08-01

    Colitis-associated cancers arise in the setting of chronic inflammation wherein an "inflammation-dysplasia-carcinoma" sequence prevails. Based on our previous findings in which the proton pump inhibitor could impose significant levels of anti-inflammatory, antiangiogenic, and selective apoptosis induction beyond gastric acid suppression, we investigated whether omeprazole could prevent the development of colitis-associated cancer in a mouse model induced by repeated bouts of colitis. Omeprazole, 10 mg/kg, was given i.p. all through the experimental periods for colitis-associated carcinogenesis. Molecular changes regarding inflammation and carcinogenesis were compared between control groups and colitis-associated cancer groups treated with omeprazole in addition to chemopreventive outcome. Nine of 12 (75.0%) mice in the control group developed multiple colorectal tumors, whereas tumors were noted in only 3 of 12 (25.0%) mice treated with daily injections of omeprazole. The cancer-preventive results of omeprazole treatment was based on significant decreases in the levels of nitric oxide, thiobarbituric acid-reactive substance, and interleukin-6 accompanied with attenuated expressions of tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2. The expressions of matrix metalloproteinase (MMP)-9, MMP-11, and MT1-MMMP were significantly decreased in mice treated with omeprazole in accordance with significant decreases in the number of beta-catenin-accumulated crypts. A significant induction of apoptosis was observed in tumor tissue treated with omeprazole. Omeprazole could block the trophic effect of gastrin in colon epithelial cells. The significant anti-inflammatory, antioxidative, and antimutagenic activities of omeprazole played a cancer-preventive role against colitis-induced carcinogenesis, and our novel in vivo evidence is suggestive of chemopreventive action independent of gastric acid suppression. 2010 AACR.

  20. A Drug-Repositioning Screening Identifies Pentetic Acid as a Potential Therapeutic Agent for Suppressing the Elastase-Mediated Virulence of Pseudomonas aeruginosa

    PubMed Central

    Gi, Mia; Jeong, Junhui; Lee, Keehoon; Lee, Kang-Mu; Toyofuku, Masanori; Yong, Dong Eun

    2014-01-01

    Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 μM DTPA. Supplementation with Zn2+ or Mn2+ ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection. PMID:25246397

  1. Effects of uric acid-lowering therapy on the progression of chronic kidney disease: a systematic review and meta-analysis.

    PubMed

    Liu, Xuemei; Zhai, Tingting; Ma, Ruixia; Luo, Congjuan; Wang, Huifang; Liu, Liqiu

    2018-11-01

    Whether uric acid levels were associated with the progression of chronic kidney disease (CKD) remained controversial. This meta-analysis was aimed to assess the effect of lowering serum uric acid therapy on the progression of CKD to clarify the role of uric acid in the progression of CKD indirectly. Pubmed, Embase, the Cochrane library, CBM were searched for randomized controlled trials (RCTs) that assessed the efficiency of lowering serum uric acid therapy on the progression of CKD without language restriction. Summary estimates of weighted mean differences (WMDs) and relative risk (RR) were obtained by using random-effect or fixed-effect models. Sensitivity analyses were performed to identify the source of heterogeneity. A total of 12 randomized controlled trials with 832 CKD participants were included in the analysis. Pooled estimate for eGFR was in favor of lowering serum uric acid therapy with a mean difference (MD) of 3.88 ml/min/1.73 m 2 , 95% CI 1.26-6.49 ml/min/1.73 m 2 , p = .004 and this was consistent with results for serum creatinine. The risk of worsening of kidney function or ESRD or death was significantly decreased in the treatment group compared to the control group (RR 0.39, 95% CI 0.28-0.52, p< .01). Uric acid-lowering therapy may be effective in retarding the progression of CKD. Further randomized controlled trials should be performed to confirm the effect of lowering serum uric acid therapy on the progression of CKD.

  2. Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction.

    PubMed

    Yamakawa, Yasuaki; Tazawa, Hiroshi; Hasei, Joe; Osaki, Shuhei; Omori, Toshinori; Sugiu, Kazuhisa; Komatsubara, Tadashi; Uotani, Kouji; Fujiwara, Tomohiro; Yoshida, Aki; Kunisada, Toshiyuki; Urata, Yasuo; Kagawa, Shunsuke; Ozaki, Toshifumi; Fujiwara, Toshiyoshi

    2017-09-01

    Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  3. Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model.

    PubMed

    Esser, Alison K; Schmieder, Anne H; Ross, Michael H; Xiang, Jingyu; Su, Xinming; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Allen, John S; Williams, Todd; Wickline, Samuel A; Pan, Dipanjan; Lanza, Gregory M; Weilbaecher, Katherine N

    2016-01-01

    Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (αvβ3-Fum-PD NP). Dual anti-angiogenic therapy combining αvβ3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, αvβ3-Fum-PD NP reduced (P<0.05) endothelial cell viability without impacting macrophage viability. ZA suppressed (P<0.05) macrophage viability at high dosages but not endothelial cell proliferation. 3D MR neovascular imaging of rabbit Vx2 tumors showed no effect with ZA, whereas αvβ3-Fum-PD NP alone and with ZA decreased angiogenesis (P<0.05). Immunohistochemistry revealed decreased (P<0.05) microvascularity with αvβ3-Fum-PD NP and ZA and further microvascular reduction (P<0.05) with dual-therapy. In vivo, ZA did not decrease tumor macrophage numbers nor cancer cell proliferation, whereas αvβ3-Fum-PD-NPs reduced both measures. Dual-therapy with ZA and αvβ3-Fum-PD-NP may provide enhanced neo-adjuvant utility if macrophage ZA uptake is increased. From the Clinical Editor: Although anti-angiogenesis is one of the treatment modalities in the fight against cancer, many cancers become resistant to VEGF pathway inhibitors. In this article, the authors investigated the use of dual therapy using fumagillin, integrin-targeted lipid-encapsulated nanoparticles (αvβ3- Fum-PD NP) and zoledronic acid (ZA), in both in-vitro and in-vivo experiments. This combination approach may provide an insight to the design of future drugs against cancers. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Surfactants, Aromatic and Isoprenoid Compounds, and Fatty Acid Biosynthesis Inhibitors Suppress Staphylococcus aureus Production of Toxic Shock Syndrome Toxin 1▿

    PubMed Central

    McNamara, Peter J.; Syverson, Rae Ellen; Milligan-Myhre, Kathy; Frolova, Olga; Schroeder, Sarah; Kidder, Joshua; Hoang, Thanh; Proctor, Richard A.

    2009-01-01

    Menstrual toxic shock syndrome is a rare but potentially life-threatening illness manifest through the actions of Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1). Previous studies have shown that tampon additives can influence staphylococcal TSST-1 production. We report here on the TSST-1-suppressing activity of 34 compounds that are commonly used additives in the pharmaceutical, food, and perfume industries. Many of the tested chemicals had a minimal impact on the growth of S. aureus and yet were potent inhibitors of TSST-1 production. The TSST-1-reducing compounds included surfactants with an ether, amide, or amine linkage to their fatty acid moiety (e.g., myreth-3-myristate, Laureth-3, disodium lauroamphodiacetate, disodium lauramido monoethanolamido, sodium lauriminodipropionic acid, and triethanolamine laureth sulfate); aromatic compounds (e.g. phenylethyl and benzyl alcohols); and several isoprenoids and related compounds (e.g., terpineol and menthol). The membrane-targeting and -altering effects of the TSST-1-suppressing compounds led us to assess the activity of molecules that are known to inhibit fatty acid biosynthesis (e.g., cerulenin, triclosan, and hexachlorophene). These compounds also reduced S. aureus TSST-1 production. This study suggests that more additives than previously recognized inhibit the production of TSST-1. PMID:19223628

  5. Dual Therapy Treatment Strategies for the Management of Patients Infected with HIV: A Systematic Review of Current Evidence in ARV-Naive or ARV-Experienced, Virologically Suppressed Patients.

    PubMed

    Baril, Jean-Guy; Angel, Jonathan B; Gill, M John; Gathe, Joseph; Cahn, Pedro; van Wyk, Jean; Walmsley, Sharon

    2016-01-01

    We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the

  6. Jasmonic acid-mediated defense suppresses brassinosteroid-mediated susceptibility to Rice black streaked dwarf virus infection in rice.

    PubMed

    He, Yuqing; Zhang, Hehong; Sun, Zongtao; Li, Junmin; Hong, Gaojie; Zhu, Qisong; Zhou, Xuebiao; MacFarlane, Stuart; Yan, Fei; Chen, Jianping

    2017-04-01

    Plant hormones play a vital role in plant immune responses. However, in contrast to the relative wealth of information on hormone-mediated immunity in dicot plants, little information is available on monocot-virus defense systems. We used a high-throughput-sequencing approach to compare the global gene expression of Rice black-streaked dwarf virus (RBSDV)-infected rice plants with that of healthy plants. Exogenous hormone applications and transgenic rice were used to test RBSDV infectivity and pathogenicity. Our results revealed that the jasmonic acid (JA) pathway was induced while the brassinosteroid (BR) pathway was suppressed in infected plants. Foliar application of methyl jasmonate (MeJA) or brassinazole (BRZ) resulted in a significant reduction in RBSDV incidence, while epibrassinolide (BL) treatment increased RBSDV infection. Infection studies using coi1-13 and Go mutants demonstrated JA-mediated resistance and BR-mediated susceptibility to RBSDV infection. A mixture of MeJA and BL treatment resulted in a significant reduction in RBSDV infection compared with a single BL treatment. MeJA application efficiently suppressed the expression of BR pathway genes, and this inhibition depended on the JA coreceptor OsCOI1. Collectively, our results reveal that JA-mediated defense can suppress the BR-mediated susceptibility to RBSDV infection. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  7. 18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.

    PubMed

    Zhou, Jieru; Cai, Wei; Jin, Min; Xu, Jingwei; Wang, Yanan; Xiao, Yichuan; Hao, Li; Wang, Bei; Zhang, Yanyun; Han, Jie; Huang, Rui

    2015-09-02

    Microglia are intrinsic immune cells in the central nervous system (CNS). The under controlled microglia activation plays important roles in inflammatory demyelination diseases, such as multiple sclerosis (MS). However, the means to modulate microglia activation as a therapeutic modality and the underlying mechanisms remain elusive. Here we show that administration of 18β-glycyrrhetinic acid (GRA), by using both preventive and therapeutic treatment protocols, significantly suppresses disease severity of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The treatment effect of GRA on EAE is attributed to its regulatory effect on microglia. GRA-modulated microglia significantly decreased pro-inflammatory profile in the CNS through suppression of MAPK signal pathway. The ameliorated CNS pro-inflammatory profile prevented the recruitment of encephalitogenic T cells into the CNS, which alleviated inflammation-induced demyelination. In addition, GRA treatment promoted remyelination in the CNS of EAE mice. The induced remyelination can be mediated by the overcome of inflammation-induced blockade of brain-derived neurotrophic factor expression in microglia, as well as enhancing oligodendrocyte precursor cell proliferation. Collectively, our results demonstrate that GRA-modulated microglia suppresses EAE through inhibiting microglia activation-mediated CNS inflammation, and promoting neuroprotective effect of microglia, which represents a potential therapeutic strategy for MS and maybe other neuroinflammatory diseases associated with microglia activation.

  8. MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

    PubMed Central

    Cogoi, Susanna; Zorzet, Sonia; Rapozzi, Valentina; Géci, Imrich; Pedersen, Erik B.; Xodo, Luigi E.

    2013-01-01

    KRAS mutations are primary genetic lesions leading to pancreatic cancer. The promoter of human KRAS contains a nuclease-hypersensitive element (NHE) that can fold in G4-DNA structures binding to nuclear proteins, including MAZ (myc-associated zinc-finger). Here, we report that MAZ activates KRAS transcription. To knockdown oncogenic KRAS in pancreatic cancer cells, we designed oligonucleotides that mimic one of the G-quadruplexes formed by NHE (G4-decoys). To increase their nuclease resistance, two locked nucleic acid (LNA) modifications were introduced at the 3′-end, whereas to enhance the folding and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased the Kaplan–Meier median survival time by 70%. Together, our data show that MAZ-specific G4-decoys mimicking a KRAS quadruplex are promising for pancreatic cancer therapy. PMID:23471001

  9. A Clostridium Group IV Species Dominates and Suppresses a Mixed Culture Fermentation by Tolerance to Medium Chain Fatty Acids Products

    PubMed Central

    Andersen, Stephen J.; De Groof, Vicky; Khor, Way Cern; Roume, Hugo; Props, Ruben; Coma, Marta; Rabaey, Korneel

    2017-01-01

    A microbial community is engaged in a complex economy of cooperation and competition for carbon and energy. In engineered systems such as anaerobic digestion and fermentation, these relationships are exploited for conversion of a broad range of substrates into products, such as biogas, ethanol, and carboxylic acids. Medium chain fatty acids (MCFAs), for example, hexanoic acid, are valuable, energy dense microbial fermentation products, however, MCFA tend to exhibit microbial toxicity to a broad range of microorganisms at low concentrations. Here, we operated continuous mixed population MCFA fermentations on biorefinery thin stillage to investigate the community response associated with the production and toxicity of MCFA. In this study, an uncultured species from the Clostridium group IV (related to Clostridium sp. BS-1) became enriched in two independent reactors that produced hexanoic acid (up to 8.1 g L−1), octanoic acid (up to 3.2 g L−1), and trace concentrations of decanoic acid. Decanoic acid is reported here for the first time as a possible product of a Clostridium group IV species. Other significant species in the community, Lactobacillus spp. and Acetobacterium sp., generate intermediates in MCFA production, and their collapse in relative abundance resulted in an overall production decrease. A strong correlation was present between the community composition and both the hexanoic acid concentration (p = 0.026) and total volatile fatty acid concentration (p = 0.003). MCFA suppressed species related to Clostridium sp. CPB-6 and Lactobacillus spp. to a greater extent than others. The proportion of the species related to Clostridium sp. BS-1 over Clostridium sp. CPB-6 had a strong correlation with the concentration of octanoic acid (p = 0.003). The dominance of this species and the increase in MCFA resulted in an overall toxic effect on the mixed community, most significantly on the Lactobacillus spp., which resulted in a decrease in total

  10. Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms.

    PubMed

    Liu, Jia; Wu, Ning; Ma, Leina; Liu, Ming; Liu, Ge; Zhang, Yuyan; Lin, Xiukun

    2014-01-01

    Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.

  11. Difference in the action mechanism of radon inhalation and radon hot spring water drinking in suppression of hyperuricemia in mice.

    PubMed

    Etani, Reo; Kataoka, Takahiro; Kanzaki, Norie; Sakoda, Akihiro; Tanaka, Hiroshi; Ishimori, Yuu; Mitsunobu, Fumihiro; Yamaoka, Kiyonori

    2016-06-01

    Although radon therapy is indicated for hyperuricemia, the underlying mechanisms of action have not yet been elucidated in detail. Therefore, we herein examined the inhibitory effects of radon inhalation and hot spring water drinking on potassium oxonate (PO)-induced hyperuricemia in mice. Mice inhaled radon at a concentration of 2000 Bq/m(3) for 24 h or were given hot spring water for 2 weeks. Mice were then administrated PO at a dose of 500 mg/kg. The results obtained showed that serum uric acid levels were significantly increased by the administration of PO. Radon inhalation or hot spring water drinking significantly inhibited elevations in serum uric acid levels through the suppression of xanthine oxidase activity in the liver. Radon inhalation activated anti-oxidative functions in the liver and kidney. These results suggest that radon inhalation inhibits PO-induced hyperuricemia by activating anti-oxidative functions, while hot spring water drinking may suppress PO-induced elevations in serum uric acid levels through the pharmacological effects of the chemical compositions dissolved in it. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  12. The effects of thyrotropin-suppressing therapy on bone metabolism in patients with well-differentiated thyroid carcinoma.

    PubMed

    Kim, Mee Kyoung; Yun, Kyung-Jin; Kim, Min-Hee; Lim, Dong-Jun; Kwon, Hyuk-Sang; Song, Ki-Ho; Kang, Moo-Il; Baek, Ki Hyun

    2015-02-01

    Studies on the effects of levothyroxine (LT4) therapy on bone and bone metabolism have yielded conflicting results. This 1-year prospective study examined whether LT4 in patients with well-differentiated thyroid carcinoma (DTC) is a risk factor for bone mass loss and the subsequent development of osteoporosis. We examined 93 patients with DTC over 12months after initiating LT4 therapy (early postoperative period). We examined another 33 patients on long-term LT4 therapy for DTC (late postoperative period). Dual energy X-ray absorptiometry was performed at baseline and after 1year. The mean bone losses during the early postoperative period in the lumbar spine, femoral neck, and total hip, calculated as the percentage change between levels at baseline and 12months, were -0.88, -1.3 and -0.81%, respectively. Bone loss was more evident in postmenopausal women (lumbar spine -2.1%, femoral neck -2.2%, and hip -2.1%; all P<0.05). We compared the changes in annual bone mineral density (BMD) in postmenopausal women according to calcium/vitamin D supplementation. Bone loss tended to be higher in the postmenopausal women receiving no supplementation. There was no decrease in BMD among patients during the late postoperative period. The mean bone loss was generally greater in the early than in the late postoperative group, and this was significant at the lumbar spine (P=0.041) and femoral neck (P=0.010). TSH-suppressive levothyroxine therapy accelerates bone loss, predominantly in postmenopausal women and exclusively during the early post-thyroidectomy period. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Toxins, Butyric Acid, and Other Short-Chain Fatty Acids Are Coordinately Expressed and Down-Regulated by Cysteine in Clostridium difficile

    PubMed Central

    Karlsson, Sture; Lindberg, Anette; Norin, Elisabeth; Burman, Lars G.; Åkerlund, Thomas

    2000-01-01

    It was recently found that a mixture of nine amino acids down-regulate Clostridium difficile toxin production when added to peptone yeast extract (PY) cultures of strain VPI 10463 (S. Karlsson, L. G. Burman, and T. Åkerlund, Microbiology 145:1683–1693, 1999). In the present study, seven of these amino acids were found to exhibit a moderate suppression of toxin production, whereas proline and particularly cysteine had the greatest impact, on both reference strains (n = 6) and clinical isolates (n = 28) of C. difficile (>99% suppression by cysteine in the highest toxin-producing strain). Also, cysteine derivatives such as acetylcysteine, glutathione, and cystine effectively down-regulated toxin expression. An impact of both cysteine and cystine but not of thioglycolate on toxin yield indicated that toxin expression was not regulated by the oxidation-reduction potential. Several metabolic pathways, including butyric acid and butanol production, were coinduced with the toxins in PY and down-regulated by cysteine. The enzyme 3-hydroxybutyryl coenzyme A dehydrogenase, a key enzyme in solventogenesis in Clostridium acetobutylicum, was among the most up-regulated proteins during high toxin production. The addition of butyric acid to various growth media induced toxin production, whereas the addition of butanol had the opposite effect. The results indicate a coupling between specific metabolic processes and toxin expression in C. difficile and that certain amino acids can alter these pathways coordinately. We speculate that down-regulation of toxin production by the administration of such amino acids to the colon may become a novel approach to prophylaxis and therapy for C. difficile-associated diarrhea. PMID:10992498

  14. Iatrogenic osteoporosis, bilateral HIP osteonecrosis, and secondary adrenal suppression in an HIV-infected man receiving inhaled corticosteroids and ritonavir-boosted highly active antiretroviral therapy.

    PubMed

    Kaviani, Nargess; Bukberg, Phillip; Manessis, Anastasios; Yen, Vincent; Young, Iven

    2011-01-01

    To report the first case of severe osteoporosis associated with a vertebral pathologic fracture and osteonecrosis of femoral heads in an HIV-infected man receiving inhaled corticosteroids and ritonavir-boosted antiretroviral therapy. We describe an HIV-infected man with severe osteoporosis, bilateral hip osteonecrosis, and secondary adrenal suppression, including detailed clinical, laboratory, and radiographic data, and review the related literature. A 60-year-old man with a 15-year history of HIV infection and a medical history of long-standing bronchiectasis treated with inhaled corticosteroids and hypogonadism treated with testosterone was referred to the endocrinology clinic after experiencing an osteoporotic vertebral fracture. He was taking ritonavir-boosted antiretroviral therapy. Osteonecrosis of both hips was also diagnosed, which required total hip replacement therapy. Laboratory evaluation revealed adrenal insufficiency due to increased effect of exogenous inhaled steroids and no other secondary causes of osteoporosis. A bone densitometry study showed osteoporosis of both hips and the lumbar spine. He was treated with intravenous pamidronate. During treatment, he developed bilateral femoral fractures after minor trauma. Given the potential for increased serum levels of inhaled corticosteroids in patients taking ritonavir-boosted highly active antiretroviral therapy, attention must be paid to the risk of bone loss in HIV-infected patients taking inhaled corticosteroids. Prescribing calcium and vitamin D supplementation and considering early osteoporosis screening are reasonable measures for this patient population. Interaction between inhaled corticosteroids and ritonavir may increase risk of hypothalamus-pituitary-adrenal axis suppression.

  15. Ursolic acid improves domoic acid-induced cognitive deficits in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wu, Dong-mei; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, Jiangsu Province; Lu, Jun, E-mail: lu-jun75@163.com

    Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitivemore » deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.« less

  16. Growth in Virologically Suppressed HIV-Positive Children on Antiretroviral Therapy: Individual and Population-level References.

    PubMed

    Keiser, Olivia; Blaser, Nello; Davies, Mary-Ann; Wessa, Patrick; Eley, Brian; Moultrie, Harry; Rabie, Helena; Technau, Karl-Günther; Ndirangu, James; Garone, Daniela; Giddy, Janet; Grimwood, Ashraf; Gsponer, Thomas; Egger, Matthias

    2015-10-01

    Combination antiretroviral therapy (ART) suppresses viral replication in HIV-infected children. The growth of virologically suppressed children on ART has not been well documented. We aimed to develop dynamic reference curves for weight-for-age Z scores (WAZ) and height-for-age Z scores (HAZ). Children aged <11 years at ART initiation with continuously undetectable viral loads (<400 copies/mL) treated at 7 South African ART programs with routine viral load monitoring were included. We used multilevel models to define trajectories of WAZ and HAZ up to 3 years and developed a web application to monitor trajectories in individual children. A total of 4876 children were followed for 7407 person-years. Analyses were stratified by baseline Z scores and age, which were the most important predictors of growth response. The youngest children showed the most pronounced increase in weight and height initially but catch-up growth stagnated after 1-2 years. Three years after starting ART, WAZ ranged from -2.2 [95% prediction interval (PrI), -5.6 to 0.8] in children with baseline age >5 years and Z score less than -3 to 0.0 (95% PrI, -2.7 to 2.4) in children with baseline age <2 years and WAZ greater than -1. For HAZ, the corresponding range was -2.3 (95% PrI, -4.9 to 0.3) in children with baseline age >5 years and Z score less than -3 to 0.3 (95% PrI, -3.1 to 3.4) in children with baseline age 2-5 years and HAZ greater than -1. We have developed an online tool to calculate reference trajectories in fully suppressed children. The web application could help to define "optimal" growth response and identify children with treatment failure.

  17. Rutin suppresses palmitic acids-triggered inflammation in macrophages and blocks high fat diet-induced obesity and fatty liver in mice.

    PubMed

    Gao, Mingming; Ma, Yongjie; Liu, Dexi

    2013-11-01

    To elucidate the mechanism of rutin in blocking macrophage-mediated inflammation and high fat diet-induced obesity and fatty liver. Both in vitro and in vivo approaches were taken in evaluating the effects of rutin on palmitic acids-triggered inflammation in cultured macrophages, and on weight gain and development of fatty liver of mice fed a high fat diet. Palmitic acids increase mRNA levels of pro-inflammatory cytokines, and elevate the production of TNFα in cultured macrophages. Pre-exposure of rutin to cells greatly suppressed these elevations. The suppressed inflammation by rutin was correlated with a decrease in transcription of genes responsible for ER stress and production of reactive oxygen species. In vivo, rutin protects mice from high fat diet-induced obesity, fatty liver and insulin resistance. The protective effects were associated with lack of hypertrophy and crown-like structures in the white adipose tissue, decreased mRNA levels of marker genes for macrophages including F4/80, Cd11c and Cd68, and repressed transcription of genes involved in chronic inflammation such as Mcp1 and Tnfα in white adipose tissue. In addition, rutin increases the expression of genes responsible for energy expenditure in brown adipose tissue including Pgc1α and Dio2. Furthermore, rutin suppresses transcription of Srebp1c and Cd36 in the liver, leading to a blockade of fatty liver development. These results suggest that supplementation of rutin is a promising strategy for blocking macrophage-mediated inflammation and inflammation-induced obesity and its associated complications.

  18. Stimulation of hepatocytic AMP-activated protein kinase by okadaic acid and other autophagy-suppressive toxins

    PubMed Central

    2004-01-01

    Autophagic activity in isolated rat hepatocytes is strongly suppressed by OA (okadaic acid) and other PP (protein phosphatase)-inhibitory toxins as well as by AICAR (5-aminoimidazole-4-carboxamide riboside), a direct activator of AMPK (AMP-activated protein kinase). To investigate whether AMPK is a mediator of the effects of the toxin, a phosphospecific antibody directed against the activation of phosphorylation of the AMPK α (catalytic)-subunit at Thr172 was used to assess the activation status of this enzyme. AICAR as well as all the toxins tested (OA, microcystin-LR, calyculin A, cantharidin and tautomycin) induced strong, dose-dependent AMPKα phosphorylation, correlating with AMPK activity in situ (in intact hepatocytes) as measured by the AMPK-dependent phosphorylation of acetyl-CoA carboxylase at Ser79. All treatments induced the appearance of multiple, phosphatase-sensitive, low-mobility forms of the AMPK α-subunit, consistent with phosphorylation at several sites other than Thr172. The flavonoid naringin, an effective antagonist of OA-induced autophagy suppression, inhibited the AMPK phosphorylation and mobility shifting induced by AICAR, OA or microcystin, but not the changes induced by calyculin A or cantharidin. AMPK may thus be activated both by a naringin-sensitive and a naringin-resistant mechanism, probably involving the PPs PP2A and PP1 respectively. Neither the Thr172-phosphorylating protein kinase LKB1 nor the Thr172-dephosphorylating PP, PP2C, were mobility-shifted after treatment with toxins or AICAR, whereas a slight mobility shifting of the regulatory AMPK β-subunit was indicated. Immunoblotting with a phosphospecific antibody against pSer108 at the β-subunit revealed a naringin-sensitive phosphorylation induced by OA, microcystin and AICAR and a naringin-resistant phosphorylation induced by calyculin A and cantharidin, suggesting that β-subunit phosphorylation could play a role in AMPK activation. Naringin antagonized the autophagy-suppressive

  19. Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation

    PubMed Central

    Batumalaie, Kalaivani; Amin, Muhammad Arif; Murugan, Dharmani Devi; Sattar, Munavvar Zubaid Abdul; Abdullah, Nor Azizan

    2016-01-01

    Activation of inflammatory pathways via reactive oxygen species (ROS) by free fatty acids (FFA) in obesity gives rise to insulin resistance and endothelial dysfunction. Withaferin A (WA), possesses both antioxidant and anti-inflammatory properties and therefore would be a good strategy to suppress palmitic acid (PA)-induced oxidative stress and inflammation and hence, insulin resistance and dysfunction in the endothelium. Effect of WA on PA-induced insulin resistance in human umbilical vein endothelial cells (HUVECs) was determined by evaluating insulin signaling mechanisms whilst effect of this drug on PA-induced endothelial dysfunction was determined in acetylcholine-mediated relaxation in isolated rat aortic preparations. WA significantly inhibited ROS production and inflammation induced by PA. Furthermore, WA significantly decreased TNF-α and IL-6 production in endothelial cells by specifically suppressing IKKβ/NF-κβ phosphorylation. WA inhibited inflammation-stimulated IRS-1 serine phosphorylation and improved the impaired insulin PI3-K signaling, and restored the decreased nitric oxide (NO) production triggered by PA. WA also decreased endothelin-1 and plasminogen activator inhibitor type-1 levels, and restored the impaired endothelium-mediated vasodilation in isolated aortic preparations. These findings suggest that WA inhibited both ROS production and inflammation to restore impaired insulin resistance in cultured endothelial cells and improve endothelial dysfunction in rat aortic rings. PMID:27250532

  20. Decreased HIV Type 1 Transcription in CCR5-Δ32 Heterozygotes During Suppressive Antiretroviral Therapy

    PubMed Central

    Wang, Charlene; Abdel-Mohsen, Mohamed; Strain, Matthew C.; Lada, Steven M.; Yukl, Steven; Cockerham, Leslie R.; Pilcher, Christopher D.; Hecht, Frederick M.; Sinclair, Elizabeth; Liegler, Teri; Richman, Douglas D.; Deeks, Steven G.; Pillai, Satish K.

    2014-01-01

    Individuals who are heterozygous for the CCR5-Δ32 mutation provide a natural model to examine the effects of reduced CCR5 expression on human immunodeficiency virus (HIV) persistence. We evaluated the HIV reservoir in 18 CCR5-Δ32 heterozygotes and 54 CCR5 wild-type individuals during suppressive antiretroviral therapy. Cell-associated HIV RNA levels (P = .035), RNA to DNA transcriptional ratios (P = .013), and frequency of detectable HIV 2–long terminal repeat circular DNA (P = .013) were significantly lower in CD4+ T cells from CCR5-Δ32 heterozygotes. Cell-associated HIV RNA was significantly correlated with CCR5 surface expression on CD4+ T cells (r2 = 0.136; P = .002). Our findings suggest that curative strategies should further explore manipulation of CCR5. PMID:24935955

  1. The role of free fatty acids in the inflammatory and cardiometabolic profile in adolescents with metabolic syndrome engaged in interdisciplinary therapy.

    PubMed

    Masquio, Deborah Cristina Landi; de Piano-Ganen, Aline; Oyama, Lila Missae; Campos, Raquel Munhoz da Silveira; Santamarina, Aline Boveto; de Souza, Gabriel Inácio de Morais Honorato; Gomes, Aline Dal'Olio; Moreira, Renata Guimarães; Corgosinho, Flávia Campos; do Nascimento, Claudia Maria Oller; Tock, Lian; Tufik, Sergio; de Mello, Marco Túlio; Dâmaso, Ana R

    2016-07-01

    The purpose of the present study was to evaluate if interdisciplinary therapy can influence the cardiometabolic and serum free fatty acid profile. The second aim was to evaluate if there is an association between serum free fatty acids, inflammation and cardiometabolic biomarkers in obese adolescents with and without metabolic syndrome submitted to a long-term interdisciplinary therapy. The study involved 108 postpuberty obese adolescents, who were divided according to metabolic syndrome (MetS) diagnosis: MetS (n=32) and Non-MetS (n=76). The interdisciplinary therapy consisted of a 1-year period of nutrition, psychology, physical exercise and clinical support. After therapy, both groups improved metabolic, inflammatory (leptin, adiponectin, leptin/adiponectin ratio, adiponectin/leptin ratio and C-reactive protein) and cardiometabolic profile (PAI-1 and ICAM). Metabolic syndrome prevalence reduced from 28.70% to 12.96%. Both groups reduced myristic acid (C14:0) and increased docosahexaenoic acid (DHA, C22:6n3), heneicosapentaenoic acid (HPA, C21:5n3) and arachidonic acid (C20:4n6). After adjustment for metabolic syndrome and the number of metabolic syndrome parameters, multiple regression analysis showed that changes in VCAM and PAI-1 were negatively associated with changes in cis-linoleic acid (C18:2n6c). Additionally, changes in trans-linoleic acid (C18:2n6t) were also positively associated with these biomarkers. Moreover, leptin and leptin/adiponectin ratio were negatively associated with changes in docosapentaenoic acid (DPA, C22:5n3) and stearidonic acid (SDA, C18:4n3). Adiponectin/leptin ratio was positively associated with docosapentaenoic acid (DPA, C22:5n3). Changes in adiponectin were positively correlated with changes in omega 3, such as heneicosapentaenoic acid (HPA, C21:5n3) and docosapentaenoic acid (DPA, C22:5n3). Results support that interdisciplinary therapy can control inflammatory and cardiometabolic profile in obese adolescents. Moreover, serum

  2. Significance of Ovarian Function Suppression in Endocrine Therapy for Breast Cancer in Pre-Menopausal Women

    PubMed Central

    Scharl, A.; Salterberg, A.

    2016-01-01

    Ovarian function suppression (OFS) for treating breast cancer in pre-menopausal women was introduced for the first time in the late 19th century as bilateral oophorectomy. It was not until the 1960s that the oestrogen receptor was identified and a test for detecting endocrine sensitivity of the breast cancer was developed. A weakness of early trials on OFS for breast cancer treatment is therefore their failure to take receptor sensitivity into account when selecting participants. A meta-analysis performed in the early 1990s first proved that adjuvant OFS significantly improved the cure rate of oestrogen receptor-positive breast cancer in pre-menopausal women regardless of whether it was carried out through oophorectomy, radiation-induced ablation or drug therapy. In the 1970s, tamoxifen was synthesized. It became one of the most important cancer drugs and today constitutes the gold standard for endocrine adjuvant therapy. Taking tamoxifen for a five-year period lowers mortality by 30 % over 15 years. Ten years of tamoxifen therapy reduces mortality even further, with increased side effects, however. Research over the past ten years has proven that for post-menopausal women, aromatase inhibitors have benefits over tamoxifen. Current trial results have rekindled the debate about the combination of OFS with tamoxifen or with aromatase inhibitors for adjuvant breast cancer treatment of pre-menopausal women. These trials have reported an improvement in disease-free survival in patients with a high risk of recurrence when they are treated with a combination of OFS plus tamoxifen or aromatase inhibitors, especially in women younger than 35. However, combination therapy causes significantly more side effects, which could negatively impact compliance. Endocrine treatments administered over a period of many years show waning compliance, which tends to be only around 50 % after five years. Inadequate compliance compromises efficacy and increases the risk of mortality. For

  3. Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

    PubMed Central

    Viola, Joana R.; Rafael, Diana F.; Wagner, Ernst; Besch, Robert; Ogris, Manfred

    2013-01-01

    Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed. PMID:23634303

  4. Use of a Risk-Stratification Tool in Identification of Potential Adrenal Suppression Preceding Steroid Injection Therapy in Chronic Pain Patients.

    PubMed

    Goel, Aneesh Paul; Nguyen, Vu Huy; Hamill-Ruth, Robin

    2015-12-01

    Patients who present for steroid injections are not routinely screened for potential hypothalamic-pituitary-adrenal (HPA) axis suppression from previous steroid exposure. Patients often receive various steroid therapies that are not reported by the patient or recorded in available medical records. Yet, HPA axis suppression has been reported with a single intra-articular injection. An IRB-approved quality improvement questionnaire was implemented to comprehensively screen patients for risk of HPA axis suppression secondary to prior and/or concurrent corticosteroid use. This questionnaire was given to adult patients seen in a University Pain Management Clinic, who were being considered for a steroid injection, to define the extent of exposure to corticosteroids either by mouth, topically, inhaled, or systemic/local injection within the past 6 months. Two hundred patients completed the questionnaire. Eighty-nine patients (44.5%) screened positive for significant steroid exposure with a screen score of three or above. The average score for the screen positive group was 6.31 ± 3.47 (range 3-22). Women were 1.9 times more likely to screen positive than men (53.4% vs 27.5%, P < 0.0004). Otherwise, the screen positive and screen negative groups were similar in demographic characteristics (age, BMI, and diabetes status). Our results suggest that patients receive steroids from many sources and may be at risk for HPA axis suppression. Further testing is necessary to determine if these patients indeed have biochemical evidence of adrenal suppression. Utilization of a screening questionnaire might help identify patients who should be considered for HPA axis testing prior to steroid injections. Wiley Periodicals, Inc.

  5. Effect of metformin therapy on circulating amino acids in a randomized trial: the CAMERA study.

    PubMed

    Preiss, D; Rankin, N; Welsh, P; Holman, R R; Kangas, A J; Soininen, P; Würtz, P; Ala-Korpela, M; Sattar, N

    2016-11-01

    To investigate whether metformin therapy alters circulating aromatic and branched-chain amino acid concentrations, increased levels amino acid concentrations, increased levels of which have been found to predict Type 2 diabetes. In the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) study (NCT00723307), 173 individuals without Type 2 diabetes, but with coronary disease, were randomized to metformin (n=86) or placebo (n=87) for 18 months. Plasma samples, taken every 6 months, were analysed using quantitative nuclear magnetic resonance spectroscopy. Ten metabolites consisting of eight amino acids [three branched-chain (isoleucine, leucine, valine), three aromatic (tyrosine, phenylalanine, histidine) and two other amino acids (alanine, glutamine)], lactate and pyruvate were quantified and analysed using repeated-measures models. On-treatment analyses were conducted to investigate whether amino acid changes were dependent on changes in weight, fat mass or insulin resistance estimated using homeostasis model assessment (HOMA-IR). Tyrosine decreased [-6.1 μmol/l (95% CI -8.5, -3.7); P<0.0001], while alanine [42 umol/l (95% CI 25, 59); P<0.0001] increased in the metformin-treated group compared with the placebo-treated group. Decreases in phenylalanine [-2.0 μmol/l (95% CI -3.6, -0.3); P=0.018] and increases in histidine [2.3 μmol/l (95% CI 0.1, 4.6); P=0.045] were also observed in the metformin group, although these changes were less statistically robust. Changes in these four amino acids were not accounted for by changes in weight, fat mass or HOMA-IR values. Levels of branched-chain amino acids, glutamine, pyruvate and lactate were not altered by metformin therapy. Metformin therapy results in a sustained and specific pattern of changes in aromatic amino acid and alanine concentrations. These changes are independent of any effects on weight and insulin sensitivity. Any causal link to metformin's unexplained cardiometabolic benefit requires further

  6. Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yang, Ping; Fu, Shilong; Cao, Zhifei

    Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressivemore » ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice

  7. RNAi trigger fragment truncation attenuates soybean FAD2-1 transcript suppression and yields intermediate oil phenotypes.

    PubMed

    Wagner, Nicholas; Mroczka, Andrew; Roberts, Peter D; Schreckengost, William; Voelker, Toni

    2011-09-01

    Suppression of the microsomal ω6 oleate desaturase during the seed development of soybean (Glycine max) with the 420-bp soybean FAD2-1A intron as RNAi trigger shifts the conventional fatty acid composition of soybean oil from 20% oleic and 60% polyunsaturates to one containing greater than 80% oleic acid and less than 10% polyunsaturates. To determine whether RNAi could be attenuated by reducing the trigger fragment length, transgenic plants were generated to express successively shorter 5' or 3' deletion derivatives of the FAD2-1A intron. We observed a gradual reduction in transcript suppression with shorter trigger fragments. Fatty acid composition was less affected with shorter triggers, and triggers less than 60 bp had no phenotypic effect. No trigger sequences conferring significantly higher or lower suppression efficiencies were found, and the primary determinant of suppression effect was sequence length. The observed relationship of transcript suppression with the induced fatty acid phenotype indicates that RNAi is a saturation process and not a step change between suppressed and nonsuppressed states and intermediate suppression states can be achieved. © 2010 Monsanto. Plant Biotechnology Journal © 2010 Society for Experimental Biology and Blackwell Publishing Ltd.

  8. Legionella Pneumophila and Dendrimers-Mediated Antisense Therapy.

    PubMed

    Pashaei-Asl, Roghiyeh; Khodadadi, Khodadad; Pashaei-Asl, Fatima; Haqshenas, Gholamreza; Ahmadian, Nasser; Pashaiasl, Maryam; Hajihosseini Baghdadabadi, Reza

    2017-06-01

    Finding novel and effective antibiotics for treatment of Legionella disease is a challenging field. Treatment with antibiotics usually cures Legionella infection; however, if the resultant disease is not timely recognized and treated properly, it leads to poor prognosis and high case fatality rate. Legionella pneumophila DrrA protein (Defects in Rab1 recruitment protein A)/also known as SidM affects host cell vesicular trafficking through modification of the activity of cellular small guanosine triphosphatase )GTPase( Rab (Ras-related in brain) function which facilitates intracellular bacterial replication within a supporter vacuole. Also, Legionella pneumophila LepA and LepB (Legionella effector protein A and B) proteins suppress host-cell Rab1 protein's function resulting in the cell lysis and release of bacteria that subsequently infect neighbour cells. Legionella readily develops resistant to antibiotics and, therefore, new drugs with different modes of action and therapeutic strategic approaches are urgently required among antimicrobial drug therapies;gene therapy is a novel approach for Legionnaires disease treatment. On the contrary to the conventional treatment approaches that target bacterial proteins, new treatment interventions target DNA (Deoxyribonucleic acid), RNA (Ribonucleic acid) species, and different protein families or macromolecular complexes of these components. The above approaches can overcome the problems in therapy of Legionella infections caused by antibiotics resistance pathogens. Targeting Legionella genes involved in manipulating cellular vesicular trafficking using a dendrimer-mediated antisense therapy is a promising approach to inhibit bacterial replication within the target cells.

  9. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARa and T- and B-cell targeting

    EPA Pesticide Factsheets

    Dosing information, body weights during exposure and immune system endpoints. This dataset is associated with the following publication:DeWitt, J., W. Williams , J. Creech, and R. Luebke. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting. JOURNAL OF IMMUNOTOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, USA, 13(1): 38-45, (2016).

  10. Effect of insulin sensitizer therapy on amino acids and their metabolites.

    PubMed

    Irving, Brian A; Carter, Rickey E; Soop, Mattias; Weymiller, Audrey; Syed, Husnain; Karakelides, Helen; Bhagra, Sumit; Short, Kevin R; Tatpati, Laura; Barazzoni, Rocco; Nair, K Sreekumaran

    2015-06-01

    Prior studies have reported that elevated concentrations of several plasma amino acids (AA), particularly branched chain (BCAA) and aromatic AA predict the onset of type 2 diabetes. We sought to test the hypothesis that circulating BCAA, aromatic AA and related AA metabolites decline in response to the use of insulin sensitizing agents in overweight/obese adults with impaired fasting glucose or untreated diabetes. We performed a secondary analysis of a randomized, double-blind, placebo, controlled study conducted in twenty five overweight/obese (BMI ~30kg/m(2)) adults with impaired fasting glucose or untreated diabetes. Participants were randomized to three months of pioglitazone (45mg per day) plus metformin (1000mg twice per day, N=12 participants) or placebo (N=13). We measured insulin sensitivity by the euglycemic-hyperinsulinemic clamp and fasting concentrations of AA and AA metabolites using ultra-pressure liquid chromatography tandem mass spectrometry before and after the three-month intervention. Insulin sensitizer therapy that significantly enhanced insulin sensitivity reduced 9 out of 33 AA and AA metabolites measured compared to placebo treatment. Moreover, insulin sensitizer therapy significantly reduced three functionally clustered AA and metabolite pairs: i) phenylalanine/tyrosine, ii) citrulline/arginine, and iii) lysine/α-aminoadipic acid. Reductions in plasma concentrations of several AA and AA metabolites in response to three months of insulin sensitizer therapy support the concept that reduced insulin sensitivity alters AA and AA metabolites. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Relationship of postprandial nonesterified fatty acids, adipokines, and insulin across gender in human immunodeficiency virus-positive patients undergoing highly active antiretroviral therapy.

    PubMed

    Lu, Guijing; Thomas-Geevarghese, Asha; Anuurad, Erdembileg; Raghavan, Subhashree; Minolfo, Robert; Ormsby, Bernard; Karmally, Wahida; El-Sadr, Wafaa M; Albu, Jeanine; Berglund, Lars

    2009-06-01

    Metabolic derangements are common in human immunodeficiency virus (HIV)-positive subjects undergoing antiretroviral therapy, but little is known about postprandial conditions. We investigated the relationship between leptin, adiponectin, nonesterified fatty acids (NEFA), and insulin in response to a day-long meal pattern and evaluated gender differences in HIV-positive men (n = 12) and women (n = 13) undergoing highly active antiretroviral therapy (HAART). For both men and women, a significant decrease in postprandial NEFA levels was observed following breakfast (0.53 vs. 0.22 mmol/L, P < 0.001, baseline and at 3 hours, respectively), whereas day-long postprandial leptin and adiponectin levels showed small nonsignificant oscillations. In contrast to NEFA and adiponectin, postprandial leptin levels were significantly higher among women compared to men (P < 0.05). Postprandial NEFA levels correlated positively with fasting insulin levels (r(2) = 0.25, P = 0.016), and the postbreakfast decrease in NEFA levels correlated significantly with the postbreakfast increase in insulin levels (r(2) = 0.17, P = 0.038). No significant association between postprandial adipokines and insulin was observed. In HAART-treated, HIV-infected men and women, levels of NEFA, but not adipokines, showed significant postprandial variation. Furthermore, food intake resulted in significant NEFA suppression in proportion to the food-stimulated insulin increase.

  12. Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes

    PubMed Central

    Pérez-Santiago, Josué; Ouchi, Dan; Urrea, Victor; Carrillo, Jorge; Cabrera, Cecilia; Villà-Freixa, Jordi; Puig, Jordi; Paredes, Roger; Negredo, Eugènia; Clotet, Bonaventura; Massanella, Marta; Blanco, Julià

    2016-01-01

    Background: The failure to increase CD4+ T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4+ T-cell homeostasis and impacts clinical evolution. Methods: We evaluated different definitions of immunodiscordance based on CD4+ T-cell counts (cutoff) or CD4+ T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals. Results: Cutoff definition of CD4+ cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4+ T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4+ T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4+ T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4+ values were maintained in these participants over time. Conclusion: A cutoff value of CD4+ T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup

  13. HIV-Infected Ugandan Women on Antiretroviral Therapy Maintain HIV-1 RNA Suppression Across Periconception, Pregnancy, and Postpartum Periods.

    PubMed

    Matthews, Lynn T; Ribaudo, Heather B; Kaida, Angela; Bennett, Kara; Musinguzi, Nicholas; Siedner, Mark J; Kabakyenga, Jerome; Hunt, Peter W; Martin, Jeffrey N; Boum, Yap; Haberer, Jessica E; Bangsberg, David R

    2016-04-01

    HIV-infected women risk sexual and perinatal HIV transmission during conception, pregnancy, childbirth, and breastfeeding. We compared HIV-1 RNA suppression and medication adherence across periconception, pregnancy, and postpartum periods, among women on antiretroviral therapy (ART) in Uganda. We analyzed data from women in a prospective cohort study, aged 18-49 years, enrolled at ART initiation and with ≥1 pregnancy between 2005 and 2011. Participants were seen quarterly. The primary exposure of interest was pregnancy period, including periconception (3 quarters before pregnancy), pregnancy, postpartum (6 months after pregnancy outcome), or nonpregnancy related. Regression models using generalized estimating equations compared the likelihood of HIV-1 RNA ≤400 copies per milliliter, <80% average adherence based on electronic pill caps (medication event monitoring system), and likelihood of 72-hour medication gaps across each period. One hundred eleven women contributed 486 person-years of follow-up. Viral suppression was present at 89% of nonpregnancy, 97% of periconception, 93% of pregnancy, and 89% of postpartum visits, and was more likely during periconception (adjusted odds ratio, 2.15) compared with nonpregnant periods. Average ART adherence was 90% [interquartile range (IQR), 70%-98%], 93% (IQR, 82%-98%), 92% (IQR, 72%-98%), and 88% (IQR, 63%-97%) during nonpregnant, periconception, pregnant, and postpartum periods, respectively. Average adherence <80% was less likely during periconception (adjusted odds ratio, 0.68), and 72-hour gaps per 90 days were less frequent during periconception (adjusted relative risk, 0.72) and more frequent during postpartum (adjusted relative risk, 1.40). Women with pregnancy were virologically suppressed at most visits, with an increased likelihood of suppression and high adherence during periconception follow-up. Increased frequency of 72-hour gaps suggests a need for increased adherence support during postpartum periods.

  14. Encapsulation of ferulic acid ethyl ester in caseinate to suppress off-flavor formation in UHT milk.

    PubMed

    Guan, Yongguang; Zhong, Qixin

    2017-12-15

    Phenolic compounds can principally suppress the off-flavor development in ultrahigh temperature (UHT) treated milk, but little has been studied for lipophilic phenolic compounds that are to be encapsulated for even distribution in milk. The objective of this work was to study physicochemical properties of ferulic acid ethyl ester (FAEE) encapsulated in sodium caseinate and the inhibition of volatile formation after UHT processing. The capsules had an average hydrodynamic diameter of 246.2±10.9nm, a polydispersity index of 0.26±0.01, and a zeta-potential of -31.72±0.74mV. The capsules and the encapsulated FAEE were stable after heating at 138°C for 16min and UV radiation at 365nm for 32h. The encapsulated FAEE at a level of 0.18-1.42mg/mL suppressed the formation of 2-acetyl-2-thiazoline in model UHT milk by 32.8-63.2% after 30-day storage at 30°C. Therefore, FAEE encapsulated in caseinate can be potentially used to improve the quality of UHT milk. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Astringent compounds suppress taste responses in gerbil.

    PubMed

    Schiffman, S S; Suggs, M S; Simon, S A

    1992-11-06

    Astringent tastes are generally considered those that induce long-lasting puckering and drying sensations on the tongue and membranes of the oral cavity. Electrophysiological recordings were made here from the whole chorda tympani nerve in gerbil to understand the interactive effect of astringent-tasting molecules with a broad spectrum of tastants including mono- and divalent salts, bitter compounds, acids, and sweeteners. The astringent tasting compounds were tannic acid (24 mM at pH's 2.9 and 5.5), aluminum ammonium sulfate (30 mM), aluminum potassium sulfate (10 mM) and gallic acid (30 mM). Hydrochloric acid (1 mM, pH 2.9) was also tested to control for acidity, since aqueous solutions of astringent-tasting compounds are acidic. Adaptation of the tongue to tannic acid (24 mM) at both pH 2.9 and 5.5 markedly inhibited responses elicited by salts, acids, sweeteners, and bitter-tasting compounds. The degree of the inhibition at these two pH values is about the same which suggests that tannic acid itself (as opposed to acidity) may produce this inhibition. Chorda tympani responses to sweeteners were completely suppressed by tannic acid; responses to KCl, NH4Cl, and urea were the least suppressed. The aluminum salts also inhibited the chorda tympani responses to all stimuli tested. Gallic acid, which is weakly astringent, had minimal effects on the chorda tympani responses to the test compounds. These data suggest that both tannic acid and the aluminum salts inhibit a variety of transport pathways and receptors in taste cells for a broad spectrum of tastants. The inhibition of some of these pathways may contribute to the astringent taste sensation.

  16. Dietary Karaya Saponin and Rhodobacter capsulatus Exert Hypocholesterolemic Effects by Suppression of Hepatic Cholesterol Synthesis and Promotion of Bile Acid Synthesis in Laying Hens.

    PubMed

    Afrose, Sadia; Hossain, Md Sharoare; Salma, Ummay; Miah, Abdul Gaffar; Tsujii, Hirotada

    2010-01-01

    This study was conducted to elucidate the mechanism underlying the hypolipidemic action of karaya saponin or Rhodobacter (R.) capsulatus. A total of 40 laying hens (20-week-old) were assigned into four dietary treatment groups and fed a basal diet (as a control) or basal diets supplemented with either karaya saponin, R. capsulatus, or both for 60 days. The level of serum low-density-lipoprotein cholesterol and the levels of cholesterol and triglycerides in the serum, liver, and egg yolk were reduced by all the supplementations (P < .05). Liver bile acid concentration and fecal concentrations of cholesterol, triacylglycerol, and bile acid were simultaneously increased by the supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus (P < .05). The supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus suppressed the incorporation of (14)C from 1-(14)C-palmitic acid into the fractions of total lipids, phospholipids, triacylglycerol, and cholesterol in the liver in vitro (P < .05). These findings suggest that the hypocholesterolemic effects of karaya saponin and R. capsulatus are caused by the suppression of the cholesterol synthesis and the promotion of cholesterol catabolism in the liver.

  17. MODERATING INFLUENCE OF THE DRINKING WATER DISINFECTION BY-PRODUCT DIBROMOACETIC ACID ON A DITHIOCARBAMATE-INDUCED SUPPRESSION OF THE LUTEINIZING HORMONE SURGE IN FEMALE RATS.

    EPA Science Inventory

    The disinfection by-product dibromoacetic acid (DBA) has been found in female rats to increase circulating concentrations of both estradiol (E2) and estrone (E1). This effect is apparently due, at least in part, to a suppression in hepatic catabolism. The present study investigat...

  18. Pseudolaric acid B attenuates atherosclerosis progression and inflammation by suppressing PPARγ-mediated NF-κB activation.

    PubMed

    Li, Tan; Wang, Wei; Li, Yu-Xiu; Li, Xiao; Ji, Wen-Jie; Ma, Yong-Qiang; Chen, Hong; Zhao, Ji-Hong; Zhou, Xin

    2018-06-01

    Atherosclerosis is a progressive disease of large arteries characterized with chronic inflammation and aberrant immune response. Pseudolaric acid B (PB) has been found to exert multiple effects by inhibiting inflammatory response. However, there is no comprehensive assessment of the effects of PB on atherosclerosis using relevant in vivo and in vitro models. Male ApoE -/- mice were treated with PB orally with a high fat diet (HFD) to clarify its anti-atherosclerotic activities. RAW264.7 macrophage line, a well-accepted cell model of atherosclerosis, was used to investigate anti-inflammatory effects and molecular mechanisms of PB. PB significantly attenuated atherosclerotic lesions by modulating plasma lipid profiles as well as inhibiting inflammatory responses in macrophages of atherosclerotic mice. Meanwhile, PB markedly suppressed the expression of pro-inflammatory cytokines, and regulated cholesterol efflux related genes in oxidative low density lipoprotein (ox-LDL)-loaded macrophages. The cellular uptake of Dil-labeled ox-LDL was significantly inhibited by PB either. Moreover, the ability of PB to suppress nuclear factor kappa B (NF-κB) and activate peroxisome proliferator-activated receptor gamma (PPARγ) was confirmed using luciferase reporter assays. Conversely, the selective PPARγ antagonist GW9662 reversed the influence of PB in macrophages. Together, these findings indicate that PB exerts its protective effects on atherosclerosis by inhibiting macrophage-mediated inflammatory response and cellular ox-LDL uptake, and promoting cholesterol efflux by suppressing NF-κB activation PPARγ-dependently. Therefore, PB may be a promising agent for inflammatory and atherosclerotic diseases. Copyright © 2018. Published by Elsevier B.V.

  19. Optimizing prevention of HIV mother to child transmission: Duration of antiretroviral therapy and viral suppression at delivery among pregnant Malawian women

    PubMed Central

    Miller, William C.; Tang, Jennifer H.; Hoffman, Irving F.; Mthiko, Bryan C.; Phulusa, Jacob; John, Mathias; Jumbe, Allan; Hosseinipour, Mina C.

    2018-01-01

    Background Effective antiretroviral therapy during pregnancy minimizes the risk of vertical HIV transmission. Some women present late in their pregnancy for first antenatal visit; whether these women achieve viral suppression by delivery and how suppression varies with time on ART is unclear. Methods We conducted a prospective cohort study of HIV-infected pregnant women initiating antiretroviral therapy for the first time at Bwaila Hospital in Lilongwe, Malawi from June 2015 to November 2016. Multivariable Poisson models with robust variance estimators were used to estimate risk ratios (RR) and 95% confidence intervals (CI) of the association between duration of ART and both viral load (VL) ≥1000 copies/ml and VL ≥40 copies/ml at delivery. Results Of the 252 women who had viral load testing at delivery, 40 (16%) and 78 (31%) had VL ≥1000 copies/ml and VL ≥40 copies/ml, respectively. The proportion of women with poor adherence to ART was higher among women who were on ART for ≤12 weeks (9/50 = 18.0%) than among those who were on ART for 13–35 weeks (18/194 = 9.3%). Compared to women who were on ART for ≤12 weeks, women who were on ART for 13–20 weeks (RR = 0.52; 95% CI: 0.36–0.74) or 21–35 weeks (RR = 0.26; 95% CI: 0.14–0.48) had a lower risk of VL ≥40 copies/ml at delivery. Similar comparisons for VL ≥1000 copies/ml at delivery showed decrease in risk although not significant for those on ART 13–20 weeks. Conclusion Longer duration of ART during pregnancy was associated with suppressed viral load at delivery. Early ANC attendance in pregnancy to facilitate prompt ART initiation for HIV-positive women is essential in the effort to eliminate HIV vertical transmission. PMID:29614083

  20. Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy

    PubMed Central

    Wickens, Jennifer M.; Alsaab, Hashem O.; Kesharwani, Prashant; Bhise, Ketki; Amin, Mohd Cairul Iqbal Mohd; Tekade, Rakesh Kumar; Gupta, Umesh; Iyer, Arun K.

    2016-01-01

    The cluster-determinant 44 (CD44) receptor has a high affinity for hyaluronic acid (HA) binding and is a desirable receptor for active targeting based on its overexpression in cancer cells compared with normal body cells. The nanocarrier affinity can be increased by conjugating drug-loaded carriers with HA, allowing enhanced cancer cell uptake via the HA-CD44 receptor-mediated endocytosis pathway. In this review, we discuss recent advances in HA-based nanocarriers and micelles for cancer therapy. In vitro and in vivo experiments have repeatedly indicated HA-based nanocarriers to be a target-specific drug and gene delivery platform with great promise for future applications in clinical cancer therapy. PMID:28017836

  1. Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy.

    PubMed

    Wickens, Jennifer M; Alsaab, Hashem O; Kesharwani, Prashant; Bhise, Ketki; Amin, Mohd Cairul Iqbal Mohd; Tekade, Rakesh Kumar; Gupta, Umesh; Iyer, Arun K

    2017-04-01

    The cluster-determinant 44 (CD44) receptor has a high affinity for hyaluronic acid (HA) binding and is a desirable receptor for active targeting based on its overexpression in cancer cells compared with normal body cells. The nanocarrier affinity can be increased by conjugating drug-loaded carriers with HA, allowing enhanced cancer cell uptake via the HA-CD44 receptor-mediated endocytosis pathway. In this review, we discuss recent advances in HA-based nanocarriers and micelles for cancer therapy. In vitro and in vivo experiments have repeatedly indicated HA-based nanocarriers to be a target-specific drug and gene delivery platform with great promise for future applications in clinical cancer therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Effect of essential amino acids on enteroids: Methionine deprivation suppresses proliferation and affects differentiation in enteroid stem cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Saito, Yuki; Iwatsuki, Ken; Hanyu, Hikaru

    We investigated the effects of essential amino acids on intestinal stem cell proliferation and differentiation using murine small intestinal organoids (enteroids) from the jejunum. By selectively removing individual essential amino acids from culture medium, we found that 24 h of methionine (Met) deprivation markedly suppressed cell proliferation in enteroids. This effect was rescued when enteroids cultured in Met deprivation media for 12 h were transferred to complete medium, suggesting that Met plays an important role in enteroid cell proliferation. In addition, mRNA levels of the stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) decreased in enteroids grown in Met deprivationmore » conditions. Consistent with this observation, Met deprivation also attenuated Lgr5-EGFP fluorescence intensity in enteroids. In contrast, Met deprivation enhanced mRNA levels of the enteroendocrine cell marker chromogranin A (ChgA) and markers of K cells, enterochromaffin cells, goblet cells, and Paneth cells. Immunofluorescence experiments demonstrated that Met deprivation led to an increase in the number of ChgA-positive cells. These results suggest that Met deprivation suppresses stem cell proliferation, thereby promoting differentiation. In conclusion, Met is an important nutrient in the maintenance of intestinal stem cells and Met deprivation potentially affects cell differentiation. - Highlights: • Met influences the proliferation of enteroids. • Met plays a crucial role in the maintenance of stem cells. • Met deprivation potentially promotes differentiation into secretory cells.« less

  3. Herbert Falk: a vital force in the renaissance of bile acid research and bile acid therapy.

    PubMed

    Hofmann, Alan F

    2011-01-01

    Herbert Falk died on August 8, 2008, after a long illness. It was his vision that initiated the Bile Acid Meetings and brought to market chenodeoxycholic acid and ursodeoxycholic acid for the dissolution of cholesterol gallstones as well as the successful treatment of cholestatic liver disease. The 1st Bile Acid Meeting was a small workshop held at the University Hospital of Freiburg in 1970. Great interest in the topic was evident at that small meeting and led to a larger meeting in 1972, whose scope included both the basic and clinical aspects of bile acids. These meetings have continued at biennial intervals, the 2010 meeting being the 21st. The program has always included discussions of the most fundamental aspects of bile acid biosynthesis and metabolism as well as clinical applications of bile acid therapy. The meetings featured brief presentations, ample time for discussion, and imaginative social programs. They have always been flawlessly organized. Social programs usually included a hike through the beautiful countryside of the Black Forest followed by dinner in a rustic restaurant. Herbert Falk took part in these programs, personally welcoming every participant. In the warm glow of the 'Badische' hospitality, friendships developed, and scientific collaborations were often arranged. From a scientific standpoint, there has been enormous progress in understanding the chemistry and biology of bile acids. Herbert Falk established the Windaus Prize in 1978, and the prize has been given to individuals whose contributions moved the field forward. These bile acid meetings have been marvelous, rewarding experiences. We must all be grateful to Herbert Falk's vision in establishing the Falk Foundation that has so generously sponsored these meetings. We also express our gratitude to his widow, Ursula Falk, who continues this worthy tradition. Copyright © 2011 S. Karger AG, Basel.

  4. Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARα and CB1 receptors.

    PubMed

    Rock, Erin M; Moreno-Sanz, Guillermo; Limebeer, Cheryl L; Petrie, Gavin N; Angelini, Roberto; Piomelli, Daniele; Parker, Linda A

    2017-11-01

    Effective treatments of nausea are limited. In this study we evaluated the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937, to suppress acute and anticipatory nausea in rats and examined the pharmacological mechanism of this effect. We investigated the potential of URB937 (administered i.p.) to reduce the establishment of lithium chloride-induced conditioned gaping (model of acute nausea) and to reduce the expression of contextually-elicited conditioned gaping (model of anticipatory nausea) in rats. The role of CB 1 receptors, CB 2 receptors and PPARα in the anti-nausea effect of URB937 was examined. The potential of URB937 to suppress FAAH activity in tissue collected from the area postrema (AP), prefrontal cortex (PFC), liver and duodenum and to elevate levels of FAAH substrates - anandamide (AEA), N-oleoylethanolamide (OEO) and N-palmitoylethanolamide (PEA) - in the AP was also evaluated. URB937 reduced acute nausea by a PPARα-dependent mechanism and reduced anticipatory nausea by a CB 1 receptor-dependent mechanism. The PPARα agonist, GW7647, similarly attenuated acute nausea. URB937 reduced FAAH activity in the liver and the duodenum but not in the PFC. In addition, URB937 reduced FAAH activity and elevated levels of fatty-acid ethanolamides in the AP, a brain region that is not protected by the blood-brain barrier. The anti-nausea action of URB937 may occur in the AP and may involve PPARα to suppress acute nausea and CB 1 receptors to suppress anticipatory nausea. © 2017 The British Pharmacological Society.

  5. Dynamic compressive loading enhances cartilage matrix synthesis and distribution and suppresses hypertrophy in hMSC-laden hyaluronic acid hydrogels.

    PubMed

    Bian, Liming; Zhai, David Y; Zhang, Emily C; Mauck, Robert L; Burdick, Jason A

    2012-04-01

    Mesenchymal stem cells (MSCs) are being recognized as a viable cell source for cartilage repair, and there is growing evidence that mechanical signals play a critical role in the regulation of stem cell chondrogenesis and in cartilage development. In this study we investigated the effect of dynamic compressive loading on chondrogenesis, the production and distribution of cartilage specific matrix, and the hypertrophic differentiation of human MSCs encapsulated in hyaluronic acid (HA) hydrogels during long term culture. After 70 days of culture, dynamic compressive loading increased the mechanical properties, as well as the glycosaminoglycan (GAG) and collagen contents of HA hydrogel constructs in a seeding density dependent manner. The impact of loading on HA hydrogel construct properties was delayed when applied to lower density (20 million MSCs/ml) compared to higher seeding density (60 million MSCs/ml) constructs. Furthermore, loading promoted a more uniform spatial distribution of cartilage matrix in HA hydrogels with both seeding densities, leading to significantly improved mechanical properties as compared to free swelling constructs. Using a previously developed in vitro hypertrophy model, dynamic compressive loading was also shown to significantly reduce the expression of hypertrophic markers by human MSCs and to suppress the degree of calcification in MSC-seeded HA hydrogels. Findings from this study highlight the importance of mechanical loading in stem cell based therapy for cartilage repair in improving neocartilage properties and in potentially maintaining the cartilage phenotype.

  6. METHOD OF SUPPRESSING GASTROINTESTINAL UREASE ACTIVITY

    DOEpatents

    Visek, W.J.

    1963-04-23

    This patent shows a method of increasing the growth rate of chicks. Certain diacyl substituted ureas such as alloxan, murexide, and barbituric acid are added to their feed, thereby suppressing gastrointestinal urease activity and thus promoting growth. (AEC)

  7. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies.

    PubMed

    Pellegrini, Paola; Strambi, Angela; Zipoli, Chiara; Hägg-Olofsson, Maria; Buoncervello, Maria; Linder, Stig; De Milito, Angelo

    2014-04-01

    Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies.

  8. Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study.

    PubMed

    Assis, David N; Abdelghany, Osama; Cai, Shi-Ying; Gossard, Andrea A; Eaton, John E; Keach, Jill C; Deng, Yanhong; Setchell, Kenneth D R; Ciarleglio, Maria; Lindor, Keith D; Boyer, James L

    2017-02-01

    To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

  9. Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas

    PubMed Central

    Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

    2013-01-01

    The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. PMID:24092664

  10. CD8+ lymphocytes are required to maintain virus suppression in SIV-infected macaques treated with short-term antiretroviral therapy

    PubMed Central

    Cartwright, Emily K.; Spicer, Lori; Smith, S. Abigail; Lee, David; Fast, Randy; Paganini, Sara; Lawson, Benton O.; Nega, Melon; Easley, Kirk; Schmitz, Joern E.; Bosinger, Steven E.; Paiardini, Mirko; Chahroudi, Ann; Vanderford, Thomas H.; Estes, Jacob D.; Lifson, Jeffrey D.; Derdeyn, Cynthia A.; Silvestri, Guido

    2016-01-01

    Infection with HIV persists despite suppressive antiretroviral therapy (ART) and treatment interruption results in rapid viral rebound. Antibody-mediated CD8+ lymphocyte depletion in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) shows these cells contribute to virus control in untreated animals. However, the contribution of CD8+ lymphocytes to maintaining virus suppression under ART remains unknown. We showed that in SIV-infected RMs treated with short-term ART (i.e., 8-32 weeks), depletion of CD8+ lymphocytes resulted in increased plasma viremia in all animals, and that repopulation of CD8+ T cells was associated with prompt reestablishment of virus control. Although the number of SIV-DNA-positive cells remained unchanged after CD8 depletion and reconstitution, the frequency of SIV-infected CD4+ T cells pre-depletion positively correlated with both peak and area-under-the-curve of viremia post-depletion. These results suggest a role for CD8+ T cells in controlling virus production during ART, thus providing rationale to explore immunotherapeutic approaches in ART-treated HIV-infected individuals. PMID:27653601

  11. 18β-Glycyrrhetinic acid suppresses TNF-α induced matrix metalloproteinase-9 and vascular endothelial growth factor by suppressing the Akt-dependent NF-κB pathway.

    PubMed

    Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Dilshara, Matharage Gayani; Park, Sang Rul; Choi, Yung Hyun; Hyun, Jin-Won; Chang, Weon-Young; Kim, Gi-Young

    2014-08-01

    Little is known about the molecular mechanism through which 18β-glycyrrhetinic acid (GA) inhibits metastasis and invasion of cancer cells. Therefore, this study aimed to investigate the effects of GA on the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in various types of cancer cells. We found that treatment with GA reduces tumor necrosis factor-α (TNF-α)-induced Matrigel invasion with few cytotoxic effects. Our findings also showed that MMP-9 and VEGF expression increases in response to TNF-α; however, GA reverses their expression. In addition, GA inhibited inhibitory factor kappa B degradation, sustained nuclear factor-kappa B (NF-κB) subunits, p65 and p50, in the cytosol compartments, and consequently suppressed the TNF-α-induced DNA-binding activity and luciferase activity of NF-κB. Specific NF-κB inhibitors, pyrrolidine dithiocarbamate, MG132, and PS-1145, also attenuated TNF-α-mediated MMP-9 and VEGF expression as well as activity by suppressing their regulatory genes. Furthermore, phosphorylation of TNF-α-induced phosphatidyl-inositol 3 kinase (PI3K)/Akt was significantly downregulated in the presence of GA accompanying with the inhibition of NF-κB activity, and as presumed, the specific PI3K/Akt inhibitor LY294002 significantly decreased MMP-9 and VEGF expression as well as activity. These results suggest that GA operates as a potential anti-invasive agent by downregulating MMP-9 and VEGF via inhibition of PI3K/Akt-dependent NF-κB activity. Taken together, GA might be an effective anti-invasive agent by suppressing PI3K/Akt-mediated NF-κB activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Rosmarinus officinalis Extract Suppresses Propionibacterium acnes–Induced Inflammatory Responses

    PubMed Central

    Tsai, Tsung-Hsien; Chuang, Lu-Te; Lien, Tsung-Jung; Liing, Yau-Rong; Chen, Wei-Yu

    2013-01-01

    Abstract Propionibacterium acnes is a key pathogen involved in the progression of acne inflammation. The development of a new agent possessing antimicrobial and anti-inflammatory activity against P. acnes is therefore of interest. In this study, we investigated the inhibitory effect of rosemary (Rosmarinus officinalis) extract on P. acnes–induced inflammation in vitro and in vivo. The results showed that ethanolic rosemary extract (ERE) significantly suppressed the secretion and mRNA expression of proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and tumor necrosis factor-α in P. acnes–stimulated monocytic THP-1 cells. In an in vivo mouse model, concomitant intradermal injection of ERE attenuated the P. acnes–induced ear swelling and granulomatous inflammation. Since ERE suppressed the P. acnes–induced nuclear factor kappa-B (NF-κB) activation and mRNA expression of Toll-like receptor (TLR) 2, the suppressive effect of ERE might be due, at least partially, to diminished NF-κB activation and TLR2-mediated signaling pathways. Furthermore, three major constituents of ERE, carnosol, carnosic acid, and rosmarinic acid, exerted different immumodulatory activities in vitro. In brief, rosmarinic acid significantly suppressed IL-8 production, while the other two compounds inhibited IL-1β production. Further study is needed to explore the role of bioactive compounds of rosemary in mitigation of P. acnes–induced inflammation. PMID:23514231

  13. Estrogen suppresses melatonin-enhanced hyperactivation of hamster spermatozoa

    PubMed Central

    FUJINOKI, Masakatsu; TAKEI, Gen L.

    2015-01-01

    Hamster sperm hyperactivation is enhanced by progesterone, and this progesterone-enhanced hyperactivation is suppressed by 17β-estradiol (17βE2) and γ-aminobutyric acid (GABA). Although it has been indicated that melatonin also enhances hyperactivation, it is unknown whether melatonin-enhanced hyperactivation is also suppressed by 17βE2 and GABA. In the present study, melatonin-enhanced hyperactivation was significantly suppressed by 17βE2 but not by GABA. Moreover, suppression of melatonin-enhanced hyperactivation by 17βE2 occurred through non-genomic regulation via the estrogen receptor (ER). These results suggest that enhancement of hyperactivation is regulated by melatonin and 17βE2 through non-genomic regulation. PMID:25959801

  14. Acidic Polysaccharide Extracts from Gastrodia Rhizomes Suppress the Atherosclerosis Risk Index through Inhibition of the Serum Cholesterol Composition in Sprague Dawley Rats Fed a High-Fat Diet

    PubMed Central

    Kim, Kui-Jin; Lee, Ok-Hwan; Han, Chan-Kyu; Kim, Young-Chan; Hong, Hee-Do

    2012-01-01

    Obesity is associated with a broad spectrum of cardio-metabolic disturbances, including atherosclerosis and cardiovascular disease (CDV). A high-fat diet has been shown to cause an elevation of the plasma cholesterol levels in humans, and the control of serum cholesterol has been demonstrated to be important in the prevention of CVD and atherosclerosis. The aims of this study were to demonstrate that crude and acidic polysaccharide extracts from Gastrodia rhizomes suppress atherosclerosis through the regulation of serum lipids in Sprague Dawley (SD) rats fed a high-fat diet. We examined the concentrations of serum lipids, including total cholesterol, triglycerides, high-density lipoproteins (HDL) cholesterol, and low-density lipoproteins (LDL) cholesterol, in SD rats fed a high-fat diet and evaluated the atherogenic index. Here, we show that both crude and acidic polysaccharide extracts from Gastrodia rhizomes inhibited the total cholesterol and LDL levels. Moreover, there was a significantly suppressed atherosclerosis risk due to the acidic polysaccharide extract from Gastrodia rhizome. Taken together, our results suggested that acidic polysaccharide extracts from Gastrodia rhizomes might be beneficial for lowering the incidence of CVD and atherosclerosis by reducing the de novo synthesis of total cholesterol and the LDL levels. PMID:22408412

  15. Acidic polysaccharide extracts from Gastrodia Rhizomes suppress the atherosclerosis risk index through inhibition of the serum cholesterol composition in Sprague Dawley rats fed a high-fat diet.

    PubMed

    Kim, Kui-Jin; Lee, Ok-Hwan; Han, Chan-Kyu; Kim, Young-Chan; Hong, Hee-Do

    2012-01-01

    Obesity is associated with a broad spectrum of cardio-metabolic disturbances, including atherosclerosis and cardiovascular disease (CDV). A high-fat diet has been shown to cause an elevation of the plasma cholesterol levels in humans, and the control of serum cholesterol has been demonstrated to be important in the prevention of CVD and atherosclerosis. The aims of this study were to demonstrate that crude and acidic polysaccharide extracts from Gastrodia rhizomes suppress atherosclerosis through the regulation of serum lipids in Sprague Dawley (SD) rats fed a high-fat diet. We examined the concentrations of serum lipids, including total cholesterol, triglycerides, high-density lipoproteins (HDL) cholesterol, and low-density lipoproteins (LDL) cholesterol, in SD rats fed a high-fat diet and evaluated the atherogenic index. Here, we show that both crude and acidic polysaccharide extracts from Gastrodia rhizomes inhibited the total cholesterol and LDL levels. Moreover, there was a significantly suppressed atherosclerosis risk due to the acidic polysaccharide extract from Gastrodia rhizome. Taken together, our results suggested that acidic polysaccharide extracts from Gastrodia rhizomes might be beneficial for lowering the incidence of CVD and atherosclerosis by reducing the de novo synthesis of total cholesterol and the LDL levels.

  16. Antiretroviral therapy: current drugs.

    PubMed

    Pau, Alice K; George, Jomy M

    2014-09-01

    The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date. Published by Elsevier Inc.

  17. Methods for suppressing isomerization of olefin metathesis products

    DOEpatents

    Firth, Bruce E.; Kirk, Sharon E.

    2015-10-27

    A method for suppressing isomerization of an olefin metathesis product produced in a metathesis reaction includes adding an isomerization suppression agent that includes nitric acid to a mixture that includes the olefin metathesis product and residual metathesis catalyst from the metathesis reaction under conditions that are sufficient to passivate at least a portion of the residual metathesis catalyst. Methods of refining a natural oil are described.

  18. Dynamics of Interocular Suppression in Amblyopic Children during Electronically Monitored Occlusion Therapy: First Insight.

    PubMed

    Kehrein, Stephan; Kohnen, Thomas; Fronius, Maria

    2016-06-01

    Interocular suppression is assumed to be the mechanism leading to impaired visual acuity, especially in strabismic amblyopia. Little is known about the dynamics of suppression during treatment. The aim of our study was to assess the development of the depth of suppression and its relation to changes in visual acuity during electronically monitored occlusion treatment. In a prospective pilot study, 15 amblyopes (8 with and 7 without strabismus) aged 5 to 16 years (mean 10.24 years) were examined before initiation of patching and then every 3 to 6 weeks for 4 months. To quantify suppression, a red filter ladder (Sbisa bar) was used, attenuating the image of the dominant eye until the patients reported a binocular perception (diplopia, rivalry, color mixture) or a change in eye dominance. Acuity was assessed with crowded Landolt rings. Daily occlusion was recorded using occlusion dose monitors. The depth of interocular suppression showed a biphasic change: it increased significantly during the first month (P=0.02), while visual acuity improved (mean 0.14 log units ±0.13; P<0.01). During the following 3 months, median suppression decreased back to the initial values. This reduction in suppression was more pronounced in anisometropic patients without strabismus than in amblyopes with strabismus. The average visual acuity steadily improved (P<0.01) during the 4 months of treatment. Mean recorded patching dose rate was 3.91 h/d. The correlation between mean daily occlusion and suppression changes was not statistically significant. This first insight into the functional changes during electronically monitored patching suggests a complex relationship between visual acuity and interocular suppression that seems to be influenced by the presence of strabismus. Knowledge of the dynamics of interocular suppression is crucial for enhancing the outcome of occlusion treatment and also for the evaluation of its future role compared to emerging dichoptic treatments.

  19. Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

    PubMed

    Song, Kyung-A; Niederst, Matthew J; Lochmann, Timothy L; Hata, Aaron N; Kitai, Hidenori; Ham, Jungoh; Floros, Konstantinos V; Hicks, Mark A; Hu, Haichuan; Mulvey, Hillary E; Drier, Yotam; Heisey, Daniel A R; Hughes, Mark T; Patel, Neha U; Lockerman, Elizabeth L; Garcia, Angel; Gillepsie, Shawn; Archibald, Hannah L; Gomez-Caraballo, Maria; Nulton, Tara J; Windle, Brad E; Piotrowska, Zofia; Sahingur, Sinem E; Taylor, Shirley M; Dozmorov, Mikhail; Sequist, Lecia V; Bernstein, Bradley; Ebi, Hiromichi; Engelman, Jeffrey A; Faber, Anthony C

    2018-01-01

    Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR -mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR -mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR -mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR -mutant lung cancers, as it was also observed in KRAS -mutant lung cancers and large datasets, including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197-208. ©2017 AACR . ©2017 American Association for Cancer Research.

  20. Granulocyte Colony-Stimulating Factor and Azole Antifungal Therapy in Murine Aspergillosis: Role of Immune Suppression

    PubMed Central

    Graybill, John R.; Bocanegra, Rosie; Najvar, Laura K.; Loebenberg, David; Luther, Mike F.

    1998-01-01

    Outbred ICR mice were immune suppressed either with hydrocortisone or with 5-fluorouracil and were infected intranasally with Aspergillus fumigatus. Beginning 3 days before infection some groups of mice were given recombinant human granulocyte colony-stimulating factor (G-CSF), SCH56592 (an antifungal triazole), or both. Corticosteroid-pretreated mice responded to SCH56592 and had reduced counts in lung tissue and prolonged survival. In these mice, G-CSF strongly antagonized the antifungal activity of SCH56592. Animals treated with both agents developed large lung abscesses with polymorphonuclear leukocytes and large amounts of Aspergillus. In contrast, mice made neutropenic with 5-fluorouracil and then infected with A. fumigatus conidia benefited from either G-CSF or triazoles, and the effect of the combination was additive rather than antagonistic. Host predisposing factors contribute in different ways to the outcome of growth factor therapy in aspergillosis. PMID:9756743

  1. Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion.

    PubMed

    Nishida, Haruyuki; Fujimori, Ikuo; Arikawa, Yasuyoshi; Hirase, Keizo; Ono, Koji; Nakai, Kazuo; Inatomi, Nobuhiro; Hori, Yasunobu; Matsukawa, Jun; Fujioka, Yasushi; Imanishi, Akio; Fukui, Hideo; Itoh, Fumio

    2017-07-01

    With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway.

    PubMed

    Pramanik, Kartick C; Kudugunti, Shashi K; Fofaria, Neel M; Moridani, Majid Y; Srivastava, Sanjay K

    2013-09-01

    Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE

  3. Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway

    PubMed Central

    Srivastava, Sanjay K.

    2013-01-01

    Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE

  4. Triacylglycerol mobilization is suppressed by brefeldin A in Chlamydomonas reinhardtii

    PubMed Central

    Kato, Naohiro; Dong, Trung; Bailey, Michael; Lum, Tony; Ingram, Drury

    2013-01-01

    Brefeldin A suppresses vesicle trafficking by inhibiting exchange of GDP for GTP in ADP-ribosylation factor. We report that brefeldin A suppresses mobilization of triacylglycerols in Chlamydomonas reinhardtii, a model organism of green microalgae. Analyses revealed that brefeldin A causes Chlamydomonas to form lipid droplets in which triacylglycerols accumulate in a dose-dependent manner. Pulse labeling experiment using fluorescent fatty acids suggested that brefeldin A inhibits the cells from degrading fatty acids. The experiment also revealed that the cells transiently form novel compartments that accumulate exogenously added fatty acids in the cytoplasm, designated fatty acid-induced microbodies (FAIMs). Brefeldin A up-regulates the formation of FAIMs, whereas nitrogen deprivation that up-regulates triacylglycerol synthesis in Chlamydomonas does not cause the cells to form FAIMs. These results underscore the role of the vesicle trafficking machinery in triacylglycerol metabolism in green microalgae. PMID:23872273

  5. Dietary Karaya Saponin and Rhodobacter capsulatus Exert Hypocholesterolemic Effects by Suppression of Hepatic Cholesterol Synthesis and Promotion of Bile Acid Synthesis in Laying Hens

    PubMed Central

    Afrose, Sadia; Hossain, Md. Sharoare; Salma, Ummay; Miah, Abdul Gaffar; Tsujii, Hirotada

    2010-01-01

    This study was conducted to elucidate the mechanism underlying the hypolipidemic action of karaya saponin or Rhodobacter (R.) capsulatus. A total of 40 laying hens (20-week-old) were assigned into four dietary treatment groups and fed a basal diet (as a control) or basal diets supplemented with either karaya saponin, R. capsulatus, or both for 60 days. The level of serum low-density-lipoprotein cholesterol and the levels of cholesterol and triglycerides in the serum, liver, and egg yolk were reduced by all the supplementations (P < .05). Liver bile acid concentration and fecal concentrations of cholesterol, triacylglycerol, and bile acid were simultaneously increased by the supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus (P < .05). The supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus suppressed the incorporation of 14C from 1-14C-palmitic acid into the fractions of total lipids, phospholipids, triacylglycerol, and cholesterol in the liver in vitro (P < .05). These findings suggest that the hypocholesterolemic effects of karaya saponin and R. capsulatus are caused by the suppression of the cholesterol synthesis and the promotion of cholesterol catabolism in the liver. PMID:21490913

  6. Ceriporic acid B, an extracellular metabolite of Ceriporiopsis subvermispora, suppresses the depolymerization of cellulose by the Fenton reaction.

    PubMed

    Rahmawati, Noor; Ohashi, Yasunori; Watanabe, Takahito; Honda, Yoichi; Watanabe, Takashi

    2005-01-01

    The white rot fungus, Ceriporiopsis subvermispora, is able to degrade lignin in wood without intensive damage to cellulose. Since lignin biodegradation by white rot fungi proceeds by radical reactions, accompanied by the production of a large amount of Fe3+-reductant phenols and reductive radical species in the presence of iron ions, molecular oxygen, and H2O2, C. subvermispora has been proposed to possess a biological system which suppresses the production of a cellulolytic active oxygen species, *OH, by the Fenton reaction. In the present paper, we demonstrate that 1-nonadecene-2,3-dicarboxylic acid (ceriporic acid B), an extracellular metabolite of C. subvermispora, strongly inhibited *OH production and the depolymerization of cellulose by the Fenton reaction in the presence of iron ions, cellulose, H2O2, and a reductant for Fe3+, hydroquinone (HQ), at the physiological pH of the fungus.

  7. BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling

    PubMed Central

    Vin, Harina; Ojeda, Sandra S; Ching, Grace; Leung, Marco L; Chitsazzadeh, Vida; Dwyer, David W; Adelmann, Charles H; Restrepo, Monica; Richards, Kristen N; Stewart, Larissa R; Du, Lili; Ferguson, Scarlett B; Chakravarti, Deepavali; Ehrenreiter, Karin; Baccarini, Manuela; Ruggieri, Rosamaria; Curry, Jonathan L; Kim, Kevin B; Ciurea, Ana M; Duvic, Madeleine; Prieto, Victor G; Ullrich, Stephen E; Dalby, Kevin N; Flores, Elsa R; Tsai, Kenneth Y

    2013-01-01

    Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001 PMID:24192036

  8. [Experiences in half-side treatment with tar additive to cignolin-salicylic-acid-white-vaseline therapy of psoriasis vulgaris].

    PubMed

    Schulze, H J; Steigleder, G K

    1984-05-15

    As shown in bilateral comparison studies addition of crude coal tar (T) to standard antipsoriatic therapy with dithranol and salicylic acid in white petrolatum (CVS) diminished the dithranol-irritation; consequently, accelerated application of increasing dithranol-concentrations shortened the duration of TCSV -therapy.

  9. Work productivity improvement after acid suppression in patients with uninvestigated dyspepsia.

    PubMed

    Bytzer, Peter; Langkilde, Lars K; Christensen, Erik; Meineche-Schmidt, Villy

    2012-07-01

    Lost productivity accounts for a significant part of the costs caused by gastrointestinal symptoms. We aimed to describe selfreported productivity in patients presenting with dyspepsia. Data were sourced from a randomized, double-blinded study of two weeks of esomeprazole 40 mg or placebo in 805 primary-care patients with uninvestigated dyspepsia. Work productivity was tested using the Work Productivity and Activity Impairment questionnaire. Treatment effect on work productivity loss was tested according to the likelihood of treatment response. A total of 401/805 employed patients were included in the analysis. The average work productivity loss in the past seven days was 10.5 working hours/week. The productivity loss grew with increasing severity of symptoms at baseline. Following two weeks of treatment, the mean improvement in work productivity was significantly higher for both absenteeism (1 hour versus 0.1 hour, p < 0.05) and presenteeism (5.3 hours versus 4.3 hours, p < 0.05) in patients treated with esomeprazole versus placebo. The most substantial improvement was seen in patients who, based on baseline symptoms, were assessed to be likely treatment responders. Dyspepsia symptoms represent a significant economic burden in terms of lost productivity. The RESPONSE algorithm is successful in determining which patients will benefit from acid suppression in terms of enhanced productivity.

  10. Alcohol use and depression: link with adherence and viral suppression in adult patients on antiretroviral therapy in rural Lesotho, Southern Africa: a cross-sectional study.

    PubMed

    Cerutti, Bernard; Broers, Barbara; Masetsibi, Motlomelo; Faturiyele, Olatunbosun; Toti-Mokoteli, Likabelo; Motlatsi, Mokete; Bader, Joelle; Klimkait, Thomas; Labhardt, Niklaus D

    2016-09-08

    Depression and alcohol use disorder have been shown to be associated with poor adherence to antiretroviral therapy (ART). Studies examining their association with viral suppression in rural Africa are, however, scarce. This study reports prevalence of depressive symptoms and alcohol use disorder, and their potential association with adherence and viral suppression in adult patients on ART in ten clinics in rural Lesotho, Southern Africa. Among 1,388 adult patients (69 % women), 80.7 % were alcohol abstinent, 6.3 % were hazardous drinkers (men: 10.7 %, women: 4.4 %, p < 0.001). The prevalence of depressive symptoms was 28.8 % (men 20.2 %, women 32.7 %, p < 0.001). Both alcohol consumption (adjusted odds-ratio: 2.09, 95 % CI: 1.58-2.77) and alcohol use disorder (2.73, 95 % CI: 1.68-4.42) were significantly associated with poor adherence. There was, however, no significant association with viral suppression. Whereas the results of this study confirm previously reported association of alcohol use disorder with adherence to ART, there was no association with viral suppression. April 28th 2014; NCT02126696 .

  11. An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers.

    PubMed

    Morelli, G; Chen, H; Rossiter, G; Rege, B; Lu, Y

    2011-04-01

    Novel rabeprazole extended-release (ER) formulations were developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole-ER formulations vs. esomeprazole 40 mg and rabeprazole delayed-release (DR) 20 mg. Helicobacter pylori-negative healthy subjects were randomised to receive one of eight treatments once daily for 5 days. Twenty-four-hour intragastric pH was monitored on days -1, 1 and 5. Rabeprazole plasma concentrations were measured on day 5. A total of 248 subjects (N=31/group) were enrolled in the study. On day 5, rabeprazole-ER groups provided mean durations of 18.5-20.2 h (77.0-84.1% of 24-h) with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h/66.1% of 24-h) and rabeprazole-DR 20 mg (15.2 h/63.2% of 24-h). A similar increase was observed on day 1. While percentage of daytime (8 am-10 pm) with intragastric pH >4.0 on day 5 was overall similar across the groups, percentage of night-time (10 pm-8 am) with intragastric pH >4.0 was higher with the rabeprazole-ER groups (57.0-72.4%) vs. esomeprazole 40 mg (32.8%) and rabeprazole-DR 20 mg (34.0%). Rabeprazole-ER once daily for 5 days demonstrated a significantly longer duration of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole-DR 20 mg. The increase in acid suppression was predominantly due to prolonged acid suppression during the night-time; this was supported by the extended-release pharmacokinetic characteristics. © 2011 Blackwell Publishing Ltd.

  12. Efficacy of homocysteine lowering therapy with folic acid in stroke prevention: a meta-analysis

    PubMed Central

    Lee, Meng; Hong, Keun-Sik; Chang, Shen-Chih; Saver, Jeffrey L.

    2010-01-01

    Background and Purpose Although lower serum homocysteine concentration is associated with a reduced risk of stroke in epidemiologic studies, randomized controlled trials (RCTs) have yielded mixed findings regarding the effect of therapeutic homocysteine lowering on stroke prevention. We performed a meta-analysis of RCTs to assess the efficacy of folic acid supplementation in the prevention of stroke. Methods Salient trials were identified by formal literature search. Relative risk (RR) with 95% confidence interval (CI) was used as a measure of the association between folic acid supplementation and risk of stroke, pooling data across trials using a fixed-effects model. Results The search identified 13 RCTs of folic acid therapy to reduce homocysteine, enrolling 39,005 participants, in which stroke was reported as an outcome measure. Across all trials, folic acid supplementation was associated with a trend toward mild benefit that did not reach statistical significance in reducing the risk of stroke (RR 0.93, 95% CI 0.85-1.03; p=0.16). The RR for non-secondary prevention trials was 0.89 (95% CI 0.79-0.99; p=0.03). In stratified analyses, a greater beneficial effect was seen in the trials testing combination therapy of folic acid plus vitamins B6 and B12 (RR 0.83, 0.71-0.97; p=0.02) and in the trials which disproportionately enrolled male patients (men/women > 2, RR 0.84, 0.74-0.94; p=0.003). Conclusions Folic acid supplementation did not demonstrate a major effect in averting stroke. However, potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in male patients, merit further investigation. PMID:20413740

  13. Suppressive effects of Calendula micrantha essential oil and gibberelic acid (PGR) on repro ductive potential of the Mediterranean fruit fly Ceratitis capitata Wied. (Diptera: Tephritidae).

    PubMed

    Hussein, Karam T

    2005-08-01

    The volatile oil of Calendula micrtantha plant was extracted and the components were identified by Gc/Ms. Adulticidal efficiency of the volatile oil and gibberelic acid "plant growth promoting hormone" as well as their mixture was assessed against the Mediterranean fruit fly Ceratitis capitata. The result showed that the two compounds capable have characteristic resembling to insect juvenile hormones and have suppressive effect on reproductive potential. They induced the significant disturbances in the ovarian protein fraction and the amino acids patterns.

  14. Suppressive effect of viscous dietary fiber on elevations of uric acid in serum and urine induced by dietary RNA in rats is associated with strength of viscosity.

    PubMed

    Koguchi, Takashi; Nakajima, Hisao; Koguchi, Hiromi; Wada, Masahiro; Yamamoto, Yuji; Innami, Satoshi; Maekawa, Akio; Tadokoro, Tadahiro

    2003-10-01

    This study was performed to clarify how dietary fiber (DF) with different viscosities would be associated with dietary RNA metabolism. Male Wistar strain rats, four weeks old, were fed diets containing a 3% (w/w) yeast RNA and a 5% (w/w) viscous DF for five days. Viscosity of DF samples used, in order of strength, were xanthan gum (XG) > guar gum (GG) > locust bean gum (LBG) > karaya gum (KG) > pectin (PE) = arabic gum (AG) > CM-cellulose (CMC) = inulin (IN). The serum uric acid concentration in the viscous DF groups significantly decreased as compared with that in the cellulose (CL) group. The urinary excretions of uric acid and allantoin in the respective groups given AG, GG, IN, KG, PE, and XG were significantly suppressed as compared with those in the CL group. The fecal RNA excretion was markedly increased in the IN, KG, PE, and XG groups in comparison to the CL group. The DF with high viscosity significantly suppressed RNA digestion by RNase A and decreased uptakes of 14C-labeled adenosine and adenosine 5'-monophosphate (5'-AMP) in rat jejunum. The results reveal that the suppressive effect of DF on elevation of serum uric acid concentration induced by dietary RNA in rats is associated with the strength of DF viscosity. The mechanism by which this is accomplished is suggested to be attributed to the inhibitions of digestion for dietary RNA and/or absorption of the hydrolyzed compounds.

  15. The regional extent of suppression: strabismics versus nonstrabismics.

    PubMed

    Babu, Raiju Jacob; Clavagnier, Simon R; Bobier, William; Thompson, Benjamin; Hess, Robert F

    2013-10-09

    Evidence is accumulating that suppression may be the cause of amblyopia rather than a secondary consequence of mismatched retinal images. For example, treatment interventions that target suppression may lead to better binocular and monocular outcomes. Furthermore, it has recently been demonstrated that the measurement of suppression may have prognostic value for patching therapy. For these reasons, the measurement of suppression in the clinic needs to be improved beyond the methods that are currently available, which provide a binary outcome. We describe a novel quantitative method for measuring the regional extent of suppression that is suitable for clinical use. The method involves a dichoptic perceptual matching procedure at multiple visual field locations. We compare a group of normal controls (mean age: 28 ± 5 years); a group with strabismic amblyopia (four with microesotropia, five with esotropia, and one with exotropia; mean age: 35 ± 10 years); and a group with nonstrabismic anisometropic amblyopia (mean age: 33 ± 12 years). The extent and magnitude of suppression was similar for observers with strabismic and nonstrabismic amblyopia. Suppression was strongest within the central field and extended throughout the 20° field that we measured. Suppression extends throughout the central visual field in both strabismic and anisometropic forms of amblyopia. The strongest suppression occurs within the region of the visual field corresponding to the fovea of the fixing eye.

  16. Rates of Initial Virological Suppression and Subsequent Virological Failure After Initiating Highly Active Antiretroviral Therapy: The Impact of Aboriginal Ethnicity and Injection Drug Use

    PubMed Central

    Martin, L.J.; Houston, S.; Yasui, Y.; Wild, T.C.; Saunders, L.D.

    2010-01-01

    Objectives: To compare rates of initial virological suppression and subsequent virological failure by Aboriginal ethnicity after starting highly active antiretroviral therapy (HAART). Methods: We conducted a retrospective cohort study of antiretroviral-naïve HIV-patients starting HAART in January 1999-June 2005 (baseline), followed until December 31, 2005 in Alberta, Canada. We compared the odds of achieving initial virological suppression (viral load <500 copies/mL) by Aboriginal ethnicity using logistic regression and, among those achieving suppression, rates of virological failure (the first of two consecutive viral loads > 1000 copies/mL) by Aboriginal ethnicity using cumulative incidence curves and Cox proportional hazards models. Sex, injection drug use as an HIV exposure category (IDU), baseline age, CD4 cell count, viral load, calendar year, and HAART regimen were considered as potential confounders. Results: Of 461 study patients, 37% were Aboriginal and 48% were IDUs; 71% achieved initial virological suppression and were followed for 730.4 person-years. After adjusting for confounding variables, compared to non-Aboriginals with other exposures, the odds of achieving initial virological suppression were lower for Aboriginal IDUs (odds ratio (OR)=0.33, 95% CI=0.19-0.60, p=0.0002), non-Aboriginal IDUs (OR=0.30, 95% CI=0.15-0.60, p=0.0006), and Aboriginals with other exposures (OR=0.38, 95% CI=0.21-0.67, p=0.0009). Among those achieving suppression, Aboriginals experienced higher virological failure rates ≥1 year after suppression (hazard ratio=3.35, 95% CI=1.68-6.65, p=0.0006). Conclusions: Future research should investigate adherence among Aboriginals and IDUs treated with HAART and explore their treatment experiences to assess ways to improve outcomes. PMID:21187007

  17. Relationship of Postprandial Nonesterified Fatty Acids, Adipokines, and Insulin Across Gender in Human Immunodeficiency Virus–Positive Patients Undergoing Highly Active Antiretroviral Therapy

    PubMed Central

    Lu, Guijing; Thomas-Geevarghese, Asha; Anuurad, Erdembileg; Raghavan, Subhashree; Minolfo, Robert; Ormsby, Bernard; Karmally, Wahida; El-Sadr, Wafaa M.; Albu, Jeanine

    2009-01-01

    Abstract Background Metabolic derangements are common in human immunodeficiency virus (HIV)-positive subjects undergoing antiretroviral therapy, but little is known about postprandial conditions. Methods We investigated the relationship between leptin, adiponectin, nonesterified fatty acids (NEFA), and insulin in response to a day-long meal pattern and evaluated gender differences in HIV-positive men (n = 12) and women (n = 13) undergoing highly active antiretroviral therapy (HAART). Results For both men and women, a significant decrease in postprandial NEFA levels was observed following breakfast (0.53 vs. 0.22 mmol/L, P < 0.001, baseline and at 3 hours, respectively), whereas day-long postprandial leptin and adiponectin levels showed small nonsignificant oscillations. In contrast to NEFA and adiponectin, postprandial leptin levels were significantly higher among women compared to men (P < 0.05). Postprandial NEFA levels correlated positively with fasting insulin levels (r2 = 0.25, P = 0.016), and the postbreakfast decrease in NEFA levels correlated significantly with the postbreakfast increase in insulin levels (r2 = 0.17, P = 0.038). No significant association between postprandial adipokines and insulin was observed. Conclusions In HAART-treated, HIV-infected men and women, levels of NEFA, but not adipokines, showed significant postprandial variation. Furthermore, food intake resulted in significant NEFA suppression in proportion to the food-stimulated insulin increase. PMID:19320559

  18. Future of cell and gene therapies for Parkinson's disease.

    PubMed

    Isacson, Ole; Kordower, Jeffrey H

    2008-12-01

    The experimental field of restorative neurology continues to advance with implantation of cells or transfer of genes to treat patients with neurological disease. Both strategies have generated a consensus that demonstrates their capacity for structural and molecular brain modification in the adult brain. However, both approaches have yet to successfully address the complexities to make such novel therapeutic modalities work in the clinic. Prior experimental cell transplantation to patients with PD utilized dissected pieces of fetal midbrain tissue, containing mixtures of cells and neuronal types, as donor cells. Stem cell and progenitor cell biology provide new opportunities for selection and development of large batches of specific therapeutic cells. This may allow for cell composition analysis and dosing to optimize the benefit to an individual patient. The biotechnology used for cell and gene therapy for treatment of neurological disease may eventually be as advanced as today's pharmaceutical drug-related design processes. Current gene therapy phase 1 safety trials for PD include the delivery of a growth factor (neurturin via the glial cell line-derived neurotrophic factor receptor) and a transmitter enzyme (glutamic acid decarboxylase and aromatic acid decarboxylase). Many new insights from cell biological and molecular studies provide opportunities to selectively express or suppress factors relevant to neuroprotection and improved function of neurons involved in PD. Future gene and cell therapies are likely to coexist with classic pharmacological therapies because their use can be tailored to individual patients' underlying disease process and need for neuroprotective or restorative interventions.

  19. HSP90 Inhibition Suppresses Lipopolysaccharide-Induced Lung Inflammation In Vivo

    PubMed Central

    Lilja, Andrew; Weeden, Clare E.; McArthur, Kate; Nguyen, Thao; Donald, Alastair; Wong, Zi Xin; Dousha, Lovisa; Bozinovski, Steve; Vlahos, Ross; Burns, Christopher J.; Asselin-Labat, Marie-Liesse; Anderson, Gary P.

    2015-01-01

    Inflammation is an important component of cancer diathesis and treatment-refractory inflammation is a feature of many chronic degenerative lung diseases. HSP90 is a 90kDa protein which functions as an ATP-dependent molecular chaperone that regulates the signalling conformation and expression of multiple protein client proteins especially oncogenic mediators. HSP90 inhibitors are in clinical development as cancer therapies but the myeleosuppressive and neutropenic effect of first generation geldanamycin-class inhibitors has confounded studies on the effects on HSP90 inhibitors on inflammation. To address this we assessed the ability of Ganetespib, a non-geldanamycin HSP90 blocker, to suppress lipopolysaccharide (LPS)-induced cellular infiltrates, proteases and inflammatory mediator and transcriptional profiles. Ganetespib (10–100mg/kg, i.v.) did not directly cause myelosuppression, as assessed by video micrography and basal blood cell count, but it strongly and dose-dependently suppressed LPS-induced neutrophil mobilization into blood and neutrophil- and mononuclear cell-rich steroid-refractory lung inflammation. Ganetespib also suppressed B cell and NK cell accumulation, inflammatory cytokine and chemokine induction and MMP9 levels. These data identify non-myelosuppresssive HSP90 inhibitors as potential therapies for inflammatory diseases refractory to conventional therapy, in particular those of the lung. PMID:25615645

  20. Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling.

    PubMed

    Roh, Kyung-Baeg; Jung, Eunsun; Park, Deokhoon; Lee, Jongsung

    2013-08-01

    Eotaxin-1 is a potent chemoattractant for eosinophils and a critical mediator during the development of eosinophilic inflammation. Fumaric acid is an intermediate product of the citric acid cycle, which is source of intracellular energy. Although fumaric acid ameliorates psoriasis and multiple sclerosis, its involvement in eotaxin-1-mediated effects has not been assessed. In this study, we investigated the effects of fumaric acid on eotaxin-1 expression in a mouse fibroblast cell line. We found that fumaric acid significantly inhibited tumor necrosis factor-α (TNF-α-induced eotaxin-1 expression. This fumaric acid effect was mediated through the inhibition of p38 mitogen-activated protein kinase (MAPK)-dependent nuclear factor (NF)-κB signaling. We also found that fumaric acid operates downstream of MEKK3 during TNF-α-induced NF-κB signaling, which upregulated eotaxin-1 expression. In addition, fumaric acid attenuated expression of CC-chemokine receptor 3 (CCR3), an eotaxin-1 receptor, and adhesion molecules that play important roles in eosinophil binding to induce allergic inflammation. Taken together, these findings indicate that inhibiting TNF-α-induced eotaxin-1 expression by fumaric acid occurs primarily through suppression of NF-κB signaling, which is mediated by inhibiting p38 MAPK and suggest that fumaric acid may be used as a complementary treatment option for eotaxin-1-mediated diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Quantitative measurement of interocular suppression in anisometropic amblyopia: a case-control study.

    PubMed

    Li, Jinrong; Hess, Robert F; Chan, Lily Y L; Deng, Daming; Yang, Xiao; Chen, Xiang; Yu, Minbin; Thompson, Benjamin

    2013-08-01

    The aims of this study were to assess (1) the relationship between interocular suppression and visual function in patients with anisometropic amblyopia, (2) whether suppression can be simulated in matched controls using monocular defocus or neutral density filters, (3) the effects of spectacle or rigid gas-permeable contact lens correction on suppression in patients with anisometropic amblyopia, and (4) the relationship between interocular suppression and outcomes of occlusion therapy. Case-control study (aims 1-3) and cohort study (aim 4). Forty-five participants with anisometropic amblyopia and 45 matched controls (mean age, 8.8 years for both groups). Interocular suppression was assessed using Bagolini striated lenses, neutral density filters, and an objective psychophysical technique that measures the amount of contrast imbalance between the 2 eyes that is required to overcome suppression (dichoptic motion coherence thresholds). Visual acuity was assessed using a logarithm minimum angle of resolution tumbling E chart and stereopsis using the Randot preschool test. Interocular suppression assessed using dichoptic motion coherence thresholds. Patients exhibited significantly stronger suppression than controls, and stronger suppression was correlated significantly with poorer visual acuity in amblyopic eyes. Reducing monocular acuity in controls to match that of cases using neutral density filters (luminance reduction) resulted in levels of interocular suppression comparable with that in patients. This was not the case for monocular defocus (optical blur). Rigid gas-permeable contact lens correction resulted in less suppression than spectacle correction, and stronger suppression was associated with poorer outcomes after occlusion therapy. Interocular suppression plays a key role in the visual deficits associated with anisometropic amblyopia and can be simulated in controls by inducing a luminance difference between the eyes. Accurate quantification of suppression

  2. 16(R)-hydroxyeicosatetraenoic acid, a novel cytochrome P450 product of arachidonic acid, suppresses activation of human polymorphonuclear leukocyte and reduces intracranial pressure in a rabbit model of thromboembolic stroke.

    PubMed

    Bednar, M M; Gross, C E; Russell, S R; Fuller, S P; Ahern, T P; Howard, D B; Falck, J R; Reddy, K M; Balazy, M

    2000-12-01

    Activated polymorphonuclear leukocytes (PMNs) have been suggested to contribute to the development of increased intracranial pressure (ICP). We recently demonstrated that human PMNs produce a novel cytochrome P450-derived arachidonic acid metabolite, 1 6(R)-hydroxyeicosatetraenoic acid [16(R)-HETE], that modulates their function. It was thus of interest to examine this novel mediator in an acute stroke model. 16-HETE was assessed initially in a variety of human PMN and platelet in vitro assays and subsequently in an established rabbit model of thromboembolic stroke. A total of 50 rabbits completed a randomized, blinded, four-arm study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were completed 7 hours after autologous clot embolization. The primary end point for efficacy was the suppression of increased ICP. In in vitro assays, 16(R)-HETE selectively inhibited human PMN adhesion and aggregation and leukotriene B4 synthesis. In the thromboembolic stroke model, animals that received 16(R)-HETE demonstrated significant suppression of increased ICP (7.7 +/- 1.2 to 13.1 +/- 2.7 mm Hg, baseline versus final 7-h time point, mean +/- standard error), compared with either the vehicle-treated group (7.7 +/- 0.9 to 15.8 +/- 2.6 mm Hg) or the tissue plasminogen activator-treated group (7.6 +/- 0.6 to 13.7 +/- 2.1 mm Hg). The group that received the combination of 16(R)-HETE plus tissue plasminogen activator demonstrated no significant change in ICP for the duration of the protocol (8.6 +/- 0.6 to 11.1 +/- 1.2 mm Hg). 16(R)-HETE suppresses the development of increased ICP in a rabbit model of thromboembolic stroke and may serve as a novel therapeutic strategy in ischemic and inflammatory pathophysiological states.

  3. Suppression of gastric cancer dissemination by ephrin-B1-derived peptide.

    PubMed

    Tanaka, Masamitsu; Kamata, Reiko; Yanagihara, Kazuyoshi; Sakai, Ryuichi

    2010-01-01

    Interaction of the Eph family of receptor protein tyrosine kinases and their ligands, ephrin family members, induces bidirectional signaling through cell-cell contacts. High expression of B-type ephrin is associated with high invasion potential of tumors, and we previously observed that signaling through the C-terminus of ephrin-B1 mediates the migration and invasion of cells, and is involved in the promotion of carcinomatous peritonitis in vivo. Here we show that the intracellular introduction of a synthetic peptide derived from ephrin-B1 C-terminus blocks ephrin-B1 mediated signaling in scirrhous gastric cancer cells. Treatment of cancer cells with a fusion peptide consisting of HIV-TAT and amino acids 331-346 of ephrin-B1 (PTD-EFNB1-C) suppressed the activation of RhoA, mediated by the association of ephrin-B1 with an adaptor protein Dishevelled, and also inhibited extracellular secretion of metalloproteinase. Moreover, injection of PTD-EFNB1-C peptide into the peritoneal cavity of nude mice suppressed carcinomatous peritonitis of intraperitoneally transplanted scirrhous gastric cancer cells. These results indicate the possible application of ephrin-B1 C-terminal peptide to develop novel protein therapy for scirrhous gastric carcinoma, especially in the stage of tumor progression, including peritoneal dissemination.

  4. Glycyrrhetinic acid suppressed hmgb1 release by up-regulation of Sirt6 in nasal inflammation.

    PubMed

    Chen, D; Bellussi, L M; Cocca, S; Wang, J; Passali, G C; Hao, X; Chen, L; Passali, D

    2017-01-01

    To extend our understanding of previous studies on the pathogenesis and mechanism of high mobility group box 1 (HMGB1) in chronic rhinosinusitis with nasal polyps (CRSwNP), here we show that Sirtuin 6 (Sirt6), one of the Sirtuin family members which are widely studied in aging, DNA repair, metabolism, inflammation and cancer, was expressed in normal nasal mucosa using immunohistochemical staining and Western blot assay. Sirt6 expression levels were decreased in CRSwNP tissue. Sirt6 expression levels were modulated by small interfering RNA transfection in human nasal epithelial cells (HNE). We found that depletion of Sirt6 suppressed the number of human nasal epithelial cell cilia, and dramatically induced HMGB1 translocation from nucleus to cytoplasm in the HNE cells. Glycyrrhizic acid (GA) and glycyrrhetinic acid (GTA) are specific chemical compounds that may be isolated from the licorice plant. GTA has been shown to have anti-inflammatory and anti-allergic activity: it binds selectively to HMGB1 protein released extra-cellularly and inhibits its cytokine activities through a scavenger mechanism on the protein accumulation. In an in vitro study we used the 18-β-stereoisomer of GTA to enhance Sirt6 expression levels, inhibiting through this mechanism the translocation of HMGB1 protein from nucleus and reversing its extracellular accumulation stimulated by lipopolysaccharides. These findings reveal a previously unknown role for nasal mucosa steady-state conditions in the control of Sirt6 activity, and provide evidence for a relationship between HMGB1 and Sirt6 in CRSwNP, and promising benefits of glycyrrhetinic acid for CRSwNP patients.

  5. Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity

    PubMed Central

    Labonté, Eric D.; Pfluger, Paul T.; Cash, James G.; Kuhel, David G.; Roja, Juan C.; Magness, Daniel P.; Jandacek, Ronald J.; Tschöp, Matthias H.; Hui, David Y.

    2010-01-01

    Decrease in fat catabolic rate on consuming a high-fat diet contributes to diet-induced obesity. This study used group 1B phospholipase A2 (Pla2g1b)-deficient mice, which are resistant to hyperglycemia, to test the hypothesis that Pla2g1b and its lipolytic product lysophospholipid suppress hepatic fat utilization and energy metabolism in promoting diet-induced obesity. The metabolic consequences of hypercaloric diet, including body weight gain, energy expenditure, and fatty acid oxidation, were compared between Pla2g1b+/+ and Pla2g1b−/− mice. The Pla2g1b−/− mice displayed normal energy balance when fed chow, but were resistant to obesity when challenged with a hypercaloric diet. Obesity resistance in Pla2g1b−/− mice is due to their ability to maintain elevated energy expenditure and core body temperature when subjected to hypercaloric diet, which was not observed in Pla2g1b+/+ mice. The Pla2g1b−/− mice also displayed increased postprandial hepatic fat utilization due to increased expression of peroxisome proliferator-activated receptor (PPAR)-α, PPAR-δ, PPAR-γ, cd36/Fat, and Ucp2, which coincided with reduced postprandial plasma lysophospholipid levels. Lysophospholipids produced by Pla2g1b hydrolysis suppress hepatic fat utilization and down-regulate energy expenditure, thereby preventing metabolically beneficial adaptation to a high-fat diet exposure in promoting diet-induced obesity and type 2 diabetes.—Labonté, E. D., Pfluger, P. T., Cash, J. G., Kuhel, D. G., Rojas, J. C., Magness, D. P., Jandacek, R. J., Tschöp, M. H., Hui, D. Y. Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity. PMID:20215528

  6. 18β-Glycyrrhetinic Acid, a Novel Naturally Derived Agent, Suppresses Prolactin Hyperactivity and Reduces Antipsychotic-Induced Hyperprolactinemia in In Vitro and In Vivo Models.

    PubMed

    Wang, Di; Zhang, Yongfeng; Wang, Chunyue; Jia, Dongxu; Cai, Guangsheng; Lu, Jiahui; Wang, Di; Zhang, Zhang-Jin

    2016-09-01

    The purpose of this study was to examine the effects of 18β-glycyrrhetinic acid (GA), a novel naturally derived agent, in suppressing prolactin (PRL) hyperactivity and reducing antipsychotic-induced hyperprolactinemia (hyperPRL) and the underlying mechanisms in in vitro and in vivo models. GA treatment for 24 h inhibited PRL synthesis and secretion in MMQ cells and cultured pituitary cells in a dose-dependent fashion; but this effect was not reproduced in GH3 cells that lack the expression of functional dopamine D2 receptors. GA suppressed elevated PRL level and growth hormone, and normalized several sex hormones in a rat model of hyperPRL, produced by repeated injection of the dopamine blocker metoclopramide. GA also modulated the expression 5-HT1A and 5-HT2A receptors in both in vivo and in vitro models. These results indicate that GA is effective in suppressing PRL hyperactivity caused by the blockade of dopamine D2 receptors. This suppressive effect of GA may be related to its modulation of the serotonergic system. This study provides additional evidence in support of GA as an adjunct for the treatment of hyperPRL.

  7. Suppression of Androgen Receptor Transactivation by Akt Kinase

    DTIC Science & Technology

    2005-01-01

    with the potential to be particularly effective. A therapy Endocrine Societcs 84th Annual Meeting, San Francisco, June 19-22,2002, that suppresses the...PI3K/Akt pathway combined with classic p. 526 (abstr.), Endocrine Society Press, Bethesda, MD ablation therapy could reach the maximal effect in 10...10):2409-2423 Printed in U.S.A. Copyright © 2004 by The Endocrine Society do!: 10.1210/me.2004-0117 Regulation of Androgen Receptor Signaling by PTEN

  8. Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPAR{sub β/δ} in HepG2 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Luo, Guanghua; Shi, Yuanping; Zhang, Jun

    Highlights: • Palmitic acid significantly inhibited APOM gene expression in HepG2 cells. • Palmitic acid could obviously increase PPARB/D mRNA levels in HepG2 cells. • PPAR{sub β/δ} antagonist, GSK3787, had no effect on APOM expression. • GSK3787 could reverse the palmitic acid-induced down-regulation of APOM expression. • Palmitic acid induced suppression of APOM expression is mediated via the PPAR{sub β/δ} pathway. - Abstract: It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important formore » further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPAR{sub β/δ}) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPAR{sub β/δ} pathway.« less

  9. β-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice.

    PubMed

    Johnson, Mark C; Garland, Alaina L; Nicolson, Sarah C; Li, Chengwen; Samulski, R Jude; Wang, Bo; Tisch, Roland

    2013-11-01

    Interleukin-2 (IL-2) is a critical cytokine for the homeostasis and function of forkhead box p3-expressing regulatory T cells (Foxp3(+)Tregs). Dysregulation of the IL-2-IL-2 receptor axis is associated with aberrant Foxp3(+)Tregs and T cell-mediated autoimmune diseases such as type 1 diabetes. Treatment with recombinant IL-2 has been reported to enhance Foxp3(+)Tregs and suppress different models of autoimmunity. However, efficacy of IL-2 therapy is dependent on achieving sufficient levels of IL-2 to boost tissue-resident Foxp3(+)Tregs while avoiding the potential toxic effects of systemic IL-2. With this in mind, adeno-associated virus (AAV) vector gene delivery was used to localize IL-2 expression to the islets of NOD mice. Injection of a double-stranded AAV vector encoding IL-2 driven by a mouse insulin promoter (dsAAVmIP-IL2) increased Foxp3(+)Tregs in the islets but not the draining pancreatic lymph nodes. Islet Foxp3(+)Tregs in dsAAVmIP-IL2-treated NOD mice exhibited enhanced fitness marked by increased expression of Bcl-2, proliferation, and suppressor function. In contrast, ectopic IL-2 had no significant effect on conventional islet-infiltrating effector T cells. Notably, β-cell-specific IL-2 expression suppressed late preclinical type 1 diabetes in NOD mice. Collectively, these findings demonstrate that β-cell-specific IL-2 expands an islet-resident Foxp3(+)Tregs pool that effectively suppresses ongoing type 1 diabetes long term.

  10. Acetylsalicylic Acid Daily vs Acetylsalicylic Acid Every 3 Days in Healthy Volunteers: Effect on Platelet Aggregation, Gastric Mucosa, and Prostaglandin E2 Synthesis.

    PubMed

    Ferreira, Plinio Minghin Freitas; Gagliano-Jucá, Thiago; Zaminelli, Tiago; Sampaio, Marinalva Ferreira; Blackler, Rory Willian; Trevisan, Miriam da Silva; Novaes Magalhães, Antônio Frederico; De Nucci, Gilberto

    2016-07-01

    Substantial platelet inhibition was observed 3 days after a single administration of acetylsalicylic acid 81 mg to healthy volunteers. Here we investigate prostaglandin E2 (PGE2 ) antrum concentrations and gastrointestinal symptoms in two treatment groups: one receiving losartan and acetylsalicylic acid every day and the other receiving losartan every day and acetylsalicylic acid every 3 days. Twenty-eight healthy volunteers from both sexes received either 50 mg losartan and acetylsalicylic acid 81 mg daily or 50 mg losartan and acetylsalicylic acid 81 every 3 days with placebo on the other days. Therapy was delivered for 30 days for both groups. Gastric endoscopy was performed before and after treatment period. Biopsies were collected for PGE2 quantification. Platelet function tests were carried out before and during treatment and TXB2 release on platelet rich plasma was measured. The every 3 day low-dose acetylsalicylic acid regimen produced complete inhibition of platelet aggregation compared to the daily treatment. Thromboxane B2 release was substantially abolished for both groups during treatment. There was no significant difference on the endoscopic score of both treatment groups after the 30-day treatment (P = .215). There was over 50% suppression of antrum PGE2 content on volunteers receiving acetylsalicylic acid daily (P = .0016), while for the every 3 day dose regimen there was no significant difference between pre and post-treatment antrum PGE2 dosages (P = .4193). Since PGE2 is involved in gastric healing, we understand that this new approach could be safer and as efficient as the standard daily therapy on a long-term basis. © 2015, The American College of Clinical Pharmacology.

  11. Novel theranostic nanoplatform for complete mice tumor elimination via MR imaging-guided acid-enhanced photothermo-/chemo-therapy.

    PubMed

    Li, Bei; Tang, Jie; Chen, Weiyu; Hao, Guanyu; Kurniawan, Nyoman; Gu, Zi; Xu, Zhi Ping

    2018-05-31

    Non-invasive imaging-guided tumor therapy requires new-generation bio-nanomaterials to sensitively respond to the unique tumor microenvironment for precise diagnosis and efficient treatment. Here, we report such a theranostic nanoplatform by engineering defect-rich multifunctional Cu-doped layered double hydroxide (Cu-LDH) nanoparticles, which integrates pH-sensitive T 1 -magnetic resonance imaging (MRI), acid-enhanced photothermal therapy and heat-facilitated chemotherapy. As characterized with EXAFS and XPS, smaller Cu-LDH nanoparticles possess a considerable amount of defects around Cu cations, an advantageous microstructure that enables a high photothermal conversion of 808 nm NIR laser (53.1%). The exposure of CuOH octahedra on the LDH surface makes the photothermal conversion significantly acid-enhanced (53.1% at pH 7.0 vs. 81.9% at pH 5.0). This Cu peculiar microstructure also makes T 1 -MRI very pH-sensitive, a desirable guide for subsequent tumor photothermal therapy. Combined photothermal therapy and chemotherapy lead to nearly complete elimination of tumor tissues in vivo with a low injection dose of agents. Therefore, this novel defect-rich Cu-LDH nanoplatform is one of promising tumor-specific nanotheranostic agents for non-invasive imaging-guided combinational therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. Delivery of small interfering RNA against Nogo-B receptor via tumor-acidity responsive nanoparticles for tumor vessel normalization and metastasis suppression.

    PubMed

    Wang, Bin; Ding, Yanping; Zhao, Xiaozheng; Han, Xuexiang; Yang, Na; Zhang, Yinlong; Zhao, Ying; Zhao, Xiao; Taleb, Mohammad; Miao, Qing Robert; Nie, Guangjun

    2018-08-01

    Nogo-B receptor (NgBR) plays fundamental roles in regulating angiogenesis, vascular development, and the epithelial-mesenchymal transition (EMT) of cancer cells. However, the therapeutic effect of NgBR blockade on tumor vasculature and malignancy is unknown, investigations on which requires an adequate delivery system for small interfering RNA against NgBR (NgBR siRNA). Here a surface charge switchable polymeric nanoparticle that was sensitive to the slightly acidic tumor microenvironment was developed for steady delivery of NgBR siRNA to tumor tissues. The nanoformulation was constructed by conjugating 2, 3-dimethylmaleic anhydride (DMMA) molecules to the surface amines of micelles formed by cationic co-polymer poly(lactic-co-glycolic acid) 2 -poly(ethylenimine) and subsequent absorption of NgBR siRNAs. The nanoparticles remained negatively charged in physiological condition and smartly converted to positive surface charge due to tumor-acidity-activated shedding of DMMA. The charge conversion facilitated cellular uptake of siRNAs and in turn efficiently depleted the expression of NgBR in tumor-bearing tissues. Silencing of NgBR suppressed endothelial cell migration and tubule formation, and reverted the EMT process of breast cancer cells. Delivery of the nanoformulation to mice bearing orthotopic breast carcinoma showed no effect on tumor growth, but led to remarkable decrease of distant metastasis by normalizing tumor vessels and suppressing the EMT of breast cancer cells. This study demonstrated that NgBR is a promising therapeutic target in abnormal tumor vasculature and aggressive cancer cells, and the tumor-responsive nanoparticle with the feature of charge transformation offers great potential for tumor-specific delivery of gene therapeutics. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. A Strategy Using Photodynamic Therapy and Clofibric Acid to Treat Peritoneal Dissemination of Ovarian Cancer.

    PubMed

    Yokoyama, Yoshihito; Shigeto, Tatsuhiko; Miura, Rie; Kobayashi, Asami; Mizunuma, Makito; Yamauchi, Aisa; Futagami, Masayuki; Mizunuma, Hideki

    2016-01-01

    The current study examined the effectiveness of concurrent therapy using photodynamic therapy (PDT) and clofibric acid (CA) to treat peritoneal carcinomatosis resulting from ovarian cancer. Nude rats were used to create a model of peritoneal carcinomatosis resulting from ovarian cancer and the effectiveness of PDT with 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA-PDT) was determined. The survival time of rats receiving that therapy was compared to the survival time of a control group. Rats with peritoneal carcinomatosis resulting from ovarian cancer were divided into 3 groups: a group that received debulking surgery (DS) alone, a group that received DS+methyl-ALA-PDT, and a group that received DS+methyl-ALA-PDT+CA. The survival time of the 3 groups was compared. Protoporphyrin, a metabolite of methyl-ALA, produces a photochemical action when activated by light. The level of protoporphyrin (the concentration) that reached organs in the abdomen was measured with HPLC. Rats receiving methyl- ALA-PDT had a significantly longer survival time compared to the controls. Rats with peritoneal carcinomatosis that received DS+methyl-ALA-PDT+CA had a significantly longer survival time compared to the rats that received DS alone. Some of the rats that received concurrent therapy survived for a prolonged period. Protoporphyrin was highly concentrated in peritoneal metastases, but only small amounts reached major organs in the abdomen. PDT was not found to result in necrosis in the intestines. The results indicated that concurrent therapy consisting of PDT with methyl-ALA and CA is effective at treating peritoneal carcinomatosis resulting from ovarian cancer without damaging organs.

  14. Resistin Regulates Fatty Acid Β Oxidation by Suppressing Expression of Peroxisome Proliferator Activator Receptor Gamma-Coactivator 1α (PGC-1α).

    PubMed

    He, Fang; Jin, Jie-Qiong; Qin, Qing-Qing; Zheng, Yong-Qin; Li, Ting-Ting; Zhang, Yun; He, Jun-Dong

    2018-01-01

    Abnormal fatty acid β oxidation has been associated with obesity and type 2 diabetes. Resistin is an adipokine that has been considered as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. However, the effect of resistin on fatty acid β oxidation needs to be elucidated. We detected the effects of resistin on the expression of fatty acid oxidation (FAO) transcriptional regulatory genes, the fatty acid transport gene, and mitochondrial β-oxidation genes using real-time PCR. The rate of FAO was measured using 14C-palmitate. Immunofluorescence assay and western blot analysis were used to explore the underlying molecular mechanisms. Resistin leads to a reduction in expression of the FAO transcriptional regulatory genes ERRα and NOR1, the fatty acid transport gene CD36, and the mitochondrial β-oxidation genes CPT1, MCAD, and ACO. Importantly, treatment with resistin led to a reduction in the rate of cellular fatty acid oxidation. In addition, treatment with resistin reduced phosphorylation of acetyl CoA carboxylase (ACC) (inhibitory). Mechanistically, resistin inhibited the activation of CREB, resulting in suppression of PGC-1α. Importantly, overexpressing PGC-1α can rescue the inhibitory effects of resistin on fatty acid β oxidation. Activating the transcriptional activity of CREB using small molecular chemicals is a potential pharmacological strategy for preventing the inhibitory effects of resistin on fatty acid β oxidation. © 2018 The Author(s). Published by S. Karger AG, Basel.

  15. Suppression of AMF/PGI-mediated tumorigenic activities by ursolic acid in cultured hepatoma cells and in a mouse model.

    PubMed

    Shih, Wen-Ling; Yu, Feng-Ling; Chang, Ching-Dong; Liao, Ming-Huei; Wu, Hung-Yi; Lin, Ping-Yuan

    2013-10-01

    Our previous studies demonstrated that autocrine motility factor/phosphoglucose isomerase (AMF/PGI) possesses tumorigenic activities through the modulation of intracellular signaling. We then investigated the effects of ursolic acid (UA), oleanolic acid (OA), tangeretin, and nobiletin against AMF/PGI-mediated oncogenesis in cultured stable Huh7 and Hep3B cells expressing wild-type or mutated AMF/PGI and in a mouse model in this study. The working concentrations of the tested compounds were lower than their IC10 , which was determined by Brdu incorporation and colony formation assay. Only UA efficiently suppressed the AMF/PGI-induced Huh7 cell migration and MMP-3 secretion. Additionally, UA inhibited the AMF/PGI-mediated protection against TGF-β-induced apoptosis in Hep3B cells, whereas OA, tangeretin, and nobiletin had no effect. In Huh7 cells and tumor tissues, UA disrupted the Src/RhoA/PI 3-kinase signaling and complex formation induced by AMF/PGI. In the Hep3B system, UA dramatically suppressed AMF/PGI-induced anti-apoptotic signaling transmission, including Akt, p85, Bad, and Stat3 phosphorylation. AMF/PGI enhances tumor growth, angiogenesis, and pulmonary metastasis in mice, which is correlated with its enzymatic activity, and critically, UA intraperitoneal injection reduces the tumorigenesis in vivo, enhances apoptosis in tumor tissues and also prolongs mouse survival. Combination of sub-optimal dose of UA and cisplatin, a synergistic tumor cell-killing effects was found. Thus, UA modulates intracellular signaling and might serve as a functional natural compound for preventing or alleviating hepatocellular carcinoma. © 2012 Wiley Periodicals, Inc.

  16. Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas.

    PubMed

    Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

    2013-10-01

    The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  17. Effects of rare sugar D-allulose on acid production and probiotic activities of dairy lactic acid bacteria.

    PubMed

    Kimoto-Nira, H; Moriya, N; Hayakawa, S; Kuramasu, K; Ohmori, H; Yamasaki, S; Ogawa, M

    2017-07-01

    It has recently been reported that the rare sugar d-allulose has beneficial effects, including the suppression of postprandial blood glucose elevation in humans, and can be substituted for sucrose as a low-calorie food ingredient. To examine the applications of d-allulose in the dairy industry, we investigated the effects of d-allulose on the acid production of 8 strains of yogurt starter (Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus) and 4 strains of lactococci, including potential probiotic candidates derived from dairy products. Acid production by 2 L. delbrueckii ssp. bulgaricus yogurt starter strains in milk was suppressed by d-allulose, but this phenomenon was also observed in some strains with another sugar (xylose), a sugar alcohol (sorbitol), or both. In contrast, among the dairy probiotic candidates, Lactococcus lactis H61, which has beneficial effects for human skin when drunk as part of fermented milk, was the only strain that showed suppression of acid production in the presence of d-allulose. Strain H61 did not metabolize d-allulose. We did not observe suppression of acid production by strain H61 with the addition of xylose or sorbitol, and xylose and sorbitol were not metabolized by strain H61. The acid production of strain H61 after culture in a constituted medium (tryptone-yeast extract-glucose broth) was also suppressed with the addition of d-allulose, but growth efficiency and sugar fermentation style were not altered. Probiotic activities-such as the angiotensin-converting enzyme inhibitory activity of H61-fermented milk and the superoxide dismutase activity of H61 cells grown in tryptone-yeast extract-glucose broth-were not affected by d-allulose. d-Allulose may suppress acid production in certain lactic acid bacteria without altering their probiotic activity. It may be useful for developing new probiotic dairy products from probiotic strains such as Lactococcus lactis H61. Copyright © 2017 American Dairy Science

  18. Methyl - aminolevulinic acid photodynamic therapy and topical tretinoin in a patient with vulvar extramammary Paget's disease.

    PubMed

    Magnano, Michela; Loi, Camilla; Bardazzi, Federico; Burtica, Elena Cleopatra; Patrizi, Annalisa

    2013-01-01

    Extramammary Paget's disease is a rare neoplasm of apocrine gland-bearing areas of the skin. The most common site of presentation is the vulva. Surgery is the most frequently reported therapy so far; however, it is invasive and it is complicated by a high rate of recurrence. For this reason, several less-invasive treatments have been recently proposed, including photodynamic therapy. We describe in this article the case of an 84-year-old patient with a noninvasive vulvar extramammary Paget's disease successfully treated with methyl-aminolevulinic acid photodynamic therapy associated with topical tretinoin. © 2013 Wiley Periodicals, Inc.

  19. Relationship between hunger, adherence to antiretroviral therapy and plasma HIV RNA suppression among HIV-positive illicit drug users in a Canadian setting.

    PubMed

    Anema, Aranka; Kerr, Thomas; Milloy, M-J; Feng, Cindy; Montaner, Julio S G; Wood, Evan

    2014-04-01

    Food insecurity may be a barrier to achieving optimal HIV treatment-related outcomes among illicit drug users. This study therefore, aimed to assess the impact of severe food insecurity, or hunger, on plasma HIV RNA suppression among illicit drug users receiving antiretroviral therapy (ART). A cross-sectional Multivariate logistic regression model was used to assess the potential relationship between hunger and plasma HIV RNA suppression. A sample of n = 406 adults was derived from a community-recruited open prospective cohort of HIV-positive illicit drug users, in Vancouver, British Columbia (BC), Canada. A total of 235 (63.7%) reported "being hungry and unable to afford enough food," and 241 (59.4%) had plasma HIV RNA < 50 copies/ml. In unadjusted analyses, self-reported hunger was associated with lower odds of plasma HIV RNA suppression (Odds Ratio = 0.59, 95% confidence interval [CI]: 0.39-0.90, p = 0.015). In multivariate analyses, this association was no longer significant after controlling for socio-demographic, behavioral, and clinical characteristics, including 95% adherence (Adjusted Odds Ratio [AOR] = 0.65, 95% CI: 0.37-1.10, p = 0.105). Multivariate models stratified by 95% adherence found that the direction and magnitude of this association was not significantly altered by the adherence level. Hunger was common among illicit drug users in this setting. Although, there was an association between hunger and lower likelihood of plasma HIV RNA suppression, this did not persist in adjusted analyses. Further research is warranted to understand the social-structural, policy, and physical factors shaping the HIV outcomes of illicit drug users.

  20. Iso-α-acids, Bitter Components of Beer, Prevent Inflammation and Cognitive Decline Induced in a Mouse Model of Alzheimer's Disease*

    PubMed Central

    Ano, Yasuhisa; Dohata, Atsushi; Taniguchi, Yoshimasa; Hoshi, Ayaka; Uchida, Kazuyuki; Takashima, Akihiko; Nakayama, Hiroyuki

    2017-01-01

    Alongside the rapid growth in aging populations worldwide, prevention and therapy for age-related memory decline and dementia are in great demand to maintain a long, healthy life. Here we found that iso-α-acids, hop-derived bitter compounds in beer, enhance microglial phagocytosis and suppress inflammation via activation of the peroxisome proliferator-activated receptor γ. In normal mice, oral administration of iso-α-acids led to a significant increase both in CD11b and CD206 double-positive anti-inflammatory type microglia (p < 0.05) and in microglial phagocytosis in the brain. In Alzheimer's model 5xFAD mice, oral administration of iso-α-acids resulted in a 21% reduction in amyloid β in the cerebral cortex as observed by immunohistochemical analysis, a significant reduction in inflammatory cytokines such as IL-1β and chemokines including macrophage inflammatory protein-1α in the cerebral cortex (p < 0.05) and a significant improvement in a novel object recognition test (p < 0.05), as compared with control-fed 5xFAD mice. The differences in iso-α-acid-fed mice were due to the induction of microglia to an anti-inflammatory phenotype. The present study is the first to report that amyloid β deposition and inflammation are suppressed in a mouse model of Alzheimer's disease by a single component, iso-α-acids, via the regulation of microglial activation. The suppression of neuroinflammation and improvement in cognitive function suggests that iso-α-acids contained in beer may be useful for the prevention of dementia. PMID:28087694

  1. Efflux inhibitor suppresses Streptococcus mutans virulence properties.

    PubMed

    Zeng, Huihui; Liu, Jia; Ling, Junqi

    2017-04-01

    It is well established that efflux pumps play important roles in bacterial pathogenicity and efflux inhibitors (EIs) have been proved to be effective in suppressing bacterial virulence properties. However, little is known regarding the EI of Streptococcus mutans, a well-known caries-inducing bacterium. In this study, we identified the EI of S. mutans through ethidium bromide efflux assay and investigated how EI affected S. mutans virulence regarding the cariogenicity and stress response. Results indicated that reserpine, the identified EI, suppressed acid tolerance, mutacin production and transformation efficiency of S. mutans, and modified biofilm architecture and extracellular polysaccharide distribution. Suppressed glycosyltransferase activity was also noted after reserpine exposure. The data from quantitative real-time-PCR demonstrated that reserpine significantly altered the expression profile of quorum-sensing and virulence-associated genes. These findings suggest that reserpine represents a promising adjunct anticariogenic agent in that it suppresses virulence properties of S. mutans. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Report on the analysis of common beverages spiked with gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) using NMR and the PURGE solvent-suppression technique.

    PubMed

    Lesar, Casey T; Decatur, John; Lukasiewicz, Elaan; Champeil, Elise

    2011-10-10

    In forensic evidence, the identification and quantitation of gamma-hydroxybutyric acid (GHB) in "spiked" beverages is challenging. In this report, we present the analysis of common alcoholic beverages found in clubs and bars spiked with gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL). Our analysis of the spiked beverages consisted of using (1)H NMR with a water suppression method called Presaturation Utilizing Relaxation Gradients and Echoes (PURGE). The following beverages were analyzed: water, 10% ethanol in water, vodka-cranberry juice, rum and coke, gin and tonic, whisky and diet coke, white wine, red wine, and beer. The PURGE method allowed for the direct identification and quantitation of both compounds in all beverages except red and white wine where small interferences prevented accurate quantitation. The NMR method presented in this paper utilizes PURGE water suppression. Thanks to the use of a capillary internal standard, the method is fast, non-destructive, sensitive and requires no sample preparation which could disrupt the equilibrium between GHB and GBL. Published by Elsevier Ireland Ltd.

  3. Tumor acidity-activatable TAT targeted nanomedicine for enlarged fluorescence/magnetic resonance imaging-guided photodynamic therapy.

    PubMed

    Gao, Meng; Fan, Feng; Li, Dongdong; Yu, Yue; Mao, Kuirong; Sun, Tianmeng; Qian, Haisheng; Tao, Wei; Yang, Xianzhu

    2017-07-01

    Nanoparticles simultaneously integrated the photosensitizers and diagnostic agents represent an emerging approach for imaging-guided photodynamic therapy (PDT). However, the diagnostic sensitivity and therapeutic efficacy of nanoparticles as well as the heterogeneity of tumors pose tremendous challenges for clinical imaging-guided PDT treatment. Herein, a polymeric nanoparticle with tumor acidity (pH e )-activatable TAT targeting ligand that encapsulates the photosensitizer chlorin e6 (Ce6) and chelates contrast agent Gd 3+ is successfully developed for fluorescence/magnetic resonance (MR) dual-model imaging-guided precision PDT. We show clear evidence that the resulting nanoparticle DA TAT-NP [its TAT lysine residues' amines was modified by 2,3-dimethylmaleic anhydride (DA)] efficiently avoids the rapid clearance by reticuloendothelial system (RES) by masking of the TAT peptide, resulting in the significantly prolonged circulation time in the blood. Once accumulating in the tumor tissues, DA TAT-NP is reactivated by tumor acidity to promote cellular uptake, resulting in enlarged fluorescence/MR imaging signal intensity and elevated in vivo PDT therapeutic effect. This concept provides new avenues to design tumor acidity-activatable targeted nanoparticles for imaging-guided cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. The suppression of the N-nitrosating reaction by chlorogenic acid.

    PubMed Central

    Kono, Y; Shibata, H; Kodama, Y; Sawa, Y

    1995-01-01

    N-Nitrosation of a model aromatic amine (2,3-diamino-naphthalene) by the N-nitrosating agent produced by nitrite in acidic solution was inhibited by a polyphenol, chlorogenic acid, which is an ester of caffeic acid quinic acid. Caffeic acid also inhibited the N-nitrosation, but quinic acid did not. 1,2-Benzenediols and 3,4-dihydroxybenzoic acid had inhibitory activities. Chlorogenic acid, caffeic acid, 1,2-benzenediols and 3,4-dihydroxybenzoic acid were able to scavenge the stable free radical, 1,1-diphenyl-2-picrylhydrazyl. Chlorogenic acid was found to be nitrated by acidic nitrite. The kinetic studies and the nitration observed only by bubbling of nitric oxide plus nitrogen dioxide gases indicated that the nitrating agent was nitrogen sesquioxide. The observations showed that the mechanism by which chlorogenic acid inhibited N-nitrosation of 2,3-diamino-naphthalene is due to its ability to scavenge the nitrosating agent, nitrogen sesquioxide. Chlorogenic acid may be effective not only in protecting against oxidative damage but also in inhibiting potentially mutagenic and carcinogenic reactions in vivo. PMID:8554543

  5. Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats.

    PubMed

    Shivavedi, Naveen; Kumar, Mukesh; Tej, Gullanki Naga Venkata Charan; Nayak, Prasanta Kumar

    2017-11-01

    Diabetes mellitus and depression are the common comorbid disorders affecting humans worldwide. There is an unmet need to develop therapeutic strategies to treat both diabetes mellitus and comorbid depression. The present study evaluated the effectiveness of metformin and ascorbic acid against type 2 diabetes mellitus and comorbid depression in rats. Four groups of diabetic rats were orally administered with vehicle (1mL/kg), metformin (25mg/kg), ascorbic acid (25mg/kg), or combination of metformin (25mg/kg) and ascorbic acid (25mg/kg) for 11 consecutive days. Diabetes was induced by single-dose administration of streptozotocin (65mg/kg, i.p.) with nicotinamide (120mg/kg, i.p.). Comorbid depression was induced by five inescapable foot-shocks (2mA, 2ms duration) at 10s intervals on days 1, 5, 7, and 10. One group of healthy rats received only vehicles to serve as nondiabetic control group. On day 11, animals were sacrificed, and blood and brain samples were collected from each rat following forced swim test. Plasma glucose, insulin, and corticosterone levels were estimated in plasma. The levels of monoamines, proinflammatory cytokines, and oxidative stress were measured in prefrontal cortex. The combination therapy significantly reduced immobility period, glucose, and corticosterone levels relative to diabetes with comorbid depression group. Furthermore, the combination therapy increased the levels of insulin and monoamines, and caused a significant reductions in oxidative stress and proinflammatory cytokines. In conclusion, the present study revealed that metformin and ascorbic acid combination therapy could be a potential strategy to treat type 2 diabetes mellitus and comorbid depression. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes.

    PubMed

    Zhang, Yuanyuan; Jackson, Jonathan P; St Claire, Robert L; Freeman, Kimberly; Brouwer, Kenneth R; Edwards, Jeffrey E

    2017-08-01

    Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose-dependently increased fibroblast growth factor-19 (FGF-19) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 μmol/L) to 42.7 ± 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 ± 0.8-fold, and the basolateral efflux heterodimer transporters, organic solute transporter α (OST α ) and OST β increased by 6.4 ± 0.2-fold and 42.9 ± 7.9-fold, respectively. The upregulation of BSEP and OST α and OST β, by OCA reduced the intracellular concentrations of d 8 -TCA, a model bile acid, to 39.6 ± 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid-induced toxicity observed in cholestatic diseases. © 2017 Intercept Pharmaceuticals. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and

  7. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer.

    PubMed

    Pujol, P; Daures, J P; Nsakala, N; Baldet, L; Bringer, J; Jaffiol, C

    1996-12-01

    We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.

  8. Immediate acid-suppressing effects of ranitidine hydrochloride and rabeprazole sodium following initial administration and reintroduction: A randomized, cross-over study using wireless pH monitoring capsules.

    PubMed

    Ono, Shouko; Kato, Mototsugu; Ono, Yuji; Imai, Aki; Yoshida, Takeshi; Shimizu, Yuichi; Asaka, Masahiro

    2009-04-01

    Histamine 2 receptor antagonists and proton-pump inhibitors, drugs that are widely used for the treatment of acid-related diseases, have different clinical characteristics. The objective of this study was to compare the acid-suppressing effects of ranitidine hydrochloride and those of rabeprazole sodium at the first administration and re-administration after withdrawal. The study was designed as an open-label, randomized, two-way cross-over trial. Seven Helicobacter pylori-negative healthy volunteers were enrolled in this study. Ranitidine hydrochloride (300 mg/day) or rabeprazole sodium (20 mg/day) was administered from days 1 to 7 and from days 11 to 13. The percentage of time with gastric pH < 4 and the median gastric pH were evaluated for 15 consecutive days by a Bravo capsule fixed to the stomach. On day 1, there was no significant difference between the acid-suppressing effects of the two drugs (ranitidine vs rabeprazole: not significant). Although rabeprazole sodium maintained a potent and stable effect from days 2 to 7 (ranitidine vs rabeprazole: P < 0.05), the effect of ranitidine hydrochloride was attenuated after day 4. In addition, the effect of ranitidine hydrochloride at re-administration was attenuated (days 11, 12, and 13 vs pre-administration: not significant). In view of our observations, we expect symptoms associated with gastric acidity to be more adequately controlled with rabeprazole sodium in the short term when compared to ranitidine hydrochloride.

  9. Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1.

    PubMed

    Kim, Sung-Jo; Zhang, Zhongjian; Saha, Arjun; Sarkar, Chinmoy; Zhao, Zhenwen; Xu, Yan; Mukherjee, Anil B

    2010-08-02

    Reactive oxygen species (ROS) damage brain lipids, carbohydrates, proteins, as well as DNA and may contribute to neurodegeneration. We previously reported that ER- and oxidative stress cause neuronal apoptosis in infantile neuronal ceroid lipofuscinosis (INCL), a lethal neurodegenerative storage disease, caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. Polyunsaturated fatty acids (PUFA) are essential components of cell membrane phospholipids in the brain and excessive ROS may cause oxidative damage of PUFA leading to neuronal death. Using cultured neurons and neuroprogenitor cells from mice lacking Ppt1, which mimic INCL, we demonstrate that Ppt1-deficient neurons and neuroprogenitor cells contain high levels of ROS, which may cause peroxidation of PUFA and render them incapable of providing protection against oxidative stress. We tested whether treatment of these cells with omega-3 or omega-6 PUFA protects the neurons and neuroprogenitor cells from oxidative stress and suppress apoptosis. We report here that both omega-3 and omega-6 fatty acids protect the Ppt1-deficient cells from ER- as well as oxidative stress and suppress apoptosis. Our results suggest that PUFA supplementation may have neuroprotective effects in INCL. Published by Elsevier Ireland Ltd.

  10. Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid Levels in Patients with Cystic Fibrosis with Associated Liver Disease.

    PubMed

    Colombo, Carla; Crosignani, Andrea; Alicandro, Gianfranco; Zhang, Wujuan; Biffi, Arianna; Motta, Valentina; Corti, Fabiola; Setchell, Kenneth D R

    2016-10-01

    To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20 mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD. Twenty patients with CFLD (median age 16 years, range: 2.4-35.0) prescribed UDCA therapy for at least 2 years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20 mg/kg/day) administration. During chronic UDCA administration (median duration 8 years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56 μmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70 μmol/L vs 0.40, 0.24-2.71 μmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05 μmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P < .01), but no significant changes in serum lithocholic acid concentrations were observed. These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Plant Natural Products Calycosin and Gallic Acid Synergistically Attenuate Neutrophil Infiltration and Subsequent Injury in Isoproterenol-Induced Myocardial Infarction: A Possible Role for Leukotriene B4 12-Hydroxydehydrogenase?

    PubMed Central

    Cheng, Yuanyuan; Tse, Hung Fat; Le, X. Chris; Rong, Jianhui

    2015-01-01

    Leukotriene B4 12-hydroxydehydrogenase (LTB4DH) catalyzes the oxidation of proinflammatory LTB4 into less bioactive 12-oxo-LTB4. We recently discovered that LTB4DH was induced by two different natural products in combination. We previously isolated gallic acid from Radix Paeoniae through a bioactivity-guided fractionation procedure. The purpose of this study is to test the hypothesis that LTB4DH inducers may suppress neutrophil-mediated inflammation in myocardial infarction. We first isolated the active compound(s) from another plant, Radix Astragali, by the similar strategy. By evaluating LTB4DH induction, we identified calycosin and formononetin from Radix Astragali by HPLC-ESI-MS technique. We confirmed that gallic acid and commercial calycosin or formononetin could synergistically induce LTB4DH expression in HepG2 cells and human neutrophils. Moreover, calycosin and gallic acid attenuated the effects of LTB4 on the survival and chemotaxis of neutrophil cell culture. We further demonstrated that calycosin and gallic acid synergistically suppressed neutrophil infiltration and protected cardiac integrity in the isoproterenol-induced mice model of myocardial infarction. Calycosin and gallic acid dramatically suppressed isoproterenol-induced increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level. Collectively, our results suggest that LTB4DH inducers (i.e., calycosin and gallic acid) may be a novel combined therapy for the treatment of neutrophil-mediated myocardial injury. PMID:26265982

  12. Rodlike Supramolecular Nanoassemblies of Degradable Poly(Aspartic Acid) Derivatives and Hydroxyl-Rich Polycations for Effective Delivery of Versatile Tumor-Suppressive ncRNAs.

    PubMed

    Song, Hai-Qing; Pan, Wenting; Li, Rui-Quan; Yu, Bingran; Liu, Wenjuan; Yang, Ming; Xu, Fu-Jian

    2018-03-01

    The delivery of tumor-suppressive noncoding RNAs (ncRNAs) including short ncRNAs (i.e., miRNAs) and long ncRNAs (lncRNAs) is put forward to treat tumors. In this work, novel rodlike supramolecular nanoassemblies (CNC @CB[8] @ PGEA) of degradable poly(aspartic acid) (PAsp) derivatives-grafted cellulose nanocrystals (CNCs) and hydroxyl-rich polycations (ethanolamine-functionalized poly(glycidyl methacrylate), PGEA) are proposed via typical cucurbit[8]uril (CB[8])-based host-guest interactions for delivery of different ncRNAs to treat hepatocellular carcinoma (HCC). Spindly CNCs, one kind of natural polysaccharide nanoparticles, possess good biocompatibility and unique physico-chemical properties. PGEA with abundant hydroxyl groups is one promising gene carrier with low cytotoxicity. PAsp can benefit the disassembly and degradability of nanoassemblies within cells. CNC @ CB[8]@PGEA combines the different unique properties of CNC, PGEA, and PAsp. CNC @ CB[8] @ PGEA effectively complexes the expression constructs of miR-101 (plasmid pc3.0-miR-101) and lncRNA MEG3 (plasmid pc3.0-MEG3). CNC @ CB[8] @ PGEA produces much better transfection performances than PGEA-containing assembly units. In addition, the codelivery system of CNC @ CB[8] @ PGEA/(pc3.0-MEG3+pc3.0-miR-101) nanocomplexes demonstrates better efficacy in suppressing HCC than CNC @ CB[8] @ PGEA/pc3.0-MEG3 or CNC @ CB[8] @ PGEA/pc3.0-miR-101 nanocomplexes alone. Such rodlike supramolecular nanoassemblies will provide a promising means to produce efficient delivery vectors of versatile tumor-suppressive nucleic acids. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1

    PubMed Central

    Louie, Arnold; MacGowan, Alasdair; Hope, William

    2015-01-01

    We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done? The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence? A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clinical breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like Pseudomonas aeruginosa, Acinetobacter spp., and multidrug-resistant (MDR) Enterobacteriaceae. These lessons need to be applied to our old drugs to preserve them as well and need to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a corresponding resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects. PMID:26711759

  14. A comparison of virological suppression and rebound between Indigenous and non-Indigenous persons initiating combination antiretroviral therapy in a multisite cohort of individuals living with HIV in Canada.

    PubMed

    Benoit, Anita C; Younger, Jaime; Beaver, Kerrigan; Jackson, Randy; Loutfy, Mona; Masching, Renée; Nobis, Tony; Nowgesic, Earl; O'Brien-Teengs, Doe; Whitebird, Wanda; Zoccole, Art; Hull, Mark; Jaworsky, Denise; Rachlis, Anita; Rourke, Sean; Burchell, Ann N; Cooper, Curtis; Hogg, Robert; Klein, Marina B; Machouf, Nima; Montaner, Julio; Tsoukas, Chris; Raboud, Janet

    2017-01-01

    This study compared time to virological suppression and rebound between Indigenous and non-Indigenous individuals living with HIV in Canada initiating combination antiretroviral therapy (cART). Data were from the Canadian Observational Cohort collaboration; eight studies of treatment-naive persons with HIV initiating cART after 1/1/2000. Fine and Gray models were used to estimate the effect of ethnicity on time to virological suppression (two consecutive viral loads [VLs] <50 copies/ml at least 3 months apart) after adjusting for the competing risk of death and time until virological rebound (two consecutive VLs >200 copies/ml at least 3 months apart) following suppression. Among 7,080 participants were 497 Indigenous persons of whom 413 (83%) were from British Columbia. The cumulative incidence of suppression 1 year after cART initiation was 54% for Indigenous persons, 77% for Caucasian and 80% for African, Caribbean or Black (ACB) persons. The cumulative incidence of rebound 1 year after suppression was 13% for Indigenous persons, 6% for Caucasian and 7% for ACB persons. Indigenous persons were less likely to achieve suppression than Caucasian participants (aHR=0.58, 95% CI 0.50, 0.68), but not more likely to experience rebound (aHR=1.03, 95% CI 0.84, 1.27) after adjusting for age, gender, injection drug use, men having sex with men status, province of residence, baseline VL and CD4 + T-cell count, antiretroviral class and year of cART initiation. Lower suppression rates among Indigenous persons suggest a need for targeted interventions to improve HIV health outcomes during the first year of treatment when suppression is usually achieved.

  15. Ursodeoxycholic acid suppresses eosinophilic airway inflammation by inhibiting the function of dendritic cells through the nuclear farnesoid X receptor.

    PubMed

    Willart, M A M; van Nimwegen, M; Grefhorst, A; Hammad, H; Moons, L; Hoogsteden, H C; Lambrecht, B N; Kleinjan, A

    2012-12-01

    Ursodeoxycholic acid (UDCA) is the only known beneficial bile acid with immunomodulatory properties. Ursodeoxycholic acid prevents eosinophilic degranulation and reduces eosinophil counts in primary biliary cirrhosis. It is unknown whether UDCA would also modulate eosinophilic inflammation outside the gastrointestinal (GI) tract, such as eosinophilic airway inflammation seen in asthma. The working mechanism for its immunomodulatory effect is unknown. The immunosuppressive features of UDCA were studied in vivo, in mice, in an ovalbumin (OVA)-driven eosinophilic airway inflammation model. To study the mechanism of action of UDCA, we analyzed the effect of UDCA on eosinophils, T cells, and dendritic cell (DCs). DC function was studied in greater detail, focussing on migration and T-cell stimulatory strength in vivo and interaction with T cells in vitro as measured by time-lapse image analysis. Finally, we studied the capacity of UDCA to influence DC/T cell interaction. Ursodeoxycholic acid treatment of OVA-sensitized mice prior to OVA aerosol challenge significantly reduced eosinophilic airway inflammation compared with control animals. DCs expressed the farnesoid X receptor for UDCA. Ursodeoxycholic acid strongly promoted interleukin (IL)-12 production and enhanced the migration in DCs. The time of interaction between DCs and T cells was sharply reduced in vitro by UDCA treatment of the DCs resulting in a remarkable T-cell cytokine production. Ursodeoxycholic acid-treated DCs have less capacity than saline-treated DCs to induce eosinophilic inflammation in vivo in Balb/c mice. Ursodeoxycholic acid has the potency to suppress eosinophilic inflammation outside the GI tract. This potential comprises to alter critical function of DCs, in essence, the effect of UDCA on DCs through the modulation of the DC/T cell interaction. © 2012 John Wiley & Sons A/S.

  16. Glycyrrhizic acid prevents high calorie diet-induced metabolic aberrations despite the suppression of peroxisome proliferator-activated receptor γ expression.

    PubMed

    Cheng, Hong Sheng; Yaw, Hui Ping; Ton, So Ha; Choy, Siew Mei; Kong, Joana Magdelene Xiao Fang; Abdul Kadir, Khalid

    2016-09-01

    To investigate the effects of glycyrrhizic acid supplementation on glucose and lipid metabolism in rodents consuming a high-fat, high-sucrose diet. Twenty-four male, 8-week old Sprague Dawley rats with an initial weight of 160 to 200 g were randomised into three groups (n = 6 for each group): groups A (standard rat chow), B (high-fat, high-sucrose diet), and C (high-fat, high-sucrose diet + 100 mg/kg/d of glycyrrhizic acid via oral administration). The rats were treated accordingly for 4 wk. Glycaemic parameters, lipid profile, stress hormones, and adiponectin levels were measured after the treatment. Relative gene expressions of peroxisome proliferator-activated receptor α and γ, lipoprotein lipase as well as gluconeogenic enzymatic activities in different tissues were also determined. Consumption of high-fat, high-sucrose diet triggered hyperglycaemia, insulin resistance, and dyslipidemia, which were effectively attenuated by supplementation with glycyrrhizic acid. Glycyrrhizic acid supplementation also effectively reduced circulating adrenaline, alleviated gluconeogenic enzymes overactivity, and promoted the upregulation of lipoprotein lipase expression in the cardiomyocytes and skeletal muscles. A high calorie diet also triggered hypoadiponectinaemia and suppression of peroxisome proliferator-activated receptor γ expression, which did not improve with glycyrrhizic acid treatment. Supplementation with glycyrrhizic acid could alleviate high calorie diet-induced glucose and lipid metabolic dysregulations by reducing circulatory stress hormones, normalizing gluconeogenic enzyme activities, and elevating muscular lipid uptake. The beneficial effects of these bioactivities outweighed the adverse effects caused by diet-induced repression of peroxisome proliferator-activated receptor γ expression, resulting in the maintenance of lipid and glucose homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Resolution of abnormal cardiac MRI T2 signal following immune suppression for cardiac sarcoidosis.

    PubMed

    Crouser, Elliott D; Ruden, Emily; Julian, Mark W; Raman, Subha V

    2016-08-01

    Cardiac MR (CMR) with late gadolinium enhancement is commonly used to detect cardiac damage in the setting of cardiac sarcoidosis. The addition of T2 mapping to CMR was recently shown to enhance cardiac sarcoidosis detection and correlates with increased cardiac arrhythmia risk. This study was conducted to determine if CMR T2 abnormalities and related arrhythmias are reversible following immune suppression therapy. A retrospective study of subjects with cardiac sarcoidosis with abnormal T2 signal on baseline CMR and a follow-up CMR study at least 4 months later was conducted at The Ohio State University from 2011 to 2015. Immune suppression treated participants had a significant reduction in peak myocardial T2 value (70.0±5.5 vs 59.2±6.1 ms, pretreatment vs post-treatment; p=0.017), and 83% of immune suppression treated subjects had objective improvement in cardiac arrhythmias. Two subjects who had received inadequate immune suppression treatment experienced progression of cardiac sarcoidosis. This report indicates that abnormal CMR T2 signal represents an acute inflammatory manifestation of cardiac sarcoidosis that is potentially reversible with adequate immune suppression therapy. Copyright © 2016 American Federation for Medical Research.

  18. Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

    PubMed

    Peinemann, Frank; van Dalen, Elvira C; Enk, Heike; Berthold, Frank

    2017-08-25

    Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. We used standard

  19. Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma.

    PubMed

    Mark, Tomer; Stern, Jessica; Furst, Jessica R; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N; Harpel, John; Shore, Tsiporah; Schuster, Michael W; Leonard, John P; Christos, Paul J; Coleman, Morton; Niesvizky, Ruben

    2008-07-01

    A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte-colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P < .0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.

  20. Stem Cell Mobilization with Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy on Stem Cell Collection in Multiple Myeloma

    PubMed Central

    Mark, Tomer; Stern, Jessica; Furst, Jessica R.; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N.; Harpel, John; Shore, Tsiporah; Schuster, Michael W.; Leonard, John P.; Christos, Paul J.; Coleman, Morton; Niesvizky, Ruben

    2013-01-01

    A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte- colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P<.0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide. PMID:18541199

  1. Novel, selective vitamin D analog suppresses parathyroid hormone in uremic animals and postmenopausal women.

    PubMed

    Zella, Julia B; Plum, Lori A; Plowchalk, David R; Potochoiba, Michael; Clagett-Dame, Margaret; DeLuca, Hector F

    2014-01-01

    The use of 1α-hydroxylated vitamin D therapy to control secondary hyperparathyroidism in renal failure patients has been a success story, culminating with the demonstration of increased life expectancy in patients treated with these compounds. However, hypercalcemic episodes have been a recurrent problem with these therapies and have resulted in the added use of calcium mimetics. Clearly there is good reason to search for improved vitamin D therapy. In our inventory of vitamin D compounds, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) surfaced as a potential candidate. This was based on its preferential localization in the parathyroid gland and a clear suppression of serum parathyroid hormone (PTH) levels without a change in serum calcium in a clinical trial in postmenopausal women. 2MD has now been tested in the rat 5/6-nephrectomy model of renal failure, and in postmenopausal women to determine if it can suppress serum PTH at doses that do not elevate serum calcium and serum phosphorus concentrations. Daily oral treatment of uremic rats on 2.5 ng/bw/day of 2MD dramatically suppressed PTH without a change in serum calcium or serum phosphorus. Further, PTH was suppressed in postmenopausal women after only 3 daily oral doses of 2MD that continued for 4 weeks with no change in serum calcium or serum phosphorus. These results coupled with a pharmacokinetic half-life of ~24 h suggest that 2MD given either daily or at the time of dialysis may be a superior therapy for secondary hyperparathyroidism in chronic renal failure patients.

  2. Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts.

    PubMed

    Komatsu, Yuko; Ibi, Miho; Chosa, Naoyuki; Kyakumoto, Seiko; Kamo, Masaharu; Shibata, Toshiyuki; Sugiyama, Yoshiki; Ishisaki, Akira

    2016-07-01

    Bisphosphonates (BPs) are analogues of pyrophosphate that are known to prevent bone resorption by inhibiting osteoclast activity. Nitrogen-containing BPs, such as zoledronic acid (ZA), are widely used in the treatment of osteoporosis and bone metastasis. However, despite having benefits, ZA has been reported to induce BP-related osteonecrosis of the jaw (BRONJ) in cancer patients. The molecular pathological mechanisms responsible for the development of BRONJ, including necrotic bone exposure after tooth extraction, remain to be elucidated. In this study, we examined the effects of ZA on the transforming growth factor-β (TGF‑β)-induced myofibroblast (MF) differentiation of human gingival fibroblasts (hGFs) and the migratory activity of hGFs, which are important for wound closure by fibrous tissue formation. The ZA maximum concentration in serum (Cmax) was found to be approximately 1.47 µM, which clinically, is found after the intravenous administration of 4 mg ZA, and ZA at this dose is considered appropriate for the treatment of cancer bone metastasis or bone diseases, such as Erdheim-Chester disease. At Cmax, ZA significantly suppressed i) the TGF‑β-induced promotion of cell viability, ii) the TGF‑β-induced expression of MF markers such as α-smooth muscle actin (α-SMA) and type I collagen, iii) the TGF‑β-induced migratory activity of hGFs and iv) the expression level of TGF‑β type I receptor on the surfaces of hGFs, as well as the TGF‑β-induced phosphorylation of Smad2/3. Thus, ZA suppresses TGF‑β-induced fibrous tissue formation by hGFs, possibly through the inhibition of Smad‑dependent signal transduction. Our findings partly elucidate the molecular mechanisms underlying BRONJ and may prove to be beneficial to the identification of drug targets for the treatment of this symptom at the molecular level.

  3. Effectiveness of 5-aminolevulinic acid photodynamic therapy in the treatment of hidradenitis suppurativa: a report of 5 cases.

    PubMed

    Andino Navarrete, R; Hasson Nisis, A; Parra Cares, J

    2014-01-01

    Hidradenitis suppurativa has been described as a chronic, recurrent, and disabling inflammatory disease involving the entire hair follicle. Several treatments, including photodynamic therapy, have been used, but the results have been inconsistent and recurrence is high. In this prospective study, we evaluated disease severity, quality of life, and treatment tolerance in 5 patients with moderate to severe hidradenitis suppurativa treated with photodynamic therapy using 5-aminolevulinic acid and a 635-nm light source. Treatment effectiveness was evaluated using the Sartorius severity score, the Dermatology Life Quality Index, and a visual analog scale for pain and disease activity. Significant improvements were observed with all 3 instruments and the effects remained visible at 8 weeks. Our results suggest that photodynamic therapy with 5-aminolevulinic acid and a light wavelength of 635 nm could reduce disease severity and improve quality of life in patients with difficult-to-treat hidradenitis suppurativa. Copyright © 2013 Elsevier España, S.L. y AEDV. All rights reserved.

  4. Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy?

    PubMed

    Phillips, F; Muls, A C G; Lalji, A; Andreyev, H J N

    2015-08-01

    Gastrointestinal (GI) symptoms during and after cancer therapy can significantly affect quality of life and interfere with treatment. This study assessed whether bile acid malabsorption (BAM) or bile acid diarrhoea (BAD) are important causes of diarrhoea associated with cancer treatment. A retrospective analysis was carried out of consecutive patients assessed for BAM using ((75) Se) Selenium homocholic acid taurocholate (SeHCAT) scanning, after reporting any episodes of loose stool, attending a gastroenterology clinic in a cancer centre. Between 2009 and 2013, 506 consecutive patients (54.5% male; age range: 20-91 years), were scanned. BAM/BAD was diagnosed in 215 (42.5%). It was mild in 25.6%, moderate in 29.3% and severe in 45.1%. Pelvic chemoradiation had induced BAM in > 50% of patients. BAM was also frequent after treatment for conditions not previously associated with BAM, such as anal and colorectal cancer, and was present in > 75% of patients referred after pancreatic surgery. It was also unexpectedly frequent in patients who were treated for malignancy outside the GI tract, such as breast cancer and haematological malignancy. BAM/BAD are very common and under-appreciated causes of GI symptoms after cancer treatment. Health professionals should have a low threshold in suspecting this condition, as diagnosis and treatment can significantly improve quality of life. Colorectal Disease © 2015 The Association of Coloproctology of Great Britain and Ireland.

  5. A Mathematical Model of Intermittent Androgen Suppression for Prostate Cancer

    NASA Astrophysics Data System (ADS)

    Ideta, Aiko Miyamura; Tanaka, Gouhei; Takeuchi, Takumi; Aihara, Kazuyuki

    2008-12-01

    For several decades, androgen suppression has been the principal modality for treatment of advanced prostate cancer. Although the androgen deprivation is initially effective, most patients experience a relapse within several years due to the proliferation of so-called androgen-independent tumor cells. Bruchovsky et al. suggested in animal models that intermittent androgen suppression (IAS) can prolong the time to relapse when compared with continuous androgen suppression (CAS). Therefore, IAS has been expected to enhance clinical efficacy in conjunction with reduction in adverse effects and improvement in quality of life of patients during off-treatment periods. This paper presents a mathematical model that describes the growth of a prostate tumor under IAS therapy based on monitoring of the serum prostate-specific antigen (PSA). By treating the cancer tumor as a mixed assembly of androgen-dependent and androgen-independent cells, we investigate the difference between CAS and IAS with respect to factors affecting an androgen-independent relapse. Numerical and bifurcation analyses show how the tumor growth and the relapse time are influenced by the net growth rate of the androgen-independent cells, a protocol of the IAS therapy, and the mutation rate from androgen-dependent cells to androgen-independent ones.

  6. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.

    PubMed

    Lovelace, Erica S; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard P; Zink, Erika M; Kim, Young-Mo; Kyle, Jennifer E; Webb-Robertson, Bobbie-Jo M; Waters, Katrina M; Metz, Thomas O; Farin, Federico; Oberlies, Nicholas H; Polyak, Stephen J

    2015-08-28

    Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e., 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, whereas silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

  7. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

    PubMed Central

    Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard; Zink, Erika M.; Kim, Young-Mo; Kyle, Jennifer E.; Webb-Robertson, Bobbie-Jo; Waters, Katrina M.; Metz, Thomas O.; Farin, Federico; Oberlies, Nicholas H.; Polyak, Stephen J.

    2016-01-01

    Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e. 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, while silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation. PMID:26186142

  8. Foam suppression in overloaded manure-based biogas reactors using antifoaming agents.

    PubMed

    Kougias, P G; Boe, K; Tsapekos, P; Angelidaki, I

    2014-02-01

    Foam control is an imperative need in biogas plants, as foaming is a major operational problem. In the present study, the effect of oils (rapeseed oil, oleic acid, and octanoic acid) and tributylphosphate on foam reduction and process performance in batch and continuous manure-based biogas reactors was investigated. The compounds were tested in dosages of 0.05%, 0.1% and 0.5% v/vfeed. The results showed that rapeseed oil was most efficient to suppress foam at the dosage of 0.05% and 0.1% v/vfeed, while octanoic acid was most efficient to suppress foam at dosage of 0.5% v/vfeed. Moreover, the addition of rapeseed oil also increased methane yield. In contrast, tributylphosphate, which was very efficient antifoam, was found to be inhibitory to the biogas process. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Iso-α-acids, Bitter Components of Beer, Prevent Inflammation and Cognitive Decline Induced in a Mouse Model of Alzheimer's Disease.

    PubMed

    Ano, Yasuhisa; Dohata, Atsushi; Taniguchi, Yoshimasa; Hoshi, Ayaka; Uchida, Kazuyuki; Takashima, Akihiko; Nakayama, Hiroyuki

    2017-03-03

    Alongside the rapid growth in aging populations worldwide, prevention and therapy for age-related memory decline and dementia are in great demand to maintain a long, healthy life. Here we found that iso-α-acids, hop-derived bitter compounds in beer, enhance microglial phagocytosis and suppress inflammation via activation of the peroxisome proliferator-activated receptor γ. In normal mice, oral administration of iso-α-acids led to a significant increase both in CD11b and CD206 double-positive anti-inflammatory type microglia ( p < 0.05) and in microglial phagocytosis in the brain. In Alzheimer's model 5xFAD mice, oral administration of iso-α-acids resulted in a 21% reduction in amyloid β in the cerebral cortex as observed by immunohistochemical analysis, a significant reduction in inflammatory cytokines such as IL-1β and chemokines including macrophage inflammatory protein-1α in the cerebral cortex ( p < 0.05) and a significant improvement in a novel object recognition test ( p < 0.05), as compared with control-fed 5xFAD mice. The differences in iso-α-acid-fed mice were due to the induction of microglia to an anti-inflammatory phenotype. The present study is the first to report that amyloid β deposition and inflammation are suppressed in a mouse model of Alzheimer's disease by a single component, iso-α-acids, via the regulation of microglial activation. The suppression of neuroinflammation and improvement in cognitive function suggests that iso-α-acids contained in beer may be useful for the prevention of dementia. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Studies on Synthesis of Electrochemically Exfoliated Functionalized Graphene and Polylactic Acid/Ferric Phytate Functionalized Graphene Nanocomposites as New Fire Hazard Suppression Materials.

    PubMed

    Feng, Xiaming; Wang, Xin; Cai, Wei; Qiu, Shuilai; Hu, Yuan; Liew, Kim Meow

    2016-09-28

    Practical application of functionalized graphene in polymeric nanocomposites is hampered by the lack of cost-effective and eco-friendly methods for its production. Here, we reported a facile and green electrochemical approach for preparing ferric phytate functionalized graphene (f-GNS) by simultaneously utilizing biobased phytic acid as electrolyte and modifier for the first time. Due to the presence of phytic acid, electrochemical exfoliation leads to low oxidized graphene sheets (a C/O ratio of 14.8) that are tens of micrometers large. Successful functionalization of graphene was confirmed by the appearance of phosphorus and iron peaks in the X-ray photoelectron spectrum. Further, high-performance polylactic acid/f-GNS nanocomposites are readily fabricated by a convenient masterbatch strategy. Notably, inclusion of well-dispersed f-GNS resulted in dramatic suppression on fire hazards of polylactic acid in terms of reduced peak heat-release rate (decreased by 40%), low CO yield, and formation of a high graphitized protective char layer. Moreover, obviously improvements in crystallization rate and thermal conductivities of polylactic acid nanocomposites were observed, highlighting its promising potential in practical application. This novel strategy toward the simultaneous exfoliation and functionalization for graphene demonstrates a simple yet very effective approach for fabricating graphene-based flame retardants.

  11. Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy

    PubMed Central

    Malin, SK; Samat, A; Wolski, K; Abood, B; Pothier, CE; Bhatt, DL; Nissen, S; Brethauer, SA; Schauer, PR; Kirwan, JP; Kashyap, SR

    2015-01-01

    OBJECTIVE Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown. DESIGN STAMPEDE (Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently) was a prospective, randomized controlled trial. SUBJECTS Fifty-three (body mass index: 36 ± 3 kg m−2, age: 49 ± 9 years) poorly controlled patients with T2D (HbA1c (glycated hemoglobin): 9.7 ± 2%) were randomized to IMT, IMT + RYGB or IMT + SG and underwent a mixed-meal tolerance test at baseline, 12, and 24 months for evaluation of AG suppression (postprandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion × Matsuda index). Total/android body fat (dual-energy X-ray absorptiometry) was also assessed. RESULTS RYGB and SG reduced body fat comparably (15–23 kg) at 12 and 24 months, whereas IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 months (P < 0.001). However, there was no difference in insulin secretion between SG vs IMT at 24 months (P = 0.32). Fasting AG was reduced fourfold following SG (P < 0.01) and did not change with RYGB or IMT at 24 months. AG suppression improved more following RYGB than SG or IMT at 24 months (P = 0.01 vs SG, P = 0.07 vs IMT). At 24 months, AG suppression was associated with increased postprandial glucagon-like peptide-1 (r = −0.32, P < 0.02) and decreased android fat (r = 0.38; P < 0.006). CONCLUSIONS Enhanced AG suppression persists for up to 2 years after RYGB, and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery. PMID

  12. Spinal interleukin-10 therapy to treat peripheral neuropathic pain.

    PubMed

    Milligan, Erin D; Penzkover, Kathryn R; Soderquist, Ryan G; Mahoney, Melissa J

    2012-01-01

      Current research indicates that chronic peripheral neuropathic pain includes a role for glia and the actions of proinflammatory factors. This review briefly discusses the glial and cytokine responses that occur following peripheral nerve damage in support of utilizing anti-inflammatory cytokine interleukin-10 (IL-10) therapy to suppress chronic peripheral neuropathic pain. SPINAL NONVIRAL INTERLEUKIN-10 GENE THERAPY:  IL-10 is one of the most powerful endogenous counter-regulators of proinflammatory cytokine function that acts in the nervous system. Subarachnoid (intrathecal) spinal injection of the gene encoding IL-10 delivered by nonviral vectors has several advantages over virally mediated gene transfer methods and leads to profound pain relief in several animal models. NONVIRAL GENE DELIVERY:  Lastly, data are reviewed that nonviral deoxyribonucleic acid (DNA) encapsulated by a biologically safe copolymer, poly(lactic-co-glycolic) acid (PLGA), thought to protect DNA, leads to significantly improved therapeutic gene transfer in animal models, which additionally and significantly extends pain relief.   The impact of these early studies exploring anti-inflammatory genes emphasizes the exceptional therapeutic potential of new biocompatible intrathecal nonviral gene delivery approaches such as PLGA microparticles. Ultimately, ongoing expression of therapeutic genes is a viable option to treat chronic neuropathic pain in the clinic. © 2012 International Neuromodulation Society.

  13. Clinical trial: a randomized trial of early endoscopy, Helicobacter pylori testing and empirical therapy for the management of dyspepsia in primary care.

    PubMed

    Duggan, A E; Elliott, C A; Miller, P; Hawkey, C J; Logan, R F A

    2009-01-01

    Early endoscopy, Helicobacter pylori eradication and empirical acid suppression are commonly used dyspepsia management strategies in primary care but have not been directly compared in a single trial. To compare endoscopy, H. pylori test and refer, H. pylori test and treat and empirical acid suppression for dyspepsia in primary care. Patients presenting to their general practitioner with dyspepsia were randomized to endoscopy, H. pylori'test and treat', H. pylori test and endoscope positives, or empirical therapy with symptoms, patient satisfaction, healthcare costs and cost effectiveness at 12 months being the outcomes. At 2 months, the proportion of patients reporting no or minimal dyspeptic symptoms ranged from 74% for those having early endoscopy to 55% for those on empirical therapy (P = 0.009), but at 1 year, there was little difference among the four strategies. Early endoscopy was associated with fewer subsequent consultations for dyspepsia (P = 0.003). 'Test and treat' resulted in fewer endoscopies overall and was most cost-effective over a range of cost assumptions. Empirical therapy resulted in the lowest initial costs, but the highest rate of subsequent endoscopy. Gastro-oesophageal cancers were found in four patients randomized to the H. pylori testing strategies. While early endoscopy offered some advantages 'Test and treat' was the most cost-effective strategy. In older patients, early endoscopy may be an appropriate strategy in view of the greater risk of malignant disease. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd.

  14. Prospective observational study of treatment pattern, effectiveness and safety of zoledronic acid therapy beyond 24 months in patients with multiple myeloma or bone metastases from solid tumors.

    PubMed

    Van den Wyngaert, T; Delforge, M; Doyen, C; Duck, L; Wouters, K; Delabaye, I; Wouters, C; Wildiers, H

    2013-12-01

    To study the treatment patterns, effectiveness and safety of zoledronic acid (ZOL) beyond 2 years of therapy, given the paucity of data on long-term treatment in daily clinical practice. Patients with multiple myeloma (MM) or solid tumor bone metastases (STM) and at least 24 months of regular q3-4w ZOL therapy were followed prospectively for an additional 18 months beyond the 24 months required for study entry. End-points included ZOL exposure, incidence of skeletal related events (SRE), and safety. In all, 298 evaluable patients were enrolled. The mean continuation rate of ZOL was 90.6%. Exposure to ZOL decreased with time in all patients, but was lower (50.0% vs. 67.6%; p<0.001) and with higher discontinuation rates (incidence rate ratio [IRR]=1.95; p=0.002) in MM compared to the STM group. ZOL suppressed the rate of SREs similarly during the study as compared to before inclusion (0.12 vs. 0.13 events per person-year; p=0.7). At 18 months, 84.5% remained SRE-free. In STM patients, persistent ZOL therapy was associated with lower SRE risk (hazard ratio [HR]=0.42; p=0.01), but not in MM. Renal deterioration occurred in 3.7% and osteonecrosis of the jaw (ONJ) developed in 6.0%, with dental trauma increasing ONJ risk (HR=4.67; p=0.002). Beyond 2 years of therapy, treatment patterns of ZOL were heterogeneous and SRE rates were low. The safety profile of ZOL was acceptable, and interrupting ZOL in patients with solid tumors was associated with a higher risk of SREs.

  15. Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy

    PubMed Central

    Kuroshima, Shinichiro; Mecano, Rodan B.; Tanoue, Ryuichiro; Koi, Kiyono; Yamashita, Junro

    2014-01-01

    Background Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies. Methods Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting. Results Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition. Conclusion Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss. PMID:23688101

  16. Food for thought: examining the relationship between food thought suppression and weight-related outcomes.

    PubMed

    Barnes, Rachel D; Tantleff-Dunn, Stacey

    2010-08-01

    The current study sought to extend previous eating behaviors and thought suppression literature by assessing the relationship between food thought suppression and weight-related outcomes. Three hundred and twelve overweight/obese community men and women completed self-report measures of thought suppression, weight history, and eating behaviors. Women were more likely than men to endorse food thought suppression, as were individuals who currently were dieting, when compared with those nondieters. Food thought suppression also predicted binge eating, food cravings, and other eating disordered symptoms. Results have implications for obesity and support further exploration of third wave interventions, such as Acceptance and Commitment Therapy and Mindfulness, in the treatment of obesity. 2010 Elsevier Ltd. All rights reserved.

  17. Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells.

    PubMed

    Kim, Seong-Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe-Yune; Jung, Hoe-Youn; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eunji; Baek, Nam-In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong-Tai

    2015-09-28

    Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients.

  18. Enhanced 5-aminolevulinic acid-gold nanoparticle conjugate-based photodynamic therapy using pulse laser

    NASA Astrophysics Data System (ADS)

    Xu, Hao; Yao, Cuiping; Wang, Jing; Chang, Zhennan; Zhang, Zhenxi

    2016-02-01

    The low bioavailability is a crucial limitation for the application of 5-aminolevulinic acid (ALA) in theranostics. In this research, 5-aminolevulinic acid and gold nanoparticle conjugates (ALA-GNPs) were synthesized to improve the bioavailability of ALA and to investigate the impact of ALA photodynamic therapy (ALA-PDT) in Hela cells. A 532 nm pulse laser and light-emitting diode (central wavelengths 502 nm) were jointly used as light sources in PDT research. The results show a 532 nm pulse laser can control ALA release from ALA-GNPs by adjusting the pulse laser dose. This laser control release may be attributed to the heat generation from GNPs under pulse laser irradiation, which indicates accurately adjusting the pulse laser dose to control the drug release in the cell interior can be considered as a new cellular surgery modality. Furthermore, the PDT results in Hela cells indicate the enhancement of ALA release by pulse laser before PDT can promote the efficacy of cell eradication in the light-emitting diode PDT (LED-PDT). This laser mediated drug release system can provide a new online therapy approach in PDT and it can be utilized in the optical monitor technologies based individual theranostics.

  19. Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

    PubMed Central

    Hamada, Tetsuhiro; Sato, Ayuko; Hirano, Tadamichi; Yamamoto, Takashi; Son, Gakuhei; Onodera, Masayuki; Torii, Ikuko; Nishigami, Takashi; Tanaka, Minoru; Miyajima, Atsushi; Nishiguchi, Shuhei; Fujimoto, Jiro; Tsujimura, Tohru

    2007-01-01

    To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful, as preventive and curative means, for the treatment of patients with liver damage. PMID:17640959

  20. Diagnosis and therapy of non-variceal upper gastrointestinal bleeding

    PubMed Central

    Biecker, Erwin

    2015-01-01

    Non-variceal upper gastrointestinal bleeding (UGIB) is defined as bleeding proximal to the ligament of Treitz in the absence of oesophageal, gastric or duodenal varices. The clinical presentation varies according to the intensity of bleeding from occult bleeding to melena or haematemesis and haemorrhagic shock. Causes of UGIB are peptic ulcers, Mallory-Weiss lesions, erosive gastritis, reflux oesophagitis, Dieulafoy lesions or angiodysplasia. After admission to the hospital a structured approach to the patient with acute UGIB that includes haemodynamic resuscitation and stabilization as well as pre-endoscopic risk stratification has to be done. Endoscopy offers not only the localisation of the bleeding site but also a variety of therapeutic measures like injection therapy, thermocoagulation or endoclips. Endoscopic therapy is facilitated by acid suppression with proton pump inhibitor (PPI) therapy. These drugs are highly effective but the best route of application (oral vs intravenous) and the adequate dosage are still subjects of discussion. Patients with ulcer disease are tested for Helicobacter pylori and eradication therapy should be given if it is present. Non-steroidal anti-inflammatory drugs have to be discontinued if possible. If discontinuation is not possible, cyclooxygenase-2 inhibitors in combination with PPI have the lowest bleeding risk but the incidence of cardiovascular events is increased. PMID:26558151

  1. Aerosol delivery of folate-decorated hyperbranched polyspermine complexes to suppress lung tumorigenesis via Akt signaling pathway.

    PubMed

    Luo, Cheng-Qiong; Jang, Yoonjeong; Xing, Lei; Cui, Peng-Fei; Qiao, Jian-Bin; Lee, Ah Young; Kim, Hyeon-Jeong; Cho, Myung-Haing; Jiang, Hu-Lin

    2016-11-20

    Lung cancer has been a leading cause of cancer mortality worldwide and aerosol-mediated gene therapy endows numerous advantages compared to other traditional modalities. Here, we reported a folic acid (FA)-modified hyperbranched polyspermine (HPSPE) with prominent biocompatibility for lung cancer cell targeted gene therapy. FA was decorated to the HPSPE via an amidation reaction and the physicochemical properties of nanoplexes formed with DNA were characterized. Gel electrophoresis study elucidated that the designed polymer was capable to condense DNA and protect it from degradation by DNase I. Cell viability and transfection efficiency assay in vitro and in vivo indicated its increased transfection performance with lower toxicity. Furthermore, reduced tumor numbers and down-regulation of Akt1 protein after aerosol treatment containing FA-HPSPE/shAkt1 complexes proved its therapeutic potential for lung cancer suppression. Results obtained in this study suggested that FA-HPSPE with highly biocompatibility and targeting capability while forming complexes with shAkt1 and administrated through noninvasive aerosol could be prospective for inhibiting lung tumorigenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Acidic pre-conditioning suppresses apoptosis and increases expression of Bcl-xL in coronary endothelial cells under simulated ischaemia.

    PubMed

    Kumar, S; Reusch, H P; Ladilov, Y

    2008-01-01

    Ischaemic pre-conditioning has a powerful protective potential against ischaemia-induced cell death, and acidosis is an important feature of ischaemia and can lead to apoptosis. Here we tested whether pre-conditioning with acidosis, that is, acidic pre-conditioning (APC), may protect coronary endothelial cells (EC) against apoptosis induced by simulated ischaemia. For pre-conditioning, EC were exposed fo 40 min. to acidosis (pH 6.4) followed by a 14-hrs recovery period (pH 7.4) and finally treated for 2 hrs with simulated ischaemia (glucose-free anoxia at pH 6.4). Cells undergoing apoptosis were visualized by chromatin staining or by determination of caspase-3 activity Simulated ischaemia in untreated EC increased caspase-3 activity and the number of apoptotic cell (31.3 +/- 1.3%versus 3.9 +/- 0.6% in control). APC significantly reduced the rate of apoptosis (14.2 +/- 1.3%) and caspase-3 activity. Western blot analysis exploring the under lying mechanism leading to this protection revealed suppression of the endoplasmic reticulum- (reduced cleavage of caspase-12) and mitochondria-mediated (reduced cytochrome C release) pathways of apoptosis. These effects were associated with an over-expression of the anti-apoptotic protein Bcl-xL 14 hrs after APC, whereas no effect on the expression of Bcl-2, Bax, Bak, procaspase-12, reticulum-localized chaperones (GRP78, calreticulin), HSP70, HSP32 and HSP27 could be detected. Knock-down of Bcl-xL by siRNA-treatment prevented the protective effect of APC. In conclusion, short acidic pre-treatment can protect EC against ischaemic apoptosis. The mechanism of this protection consists of suppression of the endoplasmic reticulum- and mitochondria-mediated pathways. Over-expression of the anti apoptotic protein Bcl-xL is responsible for the increased resistance to apoptosis during ischaemic insult.

  3. Carnosic acid and fisetin combination therapy enhances inhibition of lung cancer through apoptosis induction.

    PubMed

    Shi, Bin; Wang, Li-Fang; Meng, Wen-Shu; Chen, Liang; Meng, Zi-Li

    2017-06-01

    Carnosic acid is a phenolic diterpene with anti-inflammation, anticancer, anti-bacterial, anti-diabetic, as well as neuroprotective properties, which is generated by many species from Lamiaceae family. Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally flavonoid is abundantly produced in different vegetables and fruits. Fisetin has been reported to have various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Lung cancer is reported as the most common neoplasm in human world-wide. In the present study, the possible benefits of carnosic acid combined with fisetin on lung cancer in vitro and in vivo was explored. Carnosic acid and fisetin combination led to apoptosis in lung cancer cells. Caspase-3 signaling pathway was promoted in carnosic acid and fisetin co-treatment, which was accompanied by anti-apoptotic proteins of Bcl-2 and Bcl-xl decreasing and pro-apoptotic signals of Bax and Bad increasing. The death receptor (DR) of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was enhanced in carnosic acid and fisetin combined treatment. Furthermore, the mouse xenograft model in vivo suggested that carnosic acid and fisetin combined treatment inhibited lung cancer growth in comparison to the carnosic acid or fisetin monotherapy. This study supplies a novel therapy to induce apoptosis to inhibit lung cancer through caspase-3 activation.

  4. Triptolide-induced mitochondrial damage dysregulates fatty acid metabolism in mouse sertoli cells.

    PubMed

    Cheng, Yisen; Chen, Gaojian; Wang, Li; Kong, Jiamin; Pan, Ji; Xi, Yue; Shen, Feihai; Huang, Zhiying

    2018-08-01

    Triptolide is a major active ingredient of tripterygium glycosides, used for the therapy of immune and inflammatory diseases. However, its clinical applications are limited by severe male fertility toxicity associated with decreased sperm count, mobility and testicular injures. In this study, we determined that triptoide-induced mitochondrial dysfunction triggered reduction of lactate and dysregulation of fatty acid metabolism in mouse Sertoli cells. First, triptolide induced mitochondrial damage through the suppressing of proliferator-activated receptor coactivator-1 alpha (PGC-1α) activity and protein. Second, mitochondrial damage decreased lactate production and dysregulated fatty acid metabolism. Finally, mitochondrial dysfunction was initiated by the inhibition of sirtuin 1 (SIRT1) with the regulation of AMP-activated protein kinase (AMPK) in Sertoli cells after triptolide treatment. Meanwhile, triptolide induced mitochondrial fatty acid oxidation dysregulation by increasing AMPK phosphorylation. Taken together, we provide evidence that the mechanism of triptolide-induced testicular toxicity under mitochondrial injury may involve a metabolic change. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Suppression of the rice fatty-acid desaturase gene OsSSI2 enhances resistance to blast and leaf blight diseases in rice.

    PubMed

    Jiang, Chang-Jie; Shimono, Masaki; Maeda, Satoru; Inoue, Haruhiko; Mori, Masaki; Hasegawa, Morifumi; Sugano, Shoji; Takatsuji, Hiroshi

    2009-07-01

    Fatty acids and their derivatives play important signaling roles in plant defense responses. It has been shown that suppressing a gene for stearoyl acyl carrier protein fatty-acid desaturase (SACPD) enhances the resistance of Arabidopsis (SSI2) and soybean to multiple pathogens. In this study, we present functional analyses of a rice homolog of SSI2 (OsSSI2) in disease resistance of rice plants. A transposon insertion mutation (Osssi2-Tos17) and RNAi-mediated knockdown of OsSSI2 (OsSSI2-kd) reduced the oleic acid (18:1) level and increased that of stearic acid (18:0), indicating that OsSSI2 is responsible for fatty-acid desaturase activity. These plants displayed spontaneous lesion formation in leaf blades, retarded growth, slight increase in endogenous free salicylic acid (SA) levels, and SA/benzothiadiazole (BTH)-specific inducible genes, including WRKY45, a key regulator of SA/BTH-induced resistance, in rice. Moreover, the OsSSI2-kd plants showed markedly enhanced resistance to the blast fungus Magnaporthe grisea and leaf-blight bacteria Xanthomonas oryzae pv. oryzae. These results suggest that OsSSI2 is involved in the negative regulation of defense responses in rice, as are its Arabidopsis and soybean counterparts. Microarray analyses identified 406 genes that were differentially expressed (>or=2-fold) in OsSSI2-kd rice plants compared with wild-type rice and, of these, approximately 39% were BTH responsive. Taken together, our results suggest that induction of SA-responsive genes, including WRKY45, is likely responsible for enhanced disease resistance in OsSSI2-kd rice plants.

  6. Effect of gender and calendar year on time to and duration of virologic suppression among antiretroviral-naïve HIV-infected individuals initiating combination antiretroviral therapy.

    PubMed

    Raboud, Janet; Blitz, Sandra; Walmsley, Sharon; Thompson, Courtney; Rourke, Sean B; Loutfy, Mona R

    2010-01-01

    To determine the effects of gender and calendar year on time to and duration of virologic suppression among HIV-infected antiretroviral-naïve individuals initiating combination antiretroviral therapy (cART). Ontario Cohort Study antiretroviral-naïve participants who initiated cART after December 31, 1998, and who had ≥2 follow-up viral loads were included. Multivariable Cox proportional hazard models were used to estimate the effects of gender and calendar year on times to virologic suppression and rebound. Of the 840 patients, 81% were male (median age 40 years; interquartile range [IQR], 34-46). Time to virologic suppression was shorter among women (hazard ratio [HR]=1.27, P=.01) and in more recent calendar time periods (2002-2004: HR, 1.04, P=.67; 2005-2006: HR, 1.22, P=.06; 2007-2008: HR, 1.36, P=.004) compared to 1999-2001 after adjusting for age and type of cART regimens. Women had shorter times to virologic rebound (HR, 1.57; P<.01) after adjusting for age, injection drug use, and type of cART regimen. However, 14/18 (78%) women suspected to be taking cART only for prevention of mother-to-child transmission of HIV experienced virologic rebound compared to 28% of women who required cART for their own health, suggesting that the increased rate of virologic rebound was due to women stopping ART at the termination of a pregnancy if they did not need it for their own health. Rates of rebound did not differ by calendar year period. Time to virologic suppression has steadily decreased over time while duration of suppression remained stable. Time to virologic suppression was shorter for women than for men, whereas durability of virologic suppression was slightly longer for men than women. However, gender differences in virologic rebound were likely due to women discontinuing cART at the end of the pregnancy if it was not needed for their own health.

  7. Ascorbic acid deficiency leads to increased grain chalkiness in transgenic rice for suppressed of L-GalLDH.

    PubMed

    Yu, Le; Liu, Yonghai; Lu, Lina; Zhang, Qilei; Chen, Yezheng; Zhou, Liping; Chen, Hua; Peng, Changlian

    2017-04-01

    The grain chalkiness of rice (Oryza sativa L.), which determines the rice quality and price, is a major concern in rice breeding. Reactive oxygen species (ROS) plays a critical role in regulating rice endosperm chalkiness. Ascorbic acid (Asc) is a major plant antioxidant, which strictly regulates the levels of ROS. l-galactono-1, 4-lactone dehydrogenase (L-GalLDH, EC 1.3.2.3) is an enzyme that catalyzes the last step of Asc biosynthesis in higher plants. Here we show that the L-GalLDH-suppressed transgenic rice, GI-1 and GI-2, which have constitutively low (between 30% and 50%) leaf and grain Asc content compared with the wild-type (WT), exhibit significantly increased grain chalkiness. Further examination showed that the deficiency of Asc resulted in a higher lipid peroxidation and H 2 O 2 content, accompanied by a lower hydroxyl radical scavenging rate, total antioxidant capacity and photosynthetic ability. In addition, changes of the enzyme activities and gene transcript abundances related to starch synthesis were also observed in GI-1 and GI-2 grains. The results we presented here suggest a close correlation between Asc deficiency and grain chalkiness in the L-GalLDH-suppressed transgenics. Asc deficiency leads to the accumulation of H 2 O 2 , affecting antioxidant capacity and photosynthetic function, changing enzyme activities and gene transcript abundances related to starch synthesis, finally leading to the increased grain chalkiness. Copyright © 2017 Elsevier GmbH. All rights reserved.

  8. In vivo visualization of endogenous miR-21 using hyaluronic acid-coated graphene oxide for targeted cancer therapy.

    PubMed

    Hwang, Do Won; Kim, Han Young; Li, Fangyuan; Park, Ji Yong; Kim, Dohyun; Park, Jae Hyung; Han, Hwa Seung; Byun, Jung Woo; Lee, Yun-Sang; Jeong, Jae Min; Char, Kookheon; Lee, Dong Soo

    2017-03-01

    Oncogene-targeted nucleic acid therapy has been spotlighted as a new paradigm for cancer therapeutics. However, in vivo delivery issues and uncertainty of therapeutic antisense drug reactions remain critical hurdles for a successful targeted cancer therapy. In this study, we developed a fluorescence-switchable theranostic nanoplatform using hyaluronic acid (HA)-conjugated graphene oxide (GO), which is capable of both sensing oncogenic miR-21 and inhibiting its tumorigenicity simultaneously. Cy3-labeled antisense miR-21 peptide nucleic acid (PNA) probes loaded onto HA-GO (HGP21) specifically targeted CD44-positive MBA-MB231 cells and showed fluorescence recovery by interacting with endogenous miR-21 in the cytoplasm of the MBA-MB231 cells. Knockdown of endogenous miR-21 by HGP21 led to decreased proliferation and reduced migration of cancer cells, as well as the induction of apoptosis, with enhanced PTEN levels. Interestingly, in vivo fluorescence signals markedly recovered 3 h after the intravenous delivery of HGP21 and displayed signals more than 5-fold higher than those observed in the HGPscr-treated group of tumor-bearing mice. These findings demonstrate the possibility of using the HGP nanoplatform as a cancer theranostic tool in miRNA-targeted therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Omega-3 fatty acids as adjunctive therapy in Crohns disease.

    PubMed

    Macdonald, Angie

    2006-01-01

    Crohns disease is an inflammatory bowel disease that can have a significant impact on the health of those afflicted. The etiology of the disease is unknown, but genetic, environmental, dietary, and immunological factors are thought to be involved. Multiple nutrients can become depleted during active disease due to inadequate intake or malabsorption. Preventing these deficiencies is paramount in the care of those suffering from Crohns disease. Often the traditional treatments (medications) have limited effectiveness and negative side effects that inhibit their use. Enteral nutrition has promising therapeutic benefits, but its use is often limited to the pediatric population due to poor patient acceptability. Omega-3 fatty acids have been investigated for their anti-inflammatory properties as an alternative to traditional care. This article reviews the etiology of Crohns disease, nutritional deficiencies, traditional treatments, and the use of omega-3 fatty acids in the prevention of Crohns recurrence. The results from clinical trials have been conflicting, but a new fish oil preparation that limits the side effects of traditional fish oil therapy shows promise as an adjunctive treatment for Crohns disease. Continued research is needed to validate these findings.

  10. Pharmacologic suppression of target cell recognition by engineered T cells expressing chimeric T-cell receptors.

    PubMed

    Alvarez-Vallina, L; Yañez, R; Blanco, B; Gil, M; Russell, S J

    2000-04-01

    Adoptive therapy with autologous T cells expressing chimeric T-cell receptors (chTCRs) is of potential interest for the treatment of malignancy. To limit possible T-cell-mediated damage to normal tissues that weakly express the targeted tumor antigen (Ag), we have tested a strategy for the suppression of target cell recognition by engineered T cells. Jurkat T cells were transduced with an anti-hapten chTCR tinder the control of a tetracycline-suppressible promoter and were shown to respond to Ag-positive (hapten-coated) but not to Ag-negative target cells. The engineered T cells were then reacted with hapten-coated target cells at different effector to target cell ratios before and after exposure to tetracycline. When the engineered T cells were treated with tetracycline, expression of the chTCR was greatly decreased and recognition of the hapten-coated target cells was completely suppressed. Tetracycline-mediated suppression of target cell recognition by engineered T cells may be a useful strategy to limit the toxicity of the approach to cancer gene therapy.

  11. Melatonin suppresses activation of hepatic stellate cells through RORα-mediated inhibition of 5-lipoxygenase.

    PubMed

    Shajari, Shiva; Laliena, Almudena; Heegsma, Janette; Tuñón, María Jesús; Moshage, Han; Faber, Klaas Nico

    2015-10-01

    Liver fibrosis is scar tissue resulting from an uncontrolled wound-healing process in response to chronic liver injury. Liver damage generates an inflammatory reaction that activates hepatic stellate cells (HSC) that transdifferentiate from quiescent cells that control retinol metabolism to proliferative and migratory myofibroblasts that produce excessive amounts of extracellular matrix proteins, in particular collagen 1a1 (COL1A1). Although liver fibrosis is reversible, no effective drug therapy is available to prevent or reverse HSC activation. Melatonin has potent hepatoprotective properties in a variety of acute and chronic liver injury models and suppresses liver fibrosis. However, it remains unclear whether melatonin acts indirectly or directly on HSC to prevent liver fibrosis. Here, we studied the effect of melatonin on culture-activated rat HSC. Melatonin dose-dependently suppressed the expression of HSC activation markers Col1a1 and alpha-smooth muscle actin (αSMA, Acta2), as well as HSC proliferation and loss of lipid droplets. The nuclear melatonin sensor retinoic acid receptor-related orphan receptor-alpha (RORα/Nr1f1) was expressed in quiescent and activated HSC, while the membranous melatonin receptors (Mtrn1a and Mtrn1b) were not. The synthetic RORα agonist SR1078 more potently suppressed Col1a1 and αSma expression, HSC proliferation, and lipid droplet loss, while the RORα antagonist SR1001 blocked the antifibrotic features of melatonin. Melatonin and SR1078 inhibited the expression of Alox5, encoding 5-lipoxygenase (5-LO). The pharmacological 5-LO inhibitor AA861 reduced Acta2 and Col1a1 expression in activated HSC. We conclude that melatonin directly suppresses HSC activation via RORα-mediated inhibition of Alox5 expression, which provides novel drug targets to treat liver fibrosis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer

    PubMed Central

    Murray, Shannon; Witt, Kristina; Seitz, Christina; Wallerius, Majken; Xie, Hanjing; Ullén, Anders; Harmenberg, Ulrika; Lidbrink, Elisabet; Rolny, Charlotte; Andersson, John

    2017-01-01

    ABSTRACT Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co-localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFβ were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer. PMID:28920001

  13. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients.

    PubMed

    Scaglia, Fernando; Carter, Susan; O'Brien, William E; Lee, Brendan

    2004-04-01

    Urea cycle disorders (UCDs) are a group of inborn errors of hepatic metabolism caused by the loss of enzymatic activities that mediate the transfer of nitrogen from ammonia to urea. These disorders often result in life-threatening hyperammonemia and hyperglutaminemia. A combination of sodium phenylbutyrate and sodium phenylacetate/benzoate is used in the clinical management of children with urea cycle defects as a glutamine trap, diverting nitrogen from urea synthesis to alternatives routes of excretion. We have observed that patients treated with these compounds have selective branched chain amino acid (BCAA) deficiency despite adequate dietary protein intake. However, the direct effect of alternative therapy on the steady state levels of plasma branched chain amino acids has not been well characterized. We have measured steady state plasma branched chain and other essential non-branched chain amino acids in control subjects, untreated ornithine transcarbamylase deficiency females and treated null activity urea cycle disorder patients in the fed steady state during the course of stable isotope studies. Steady-state leucine levels were noted to be significantly lower in treated urea cycle disorder patients when compared to either untreated ornithine transcarbamylase deficiency females or control subjects (P<0.0001). This effect was reproduced in control subjects who had depressed leucine levels when treated with sodium phenylacetate/benzoate (P<0.0001). Our studies suggest that this therapeutic modality has a substantial impact on the metabolism of branched chain amino acids in urea cycle disorder patients. These findings suggest that better titration of protein restriction could be achieved with branched chain amino acid supplementation in patients with UCDs who are on alternative route therapy.

  14. Efficacy of Antibiotic Suppressive Therapy in Patients with a Prosthetic Joint Infection.

    PubMed

    Wouthuyzen-Bakker, Marjan; Nijman, Jasperina M; Kampinga, Greetje A; van Assen, Sander; Jutte, Paul C

    2017-01-01

    Introduction: For chronic prosthetic joint infections (PJI), complete removal of the infected prosthesis is necessary in order to cure the infection. Unfortunately, a subgroup of patients is not able to undergo a revision surgery due to high surgical risk. Alternatively, these patients can be treated with antibiotic suppressive therapy (AST) to suppress the infection. Aim: To evaluate the efficacy and tolerability of AST. Methods: We retrospectively collected data (period 2009-2015) from patients with a PJI (of hip, knee or shoulder) who were treated with AST at the University Medical Center Groningen, the Netherlands. AST was defined as antibiotic treatment for PJI that was started after the usual 3 months of antibiotic treatment. The time of follow-up was defined from the time point AST was started. Treatment was considered as failed, when the patient still experienced joint pain, when surgical intervention (debridement, removal, arthrodesis or amputation) was needed to control the infection and/or when death occurred due to the infection. Results: We included 21 patients with a median age of 67 years (range 21 - 88) and with a median follow-up of 21 months (range 3 - 81). Coagulase negative staphylococci (CNS) (n=6), S. aureus (n=6) and polymicrobial flora (n=4) were the most frequently found causative pathogens. Most patients with CNS and S. aureus were treated with minocycline (67%) and clindamycin (83%) as AST, respectively. Overall, treatment was successful in 67% of patients. Failure was due to persistent joint pain (n=1), surgical intervention because of an uncontrolled infection (n=3), and death due the infection (n=3). We observed a treatment success of 90% in patients with a 'standard' prosthesis (n=11), compared to only 50% in patients with a tumor-prosthesis (n=10). Also, treatment was successful in 83% of patients with a CNS as causative microorganism for the infection, compared to 50% in patients with a S. aureus . Patients who failed on AST had a

  15. Role of fluconazole in the long-term suppressive therapy of fungal infections in patients with artificial implants.

    PubMed

    Penk, A; Pittrow, L

    1999-12-01

    With the increased use of artificial implants the management of related infections has become an important challenge. Normally an infected implant would be removed. In many cases this might be contraindicated and drug treatment remains as the only alternative. As microbiological eradication is often impossible, especially in fungal infections at artificial implants (FIAI) long-term suppressive therapy might be required. The objective of this study was to determine the therapeutic value of fluconazole (F) in the management of FIAI. Clinical data of 56 patients (pts) with proven or suspected fungal infections and artificial implants (FIAI) subsequently treated with F were analyzed retrospectively. FIAI caused by species with intrinsic resistance to F have been excluded from the study. The following implants were involved: prosthetic valve endocarditis (PVE) 25 pts (44.6%), intraocular lenses (IL) 9 pts (16.1%), ventriculoperitoneal shunts (VPS) 6 pts (10.7%), knee prostheses (KP) 5 pts (8.9%), biliary stents (BS) 4 pts (7.1 %), venous access devices (VAS) 3 pts (5.4%), urinary stents (US) 2 pts (3.6%), breast implant and pacemaker 1 patient (1.8%) each. Underlying diseases were valve insufficiency (in PVE), cataract surgery (in IL), prematurity in newborns (in VPS), arthrosis (in KP), biliary obstruction (in BS), cystic fibrosis (in VAS), and obstructive renal calculi (in US). Candida species (C. spp.) were the most frequently detected causative agents with C. parapsilosis as the leading cause (n = 19; 33.9%). Furthermore C. albicans (n = 15; 26.8%), C. spp. and fungi not further specified (n = 8; 14.3%), C. tropicalis (n = 3; 5.4%), C. glabrata (n = 3; 5.4%), and C. lusitaniae (n = 1; 1.8%) were identified. Acremonium kiliense has been detected in 4 pts (7.1%), Cryptococcus neoformans in 2 pts (3.6 %). Histoplasma capsulatum was identified in 1 patient (1.8%). The maximum duration of treatment with F was lifelong with a maximum recorded duration of 4,5 years. The

  16. Hybrid drug combination: Combination of ferulic acid and metformin as anti-diabetic therapy.

    PubMed

    Nankar, Rakesh; Prabhakar, P K; Doble, Mukesh

    2017-12-15

    Ferulic acid, an anti-oxidant phytochemical present in several dietary components, is known to produce wide range of pharmacological effects. It is approved for use in food industry as a preservative and in sports food. Previous reports from our lab have shown synergistic interaction of ferulic acid with metformin in cell lines and diabetic rats. The purpose of this review is to compile information about anti-diabetic activity of ferulic acid in in vitro and in vivo models with special emphasis on activity of ferulic acid when combined with metformin. The mechanism of synergistic interaction between ferulic acid and metformin is also proposed after carefully studying effects of these compounds on molecules involved in glucose metabolism. Scientific literature for the purpose of this review was collected using online search engines and databases such as ScienceDirect, Scopus, PubMed and Google scholar. Ferulic acid forms resonance stabilized phenoxyl radical which scavenges free radicals and reduce oxidative stress. It improves glucose and lipid profile in diabetic rats by enhancing activities of antioxidant enzymes, superoxide dismutase and catalase in the pancreatic tissue. Combining ferulic acid with metformin improves both, in vitro glucose uptake activity and in vivo hypoglycemic activity of the latter. It is possible to reduce the dose of metformin by four folds (from 50 to 12.5 mg/kg body weight) by combining it with 10 mg of ferulic acid/kg body weight in diabetic rats. Ferulic acid improves glucose uptake through PI3-K pathway whereas metformin activates AMPK pathway to improve glucose uptake. The synergistic interaction of ferulic acid and metformin is due their action on parallel pathways which are involved in glucose uptake. Due to synergistic nature of their interaction, it is possible to reduce the dose of metformin (by combining with ferulic acid) required to achieve normoglycemia. Since the dose of metformin is reduced, the dose associated side

  17. Interfering RNA with multi-targets for efficient gene suppression in HCC cells.

    PubMed

    Li, Tiejun; Zhu, York Yuanyuan; Ji, Yi; Zhou, Songfeng

    2018-06-01

    RNA interference (RNAi) technology has been widely used in therapeutics development, especially multiple targeted RNAi strategy, which is a better method for multiple gene suppression. In the study, interfering RNAs (iRNAs) were designed for carrying two or three different siRNA sequences in different secondary structure formats (loop or cloverleaf). By using these types of iRNAs, co-inhibition of survivin and B-cell lymphoma-2 (Bcl-2) was investigated in hepatocellular carcinoma (HCC) cells, and we obtained promising gene silencing effects without showing undesirable interferon response. Furthermore, suppression effects on proliferation, invasion, and induced apoptosis in HCC cells were validated. The results suggest that long iRNAs with secondary structure may be a preferred strategy for multigenic disease therapy, especially for cancer and viral gene therapy and their iRNA drug development.

  18. Effects of dietary supplementation of ferulic acid and gamma-oryzanol on integument color and suppression of oxidative stress in cultured red sea bream, Pagrus major.

    PubMed

    Maoka, Takashi; Tanimoto, Fumio; Sano, Mitsuhiko; Tsurukawa, Kanji; Tsuno, Takuo; Tsujiwaki, Satomi; Ishimaru, Katsuya; Takii, Kenji

    2008-01-01

    The effects of ferulic acid (FA) and gamma-oryzanol (OZ) supplementation on cultured red sea bream were examined. Commercial brown fish meal diets supplemented with FA (0.01-0.5%) or OZ (0.05-0.5%) were given to zero-year, cultured red sea bream for 98 days. After the experiment, the brightness of the integument color ("L" value) of FA- and OZ-administrated fish was higher than that of control fish. Furthermore, 2-Thiobarbituric acid reactive substances (TBARS) in the liver of FA- and OZ-administrated fish was lower than in control fish. These results indicate that FA and OZ suppressed not only dark-color pigmentation but also oxidative stress in cultured red sea bream.

  19. Near-cognate suppression of amber, opal and quadruplet codons competes with aminoacyl-tRNAPyl for genetic code expansion

    PubMed Central

    O’Donoghue, Patrick; Prat, Laure; Heinemann, Ilka U.; Ling, Jiqiang; Odoi, Keturah; Liu, Wenshe R.; Söll, Dieter

    2012-01-01

    Over 300 amino acids are found in proteins in nature, yet typically only 20 are genetically encoded. Reassigning stop codons and use of quadruplet codons emerged as the main avenues for genetically encoding non-canonical amino acids (NCAAs). Canonical aminoacyl-tRNAs with near-cognate anticodons also read these codons to some extent. This background suppression leads to ‘statistical protein’ that contains some natural amino acid(s) at a site intended for NCAA. We characterize near-cognate suppression of amber, opal and a quadruplet codon in common Escherichia coli laboratory strains and find that the PylRS/tRNAPyl orthogonal pair cannot completely outcompete contamination by natural amino acids. PMID:23036644

  20. Persistence of Viral Reservoirs in Multiple Tissues after Antiretroviral Therapy Suppression in a Macaque RT-SHIV Model

    PubMed Central

    Franks, Tamera; Kiser, Rebecca; Coalter, Vicky; Smedley, Jeremy; Piatak, Michael; Mellors, John W.; Lifson, Jeffrey D.; Ambrose, Zandrea

    2013-01-01

    Although antiretroviral therapy (ART) can suppress HIV-1 replication sufficiently to eliminate measurable plasma viremia, infected cells remain and ensure viral recrudescence after discontinuation of ART. We used a macaque model of HIV-1/AIDS to evaluate the location of infected cells during ART. Twelve macaques were infected with RT-SHIVmne, a SIV containing HIV-1 reverse transcriptase, conferring sensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Ten to fourteen weeks post-infection, 6 animals were treated with 3 or 4 antiretroviral drugs for 17-20 weeks; 6 control animals remained untreated. Viral DNA (vDNA) and RNA (vRNA) were measured in peripheral blood mononuclear cells (PBMC) and at necropsy in multiple tissues by quantitative PCR and RT-PCR. The majority of virally infected cells were located in lymphoid tissues with variable levels in the gastrointestinal tract of both treated and untreated animals. Tissue viral DNA levels correlated with week 1 plasma viremia, suggesting that tissues that harbor proviral DNA are established within the first week of infection. PBMC vDNA levels did not correlate with plasma viremia or tissue levels of vDNA. vRNA levels were high in lymphoid and gastrointestinal tissues of the untreated animals; animals on ART had little vRNA expressed in tissues and virus could not be cultured from lymph node resting CD4+ cells after 17-20 weeks on ART, indicating little or no ongoing viral replication. Strategies for eradication of HIV-1 will need to target residual virus in ART suppressed individuals, which may not be accurately reflected by frequencies of infected cells in blood. PMID:24367650

  1. Adeno-Associated Viral Vector-Induced Overexpression of Neuropeptide Y Y2 Receptors in the Hippocampus Suppresses Seizures

    ERIC Educational Resources Information Center

    Woldbye, David P. D.; Angehagen, Mikael; Gotzsche, Casper R.; Elbrond-Bek, Heidi; Sorensen, Andreas T.; Christiansen, Soren H.; Olesen, Mikkel V.; Nikitidou, Litsa; Hansen, Thomas v. O.; Kanter-Schlifke, Irene; Kokaia, Merab

    2010-01-01

    Gene therapy using recombinant adeno-associated viral vectors overexpressing neuropeptide Y in the hippocampus exerts seizure-suppressant effects in rodent epilepsy models and is currently considered for clinical application in patients with intractable mesial temporal lobe epilepsy. Seizure suppression by neuropeptide Y in the hippocampus is…

  2. Uric acid therapy improves the outcomes of stroke patients treated with intravenous tissue plasminogen activator and mechanical thrombectomy.

    PubMed

    Chamorro, Ángel; Amaro, Sergio; Castellanos, Mar; Gomis, Meritxell; Urra, Xabier; Blasco, Jordi; Arenillas, Juan F; Román, Luis S; Muñoz, Roberto; Macho, Juan; Cánovas, David; Marti-Fabregas, Joan; Leira, Enrique C; Planas, Anna M

    2017-06-01

    Background Numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischemic stroke, making the search for new treatments imperative. Uric acid is an endogenous antioxidant making it a drug candidate to improve stroke outcomes. Aim To report the effects of uric acid therapy in stroke patients receiving intravenous thrombolysis and mechanical thrombectomy. Methods Forty-five patients with proximal vessel occlusions enrolled in the URICO-ICTUS trial received intravenous recombinant tissue plasminogen activator within 4.5 h after stroke onset and randomized to intravenous 1000 mg uric acid or placebo (NCT00860366). These patients also received mechanical thrombectomy because a brain computed tomogaphy angiography confirmed the lack of proximal recanalization at the end of systemic thrombolysis. The primary outcome was good functional outcome at 90 days (modified Rankin Score 0-2). Safety outcomes included mortality, symptomatic intracerebral bleeding, and gout attacks. Results The rate of successful revascularization was >80% in the uric acid and the placebo groups but good functional outcome was observed in 16 out of 24 (67%) patients treated with uric acid and 10 out of 21 (48%) treated with placebo (adjusted Odds Ratio, 6.12 (95% CI 1.08-34.56)). Mortality was observed in two out of 24 (8.3%) patients treated with uric acid and one out of 21 (4.8%) treated with placebo (adjusted Odds Ratio, 3.74 (95% CI 0.06-226.29)). Symptomatic cerebral bleeding and gout attacks were similar in both groups. Conclusions Uric acid therapy was safe and improved stroke outcomes in stroke patients receiving intravenous thrombolysis followed by thrombectomy. Validation of this simple strategy in a larger trial is urgent.

  3. Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

    PubMed

    Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R; Pistis, Marco

    2008-12-17

    Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.

  4. Predictors of viral suppression and rebound among HIV-positive men who have sex with men in a large multi-site Canadian cohort.

    PubMed

    Tanner, Zachary; Lachowsky, Nathan; Ding, Erin; Samji, Hasina; Hull, Mark; Cescon, Angela; Patterson, Sophie; Chia, Jason; Leslie, Alia; Raboud, Janet; Loutfy, Mona; Cooper, Curtis; Klein, Marina; Machouf, Nima; Tsoukas, Christos; Montaner, Julio; Hogg, Robert S

    2016-10-21

    Gay, bisexual and other men who have sex with men (MSM) are disproportionately affected by HIV in Canada. Combination antiretroviral therapy has been shown to dramatically decrease progression to AIDS, premature death and HIV transmission. However, there are no comprehensive data regarding combination antiretroviral therapy outcomes among this population. We sought to identify socio-demographic and clinical correlates of viral suppression and rebound. Our analysis included MSM participants in the Canadian Observational Cohort, a multi-site cohort of HIV-positive adults from Canada's three most populous provinces, aged ≥18 years who first initiated combination antiretroviral therapy between 2000 and 2011. We used accelerated failure time models to identify factors predicting time to suppression (2 measures <50 copies/mL ≥30 days apart) and subsequent rebound (2 measures >200 copies/mL ≥30 days apart). Of 2,858 participants, 2,448 (86 %) achieved viral suppression in a median time of 5 months (Q1-Q3: 3-7 months). Viral suppression was significantly associated with later calendar year of antiretroviral therapy initiation, no history of injection drug use, lower baseline viral load, being on an initial regimen consisting of non-nucleoside reverse-transcriptase inhibitors, and older age. Among those who suppressed, 295 (12 %) experienced viral rebound. This was associated with earlier calendar year of antiretroviral therapy initiation, injection drug use history, younger age, higher baseline CD4 cell count, and living in British Columbia. Further strategies are required to optimize combination antiretroviral therapy outcomes in men who have sex with men in Canada, specifically targeting younger MSM and those with a history of injection drug use.

  5. Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner

    PubMed Central

    Moghei, Mahshid; Tavajohi-Fini, Pegah; Beatty, Brendan

    2016-01-01

    Although leucine has many positive effects on metabolism in multiple tissues, elevated levels of this amino acid and the other branched-chain amino acids (BCAAs) and their metabolites are implicated in obesity and insulin resistance. While some controversies exist about the direct effect of leucine on insulin action in skeletal muscle, little is known about the direct effect of BCAA metabolites. Here, we first showed that the inhibitory effect of leucine on insulin-stimulated glucose transport in L6 myotubes was dampened when other amino acids were present, due in part to a 140% stimulation of basal glucose transport (P < 0.05). Importantly, we also showed that α-ketoisocaproic acid (KIC), an obligatory metabolite of leucine, stimulated mTORC1 signaling but suppressed insulin-stimulated glucose transport (−34%, P < 0.05) in an mTORC1-dependent manner. The effect of KIC on insulin-stimulated glucose transport was abrogated in cells depleted of branched-chain aminotransferase 2 (BCAT2), the enzyme that catalyzes the reversible transamination of KIC to leucine. We conclude that although KIC can modulate muscle glucose metabolism, this effect is likely a result of its transamination back to leucine. Therefore, limiting the availability of leucine, rather than those of its metabolites, to skeletal muscle may be more critical in the management of insulin resistance and its sequelae. PMID:27488662

  6. In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide

    PubMed Central

    2011-01-01

    produced no detectable inactivation of either BV-associated bacteria or vaginal lactobacilli. Moreover, at very high concentrations, H2O2 was more toxic to vaginal lactobacilli than to BV-associated bacteria. On the basis of these in vitro observations, we conclude that lactic acid, not H2O2, is likely to suppress BV-associated bacteria in vivo. PMID:21771337

  7. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer

    PubMed Central

    Pagani, Olivia; Regan, Meredith M.; Walley, Barbara A.; Fleming, Gini F.; Colleoni, Marco; Láng, István; Gomez, Henry L.; Tondini, Carlo; Burstein, Harold J.; Perez, Edith A.; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R.; Martino, Silvana; Geyer, Charles E.; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P.; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N.; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S.; Gelber, Richard D.; Goldhirsch, Aron; Francis, Prudence A.

    2014-01-01

    BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT Clinical

  8. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

    PubMed

    Pagani, Olivia; Regan, Meredith M; Walley, Barbara A; Fleming, Gini F; Colleoni, Marco; Láng, István; Gomez, Henry L; Tondini, Carlo; Burstein, Harold J; Perez, Edith A; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R; Martino, Silvana; Geyer, Charles E; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Francis, Prudence A

    2014-07-10

    Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

  9. Effects of conventional and a novel colonic-release bile acid sequestrant, A3384, on fibroblast growth factor 19 and bile acid metabolism in healthy volunteers and patients with bile acid diarrhoea.

    PubMed

    Appleby, R N; Bajor, A; Gillberg, P-G; Graffner, H; Simrén, M; Ung, K A; Walters, Jrf

    2017-04-01

    Primary bile acid diarrhoea (BAD) is associated with increased bile acid synthesis and low fibroblast growth factor 19 (FGF19). Bile acid sequestrants are used as therapy, but are poorly tolerated and may exacerbate FGF19 deficiency. The purpose of this study was to evaluate the pharmacological effects of conventional sequestrants and a colonic-release formulation preparation of colestyramine (A3384) on bile acid metabolism and bowel function in patients with BAD. Patients with seven-day 75 selenium-homocholic acid taurine (SeHCAT) scan retention <10% were randomised in a double-blind protocol to two weeks treatment with twice-daily A3384 250 mg ( n  = 6), 1 g ( n  = 7) or placebo ( n  = 6). Thirteen patients were taking conventional sequestrants at the start of the study. Symptoms were recorded and serum FGF19 and 7α-hydroxy-4-cholesten-3-one (C4) measured. Median serum FGF19 on conventional sequestrant treatment was 28% lower than baseline values in BAD ( p  < 0.05). C4 on conventional sequestrant treatment was 58% higher in BAD ( p  < 0.001). No changes were seen on starting or withdrawing A3384. A3384 improved diarrhoeal symptoms, with a median reduction of 2.2 points on a 0-10 Likert scale compared to placebo, p  < 0.05. Serum FGF19 was suppressed and bile acid production up-regulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD.

  10. Effects of conventional and a novel colonic-release bile acid sequestrant, A3384, on fibroblast growth factor 19 and bile acid metabolism in healthy volunteers and patients with bile acid diarrhoea

    PubMed Central

    Bajor, A; Gillberg, P-G; Graffner, H; Simrén, M; Ung, KA; Walters, JRF

    2016-01-01

    Background Primary bile acid diarrhoea (BAD) is associated with increased bile acid synthesis and low fibroblast growth factor 19 (FGF19). Bile acid sequestrants are used as therapy, but are poorly tolerated and may exacerbate FGF19 deficiency. Aim The purpose of this study was to evaluate the pharmacological effects of conventional sequestrants and a colonic-release formulation preparation of colestyramine (A3384) on bile acid metabolism and bowel function in patients with BAD. Methods Patients with seven-day 75selenium-homocholic acid taurine (SeHCAT) scan retention <10% were randomised in a double-blind protocol to two weeks treatment with twice-daily A3384 250 mg (n = 6), 1 g (n = 7) or placebo (n = 6). Thirteen patients were taking conventional sequestrants at the start of the study. Symptoms were recorded and serum FGF19 and 7α-hydroxy-4-cholesten-3-one (C4) measured. Results Median serum FGF19 on conventional sequestrant treatment was 28% lower than baseline values in BAD (p < 0.05). C4 on conventional sequestrant treatment was 58% higher in BAD (p < 0.001). No changes were seen on starting or withdrawing A3384. A3384 improved diarrhoeal symptoms, with a median reduction of 2.2 points on a 0–10 Likert scale compared to placebo, p < 0.05. Conclusions Serum FGF19 was suppressed and bile acid production up-regulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD. PMID:28507750

  11. Long-term viral suppression and immune recovery during first-line antiretroviral therapy: a study of an HIV-infected adult cohort in Hanoi, Vietnam.

    PubMed

    Tanuma, Junko; Matsumoto, Shoko; Haneuse, Sebastien; Cuong, Do Duy; Vu, Tuong Van; Thuy, Pham Thi Thanh; Dung, Nguyen Thi; Dung, Nguyen Thi Hoai; Trung, Nguyen Vu; Kinh, Nguyen Van; Oka, Shinichi

    2017-12-01

    Achieving viral suppression is key in the global strategy to end the HIV epidemic. However, the levels of viral suppression have yet to be described in many resource-limited settings. We investigated the time to virologic failure (VF; defined as a viral load of ≥1000 copies/ml) and changes in CD4 counts since starting antiretroviral therapy (ART) in a cohort of HIV-infected adults in Hanoi, Vietnam. Factors related to the time to VF and impaired early immune recovery (defined as not attaining an increase in 100 cells/mm 3 in CD4 counts at 24 months) were further analysed. From 1806 participants, 225 were identified as having VF at a median of 50 months of first-line ART. The viral suppression rate at 12 months was 95.5% and survival without VF was maintained above 90% until 42 months. An increase in CD4 counts from the baseline was greater in groups with lower baseline CD4 counts. A younger age (multivariate hazard ratio (HR) 0.75, vs. <30), hepatitis C (HCV)-antibody positivity (HR 1.43), and stavudine (d4T)-containing regimens (HR 1.4, vs. zidovudine (AZT)) were associated with earlier VF. Factors associated with impaired early immune recovery included the male sex (odds ratio (OR) 1.78), HCV-antibody positivity (OR 1.72), d4T-based regimens (OR 0.51, vs. AZT), and nevirapine-based regimens (OR 0.53, vs. efavirenz) after controlling for baseline CD4 counts. Durable high-rate viral suppression was observed in the cohort of patients on first-line ART in Vietnam. Our results highlight the need to increase adherence support among injection drug users and HCV co-infected patients. © 2017 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.

  12. Topical acetylsalicylic, salicylic acid and indomethacin suppress pain from experimental tissue acidosis in human skin.

    PubMed

    Steen, K H; Reeh, P W; Kreysel, H W

    1995-09-01

    Topically applied acetylsalicylic acid (ASA), salicylic acid (SA) and indomethacin were tested in an experimental pain model that provides direct nociceptor excitation through cutaneous tissue acidosis. In 30 volunteers, sustained burning pain was produced in the palmar forearm through a continuous intradermal pressure infusion of a phosphate-buffered isotonic solution (pH 5.2). In 5 different, double-blind, randomized cross-over studies with 6 volunteers each, the flow rate of the syringe pump was individually adjusted to result in constant pain ratings of around 20% (50% in study 4) on a visual analog scale (VAS). The painful skin area was then covered with either placebo or the drugs which had been dissolved in diethylether. In the first study on 6 volunteers, ASA (60 mg/ml) or lactose (placebo) in diethylether (10 ml) was applied, using both arms at 3-day intervals. Both treatments resulted in sudden and profound pain relief due to the cooling effect of the evaporating ether. With lactose, however, the mean pain rating was restored close to the baseline within 6-8 min while, with ASA, it remained significantly depressed for the rest of the observation period (another 20 min). This deep analgesia was not accompanied by a loss of tactile sensation. The further studies served to show that indomethacin (4.5 mg/ml) and SA (60 mg/ml) were equally effective as ASA (each 92-96% pain reduction) and that the antinociceptive effects were due to local but not systemic actions, since ASA and SA dis not reach measurable plasma levels up to 3 h after topical applications. With a higher flow rate of acid buffer producing more intense pain (VAS 50%). ASA and SA were still able to significantly reduce the ratings by 90% or 84%, respectively. On the other hand, by increasing the flow rate by a factor of 2 on average, during the period of fully developed drug effect it was possible to overcome the pain suppression, which suggests a competitive mechanism of (acetyl-) salicylic

  13. Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the management of gastroesophageal reflux disease: safety and clinical evidence to date

    PubMed Central

    Sugano, Kentaro

    2018-01-01

    Potassium-competitive acid blocker (P-CAB) is a class of drug that competitively blocks the potassium-binding site of H+, K+-adenosine triphosphate (ATP)ase. Although the history of this class of drugs started over 30 years ago, clinical use of two P-CABs, revaprazan and vonoprazan, were only recently approved in Korea and Japan, respectively. Among them, vonoprazan has several advantages over conventional proton-pump inhibitors (PPIs), including rapid onset of action, long duration of acid suppression, fewer interindividual variations in terms of acid suppression, and minimum dietary influence on its action. These advantages of vonoprazan have been proved in clinical trials conducted for license approvals for several acid-related diseases. In this review article, current evidence of vonoprazan in the management of gastroesophageal reflux disease (GERD) will be summarized. Since the clinical trial data, as well as postmarketed clinical data, have consistently demonstrated superiority of vonoprazan over conventional PPIs in terms of achieving healing of mucosal breaks and maintaining the healing, it may provide an excellent, if not complete, option for fulfilling some of the unmet needs for current GERD therapy. The safety problem of vonoprazan is also discussed, as more pronounced hypergastrinemia inevitably ensues with its use. PMID:29383028

  14. Neonatal hydrocortisone therapy does not have a serious suppressive effect on the later function of the hypothalamus-pituitary-adrenal axis.

    PubMed

    Takayanagi, Toshimitsu; Matsuo, Koji; Egashira, Tomoko; Mizukami, Tomoko

    2015-05-01

    This study investigated whether providing extremely low birthweight (ELBW) infants with a large amount of hydrocortisone had a serious suppressive effect on the later function of the hypothalamus-pituitary-adrenal (HPA) axis. We evaluated the function of the HPA axis in 58 ELBW infants receiving 9.0 ± 7.2 mg/kg of intravenous and 68.1 ± 34.1 mg/kg of oral hydrocortisone using a human corticotropin-releasing hormone stimulation test. The mean age at investigation was 12.0 ± 5.2 months. The response was judged to be normal when the maximum to minimum ratio of the plasma adrenocorticotropic hormone (ACTH) concentration was >2, the peak value of the serum cortisol concentration was >552 nmol/L, or the increment was >193 nmol/L than baseline concentration. Of the 58 infants studied, 51 (88%) displayed a normal response to both the ACTH and cortisol secretion and seven infants (12%) who were judged to be poor responders exhibited a peak cortisol value of >386 nmol/L without any episode of adrenal insufficiency. Providing ELBW infants with a daily low dose of long-term hydrocortisone therapy should not lead to a serious suppressive effect on the later function of the HPA axis, regardless of the administration method. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  15. Herpes Simplex Virus Suppressive Therapy in Herpes Simplex Virus-2/Human Immunodeficiency Virus-1 Coinfected Women Is Associated With Reduced Systemic CXCL10 But Not Genital Cytokines.

    PubMed

    Andersen-Nissen, Erica; Chang, Joanne T; Thomas, Katherine K; Adams, Devin; Celum, Connie; Sanchez, Jorge; Coombs, Robert W; McElrath, M Juliana; Baeten, Jared M

    2016-12-01

    Herpes simplex virus type-2 (HSV-2) may heighten immune activation and increase human immunodeficiency virus 1 (HIV-1) replication, resulting in greater infectivity and faster HIV-1 disease progression. An 18-week randomized, placebo-controlled crossover trial of 500 mg valacyclovir twice daily in 20 antiretroviral-naive women coinfected with HSV-2 and HIV-1 was conducted and HSV-2 suppression was found to significantly reduce both HSV-2 and HIV-1 viral loads both systemically and the endocervical compartment. To determine the effect of HSV-2 suppression on systemic and genital mucosal inflammation, plasma specimens, and endocervical swabs were collected weekly from volunteers in the trial and cryopreserved. Plasma was assessed for concentrations of 31 cytokines and chemokines; endocervical fluid was eluted from swabs and assayed for 14 cytokines and chemokines. Valacyclovir significantly reduced plasma CXCL10 but did not significantly alter other cytokine concentrations in either compartment. These data suggest genital tract inflammation in women persists despite HSV-2 suppression, supporting the lack of effect on transmission seen in large scale efficacy trials. Alternative therapies are needed to reduce persistent mucosal inflammation that may enhance transmission of HSV-2 and HIV-1.

  16. Resveratrol suppresses ethanol stress in winery and bottom brewery yeast by affecting superoxide dismutase, lipid peroxidation and fatty acid profile.

    PubMed

    Gharwalova, Lucia; Sigler, Karel; Dolezalova, Jana; Masak, Jan; Rezanka, Tomas; Kolouchova, Irena

    2017-11-03

    Mid-exponential cultures of two traditional biotechnological yeast species, winery Saccharomyces cerevisiae and the less ethanol tolerant bottom-fermenting brewery Saccharomyces pastorianus, were exposed to different concentrations of added ethanol (3, 5 and 8%) The degree of ethanol-induced cell stress was assessed by measuring the cellular activity of superoxide dismutase (SOD), level of lipid peroxidation products, changes in cell lipid content and fatty acid profile. The resveratrol as an antioxidant was found to decrease the ethanol-induced rise of SOD activity and suppress the ethanol-induced decrease in cell lipids. A lower resveratrol concentration (0.5 mg/l) even reduced the extent of lipid peroxidation in cells. Resveratrol also alleviated ethanol-induced changes in cell lipid composition in both species by strongly enhancing the proportion of saturated fatty acids and contributing thereby to membrane stabilization. Lower resveratrol concentrations could thus diminish the negative effects of ethanol stress on yeast cells and improve their physiological state. These effects may be utilized to enhance yeast vitality in high-ethanol-producing fermentations or to increase the number of yeast generations in brewery.

  17. Gallic acid targets acute myeloid leukemia via Akt/mTOR-dependent mitochondrial respiration inhibition.

    PubMed

    Gu, Ruixin; Zhang, Minqin; Meng, Hu; Xu, Dandan; Xie, Yonghua

    2018-06-05

    Gallic acid is one of the many phenolic acids that can be found in dietary substances and traditional medicine herbs. The anti-cancer activities of gallic acid have been shown in various cancers but its underlying molecular mechanisms are not well understood. In this study, we show Akt/mammalian target of rapamycin (mTOR)-dependent inhibition of mitochondrial respiration as a mechanism of gallic acid's action in acute myeloid leukemia (AML). Gallic acid significantly induces apoptosis of AML cell lines, primary mononuclear cells (MNC) and CD34 stem/progenitors isolated form AML patients via caspase-dependent pathway. It also significantly enhances two standard AML chemotherapeutic agents' efficacy in vitro cell culture system and in vivo xenograft model. Gallic acid inhibits dose- and time-dependent mitochondrial respiration, leading to decreased ATP production and oxidative stress. Overexpression of constitutively active Akt restores gallic acid-mediated inhibition of mTOR signaling, mitochondrial dysfunction, energy crisis and apoptosis. Our results demonstrate that mitochondrial respiration inhibition by gallic acid is a consequence of Akt/mTOR signaling suppression. Our findings suggest that combination therapy with gallic acid may enhance antileukemic efficacy of standard chemotherapeutic agents in AML. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  18. Tumor-specific RNA interference targeting Pokemon suppresses tumor growth and induces apoptosis in prostate cancer.

    PubMed

    Li, Yining; Xu, Shuxiong; Wang, Xiangwei; Shi, Hua; Sun, Zhaolin; Yang, Zhao

    2013-02-01

    To explore the exact mechanism of Pokemon in prostate cancer. Pokemon is a member of the POK family of transcriptional repressors. Its main function is suppression of the p14ARF (alternate reading frame) tumor suppressor gene. Although Pokemon expression has been found to be increased in various types of lymphoma, the exact mechanism of the gene in prostate cancer is not clear. In the present study, prostate cancer cells were transfected with the specific short hairpin ribonucleic acid (RNA) expression vector targeting Pokemon. The expression of Pokemon messenger RNA and its protein was detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cell growth and cell apoptosis were also examined using the methyl thiazolyl tetrazolium assay and flow cytometry. The results demonstrated that specific RNA interference (RNAi) could decrease the expression levels of Pokemon gene messenger RNA and protein in prostate cancer cells. In addition, that specific RNAi significantly inhibited the cell proliferation and increased the apoptotic rate. In vivo experiments showed that specific RNAi inhibited the tumorigenicity of prostate cancer cells and significantly suppressed tumor growth. Therefore, an RNAi-targeted Pokemon gene strategy could be a potential approach to prostate cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Skin-safe photothermal therapy enabled by responsive release of acid-activated membrane-disruptive polymer from polydopamine nanoparticle upon very low laser irradiation.

    PubMed

    Zhu, Rui; Gao, Feng; Piao, Ji-Gang; Yang, Lihua

    2017-07-25

    How to ablate tumor without damaging skin is a challenge for photothermal therapy. We, herein, report skin-safe photothermal cancer therapy provided by the responsive release of acid-activated hemolytic polymer (aHLP) from the photothermal polydopamine (PDA) nanoparticle upon irradiation at very low dosage. Upon skin-permissible irradiation (via an 850 nm laser irradiation at the power density of 0.4 W cm -2 ), the nanoparticle aHLP-PDA generates sufficient localized-heat to bring about mild hyperthermia treatment and consequently, responsively sheds off the aHLP polymer from its PDA nanocore; this leads to selective cytotoxicity to cancer cells under the acidic conditions of the extracellular microenvironment of tumor. As a result, our aHLP-PDA nanoparticle upon irradiation at a low dosage effectively inhibits tumor growth without damaging skin, as demonstrated using animal models. Effective in mitigating the otherwise inevitable skin damage in tumor photothermal therapy, the nanosystem reported herein offers an efficient pathway towards skin-safe photothermal therapy.

  20. The antagonistic regulation of abscisic acid-inhibited root growth by brassinosteroids is partially mediated via direct suppression of ABSCISIC ACID INSENSITIVE 5 expression by BRASSINAZOLE RESISTANT 1.

    PubMed

    Yang, Xiaorui; Bai, Yang; Shang, Jianxiu; Xin, Ruijiao; Tang, Wenqiang

    2016-09-01

    Brassinosteroids (BRs) and abscisic acid (ABA) are plant hormones that antagonistically regulate many aspects of plant growth and development; however, the mechanisms that regulate the crosstalk of these two hormones are still not well understood. BRs regulate plant growth and development by activating BRASSINAZOLE RESISTANT 1 (BZR1) family transcription factors. Here we show that the crosstalk between BRs and ABA signalling is partially mediated by BZR1 regulated gene expression. bzr1-1D is a dominant mutant with enhanced BR signalling; our results showed that bzr1-1D mutant is less sensitive to ABA-inhibited primary root growth. By RNA sequencing, a subset of BZR1 regulated ABA-responsive root genes were identified. Of these genes, the expression of a major ABA signalling component ABA INSENSITIVE 5 (ABI5) was found to be suppressed by BR and by BZR1. Additional evidences showed that BZR1 could bind strongly with several G-box cis-elements in the promoter of ABI5, suppress the expression of ABI5 and make plants less sensitive to ABA. Our study demonstrated that ABI5 is a direct target gene of BZR1, and modulating the expression of ABI5 by BZR1 plays important roles in regulating the crosstalk between the BR and ABA signalling pathways. © 2016 John Wiley & Sons Ltd.

  1. Sirolimus-eluting Biodegradable Poly-l-Lactic Acid Stent to Suppress Granulation Tissue Formation in the Rat Urethra.

    PubMed

    Kim, Kun Yung; Park, Jung-Hoon; Kim, Do Hoon; Tsauo, Jiaywei; Kim, Min Tae; Son, Woo-Chan; Kang, Sung-Gwon; Kim, Dong-Hyun; Song, Ho-Young

    2018-01-01

    Purpose To investigate the use of sirolimus-eluting biodegradable stents (SEBSs) to suppress granulation tissue formation after stent placement in a rat urethral model. Materials and Methods All experiments were approved by the animal research committee. A total of 36 male Sprague-Dawley rats were randomized into three equal groups after biodegradable stent placement. Group A received control biodegradable stents. Groups B and C received stents coated with 90 µg/cm 2 and 450 µg/cm 2 sirolimus, respectively. Six rats in each group were sacrificed after 4 weeks; the remaining rats were sacrificed after 12 weeks. The therapeutic effectiveness of SEBSs was assessed by comparing the results of retrograde urethrography and histologic examination. Analysis of variance with post hoc comparisons was used to evaluate statistical differences. Results SEBS placement was technically successful in all rats. Urethrographic and histologic examinations revealed significantly less granulation tissue formation at both time points in the rats receiving SEBSs (groups B and C) compared with those that received control stents (group A) (P < .05 for all). There were no significant differences in urethrographic and histologic findings between groups B and C (P > .05 for all). However, the mean number of epithelial layers in group B was higher than that in group C at 4 weeks after stent placement (P < .001). Apoptosis increased in group C compared with groups A and B (P < .05 for all). Conclusion The use of SEBSs suppressed granulation tissue formation secondary to stent placement in a rat urethral model; local therapy with SEBSs may be used to decrease stent-related granulation tissue formation. © RSNA, 2017.

  2. Proton Pump Inhibitors Independently Protect Against Early Allograft Injury or Chronic Rejection After Lung Transplantation.

    PubMed

    Lo, Wai-Kit; Goldberg, Hilary J; Boukedes, Steve; Burakoff, Robert; Chan, Walter W

    2018-02-01

    Acid reflux has been associated with poor outcomes following lung transplantation. Unlike surgical fundoplication, the role of noninvasive, pharmacologic acid suppression remains uncertain. To assess the relationship between post-transplant acid suppression with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) and onset of early allograft injury or chronic rejection following lung transplantation. This was a retrospective cohort study of lung transplant recipients at a tertiary center in 2007-2014. Patients with pre-transplant antireflux surgery were excluded. Time-to-event analysis using the Cox proportional hazards model was applied to assess acid suppression therapy and onset of acute or chronic rejection, defined histologically and clinically. Subgroup analyses were performed to assess PPI versus H2RA use. A total of 188 subjects (60% men, mean age 54, follow-up 554 person-years) met inclusion criteria. During follow-up, 115 subjects (61.5%) developed rejection, with all-cause mortality of 27.6%. On univariate analyses, acid suppression and BMI, but not other patient demographics, were associated with rejection. The Kaplan-Meier curve demonstrated decreased rejection with use of acid suppression therapy (log-rank p = 0.03). On multivariate analyses, acid suppression (HR 0.39, p = 0.04) and lower BMI (HR 0.67, p = 0.04) were independently predicted against rejection. Subgroup analyses demonstrated that persistent PPI use was more protective than H2RA or no antireflux medications. Post-lung transplant exposure to persistent PPI therapy results in the greatest protection against rejection in lung transplant recipients, independent of other clinical predictors including BMI, suggesting that PPI may have antireflux or anti-inflammatory effects in enhancing allograft protection.

  3. Ursolic acid suppresses leptin-induced cell proliferation in rat vascular smooth muscle cells.

    PubMed

    Yu, Ya-Mei; Tsai, Chiang-Chin; Tzeng, Yu-Wen; Chang, Weng-Cheng; Chiang, Su-Yin; Lee, Ming-Fen

    2017-07-01

    Accumulating lines of evidence indicate that high leptin levels are associated with adverse cardiovascular health in obese individuals. Proatherogenic effects of leptin include endothelial cell activation and vascular smooth muscle cell proliferation and migration. Ursolic acid (UA) has been reported to exhibit multiple biological effects including antioxidant and anti-inflammatory properties. In this study, we investigated the effect of UA on leptin-induced biological responses in rat vascular smooth muscle cells (VSMCs). A-10 VSMCs were treated with leptin in the presence or absence of UA. Intracellular reactive oxygen species (ROS) was probed by 2',7'-dichlorofluorescein diacetate. The expression of extracellular signal-regulated kinase (ERK)1/2, phospho-(ERK)1/2, nuclear factor-kappa B (NF-κB) p65 and p50, and matrix metalloproteinase-2 (MMP2) was determined by Western blotting. Immunocytochemistry and confocal laser scanning microscopy were also used for the detection of NF-κB. The secretion of MMP2 was detected by gelatin zymography. UA exhibited antioxidant activities in vitro. In rat VSMCs, UA effectively inhibited cell growth and the activity of MMP2 induced by leptin. These suppressive effects appeared by decreasing the activation of (ERK)1/2, the nuclear expression and translocation of NF-κB, and the production of ROS. UA appeared to inhibit leptin-induced atherosclerosis, which may prevent the development of obesity-induced cardiovascular diseases.

  4. Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells

    PubMed Central

    ZHAO, BING; HU, MENGCAI

    2013-01-01

    Gallic acid is a trihydroxybenzoic acid, also known as 3,4,5-trihydroxybenzoic acid, which is present in plants worldwide, including Chinese medicinal herbs. Gallic acid has been shown to have cytotoxic effects in certain cancer cells, without damaging normal cells. The objective of the present study was to determine whether gallic acid is able to inhibit human cervical cancer cell viability, proliferation and invasion and suppress cervical cancer cell-mediated angiogenesis. Treatment of HeLa and HTB-35 human cancer cells with gallic acid decreased cell viability in a dose-dependent manner. BrdU proliferation and tube formation assays indicated that gallic acid significantly decreased human cervical cancer cell proliferation and tube formation in human umbilical vein endothelial cells, respectively. Additionally, gallic acid decreased HeLa and HTB-35 cell invasion in vitro. Western blot analysis demonstrated that the expression of ADAM17, EGFR, p-Akt and p-Erk was suppressed by gallic acid in the HeLa and HTB-35 cell lines. These data indicate that the suppression of ADAM17 and the downregulation of the EGFR, Akt/p-Akt and Erk/p-Erk signaling pathways may contribute to the suppression of cancer progression by Gallic acid. Gallic acid may be a valuable candidate for the treatment of cervical cancer. PMID:24843386

  5. Suppression of BMP-7 by histone deacetylase 2 promoted apoptosis of renal tubular epithelial cells in acute kidney injury

    PubMed Central

    Ma, Taotao; Huang, Cheng; Xu, Qingqing; Yang, Yang; Liu, Yaru; Meng, Xiaoming; Li, Jun; Ye, Min; Liang, Hong

    2017-01-01

    Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by histone deacetylase (HDAC) inhibitors via epigenetic modification to enhance bone morphogenetic protein 7 (BMP-7) expression. Cisplatin upregulated the activity of HDAC2 in the kidney. Inhibition of HDAC with clinically used trichostatin A (TSA) or valproic acid (VPA) suppressed cisplatin-induced kidney injury and epithelial cell apoptosis. Overexpression of HDAC2 promotes CP-treated tubular epithelium cells apoptosis. Chromatin immunoprecipitation assay clearly detected HDAC2 assosiation with BMP-7 promoter. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by TSA or VPA in vivo and in vitro. Interestingly, administration of recombinant BMP-7 (rhBMP-7) reduced cisplatin-induced kidney dysfunction. Moreover, BMP-7 treatment suppressed epithelial cell apoptosis and small interfering RNA-based knockdown of BMP-7 expression abolished HDAC inhibitors suppression of epithelial cell apoptosis in vitro. Results of current study indicated that TSA or VPA inhibited apoptosis of renal tubular epithelial cells via promoting the level of BMP-7 epigenetically through targeting HDAC2. Hence, HDAC inhibitors could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity. PMID:29072686

  6. Valproic acid (VPA) inhibits the epithelial-mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4.

    PubMed

    Lan, Xiaopeng; Lu, Guoliang; Yuan, Chuanwei; Mao, Shaowei; Jiang, Wei; Chen, Yougen; Jin, Xunbo; Xia, Qinghua

    2016-01-01

    The epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. Previous studies have reported that valproic acid (VPA) suppresses prostate carcinoma (PCa) cell metastasis and down-regulates SMAD4 protein levels, which is the key molecule in TGF-β-induced EMT. However, the correlation between VPA and the EMT in PCa remains uncertain. Markers of the EMT in PCa cells and xenografts were molecularly assessed after VPA treatment. The expression and mono-ubiquitination of SMAD4 were also analyzed. After transfection with plasmids that express SMAD4 or short hairpin RNA for SMAD4 down-regulation, markers of EMT were examined to confirm whether VPA inhibits the EMT of PCa cells through the suppression of SMAD4. VPA induced the increase in E-cadherin (p < 0.05), and the decrease in N-cadherin (p < 0.05) and Vimentin (p < 0.05), in PCa cells and xenografts. SMAD4 mRNA and protein levels were repressed by VPA (p < 0.05), whereas the level of mono-ubiquitinated SMAD4 was increased (p < 0.05). SMAD4 knockdown significantly increased E-cadherin expression in PC3 cells, but SMAD4 over-expression abolished the VPA-mediated EMT-inhibitory effect. VPA inhibits the EMT in PCa cells via the inhibition of SMAD4 expression and the mono-ubiquitination of SMAD4. VPA could serve as a promising agent in PCa treatment, with new strategies based on its diverse effects on posttranscriptional regulation.

  7. Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice.

    PubMed

    Yan, Sheng-Lei; Wang, Zhi-Hong; Yen, Hsiu-Fang; Lee, Yi-Ju; Yin, Mei-Chin

    2016-12-01

    Ethanol was used to induce acute hepatotoxicity in mice. Effects of cinnamic acid (CA) and syringic acid (SA) post-intake for hepatic recovery from alcoholic injury was investigated. Ethanol treated mice were supplied by CA or SA at 40 or 80 mg/kg BW/day for 5 days. Results showed that ethanol stimulated protein expression of CYP2E1, p47 phox , gp91 phox , cyclooxygenase-2 and nuclear factor kappa B in liver. CA or SA post-intake restricted hepatic expression of these molecules. Ethanol suppressed nuclear factor erythroid 2-related factor (Nrf2) expression, and CA or SA enhanced Nrf2 expression in cytosolic and nuclear fractions. Ethanol increased the release of reactive oxygen species, oxidized glutathione, interleukin-6, tumor necrosis factor-alpha, nitric acid and prostaglandin E 2 . CA or SA lowered hepatic production of these oxidative and inflammatory factors. Histological data revealed that ethanol administration caused obvious foci of inflammatory cell infiltration, and CA or SA post-intake improved hepatic inflammatory infiltration. These findings support that cinnamic acid and syringic acid are potent nutraceutical agents for acute alcoholic liver disease therapy. However, potential additive or synergistic benefits of cinnamic and syringic acids against ethanol-induced hepatotoxicity need to be investigated. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. New RNAi strategy for selective suppression of a mutant allele in polyglutamine disease.

    PubMed

    Kubodera, Takayuki; Yokota, Takanori; Ishikawa, Kinya; Mizusawa, Hidehiro

    2005-12-01

    In gene therapy of dominantly inherited diseases with small interfering RNA (siRNA), mutant allele specific suppression may be necessary for diseases in which the defective gene normally has an important role. It is difficult, however, to design a mutant allele-specific siRNA for trinucleotide repeat diseases in which the difference of sequences is only repeat length. To overcome this problem, we use a new RNA interference (RNAi) strategy for selective suppression of mutant alleles. Both mutant and wild-type alleles are inhibited by the most effective siRNA, and wild-type protein is restored using the wild-type mRNA modified to be resistant to the siRNA. Here, we applied this method to spinocerebellar ataxia type 6 (SCA6). We discuss its feasibility and problems for future gene therapy.

  9. Low-Protein Diet Supplemented with Keto Acids Is Associated with Suppression of Small-Solute Peritoneal Transport Rate in Peritoneal Dialysis Patients

    PubMed Central

    Jiang, Na; Qian, Jiaqi; Lin, Aiwu; Fang, Wei; Zhang, Weiming; Cao, Liou; Wang, Qin; Ni, Zhaohui; Yao, Qiang

    2011-01-01

    Objective. We investigate whether low-protein diet would show benefits in suppressing peritoneal transport rate in peritoneal dialysis (PD) patients. Methods. This is a supplemented analysis of our previously published trial, which randomized 60 PD patients to receive low- (LP: dietary protein intake of 0.6–0.8 g/kg/d), keto-acid-supplemented low- (sLP: 0.6–0.8 g/kg/d with 0.12 g/kg/d of keto acids), or high- (HP: 1.0–1.2 g/kg/d) protein diet and lasted for one year. In this study, the variations of peritoneal transport rate were assessed. Results. While baseline D/Pcr (dialysate-to-plasma concentration ratio for creatinine at 4 hour) and D/D0glu (dialysate glucose at 4 hour to baseline dialysate glucose concentration ratio) were similar, D/Pcr in group sLP was lower, and D/D0glu was higher than those in the other two groups (P < 0.05) at 12th month. D/D0glu increased (P < 0.05), and D/Pcr tended to decrease, (P = 0.071) in group sLP. Conclusions. Low-protein diet with keto acids may benefit PD patients by maintaining peritoneum at a lower transport rate. PMID:21747999

  10. Low-protein diet supplemented with keto acids is associated with suppression of small-solute peritoneal transport rate in peritoneal dialysis patients.

    PubMed

    Jiang, Na; Qian, Jiaqi; Lin, Aiwu; Fang, Wei; Zhang, Weiming; Cao, Liou; Wang, Qin; Ni, Zhaohui; Yao, Qiang

    2011-01-01

    Objective. We investigate whether low-protein diet would show benefits in suppressing peritoneal transport rate in peritoneal dialysis (PD) patients. Methods. This is a supplemented analysis of our previously published trial, which randomized 60 PD patients to receive low- (LP: dietary protein intake of 0.6-0.8 g/kg/d), keto-acid-supplemented low- (sLP: 0.6-0.8 g/kg/d with 0.12 g/kg/d of keto acids), or high- (HP: 1.0-1.2 g/kg/d) protein diet and lasted for one year. In this study, the variations of peritoneal transport rate were assessed. Results. While baseline D/P(cr) (dialysate-to-plasma concentration ratio for creatinine at 4 hour) and D/D0(glu) (dialysate glucose at 4 hour to baseline dialysate glucose concentration ratio) were similar, D/P(cr) in group sLP was lower, and D/D0(glu) was higher than those in the other two groups (P < 0.05) at 12th month. D/D0(glu) increased (P < 0.05), and D/P(cr) tended to decrease, (P = 0.071) in group sLP. Conclusions. Low-protein diet with keto acids may benefit PD patients by maintaining peritoneum at a lower transport rate.

  11. Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sato, Keiichiro, E-mail: Sato_Keiichiro@takeda.co.jp; Awasaki, Yasuyuki; Kandori, Hitoshi

    Pioglitazone hydrochloride (PIO), a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, was administered orally for 85 weeks at 16 mg/kg/day to male rats fed either a diet containing 1.5% ammonium chloride (acid-forming diet) or a control diet to investigate the effects of urinary acidification induced by the acid-forming diet on the tumorigenic potential of PIO in the urinary bladder. The surviving animals at the end of the administration period were followed to the end of the 2-year study period without changes in the diet and were subjected to terminal necropsy on Week 104. The number of urinary microcrystals, evaluated by manualmore » counting with light microscopy and by an objective method with a laser diffraction particle size analyzer, was increased by PIO on Weeks 12 and 25 and the increases were markedly suppressed by urinary acidification. Urinary citrate was decreased by PIO throughout the study period, but no changes were seen in urinary oxalate at any timepoint. The incidences of PIO-treated males bearing at least one of the advanced proliferative changes consisting of papillary hyperplasia, nodular hyperplasia, papilloma or carcinoma were significantly decreased from 11 of 82 males fed the control diet to 2 of 80 males fed the acid-forming diet. The acid-forming diet did not show any effects on the toxicokinetic parameters of PIO and its metabolites. Microcrystalluria appears to be involved in the development of the advanced stage proliferative lesions in bladder tumorigenesis induced by PIO in male rats.« less

  12. Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats.

    PubMed

    Sato, Keiichiro; Awasaki, Yasuyuki; Kandori, Hitoshi; Tanakamaru, Zen-Yo; Nagai, Hirofumi; Baron, David; Yamamoto, Masaki

    2011-03-15

    Pioglitazone hydrochloride (PIO), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, was administered orally for 85 weeks at 16 mg/kg/day to male rats fed either a diet containing 1.5% ammonium chloride (acid-forming diet) or a control diet to investigate the effects of urinary acidification induced by the acid-forming diet on the tumorigenic potential of PIO in the urinary bladder. The surviving animals at the end of the administration period were followed to the end of the 2-year study period without changes in the diet and were subjected to terminal necropsy on Week 104. The number of urinary microcrystals, evaluated by manual counting with light microscopy and by an objective method with a laser diffraction particle size analyzer, was increased by PIO on Weeks 12 and 25 and the increases were markedly suppressed by urinary acidification. Urinary citrate was decreased by PIO throughout the study period, but no changes were seen in urinary oxalate at any timepoint. The incidences of PIO-treated males bearing at least one of the advanced proliferative changes consisting of papillary hyperplasia, nodular hyperplasia, papilloma or carcinoma were significantly decreased from 11 of 82 males fed the control diet to 2 of 80 males fed the acid-forming diet. The acid-forming diet did not show any effects on the toxicokinetic parameters of PIO and its metabolites. Microcrystalluria appears to be involved in the development of the advanced stage proliferative lesions in bladder tumorigenesis induced by PIO in male rats. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. The integration of acetic acid iontophoresis, orthotic therapy and physical rehabilitation for chronic plantar fasciitis: a case study

    PubMed Central

    Costa, Ivano A; Dyson, Anita

    2007-01-01

    A 15-year-old female soccer player presented with chronic plantar fasciitis. She was treated with acetic acid iontophoresis and a combination of rehabilitation protocols, ultrasound, athletic taping, custom orthotics and soft tissue therapies with symptom resolution and return to full activities within a period of 6 weeks. She reported no significant return of symptoms post follow-up at 2 months. Acetic acid iontophoresis has shown promising results and further studies should be considered to determine clinical effectiveness. The combination of acetic acid iontophoresis with conservative treatments may promote recovery within a shorter duration compared to the use of one-method treatment approaches. PMID:17885679

  14. Linoleic acid-menthyl ester reduces the secretion of apolipoprotein B100 in HepG2 cells.

    PubMed

    Inoue, Nao; Yamano, Naomi; Sakata, Kotaro; Arao, Keisuke; Kobayashi, Takashi; Nagao, Toshihiro; Shimada, Yuji; Nagao, Koji; Yanagita, Teruyoshi

    2009-01-01

    The effect of linoleic acid-menthyl ester (LAME) on lipid metabolism were assessed in HepG2 cells. It is well known that high level of apolipoprotein (apo) B100 in the serum is risk for atherosclerosis. Although linoleic acid (LA) treatment and LA plus L-mentol treatment increased apo B100 secretion, LAME treatment significantly decreased apo B100 secretion in HepG2 cells compared with control medium. The hypolipidemic effect of LAME was attributable to the suppression of triglyceride synthesis in HepG2 cells. It is also known that the risk of coronary heart disease is negatively related to the concentration of serum apo A-1. In the present study, LAME treatment increased apo A-1 secretion as compared with LA treatment in HepG2 cells. These results suggest that mentyl-esterification of fatty acids may be beneficial in anti-atherogenic dietary therapy.

  15. Discounting the duration of bolus exposure in impedance testing underestimates acid reflux.

    PubMed

    Vikneswaran, Namasivayam; Murray, Joseph A

    2016-06-08

    Combined impedance-pH testing (MII) allows for detection of reflux episodes regardless of pH. However impedance-based diagnosis of reflux may not routinely account for duration of the reflux episode. We hypothesize that impedance testing may be less sensitive than pH-testing in detecting acid reflux off therapy as a result of discounting duration of exposure. Baseline characteristics and reflux parameters of MII studies performed off-anti-secretory medications were analyzed. Studies on acid suppressive medication and those with recording times less than 20 h or low baseline impedance were excluded. A total of 73 consecutive MII studies were analyzed of which 31 MII studies had elevated acid exposure while 16 were abnormal by impedance criteria. MII testing off-therapy was more likely to be abnormal by pH criteria (percent time pH < 4) than impedance criteria (total reflux):[42 vs 22 % (p =0.02)]. Acid exposure (percent time pH < 4) identified more studies as abnormal than MII-detected acid reflux episodes [42 vs 34 % (p < 0.01)]. Mean acid clearance time (pH-detected) was significantly longer than median bolus clearance time (impedance-detected) in the total [98.7 s vs 12.6 s (p < 0.01)], upright [58.6 s vs 13.1 s (p < 0.01)], and recumbent positions [136.7 s vs 14.2 s (p < 0.01)] with the greatest difference seen in the recumbent position. The mean ratio of mean acid clearance time (pH-detected) and the median bolus clearance time (impedance-detected) was significantly higher in the recumbent position compared to the upright position [11. vs 5.3 (p = 0.01)]. Ambulatory impedance testing underestimates acid reflux compared to esophageal acid exposure by discounting the prolonged period of mucosal contact with each acid reflux episode, particularly in the recumbent position.

  16. Ghrelin-mediated sympathoinhibition and suppression of inflammation in sepsis

    PubMed Central

    Cheyuo, Cletus; Jacob, Asha

    2012-01-01

    Sepsis, a systemic inflammatory response to infection, continues to carry a high mortality despite advances in critical care medicine. Elevated sympathetic nerve activity in sepsis has been shown to contribute to early hepatocellular dysfunction and subsequently multiple organ failure, resulting in a poor prognosis, especially in the elderly. Thus, suppression of sympathetic nerve activity represents a novel therapeutic option for sepsis. Ghrelin is a 28-amino acid peptide shown to inhibit sympathetic nerve activity and inflammation in animal models of tissue injury. Age-related ghrelin hyporesponsiveness has also been shown to exacerbate sepsis. However, the mechanistic relationship between ghrelin-mediated sympathoinhibition and suppression of inflammation remains poorly understood. This review assesses the therapeutic potential of ghrelin in sepsis in the context of the neuroanatomical and molecular basis of ghrelin-mediated suppression of inflammation through inhibition of central sympathetic outflow. PMID:22068604

  17. Symptomless endophytic fungi suppress endogenous levels of salicylic acid and interact with the jasmonate-dependent indirect defense traits of their host, lima bean (Phaseolus lunatus).

    PubMed

    Navarro-Meléndez, Ariana L; Heil, Martin

    2014-07-01

    Symptomless ‘type II’ fungal endophytes colonize their plant host horizontally and exert diverse effects on its resistance phenotype. Here, we used wild Lima bean (Phaseolus lunatus) plants that were experimentally colonized with one of three strains of natural endophytes (Bartalinia pondoensis, Fusarium sp., or Cochliobolus lunatus) to investigate the effects of fungal colonization on the endogenous levels of salicylic acid (SA) and jasmonic acid (JA) and on two JA-dependent indirect defense traits. Colonization with Fusarium sp. enhanced JA levels in intact leaves, whereas B. pondoensis suppressed the induction of endogenous JA in mechanically damaged leaves. Endogenous SA levels in intact leaves were significantly decreased by all strains and B. pondoensis and Fusarium sp. decreased SA levels after mechanical damage. Colonization with Fusarium sp. or C. lunatus enhanced the number of detectable volatile organic compounds (VOCs) emitted from intact leaves, and all three strains enhanced the relative amount of several VOCs emitted from intact leaves as well as the number of detectable VOCs emitted from slightly damaged leaves. All three strains completely suppressed the induced secretion of extrafloral nectar (EFN) after the exogenous application of JA. Symptomless endophytes interact in complex and strain-specific ways with the endogenous levels of SA and JA and with the defense traits that are controlled by these hormones. These interactions can occur both upstream and downstream of the defense hormones.

  18. Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

    PubMed

    Qiao, Han; Wang, Ting-yu; Yan, Wei; Qin, An; Fan, Qi-ming; Han, Xiu-guo; Wang, Yu-gang; Tang, Ting-ting

    2015-09-01

    Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro. Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined. PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 μmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2. Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

  19. Advancing nutritional therapy: A novel polymeric formulation attenuates intestinal inflammation in a murine colitis model and suppresses pro-inflammatory cytokine production in ex-vivo cultured inflamed colonic biopsies.

    PubMed

    Alhagamhmad, Moftah H; Lemberg, Daniel A; Day, Andrew S; Tan, Li-Zsa; Ooi, Chee Y; Krishnan, Usha; Gupta, Nitin; Munday, John S; Leach, Steven T

    2017-04-01

    Nutritional therapy is a viable therapeutic option for the treatment of Crohn disease (CD). Therefore improving nutritional therapy would greatly benefit CD patients. The aim of this study was to define the anti-inflammatory properties of a novel nutritional polymeric formula (PF) in comparison to a currently available standard PF. Dextran sodium sulfate (DSS) was utilized to induce colitis in C57BL/6 mice with mice randomized to receive either standard PF or novel PF in addition to control groups. Changes in body weight were recorded and colonic damage was assessed histologically and biochemically. Additional experiments were also included where the cytokine response of colonic biopsies from pediatric CD patients was measured following exposure to standard PF or novel PF. DSS induced significant body weight loss, morphological changes in the colon, increased myeloperoxidase (MPO) activity and up-regulated colonic mRNA expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12 and monocyte chemoattractant protein (MCP)-1, as well as associated histological changes. Other than histological damage, these inflammatory changes were reversed by both novel and standard PF. However, the novel PF, but not standard PF, completely suppressed TNF-α, IL-6 and IL-8 levels from cultured biopsies. Newly developed nutritional formula reproducibly ameliorated DSS-induced colitis in a murine model, although this response was not measurably different to standard PF. However, the novel PF was significantly superior in suppressing inflammatory cytokine release from cultured colonic biopsies. Collectively, these findings support a possible role for novel PF in advancing nutritional therapy for CD patients. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  20. Gallic acid-capped gold nanoparticles inhibit EGF-induced MMP-9 expression through suppression of p300 stabilization and NFκB/c-Jun activation in breast cancer MDA-MB-231 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chen, Ying-Jung; Lee, Yuan-Chin; Huang, Chia-Hui

    Triple-negative breast cancers (TNBCs) are highly invasive and have a higher rate of distant metastasis. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in EGF/EGFR-mediated malignant progression and metastasis of TNBCs. Various studies have revealed that treatment with gallic acid down-regulates MMP-9 expression in cancer cells, and that conjugation of phytochemical compounds with gold nanoparticles (AuNPs) increases the anti-tumor activity of the phytochemical compounds. Thus, the effect of gallic acid-capped AuNPs (GA-AuNPs) on MMP-9 expression in EGF-treated TNBC MDA-MB-231 cells was analyzed in the present study. The so-called green synthesis of AuNPs by means of gallic acid was performed at pHmore » 10, and the resulting GA-AuNPs had spherical shape with an average diameter of approximately 50 nm. GA-AuNPs notably suppressed migration and invasion of EGF-treated cells, and inhibited EGF-induced MMP-9 up-regulation. GA-AuNPs abrogated EGF-induced Akt/p65 and ERK/c-Jun phosphorylation, leading to down-regulation of MMP-9 mRNA and protein expression in EGF-treated cells. Meanwhile, EGF-induced p300 stabilization was found to be involved in MMP-9 expression, whereas GA-AuNPs inhibited the EGF-promoted stability of the p300 protein. Although GA-AuNPs and gallic acid suppressed EGF-induced MMP-9 up-regulation via the same signaling pathway, the effective concentration of gallic acid was approximately 100-fold higher than that of GA-AuNPs for inhibition of MMP-9 expression in EGF-treated cells to a similar extent. Collectively, our data indicate that, in comparison with gallic acid, GA-AuNPs have a superior ability to inhibit EGF/EGFR-mediated MMP-9 expression in TNBC MDA-MB-231 cells. Our findings also point to a way to improve the anti-tumor activity of gallic acid. - Highlights: • Gallic acid-capped gold nanoparticles inhibit EGF-induced MMP-9 expression. • EGF-induced MMP-9 expression via p300 stabilization and NFκB/c-Jun activation. • Gallic

  1. Signal enhancement for gradient reverse-phase high-performance liquid chromatography-electrospray ionization mass spectrometry analysis with trifluoroacetic and other strong acid modifiers by postcolumn addition of propionic acid and isopropanol.

    PubMed

    Kuhlmann, F E; Apffel, A; Fischer, S M; Goldberg, G; Goodley, P C

    1995-12-01

    Trifluoroacetic acid (TFA) and other volatile strong acids, used as modifiers in reverse-phase high-performance liquid chromatography, cause signal suppression for basic compounds when analyzed by electrospray ionization mass spectrometry (ESI-MS). Evidence is presented that signal suppression is caused by strong ion pairing between the TFA anion and the protonated sample cation of basic sample molecules. The ion-pairing process "masks" the protonated sample cations from the ESI-MS electric fields by rendering them "neutral. " Weakly basic molecules are not suppressed by this process. The TFA signal suppression effect is independent from the well-known spray problem that electrospray has with highly aqueous solutions that contain TFA. This previously reported spray problem is caused by the high conductivity and surface tension of aqueous TFA solutions. A practical method to enhance the signal for most basic analytes in the presence of signal-suppressing volatile strong acids has been developed. The method employs postcolumn addition of a solution of 75% propionic acid and 25% isopropanol in a ratio 1:2 to the column flow. Signal enhancement is typically 10-50 times for peptides and other small basic molecules. Thus, peptide maps that use ESI-MS for detection can be performed at lower levels, with conventional columns, without the need to use capillary chromatography or reduced mass spectral resolution to achieve satisfactory sensitivity. The method may be used with similar results for heptafluorobutyric acid and hydrochloric acid. A mechanism for TFA signal suppression and signal enhancement by the foregoing method, is proposed.

  2. Effectors from Wheat Rust Fungi Suppress Multiple Plant Defense Responses.

    PubMed

    Ramachandran, Sowmya R; Yin, Chuntao; Kud, Joanna; Tanaka, Kiwamu; Mahoney, Aaron K; Xiao, Fangming; Hulbert, Scot H

    2017-01-01

    Fungi that cause cereal rust diseases (genus Puccinia) are important pathogens of wheat globally. Upon infection, the fungus secretes a number of effector proteins. Although a large repository of putative effectors has been predicted using bioinformatic pipelines, the lack of available high-throughput effector screening systems has limited functional studies on these proteins. In this study, we mined the available transcriptomes of Puccinia graminis and P. striiformis to look for potential effectors that suppress host hypersensitive response (HR). Twenty small (<300 amino acids), secreted proteins, with no predicted functions were selected for the HR suppression assay using Nicotiana benthamiana, in which each of the proteins were transiently expressed and evaluated for their ability to suppress HR caused by four cytotoxic effector-R gene combinations (Cp/Rx, ATR13/RPP13, Rpt2/RPS-2, and GPA/RBP-1) and one mutated R gene-Pto(Y207D). Nine out of twenty proteins, designated Shr1 to Shr9 (suppressors of hypersensitive response), were found to suppress HR in N. benthamiana. These effectors varied in the effector-R gene defenses they suppressed, indicating these pathogens can interfere with a variety of host defense pathways. In addition to HR suppression, effector Shr7 also suppressed PAMP-triggered immune response triggered by flg22. Finally, delivery of Shr7 through Pseudomonas fluorescens EtHAn suppressed nonspecific HR induced by Pseudomonas syringae DC3000 in wheat, confirming its activity in a homologous system. Overall, this study provides the first evidence for the presence of effectors in Puccinia species suppressing multiple plant defense responses.

  3. Local anaesthetic 5-aminolaeuvulinic acid photodynamic therapy in the treatment of superficial bladder cancer

    NASA Astrophysics Data System (ADS)

    Shackley, David C.

    The aim of this thesis was to study aspects of the treatment of superficial bladder carcinoma using photodynamic therapy by combining the delivery of laser light energy with the photosensitiser 5-aminolaeuvulinic acid (ALA). ALA is a novel pro-drug, which can be absorbed intravesically where it is converted in diseased urothelium and tumour to the active photosensitiser, PpK. Following whole bladder light irradiation there is release of toxic radicals, which are scavenged by oxygen causing selective necrosis (PDT). Preliminary studies on animals suggest that ALA is superior to earlier bladder PDT sensitisers in that generalised photosensitivity and bladder contracture are avoided. These problems in conjunction with the complexity of PDT whereby a general anaesthetic with rigid cystoscopy under continuous irrigation are required, have previously limited the development of this modality as a practical therapy. (Abstract shortened by ProQuest.).

  4. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy.

    PubMed

    Yarla, Nagendra Sastry; Bishayee, Anupam; Sethi, Gautam; Reddanna, Pallu; Kalle, Arunasree M; Dhananjaya, Bhadrapura Lakkappa; Dowluru, Kaladhar S V G K; Chintala, Ramakrishna; Duddukuri, Govinda Rao

    2016-10-01

    Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A 2 s (PLA 2 s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA 2 s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Combined Therapy with Rheum tanguticum Polysaccharide and Low-dose 5-ASA Ameliorates TNBS-Induced Colitis in Rats by Suppression of NF-κB.

    PubMed

    Liu, Linna; Liu, Zhenxiong; Zhang, Tian; Shi, Lei; Zhang, Wenjuan; Zhang, Yan

    2015-06-01

    The most common conventional therapy for inflammatory bowel disease in clinical practice involves the use of nonsteroidal anti-inflammatory drugs, such as 5-amino salicylic acid. However, a high dose of 5-amino salicylic acid may bring about severe side effects. Chinese people have used Rheum tanguticum as a folk remedy for gastrointestinal disease for two thousand years. Our group has isolated R. tanguticum polysaccharide 1 from R. tanguticum and verified that it can attenuate 2,4,6-trinitrobenzene sulfonic acid-induced colitis in murines/rats. The present study aims to evaluate whether the addition of R. tanguticum polysaccharide 1 can improve efficacy and limit subsequent side effects of conventional treatment (5-amino salicylic acid) in rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Sixty Sprague-Dawley male rats were randomized into five groups and treated with (1) saline (saline, 0.2 mL/day × 5, p. o.), (2) 2,4,6-trinitrobenzene sulfonic acid alone (saline, 0.2 mL/day × 5, p. o.), (3) 2,4,6-trinitrobenzene sulfonic acid + 5-amino salicylic acid (5-amino salicylic acid, 75 mg/kg/day × 5, p.o), (4) 2,4,6-trinitrobenzene sulfonic acid + R. tanguticum polysaccharide 1 (R. tanguticum polysaccharide 1, 200 mg/kg/day × 5, p. o.), and (5) 2,4,6-trinitrobenzene sulfonic acid + 5-amino salicylic acid + R. tanguticum polysaccharide 1 (5-amino salicylic acid, 25 mg/kg/day × 5, p.o; R. tanguticum polysaccharide 1, 200 mg/kg/day × 5, p. o.). All the rats were sacrificed on the 6th day after treatment using an overdose of anesthesia. A histological assessment was performed using semiquantitative scores; nuclear factor-kappa B and tumor necrosis factor-α were measured with Western blot, cyclooxygenase 1 and cyclooxygenase 2 protein expressions were investigated by RT-polymerase chain reaction, and prostoglandin E2 and inducible nitric oxide synthase productions were investigated by ELISA. The extent and

  6. Randomized, Controlled Trial of Therapy Interruption in Chronic HIV-1 Infection

    PubMed Central

    Papasavvas, Emmanouil; Kostman, Jay R; Mounzer, Karam; Grant, Robert M; Gross, Robert; Gallo, Cele; Azzoni, Livio; Foulkes, Andrea; Thiel, Brian; Pistilli, Maxwell; Mackiewicz, Agnieszka; Shull, Jane; Montaner, Luis J

    2004-01-01

    Background Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms. Methods and Findings Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1–8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4–8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen. Conclusion Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off

  7. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment

    PubMed Central

    Prasad, Sahdeo; Yadav, Vivek R.; Sung, Bokyung; Gupta, Subash C.; Tyagi, Amit K.; Aggarwal, Bharat B.

    2016-01-01

    The development of chemoresistance in human pancreatic cancer is one reason for the poor survival rate for patients with this cancer. Because multiple gene products are linked with chemoresistance, we investigated the ability of ursolic acid (UA) to sensitize pancreatic cancer cells to gemcitabine, a standard drug used for the treatment of pancreatic cancer. These investigations were done in AsPC-1, MIA PaCa-2, and Panc-28 cells and in nude mice orthotopically implanted with Panc-28 cells. In vitro, UA inhibited proliferation, induced apoptosis, suppressed NF-κB activation and its regulated proliferative, metastatic, and angiogenic proteins. UA (20 μM) also enhanced gemcitabine (200 nM)-induced apoptosis and suppressed the expression of NF-κB-regulated proteins. In the nude mouse model, oral administration of UA (250 mg/kg) suppressed tumor growth and enhanced the effect of gemcitabine (25 mg/kg). Furthermore, the combination of UA and gemcitabine suppressed the metastasis of cancer cells to distant organs such as liver and spleen. Immunohistochemical analysis showed that biomarkers of proliferation (Ki-67) and microvessel density (CD31) were suppressed by the combination of UA and gemcitabine. UA inhibited the activation of NF-κB and STAT3 and the expression of tumorigenic proteins regulated by these inflammatory transcription factors in tumor tissue. Furthermore, the combination of two agents decreased the expression of miR-29a, closely linked with tumorigenesis, in the tumor tissue. UA was found to be bioavailable in animal serum and tumor tissue. These results suggest that UA can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing inflammatory biomarkers linked to proliferation, invasion, angiogenesis, and metastasis. PMID:26909608

  8. Photodynamic therapy with 5-aminoolevulinic acid-induced porphyrins and DMSO/EDTA for basal cell carcinoma

    NASA Astrophysics Data System (ADS)

    Warloe, Trond; Peng, Qian; Heyerdahl, Helen; Moan, Johan; Steen, Harald B.; Giercksky, Karl-Erik

    1995-03-01

    Seven hundred sixty three basal cell carcinomas (BCCs) in 122 patients were treated by photodynamic therapy by 5-aminolevulinic acid (ALA) in cream topically applied, either alone, in combination with dimethyl sulphoxide (DMSO) and ethylenediaminetetraacetic acid disodium salt (EDTA), or with DMSO as a pretreatment. After 3 hours cream exposure 40 - 200 Joules/cm2 of 630 nm laser light was given. Fluorescence imaging of biopsies showed highly improved ALA penetration depth and doubled ALA-induced porphyrin production using DMSO/EDTA. Treatment response was recorded after 3 months. After a single treatment 90% of 393 superficial lesions responded completely, independent of using DMSO/EDTA. In 363 nodulo-ulcerative lesions the complete response rate increased from 67% to above 90% with DMSO/EDTA for lesions less than 2 mm thickness and from 34% to about 50% for lesions thicker than 2 mm. Recurrence rate observed during a follow-up period longer than 12 months was 2 - 5%. PDT of superficial thin BCCs with ALA-induced porphyrins and DMSO/EDTA equals surgery and radiotherapy with respect to cure rate and recurrence. Cosmetic results of ALA-based PDT seemed to be better than those after other therapies. In patients with the nevoid BCC syndrome the complete response rate after PDT was far lower.

  9. Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy.

    PubMed

    Yoo, Wooyoung; Yoo, Donghyuck; Hong, Eunmi; Jung, Eunkyeong; Go, Yebin; Singh, S V Berwin; Khang, Gilson; Lee, Dongwon

    2018-01-10

    Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide-based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde-conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid-cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid-triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT-loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Gallic acid-capped gold nanoparticles inhibit EGF-induced MMP-9 expression through suppression of p300 stabilization and NFκB/c-Jun activation in breast cancer MDA-MB-231 cells.

    PubMed

    Chen, Ying-Jung; Lee, Yuan-Chin; Huang, Chia-Hui; Chang, Long-Sen

    2016-11-01

    Triple-negative breast cancers (TNBCs) are highly invasive and have a higher rate of distant metastasis. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in EGF/EGFR-mediated malignant progression and metastasis of TNBCs. Various studies have revealed that treatment with gallic acid down-regulates MMP-9 expression in cancer cells, and that conjugation of phytochemical compounds with gold nanoparticles (AuNPs) increases the anti-tumor activity of the phytochemical compounds. Thus, the effect of gallic acid-capped AuNPs (GA-AuNPs) on MMP-9 expression in EGF-treated TNBC MDA-MB-231 cells was analyzed in the present study. The so-called green synthesis of AuNPs by means of gallic acid was performed at pH10, and the resulting GA-AuNPs had spherical shape with an average diameter of approximately 50nm. GA-AuNPs notably suppressed migration and invasion of EGF-treated cells, and inhibited EGF-induced MMP-9 up-regulation. GA-AuNPs abrogated EGF-induced Akt/p65 and ERK/c-Jun phosphorylation, leading to down-regulation of MMP-9 mRNA and protein expression in EGF-treated cells. Meanwhile, EGF-induced p300 stabilization was found to be involved in MMP-9 expression, whereas GA-AuNPs inhibited the EGF-promoted stability of the p300 protein. Although GA-AuNPs and gallic acid suppressed EGF-induced MMP-9 up-regulation via the same signaling pathway, the effective concentration of gallic acid was approximately 100-fold higher than that of GA-AuNPs for inhibition of MMP-9 expression in EGF-treated cells to a similar extent. Collectively, our data indicate that, in comparison with gallic acid, GA-AuNPs have a superior ability to inhibit EGF/EGFR-mediated MMP-9 expression in TNBC MDA-MB-231 cells. Our findings also point to a way to improve the anti-tumor activity of gallic acid. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Same-day antiretroviral therapy (ART) initiation in pregnancy is not associated with viral suppression or engagement in care: A cohort study.

    PubMed

    Langwenya, Nontokozo; Phillips, Tamsin K; Brittain, Kirsty; Zerbe, Allison; Abrams, Elaine J; Myer, Landon

    2018-06-01

    Many prevention of mother-to-child HIV transmission programmes across Africa initiate HIV-infected (HIV positive) pregnant women on lifelong antiretroviral therapy (ART) on the first day of antenatal care ("same-day" initiation). However, there are concerns that same-day initiation may limit patient preparation before starting ART and contribute to subsequent non-adherence, disengagement from care and raised viral load. We examined if same-day initiation was associated with viral suppression and engagement in care during pregnancy. Consecutive ART-eligible pregnant women making their first antenatal care (ANC) visit at a primary care facility in Cape Town, South Africa were enrolled into a prospective cohort between March 2013 and June 2014. Before July 2013, ART eligibility was based on CD4 cell count ≤350 cells/μL ("Option A"), with a 1 to 2 week delay from the first ANC visit to ART initiation for patient preparation; thereafter all women were eligible regardless of CD4 cell count ("Option B+") and offered ART on the same day as first ANC visit. Women were followed with viral load testing conducted separately from routine ART services, and engagement in ART services was measured using routinely collected clinic, pharmacy and laboratory records through 12 months postpartum. Among 628 HIV-positive women (median age, 28 years; median gestation at ART start, 21 weeks; 55% newly diagnosed with HIV), 73% initiated ART same-day; this proportion was higher under Option B+ versus Option A (85% vs. 20%). Levels of viral suppression (viral load <50 copies/mL) at delivery (74% vs. 82%) and 12 months postpartum (74% vs. 71%) were similar under same-day versus delayed initiation respectively. Findings were consistent when viral suppression was defined at <1000 copies/mL, after adjustment for demographic/clinical measures and across subgroups of age, CD4 and timing of HIV diagnosis. Time to first viral rebound following initial suppression did not differ by timing

  12. Correcting intermittent central suppression improves binocular marksmanship.

    PubMed

    Hussey, Eric S

    2007-04-01

    Intermittent central suppression (ICS) is a defect in normal binocular (two-eyed) vision that causes confusion in visual detail. ICS is a repetitive intermittent loss of visual sensation in the central area of vision. As the central vision of either eye "turns on and off", aiming errors in sight can occur that must be corrected when both eyes are seeing again. Any aiming errors in sight might be expected to interfere with marksmanship during two-eyed seeing. We compared monocular (one-eyed, patched) and binocular (two-eyed) marksmanship with pistol shooting with an Army ROTC cadet before and after successful therapy for diagnosed ICS. Pretreatment, monocular marksmanship was significantly better than binocular marksmanship, suggesting defective binocularity reduced accuracy. After treatment for ICS, binocular and monocular marksmanship were essentially the same. Results confirmed predictions that with increased visual stability from correcting the suppression, binocular and monocular marksmanship accuracies should merge.

  13. 10 Hz Amplitude Modulated Sounds Induce Short-Term Tinnitus Suppression

    PubMed Central

    Neff, Patrick; Michels, Jakob; Meyer, Martin; Schecklmann, Martin; Langguth, Berthold; Schlee, Winfried

    2017-01-01

    Objectives: Acoustic stimulation or sound therapy is proposed as a main treatment option for chronic subjective tinnitus. To further probe the field of acoustic stimulations for tinnitus therapy, this exploratory study compared 10 Hz amplitude modulated (AM) sounds (two pure tones, noise, music, and frequency modulated (FM) sounds) and unmodulated sounds (pure tone, noise) regarding their temporary suppression of tinnitus loudness. First, it was hypothesized that modulated sounds elicit larger temporary loudness suppression (residual inhibition) than unmodulated sounds. Second, with manipulation of stimulus loudness and duration of the modulated sounds weaker or stronger effects of loudness suppression were expected, respectively. Methods: We recruited 29 participants with chronic tonal tinnitus from the multidisciplinary Tinnitus Clinic of the University of Regensburg. Participants underwent audiometric, psychometric and tinnitus pitch matching assessments followed by an acoustic stimulation experiment with a tinnitus loudness growth paradigm. In a first block participants were stimulated with all of the sounds for 3 min each and rated their subjective tinnitus loudness to the pre-stimulus loudness every 30 s after stimulus offset. The same procedure was deployed in the second block with the pure tone AM stimuli matched to the tinnitus frequency, manipulated in length (6 min), and loudness (reduced by 30 dB and linear fade out). Repeated measures mixed model analyses of variance (ANOVA) were calculated to assess differences in loudness growth between the stimuli for each block separately. Results: First, we found that all sounds elicit a short-term suppression of tinnitus loudness (seconds to minutes) with strongest suppression right after stimulus offset [F(6, 1331) = 3.74, p < 0.01]. Second, similar to previous findings we found that AM sounds near the tinnitus frequency produce significantly stronger tinnitus loudness suppression than noise [vs. Pink noise: t

  14. Use of a three-color chromosome in situ suppression technique for the detection of past radiation exposure

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gebhart, E.; Neubauer, S.; Schmitt, G.

    1996-01-01

    A three-color chromosome in situ suppression technique and classical cytogenetic analysis were compared for the detection of chromosomal aberrations in blood lymphocytes of 27 patients who had undergone radiation therapies from 1 month to 9 years ago. Depending on the respective regimens of therapy, a high variability was found in the aberration data. Aberration rates depended on the interval between exposure and scoring rather than on the locally applied radiation doses, which were rather uniform among most patients. Chromosome in situ suppression was found to be superior to classical cytogenetics with respect not only to the spectrum of detectable aberrationsmore » but also to the uncovering of long-term effects of irradiation. Of particular interest were the relative stability of the frequency of radiation-induced reciprocal translocations and the utility of chromosome in situ suppression to uncover complex rearrangements. 27 refs., 4 figs.« less

  15. Knockdown of acid-sensing ion channel 1a (ASIC1a) suppresses disease phenotype in SCA1 mouse model.

    PubMed

    Vig, Parminder J S; Hearst, Scoty M; Shao, Qingmei; Lopez, Maripar E

    2014-08-01

    The mutated ataxin-1 protein in spinocerebellar ataxia 1 (SCA1) targets Purkinje cells (PCs) of the cerebellum and causes progressive ataxia due to loss of PCs and neurons of the brainstem. The exact mechanism of this cellular loss is still not clear. Currently, there are no treatments for SCA1; however, understanding of the mechanisms that regulate SCA1 pathology is essential for devising new therapies for SCA1 patients. We previously established a connection between the loss of intracellular calcium-buffering and calcium-signalling proteins with initiation of neurodegeneration in SCA1 transgenic (Tg) mice. Recently, acid-sensing ion channel 1a (ASIC1a) have been implicated in calcium-mediated toxicity in many brain disorders. Here, we report generating SCA1 Tg mice in the ASIC1a knockout (KO) background and demonstrate that the deletion of ASIC1a gene expression causes suppression of the SCA1 disease phenotype. Loss of the ASIC1a channel in SCA1/ASIC1a KO mice resulted in the improvement of motor deficit and decreased PC degeneration. Interestingly, the expression of the ASIC1 variant, ASIC1b, was upregulated in the cerebellum of both SCA1/ASIC1a KO and ASIC1a KO animals as compared to the wild-type (WT) and SCA1 Tg mice. Further, these SCA1/ASIC1a KO mice exhibited translocation of PC calcium-binding protein calbindin-D28k from the nucleus to the cytosol in young animals, which otherwise have both cytosolic and nuclear localization. Furthermore, in addition to higher expression of calcium-buffering protein parvalbumin, PCs of the older SCA1/ASIC1a KO mice showed a decrease in morphologic abnormalities as compared to the age-matched SCA1 animals. Our data suggest that ASIC1a may be a mediator of SCA1 pathogenesis and targeting ASIC1a could be a novel approach to treat SCA1.

  16. [GnRH-agonists in the therapy of endometriosis].

    PubMed

    Hoffmann, G; Spitz, J; Behrens, R

    1990-12-01

    Repeated application of GnRH agonists causes a reversible suppression of ovarian function. Suppression on estrogen release is the fundamental idea of this hormonal therapy of endometriosis. We treated twelve patients with histologically proved endometriosis with leuprolide acetate depot in a dose of 3.75 mg s.c. every 4 weeks over a period of 6 months. In the first week of therapy the estrogen level decreased to a post-menopausal niveau along with amenorrhoea during the entire period of therapy. Complaints previous to therapy such as dysmenorrhoea, pelvic pain and dyspareunia were relieved or completely disappeared after therapy. The clinical finding on palpation also diminished or disappeared. In addition to this finding pelvis copy showed a shift from severe endometriosis stage III and stage IV to stage I and stage II of the AFS classification 1985. Regular menstruation appeared in 5 to 9 weeks after the last application to all patients. Out of six cases of infertility, four patients became pregnant. Except for one case, typical menopausal symptoms appeared, such as flush, increased perspiration and sleeping disorders. During and after therapy we could not prove any changes in the lipid metabolism under estrogen therapy. Mineralization of the bone decreased under therapy by about 3%. Simultaneously, serum osteocalcin increased. Demineralization occurred with one exception within the normal range for the corresponding age. With identical efficiency but less side effects, we see therapy with GnRH agonists as an alternative to current hormonal therapy of endometriosis.

  17. Brief Report: Soluble CD163 in CMV-Infected and CMV-Uninfected Subjects on Virologically Suppressive Antiretroviral Therapy in the ICONA Cohort.

    PubMed

    Vita, Serena; Lichtner, Miriam; Marchetti, Giulia; Mascia, Claudia; Merlini, Esther; Cicconi, Paola; Vullo, Vincenzo; Viale, Pierluigi; Costantini, Andrea; DʼArminio Monforte, Antonella

    2017-03-01

    To contribute to the understanding of the role played by cytomegalovirus (CMV) in sustaining monocyte/macrophage-mediated immune activation in antiretroviral therapy treated HIV-infected subjects. We selected 23 CMV-uninfected and 46 CMV-infected HIV+ subjects, matched for age, CD4 nadir, HIV infection duration, and viral hepatitis serostatus. All subjects were on successful antiretroviral therapy since at least 1 year. A group of 16 healthy donors with similar age and sex was also included. Plasma levels of tumor necrosis factor-alpha, interleukin-6, sCD163, sCD14, and CMV immunoglobulin G levels were measured in duplicate with human enzyme-linked immunosorbent assay kits. We found significantly higher sCD163 plasma levels in HIV+CMV+ compared with HIV+CMV- subjects and healthy donors. This augmentation was confirmed also when subjects positive for hepatitis C virus-Ab were excluded from analysis. Interestingly, a correlation between anti-CMV immunoglobulin G levels and sCD163, tumor necrosis factor-alpha, interleukin-6, and sCD14 in HIV+CMV+ subjects was found. CMV coinfection could be a major driver of monocyte/macrophage activation in virally suppressed HIV+ individuals and might explain the increased risk of non-AIDS morbidity/mortality in HIV/CMV-coinfected subjects.

  18. Chalcones suppress fatty acid-induced lipid accumulation through a LKB1/AMPK signaling pathway in HepG2 cells.

    PubMed

    Zhang, Tianshun; Yamamoto, Norio; Ashida, Hitoshi

    2014-06-01

    Excessive lipid accumulation in the liver has been proposed to cause hyperlipidemia, diabetes and fatty liver disease. 4-Hydroxyderricin (4HD), xanthoangelol (XAG), cardamonin (CAR) and flavokawain B (FKB) are chalcones that have exhibited various biological effects against obesity, inflammation, and diabetes; however, little is known about the inhibitory effects of these chalcones on fatty liver disease. In the present study, we investigated the ability of 4HD, XAG, CAR, and FKB to reduce lipid accumulation in hepatocytes. When HepG2 cells were treated with a mixture of fatty acids (FAs; palmitic acid : oleic acid = 1 : 2 ratio), significant lipid accumulation was observed. Under the same experimental conditions, addition of chalcones at 5 μM significantly suppressed the FA-induced lipid accumulation. We found that the expression of sterol regulatory element-binding protein-1 (SREBP-1), a key molecule involved in lipogenesis, was decreased in these chalcone-treated cells. We also found that these chalcones increased the expression of peroxisome proliferator-activated receptor α (PPARα), which is involved in FA oxidation. Moreover, these chalcones increased phosphorylation of AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1), upstream regulators of SREBP-1 and PPARα. We confirmed that an AMPK inhibitor, compound C, reversed chalcone-induced changes in SREBP-1 and PPARα expression in the HepG2 cells. Collectively, we found that 4HD, XAG, CAR, and XAG attenuated lipid accumulation through activation of the LKB1/AMPK signaling pathway in HepG2 cells.

  19. Adaptive therapy.

    PubMed

    Gatenby, Robert A; Silva, Ariosto S; Gillies, Robert J; Frieden, B Roy

    2009-06-01

    A number of successful systemic therapies are available for treatment of disseminated cancers. However, tumor response is often transient, and therapy frequently fails due to emergence of resistant populations. The latter reflects the temporal and spatial heterogeneity of the tumor microenvironment as well as the evolutionary capacity of cancer phenotypes to adapt to therapeutic perturbations. Although cancers are highly dynamic systems, cancer therapy is typically administered according to a fixed, linear protocol. Here we examine an adaptive therapeutic approach that evolves in response to the temporal and spatial variability of tumor microenvironment and cellular phenotype as well as therapy-induced perturbations. Initial mathematical models find that when resistant phenotypes arise in the untreated tumor, they are typically present in small numbers because they are less fit than the sensitive population. This reflects the "cost" of phenotypic resistance such as additional substrate and energy used to up-regulate xenobiotic metabolism, and therefore not available for proliferation, or the growth inhibitory nature of environments (i.e., ischemia or hypoxia) that confer resistance on phenotypically sensitive cells. Thus, in the Darwinian environment of a cancer, the fitter chemosensitive cells will ordinarily proliferate at the expense of the less fit chemoresistant cells. The models show that, if resistant populations are present before administration of therapy, treatments designed to kill maximum numbers of cancer cells remove this inhibitory effect and actually promote more rapid growth of the resistant populations. We present an alternative approach in which treatment is continuously modulated to achieve a fixed tumor population. The goal of adaptive therapy is to enforce a stable tumor burden by permitting a significant population of chemosensitive cells to survive so that they, in turn, suppress proliferation of the less fit but chemoresistant

  20. Viral/Nonviral Chimeric Nanoparticles to Synergistically Suppress Leukemia Proliferation via Simultaneous Gene Transduction and Silencing

    PubMed Central

    Hong, Cheol Am; Cho, Soo Kyung; Edson, Julius A.; Kim, Jane; Ingato, Dominique; Pham, Bryan; Chuang, Anthony; Fruman, David; Kwon, Young Jik

    2017-01-01

    Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of Chronic Myelogenous Leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic anti-leukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and inter-linked pathological pathways. PMID:27472284

  1. Protective effect of α-lipoic acid against radiation-induced fibrosis in mice

    PubMed Central

    Ryu, Seung-Hee; Park, Eun-Young; Kwak, Sungmin; Heo, Seung-Ho; Ryu, Je-Won; Park, Jin-hong

    2016-01-01

    Radiation-induced fibrosis (RIF) is one of the most common late complications of radiation therapy. We found that α-lipoic acid (α-LA) effectively prevents RIF. In RIF a mouse model, leg contracture assay was used to test the in vivo efficacy of α-LA. α-LA suppressed the expression of pro-fibrotic genes after irradiation, both in vivo and in vitro, and inhibited the up-regulation of TGF-β1-mediated p300/CBP activity. Thus, α-LA prevents radiation-induced fibrosis (RIF) by inhibiting the transcriptional activity of NF-κB through inhibition of histone acetyltransferase activity. α-LA is a new therapeutic methods that can be used in the prevention-treatment of RIF. PMID:26799284

  2. Coagulation Imbalance and Neurocognitive Functioning in Older HIV+ Adults on Suppressive Antiretroviral Therapy

    PubMed Central

    Montoya, Jessica l.; Iudicello, Jennifer; Oppenheim, Hannah A.; Fazeli, Pariya l.; Potter, Michael; MA, Qing; Mills, Paul J.; Ellis, Ronald J.; Grant, Igor; Letendre, Scott l.; Moore, David J.

    2017-01-01

    Objectives To compare plasma biomarkers of coagulation between HIV-infected individuals and HIV-uninfected controls and to assess the impact of disturbances in coagulation on neurocognitive functioning in HIV. Design Cross-sectional study of 66 antiretroviral therapy-treated virally suppressed HIV-infected and 34 HIV-uninfected older (≥50 years of age) adults. Methods Participants completed standardized neurobehavioral and neuromedical assessments. Neurocognitive functioning was evaluated using a well-validated comprehensive neuropsychological battery. Plasma biomarkers associated with procoagulation (fibrinogen, p-selectin, tissue factor, and von Willebrand factor), anticoagulation (antithrombin, protein C, and thrombomodulin), fibrinolysis (d-dimer, plasminogen activator inhibitor-1, and plasminogen) were collected. Multivariable linear regression was used to test the interaction of HIV and coagulation on neurocognitive functioning. Results Most participants were male (78.0%) and non-Hispanic white (73.0%) with a mean age of 57.8 years. Among HIV-infected participants, mean estimated duration of HIV infection was 19.4 years and median current CD4+ cell count was 654 cells/mm3. Levels of soluble biomarkers of procoagulation, anticoagulation, and fibrinolysis were comparable between the HIV serostatus groups. Coagulation and HIV had an interacting effect on neurocognitive functioning, such that greater coagulation imbalance was associated with poorer neurocognitive functioning among the HIV-infected participants. The moderating effect of coagulation on neurocognition was driven by procoagulant but not anticoagulant or fibrinolytic biomarkers. Conclusions Elevated levels of procoagulants may exert a particularly detrimental effect on neurocognitive functioning among older HIV-infected persons. A better understanding of the specific role of coagulation in the etiology of HIV-associated neurocognitive disorders may lead to treatments aimed at reducing coagulopathy

  3. Natural products as potential anticonvulsants: caffeoylquinic acids.

    PubMed

    Kim, Hyo Geun; Oh, Myung Sook

    2012-03-01

    Current anticonvulsant therapies are generally directed at symptomatic treatment by suppressing excitability within the brain. Consequently, they have adverse effects such as cognitive impairment, dependence, and abuse. The need for more effective and less toxic anticonvulsants has generated renewed interest in natural products for the treatment of convulsions. Caffeoylquinic acids (CQs) are naturally occurring phenolic acids that are distributed widely in plants. There has been increasing interest in the biological activities of CQs in diseases of the central nervous system. In this issue, Nugroho et al. give evidence for the anticonvulsive effect of a CQ-rich extract from Aster glehni Franchet et Sckmidt. They optimized the extract solvent conditions, resulting in high levels of CQs and peroxynitrite-scavenging activity. Then, they investigated the sedative and anticonvulsive effects in pentobarbital- and pentylenetetrazole-induced models in mice. The CQ-rich extract significantly inhibited tonic convulsions as assessed by onset time, tonic extent, and mortality. They suggested that the CQ-rich extract from A. glehni has potential for treating convulsions. This report provides preclinical data which may be used for the development of anticonvulsants from natural products.

  4. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Abhilash, P.A.; Harikrishnan, R.; Indira, M., E-mail: indiramadambath@gmail.com

    Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4 g/kg b.wt for 90 days. After 90 days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250 mg/kg b.wt) and AA (250 mg/kg b.wt) supplemented groups and maintained for 30more » days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β{sub 1} and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α{sub 1} (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis. - Highlights: • Alcohol increases intestinal bacterial overgrowth and permeability of endotoxin. • Endotoxin mediated inflammation plays a major role in alcoholic liver fibrosis. • Ascorbic acid reduces endotoxemia, NF-κB activation and proinflammatory cytokines. • AA's action is by inhibition of SIBO, IKKβ and alteration

  5. A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice

    PubMed Central

    Kozy, Heather M.; Lum, Jeremy A.; Sweetwood, Rosemary; Chu, Mabel; Cunningham, Cameron R.; Salamon, Hugh; Lloyd, Clare M.; Coffman, Robert L.; Hessel, Edith M.

    2015-01-01

    Background CpG-containing oligodeoxynucleotides (CpG-ODN) are potent inhibitors of Th2-mediated allergic airway disease in sensitized mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease. Objective To optimize the treatment regimen and determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment. Methods A limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were given to ragweed allergen-sensitized mice chronically exposed to allergen during and after the 1018 ISS treatment regimen. Treatment effects were evaluated by measuring effect on lung Th2 cytokines and eosinophilia as well as lung dendritic cell function and T cell responses. Results Twelve intranasal 1018 ISS treatments induced significant suppression of BAL eosinophilia and IL-4, IL-5, and IL-13 levels and suppression was maintained through 13 weekly ragweed exposures administered after treatment cessation. At least 5 treatments were required for lasting Th2 suppression. CpG-ODN induced moderate Th1 responses but Th2 suppression did not require IFN-γ. Th2 suppression was associated with induction of a regulatory T cell response. Conclusion A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen. PMID:24464743

  6. Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy

    PubMed Central

    Voora, Deepak; Ortel, Thomas L.; Lucas, Joseph E.; Chi, Jen-Tsan; Becker, Richard C.; Ginsburg, Geoffrey S.

    2012-01-01

    Objectives To develop an integrated metric of non COX-1 dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. Background NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. Methods We administered 325mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. Results The PFS strongly correlated with each measure of NCDPF in each cohort. After two or four weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, p<0.0001) and was higher (p < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final - Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = −0.45), HV2 (r = −0.54), DM (r = −0.68), p<0.0001 for all. AAA remained suppressed during aspirin therapy. Conclusions The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time. PMID:22294277

  7. Iso-α-acids, bitter components of beer, prevent obesity-induced cognitive decline.

    PubMed

    Ayabe, Tatsuhiro; Ohya, Rena; Kondo, Keiji; Ano, Yasuhisa

    2018-03-19

    Dementia and cognitive decline have become worldwide public health problems, and it was recently reported that life-style related diseases and obesity are key risk factors in dementia. Iso-α-acids, hop-derived bitter components of beer, have been reported to have various physiological functions via activation of peroxisome proliferator-activated receptor γ. In this report, we demonstrated that daily intake of iso-α-acids suppresses inflammations in the hippocampus and improves cognitive decline induced by high fat diet (HFD). Body weight, epididymal fat weight, and plasma triglyceride levels were increased in HFD-fed mice, and significantly decreased in iso-α-acids supplemented HFD-fed mice. HFD feeding enhances the production of inflammatory cytokines and chemokines, such as TNF-α, which was significantly suppressed by iso-α-acids administration. HFD-induced neuroinflammation caused lipid peroxidation, neuronal loss, and atrophy in hippocampus, and those were not observed in iso-α-acids-treated mice. Furthermore, iso-α-acids intake significantly improved cognitive decline induced by HFD-feeding. Iso-α-acids are food derived components that suppressing both lipid accumulation and brain inflammation, thus iso-α-acids might be beneficial for the risk of dementia increased by obesity and lifestyle-related diseases.

  8. Reliability study of an emerging fire suppression system

    DOE PAGES

    Miller, David A.; Rossati, Lyric M.; Fritz, Nathan K.; ...

    2015-11-01

    Self-contained fire extinguishers are a robust, reliable and minimally invasive means of fire suppression for gloveboxes. Plutonium gloveboxes are known to present harsh environmental conditions for polymer materials, these include radiation damage and chemical exposure, both of which tend to degrade the lifetime of engineered polymer components. The primary component of interest in self-contained fire extinguishers is the nylon 6-6 machined tube that comprises the main body of the system.Thermo-mechanical modeling and characterization of nylon 6-6 for use in plutonium glovebox applications has been carried out. Data has been generated regarding property degradation leading to poor, or reduced, engineering performancemore » of nylon 6-6 components. In this study, nylon 6-6 tensile specimens conforming to the casing of self-contained fire extinguisher systems have been exposed to hydrochloric, nitric, and sulfuric acids. This information was used to predict the performance of a load bearing engineering component comprised of nylon 6-6 and designed to operate in a consistent manner over a specified time period. The study provides a fundamental understanding of the engineering performance of the fire suppression system and the effects of environmental degradation due to acid exposure on engineering performance. Data generated help identify the limitations of self-contained fire extinguishers. No critical areas of concern for plutonium glovebox applications of nylon 6-6 have been identified when considering exposure to mineral acid.« less

  9. Reliability study of an emerging fire suppression system

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miller, David A.; Rossati, Lyric M.; Fritz, Nathan K.

    Self-contained fire extinguishers are a robust, reliable and minimally invasive means of fire suppression for gloveboxes. Plutonium gloveboxes are known to present harsh environmental conditions for polymer materials, these include radiation damage and chemical exposure, both of which tend to degrade the lifetime of engineered polymer components. The primary component of interest in self-contained fire extinguishers is the nylon 6-6 machined tube that comprises the main body of the system.Thermo-mechanical modeling and characterization of nylon 6-6 for use in plutonium glovebox applications has been carried out. Data has been generated regarding property degradation leading to poor, or reduced, engineering performancemore » of nylon 6-6 components. In this study, nylon 6-6 tensile specimens conforming to the casing of self-contained fire extinguisher systems have been exposed to hydrochloric, nitric, and sulfuric acids. This information was used to predict the performance of a load bearing engineering component comprised of nylon 6-6 and designed to operate in a consistent manner over a specified time period. The study provides a fundamental understanding of the engineering performance of the fire suppression system and the effects of environmental degradation due to acid exposure on engineering performance. Data generated help identify the limitations of self-contained fire extinguishers. No critical areas of concern for plutonium glovebox applications of nylon 6-6 have been identified when considering exposure to mineral acid.« less

  10. FolC2-mediated folate metabolism contributes to suppression of inflammation by probiotic Lactobacillus reuteri.

    PubMed

    Thomas, Carissa M; Saulnier, Delphine M A; Spinler, Jennifer K; Hemarajata, Peera; Gao, Chunxu; Jones, Sara E; Grimm, Ashley; Balderas, Miriam A; Burstein, Matthew D; Morra, Christina; Roeth, Daniel; Kalkum, Markus; Versalovic, James

    2016-10-01

    Bacterial-derived compounds from the intestinal microbiome modulate host mucosal immunity. Identification and mechanistic studies of these compounds provide insights into host-microbial mutualism. Specific Lactobacillus reuteri strains suppress production of the proinflammatory cytokine, tumor necrosis factor (TNF), and are protective in a mouse model of colitis. Human-derived L. reuteri strain ATCC PTA 6475 suppresses intestinal inflammation and produces 5,10-methenyltetrahydrofolic acid polyglutamates. Insertional mutagenesis identified the bifunctional dihydrofolate synthase/folylpolyglutamate synthase type 2 (folC2) gene as essential for 5,10-methenyltetrahydrofolic acid polyglutamate biosynthesis, as well as for suppression of TNF production by activated human monocytes, and for the anti-inflammatory effect of L. reuteri 6475 in a trinitrobenzene sulfonic acid-induced mouse model of acute colitis. In contrast, folC encodes the enzyme responsible for folate polyglutamylation but does not impact TNF suppression by L. reuteri. Comparative transcriptomics between wild-type and mutant L. reuteri strains revealed additional genes involved in immunomodulation, including previously identified hdc genes involved in histidine to histamine conversion. The folC2 mutant yielded diminished hdc gene cluster expression and diminished histamine production, suggesting a link between folate and histadine/histamine metabolism. The identification of genes and gene networks regulating production of bacterial-derived immunoregulatory molecules may lead to improved anti-inflammatory strategies for digestive diseases. © 2016 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

  11. Fluid therapy in vomiting and diarrhea.

    PubMed

    Brown, Andrew J; Otto, Cynthia M

    2008-05-01

    Fluid therapy in the patient with vomiting and diarrhea is essential to correct hypovolemia, dehydration, acid-base imbalance, and serum electrolyte abnormalities. Prediction of acid-base or electrolyte disturbances is difficult; therefore, point of care testing is beneficial to optimize therapy. This article focuses on the pathophysiology and treatment of hypovolemia, dehydration, electrolyte disturbances, and acid-base derangements resulting from and associated with vomiting and diarrhea.

  12. How to Handle Anxiety: The Effects of Reappraisal, Acceptance, and Suppression Strategies on Anxious Arousal

    PubMed Central

    Hofmann, Stefan G.; Heering, Sanna; Sawyer, Alice T.; Asnaani, Anu

    2009-01-01

    It has been suggested that reappraisal strategies are more effective than suppression strategies for regulating emotions. Recently, proponents of the acceptance-based behavior therapy movement have further emphasized the importance of acceptance-based emotion regulation techniques. In order to directly compare these different emotion regulation strategies, 202 volunteers were asked to give an impromptu speech in front of a video camera. Participants were randomly assigned to one of three groups. The Reappraisal group was instructed to regulate their anxious arousal by reappraising the situation; the Suppression group was asked to suppress their anxious behaviors; and the Acceptance group was instructed to accept their anxiety. As expected, the Suppression group showed a greater increase in heart rate from baseline than the Reappraisal and Acceptance groups. Moreover, the Suppression group reported more anxiety than the Reappraisal group. However, the Acceptance and Suppression groups did not differ in their subjective anxiety response. These results suggest that both reappraising and accepting anxiety is more effective for moderating the physiological arousal than suppressing anxiety. However, reappraising is more effective for moderating the subjective feeling of anxiety than attempts to suppress or accept it. PMID:19281966

  13. REWARD ENHANCES TIC SUPPRESSION IN CHILDREN WITHIN MONTHS OF TIC DISORDER ONSET

    PubMed Central

    Greene, Deanna J.; Koller, Jonathan M.; Robichaux-Viehoever, Amy; Bihun, Emily C.; Schlaggar, Bradley L.; Black, Kevin J.

    2014-01-01

    Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress tics, particularly when an immediate, contingent reward is given for successful tic suppression. As a diagnosis of TS/CTD requires tics to be present for at least one year, children in these tic suppression studies had been living with tics for quite some time. Thus, it is unclear whether the ability to inhibit tics is learned over time or present at tic onset. Resolving that issue would inform theories of how tics develop and how behavior therapy for tics works. We investigated tic suppression in school-age children as close to the time of tic onset as possible, and no later than six months after onset. Children were asked to suppress their tics both in the presence and absence of a contingent reward. Results demonstrated that these children, like children with TS/CTD, have some capacity to suppress tics, and that immediate reward enhances that capacity. These findings demonstrate that the modulating effect of reward on inhibitory control of tics is present within months of tic onset, before tics have become chronic. PMID:25220075

  14. Isohormonal therapy of endocrine autoimmunity.

    PubMed

    Schloot, N; Eisenbarth, G S

    1995-06-01

    For most autoimmune disorders, the site (if any) of chronic immunization required for perpetuation of autoimmunity is unknown. However, one possible site is the target organ itself. If this were the case, feedback regulation of target cell activity might influence autoimmunity. Here, Nanette Schloot and George Eisenbarth review several recent studies suggesting that therapies that inhibit hormonal secretion of target endocrine organs, and/or modulate immunity by therapy with the isohormone, are associated with disease suppression.

  15. Photodynamic therapy using 5-aminolevulinic acid-induced photosensitization: current clinical status

    NASA Astrophysics Data System (ADS)

    Marcus, Stuart L.; Golub, Allyn L.; Shulman, D. Geoffrey

    1995-03-01

    Photodynamic therapy using 5-aminolevulinic acid-induced photosensitization (ALA PDT) via endogenous protoporphyrin IX (PpIX) synthesis has been reported as efficacious, using topical formulations, in the treatment of a variety of dermatologic diseases including superficial basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses. Application of ALA PDT to the detection and treatment of both malignant and non-malignant diseases of internal organs has recently been reported. Local internal application of ALA has been used for the detection, via PpIX fluorescence, of pathological conditions of the human urinary bladder and for selective endometrial ablation in animal model systems. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer and of colorectal cancer. This paper reviews the current clinical status of ALA PDT.

  16. Adjunct therapy for type 1 diabetes mellitus.

    PubMed

    Lebovitz, Harold E

    2010-06-01

    Insulin replacement therapy in type 1 diabetes mellitus (T1DM) is nonphysiologic. Hyperinsulinemia is generated in the periphery to achieve normal insulin concentrations in the liver. This mismatch results in increased hypoglycemia, increased food intake with weight gain, and insufficient regulation of postprandial glucose excursions. Islet amyloid polypeptide is a hormone synthesized in pancreatic beta cells and cosecreted with insulin. Circulating islet amyloid polypeptide binds to receptors located in the hindbrain and increases satiety, delays gastric emptying and suppresses glucagon secretion. Thus, islet amyloid polypeptide complements the effects of insulin. T1DM is a state of both islet amyloid polypeptide and insulin deficiency. Pramlintide, a synthetic analog of islet amyloid polypeptide, can replace this hormone in patients with T1DM. When administered as adjunctive therapy to such patients treated with insulin, pramlintide decreases food intake and causes weight loss. Pramlintide therapy is also associated with suppression of glucagon secretion and delayed gastric emptying, both of which decrease postprandial plasma glucose excursions. Pramlintide therapy improves glycemic control and lessens weight gain. Agents that decrease intestinal carbohydrate digestion (alpha-glucosidase inhibitors) or decrease insulin resistance (metformin) might be alternative adjunctive therapies in T1DM, though its benefits are marginally supported by clinical data.

  17. Innate immune reconstitution with suppression of HIV-1.

    PubMed

    Scully, Eileen P; Lockhart, Ainsley; Garcia-Beltran, Wilfredo; Palmer, Christine D; Musante, Chelsey; Rosenberg, Eric; Allen, Todd M; Chang, J Judy; Bosch, Ronald J; Altfeld, Marcus

    2016-03-17

    Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4 + T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses.

  18. Innate immune reconstitution with suppression of HIV-1

    PubMed Central

    Scully, Eileen P.; Garcia-Beltran, Wilfredo; Palmer, Christine D.; Musante, Chelsey; Rosenberg, Eric; Allen, Todd M.; Bosch, Ronald J.

    2016-01-01

    Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4+ T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses. PMID:27158667

  19. The butanol fraction of guava (Psidium cattleianum Sabine) leaf extract suppresses MMP-2 and MMP-9 expression and activity through the suppression of the ERK1/2 MAPK signaling pathway.

    PubMed

    Im, Inhwan; Park, Kyung-Ran; Kim, Sung-Moo; Kim, Chulwon; Park, Jeong Ha; Nam, Dongwoo; Jang, Hyeung-Jin; Shim, Bum Sang; Ahn, Kyoo Seok; Mosaddik, Ashik; Sethi, Gautam; Cho, Somi K; Ahn, Kwang Seok

    2012-01-01

    The leaf extract of guava (Psidium cattleianum Sabine) has traditionally been used for the treatment of diarrhea and diabetes in East Asia and other countries. Recently, the leaf extract has been employed in the therapy of cancer, bacterial infections, and inflammation in experimental models. However, the exact mechanisms of how guava leaf extract inhibits tumor metastasis and invasion are still unknown. In the present study, we investigated in detail the molecular mechanism(s) responsible for the potential antimetastatic and antiinvasive effects of the butanol fraction of guava leaf extract (GBF). Interestingly, we observed for the first time that GBF suppressed both matrix metalloproteinases (MMP)-9 and MMP-2 expression and activity in part through the downregulation of the ERK1/2 activation in lung cancer cells. Also, importantly, the major components of the GBF were identified as d-glucuronic acid, quercetin 3-glucuronide, loganin, and xanthyletin by LC-ESI-MS/MS. Collectively, our data indicate that the guava leaf could reduce the metastasis of lung cancer cells and therefore suggest that it could be advantageously used to control the metastatic process.

  20. Seahorse-derived peptide suppresses invasive migration of HT1080 fibrosarcoma cells by competing with intracellular α-enolase for plasminogen binding and inhibiting uPA-mediated activation of plasminogen.

    PubMed

    Kim, Yong-Tae; Kim, Se-kwon; Jeon, You-Jin; Park, Sun Joo

    2014-12-01

    α-Enolase is a glycolytic enzyme and a surface receptor for plasminogen. α-Enolase-bound plasminogen promotes tumor cell invasion and cancer metastasis by activating plasmin and consequently degrading the extracellular matrix degradation. Therefore, α-enolase and plasminogen are novel targets for cancer therapy. We found that the amino acid sequence of a peptide purified from enzymatic hydrolysates of seahorse has striking similarities to that of α-enolase. In this study, we report that this peptide competes with cellular α-enolase for plasminogen binding and suppresses urokinase plasminogen activator (uPA)-mediated activation of plasminogen, which results in decreased invasive migration of HT1080 fibrosarcoma cells. In addition, the peptide treatment decreased the expression levels of uPA compared to that of untreated controls. These results provide new insight into the mechanism by which the seahorse-derived peptide suppresses invasive properties of human cancer cells. Our findings suggest that this peptide could emerge as a potential therapeutic agent for cancer.

  1. Impact of hormonal therapy on intermediate risk prostate cancer treated with combination brachytherapy and external beam irradiation.

    PubMed

    Stock, Richard G; Yalamanchi, Swati; Yamalachi, Swati; Hall, Simon J; Stone, Nelson N

    2010-02-01

    We assessed the impact of androgen suppressive therapy on biochemical failure in patients with intermediate risk prostate cancer treated with brachytherapy and external beam irradiation. From 1994 to 2006, 432 patients with intermediate risk prostate cancer as defined by the National Comprehensive Cancer Network were treated with low dose rate brachytherapy and external beam irradiation with or without 9 months of androgen suppressive therapy. Gleason score was 7 in 76% of cases and prostate specific antigen was 1.4 to 20 ng/ml (median 7.6). Of the patients 350 received androgen suppressive therapy and 82 did not. The biologically effective dose was 142 to 280 Gy2 (median 206). Followup was 23 to 155 months (median 56). The overall 8-year biochemical failure-free rate using the Phoenix definition in patients with vs without androgen suppressive therapy was 92% vs 92% (p = 0.4). The therapy had no significant impact on the biochemical failure-free rate in patients with Gleason score 7 (92% vs 90.5%, p = 0.55), prostate specific antigen 10 to 20 ng/ml (92% vs 100%, p = 0.32), T2b-T2c disease (89.5% vs 97%, p = 0.27) and more than 1 intermediate risk feature (90% vs 100%, p = 0.2). We addressed the relative importance of radiation dose vs hormonal therapy for intermediate risk prostate cancer. With high biologically effective dose combination treatment androgen suppressive therapy did not have a significant impact on the 8-year biochemical failure-free rate. We question its routine use in this setting. Copyright 2010 American Urological Association. Published by Elsevier Inc. All rights reserved.

  2. The application of hyaluronic acid-derivatized carbon nanotubes in hematoporphyrin monomethyl ether-based photodynamic therapy for in vivo and in vitro cancer treatment

    PubMed Central

    Shi, Jinjin; Ma, Rourou; Wang, Lei; Zhang, Jing; Liu, Ruiyuan; Li, Lulu; Liu, Yan; Hou, Lin; Yu, Xiaoyuan; Gao, Jun; Zhang, Zhenzhong

    2013-01-01

    Carbon nanotubes (CNTs) have shown great potential in both photothermal therapy and drug delivery. In this study, a CNT derivative, hyaluronic acid-derivatized CNTs (HA-CNTs) with high aqueous solubility, neutral pH, and tumor-targeting activity, were synthesized and characterized, and then a new photodynamic therapy agent, hematoporphyrin monomethyl ether (HMME), was adsorbed onto the functionalized CNTs to develop HMME-HA-CNTs. Tumor growth inhibition was investigated both in vivo and in vitro by a combination of photothermal therapy and photodynamic therapy using HMME-HA-CNTs. The ability of HMME-HA-CNT nanoparticles to combine local specific photodynamic therapy with external near-infrared photothermal therapy significantly improved the therapeutic efficacy of cancer treatment. Compared with photodynamic therapy or photothermal therapy alone, the combined treatment demonstrated a synergistic effect, resulting in higher therapeutic efficacy without obvious toxic effects to normal organs. Overall, it was demonstrated that HMME-HA-CNTs could be successfully applied to photodynamic therapy and photothermal therapy simultaneously in future tumor therapy. PMID:23843694

  3. Radiotherapy after radical prostatectomy: does transient androgen suppression improve outcomes?

    PubMed

    King, Christopher R; Presti, Joseph C; Gill, Harcharan; Brooks, James; Hancock, Steven L

    2004-06-01

    The long-term biochemical relapse-free survival and overall survival were compared for patients receiving either radiotherapy (RT) alone or radiotherapy combined with a short-course of total androgen suppression for failure after radical prostatectomy. Between 1985 and 2001, a total of 122 patients received RT after radical prostatectomy at our institution. Fifty-three of these patients received a short-course of total androgen suppression (TAS) 2 months before and 2 months concurrent with RT with a nonsteroidal antiandrogen and an luteinizing hormone-releasing hormone (LHRH) agonist (combined therapy group); the remaining 69 patients received RT alone. Treatment failure was defined after postoperative RT as a detectable PSA >0.05 ng/mL. Clinical and treatment variables examined included: presurgical PSA, clinical T stage, pathologic Gleason sum (pGS), seminal vesicle (SV) involvement, lymph node involvement, surgical margins, pre-RT PSA, prostate dose, pelvic irradiation, indication for postoperative RT (salvage or adjuvant), and time interval between surgery and RT. Minimum follow-up after postoperative RT was 1 year and median follow-up was 5.9 years (maximum, 14 years) for patients receiving RT alone, and 3.9 years (maximum, 11 years) for patients receiving RT with TAS (combined therapy group). Kaplan-Meier analysis was performed for PSA failure-free survival (bNED) and for overall survival (OS). Cox proportional hazards multivariable analysis examined the influence all clinical and treatment variables predicting for bNED and OS. The median time to PSA failure after postoperative RT was 1.34 years for the combined therapy group and 0.97 years for the RT alone group (p = 0.19), with no failures beyond 5 years. At 5 years, the actuarial bNED rates were 57% for the combined therapy group compared with 31% for the RT alone group (p = 0.0012). Overall survival rates at 5 years were 100% for the combined therapy group compared with 87% for the RT alone group (p = 0

  4. Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism*

    PubMed Central

    Ronnebaum, Sarah M.; Joseph, Jamie W.; Ilkayeva, Olga; Burgess, Shawn C.; Lu, Danhong; Becker, Thomas C.; Sherry, A. Dean; Newgard, Christopher B.

    2008-01-01

    Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60–80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to β-cells suppressed [14C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy. PMID:18381287

  5. Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.

    PubMed

    Ronnebaum, Sarah M; Joseph, Jamie W; Ilkayeva, Olga; Burgess, Shawn C; Lu, Danhong; Becker, Thomas C; Sherry, A Dean; Newgard, Christopher B

    2008-05-23

    Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to beta-cells suppressed [(14)C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.

  6. Ursolic Acid Inhibits Leucine-Stimulated mTORC1 Signaling by Suppressing mTOR Localization to Lysosome

    PubMed Central

    Ou, Xiang; Liu, Meilian; Luo, Hairong; Dong, Lily Q.; Liu, Feng

    2014-01-01

    Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function. PMID:24740400

  7. Tranexamic acid therapy in ulcerative colitis

    PubMed Central

    Hollanders, D.; Thomson, Jean M.; Schofield, Phillip F.

    1982-01-01

    The antifibrinolytic drug tranexamic acid was assessed in controlling bleeding in 12 patients with left-sided proctocolitis. The study was designed as a double-blind cross-over trial employing a dose of 4·5 g of tranexamic acid/day together with identical placebo. A statistically significant reduction in rectal bleeding was achieved in 50% of cases with a minimum of side effects. Sigmoidoscopic grading of rectal mucosal appearances was improved. Frequency of diarrhoea and stool consistency were not altered. Tranexamic acid may have a part to play in the management of selected patients with ulcerative colitis in whom bleeding is difficult to control with orthodox treatment. PMID:6980404

  8. Rethinking the bile acid/gut microbiome axis in cancer

    PubMed Central

    Phelan, John P.; Reen, F. Jerry; Caparros-Martin, Jose A.; O'Connor, Rosemary; O'Gara, Fergal

    2017-01-01

    Dietary factors, probiotic agents, aging and antibiotics/medicines impact on gut microbiome composition leading to disturbances in localised microbial populations. The impact can be profound and underlies a plethora of human disorders, including the focus of this review; cancer. Compromised microbiome populations can alter bile acid signalling and produce distinct pathophysiological bile acid profiles. These in turn have been associated with cancer development and progression. Exposure to high levels of bile acids, combined with localised molecular/genome instability leads to the acquisition of bile mediated neoplastic alterations, generating apoptotic resistant proliferation phenotypes. However, in recent years, several studies have emerged advocating the therapeutic benefits of bile acid signalling in suppressing molecular and phenotypic hallmarks of cancer progression. These studies suggest that in some instances, bile acids may reduce cancer phenotypic effects, thereby limiting metastatic potential. In this review, we contextualise the current state of the art to propose that the bile acid/gut microbiome axis can influence cancer progression to the extent that classical in vitro cancer hallmarks of malignancy (cell invasion, cell migration, clonogenicity, and cell adhesion) are significantly reduced. We readily acknowledge the existence of a bile acid/gut microbiome axis in cancer initiation, however, in light of recent advances, we focus exclusively on the role of bile acids as potentially beneficial molecules in suppressing cancer progression. Finally, we theorise that suppressing aggressive malignant phenotypes through bile acid/gut microbiome axis modulation could uncover new and innovative disease management strategies for managing cancers in vulnerable cohorts. PMID:29383197

  9. Increase of weakly acidic gas esophagopharyngeal reflux (EPR) and swallowing-induced acidic/weakly acidic EPR in patients with chronic cough responding to proton pump inhibitors.

    PubMed

    Kawamura, O; Shimoyama, Y; Hosaka, H; Kuribayashi, S; Maeda, M; Nagoshi, A; Zai, H; Kusano, M

    2011-05-01

    Gastro-esophageal reflux disease (GERD)-related chronic cough (CC) may have multifactorial causes. To clarify the characteristics of esophagopharyngeal reflux (EPR) events in CC patients whose cough was apparently influenced by gastro-esophageal reflux (GER), we studied patients with CC clearly responding to full-dose proton pump inhibitor (PPI) therapy (CC patients). Ten CC patients, 10 GERD patients, and 10 healthy controls underwent 24-h ambulatory pharyngo-esophageal impedance and pH monitoring. Weakly acidic reflux was defined as a decrease of pH by >1 unit with a nadir pH >4. In six CC patients, monitoring was repeated after 8 weeks of PPI therapy. The number of each EPR event and the symptom association probability (SAP) were calculated. Symptoms were evaluated by a validated GERD symptom questionnaire. Weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR only occurred in CC patients, and the numbers of such events was significantly higher in the CC group than in the other two groups (P < 0.05, respectively). Symptom association probability analysis revealed a positive association between GER and cough in three CC patients. Proton pump inhibitor therapy abolished swallowing-induced acidic/weakly acidic EPR, reduced weakly acidic gas EPR, and improved symptoms (all P < 0.05). Most patients with CC responding to PPI therapy had weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR. A direct effect of acidic mist or liquid refluxing into the pharynx may contribute to chronic cough, while cough may also arise indirectly from reflux via a vago-vagal reflex in some patients. © 2011 Blackwell Publishing Ltd.

  10. Novel "Elements" of Immune Suppression within the Tumor Microenvironment.

    PubMed

    Gurusamy, Devikala; Clever, David; Eil, Robert; Restifo, Nicholas P

    2017-06-01

    Adaptive evolution has prompted immune cells to use a wide variety of inhibitory signals, many of which are usurped by tumor cells to evade immune surveillance. Although tumor immunologists often focus on genes and proteins as mediators of immune function, here we highlight two elements from the periodic table-oxygen and potassium-that suppress the immune system in previously unappreciated ways. While both are key to the maintenance of T-cell function and tissue homeostasis, they are exploited by tumors to suppress immuno-surveillance and promote metastatic spread. We discuss the temporal and spatial roles of these elements within the tumor microenvironment and explore possible therapeutic interventions for effective and promising anticancer therapies. Cancer Immunol Res; 5(6); 426-33. ©2017 AACR . ©2017 American Association for Cancer Research.

  11. Abscisic acid ameliorates atherosclerosis by suppressing macrophage and CD4+ T cell recruitment into the aortic wall

    PubMed Central

    Guri, Amir J.; Misyak, Sarah A.; Hontecillas, Raquel; Hasty, Alyssa; Liu, Dongmin; Si, Hongwei; Bassaganya-Riera, Josep

    2009-01-01

    Abscisic acid (ABA) is a natural phytohormone which improves insulin sensitivity and reduces adipose tissue inflammation when supplemented into diets of obese mice. The objective of this study was to investigate the mechanisms by which abscisic acid (ABA) prevents or ameliorates atherosclerosis. Apolipoprotein E-deficient (ApoE −/−) mice were fed high-fat diets with or without ABA for 84 days. Systolic blood pressure was assessed on days 0, 28, 56, and 72. Gene expression, immune cell infiltration, and histological lesions were evaluated in the aortic root wall. Human aortic endothelial cells were used to examine the effect of ABA on 3’, 5’-cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) production in vitro. We report that ABA-treated mice had significantly improved systolic blood pressure and decreased accumulation of F4/80+CD11b+ macrophages and CD4+ T cells in aortic root walls. At the molecular level, ABA significantly enhanced aortic endothelial nitric oxide synthase (eNOS) and tended to suppress aortic vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression and plasma MCP-1 concentrations. ABA also caused a dose-dependent increase in intracellular concentrations of cAMP and NO and upregulated eNOS mRNA expression in human aortic endothelial cells. This is the first report showing that ABA prevents or ameliorates atherosclerosis-induced hypertension, immune cell recruitment into the aortic root wall, and upregulates aortic eNOS expression in ApoE−/− mice. PMID:20092994

  12. Measurements of free and total PSA, tissue polypeptide-specific antigen (TPS), and CYFRA 21-1 in prostate cancer patients under intermittent androgen suppression therapy.

    PubMed

    Theyer, G; Dürer, A; Theyer, U; Haberl, I; Ulsperger, E; Baumgartner, G; Hamilton, G

    1999-10-01

    The present study evaluated monthly measurements of free and total prostate-specific antigen (PSA), and the tumor proliferation markers tissue polypeptide-specific antigen (TPS) and cytokeratin fragment 21-1 (CYFRA 21-1) in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). Thirty-four men received alternating cycles of 8 month androgen suppression and treatment cessation (mean duration, 10.3 months) until PSA increased to >20 microg/l. Measurements of testosterone, percentage of free PSA, TPS, and CYFRA 21-1 were performed using ELISA and RIA assays. Periods of androgen suppression resulted in reversible reductions of testosterone (from 6 +/- 0.8 to <0.58 ng/ml), PSA (from 31.2 +/- 4.5 to <1.7 microg/l), and prostatic volume (mean reduction, 22.2 +/- 4.6%), indicating apoptotic regression of the tumors. Upon treatment cessation, testosterone increased to 6.1 +/- 0.56 ng/ml within 2 months, followed by an increase of PSA to 5.8 +/- 0.8 microg/l. The mean percentage of free PSA (15.1 +/- 2.6%) exhibited no significant change during the whole IAS cycle. TPS showed a decrease of 50% after 3 months, and CYFRA 21-1 a 25% decrease after 7 months of androgen suppression treatment. During treatment cessation, TPS exceeded the normal cutoff value of 90 U/l late in tumor regrowth (9-11 months), whereas CYFRA 21-1 remained below the normal cutoff value of 3.3 ng/ml. PSA is the best and most sensitive marker of prostate cancer regression and regrowth during IAS cycles of the markers tested in this study. Free PSA constitutes approximately 15% of total PSA (range, 5-32%), and its percentage showed no significant change during IAS cycles. The TPS and CYFRA 21-1 proliferation marker changes in IAS seem to be related mainly to effects on normal androgen-dependent tissues. Copyright 1999 Wiley-Liss, Inc.

  13. Suppression of Hydroxycinnamate Network Formation in Cell Walls of Rice Shoots Grown under Microgravity Conditions in Space

    PubMed Central

    Wakabayashi, Kazuyuki; Soga, Kouichi; Hoson, Takayuki; Kotake, Toshihisa; Yamazaki, Takashi; Higashibata, Akira; Ishioka, Noriaki; Shimazu, Toru; Fukui, Keiji; Osada, Ikuko; Kasahara, Haruo; Kamada, Motoshi

    2015-01-01

    Network structures created by hydroxycinnamate cross-links within the cell wall architecture of gramineous plants make the cell wall resistant to the gravitational force of the earth. In this study, the effects of microgravity on the formation of cell wall-bound hydroxycinnamates were examined using etiolated rice shoots simultaneously grown under artificial 1 g and microgravity conditions in the Cell Biology Experiment Facility on the International Space Station. Measurement of the mechanical properties of cell walls showed that shoot cell walls became stiff during the growth period and that microgravity suppressed this stiffening. Amounts of cell wall polysaccharides, cell wall-bound phenolic acids, and lignin in rice shoots increased as the shoot grew. Microgravity did not influence changes in the amounts of cell wall polysaccharides or phenolic acid monomers such as ferulic acid (FA) and p-coumaric acid, but it suppressed increases in diferulic acid (DFA) isomers and lignin. Activities of the enzymes phenylalanine ammonia-lyase (PAL) and cell wall-bound peroxidase (CW-PRX) in shoots also increased as the shoot grew. PAL activity in microgravity-grown shoots was almost comparable to that in artificial 1 g-grown shoots, while CW-PRX activity increased less in microgravity-grown shoots than in artificial 1 g-grown shoots. Furthermore, the increases in expression levels of some class III peroxidase genes were reduced under microgravity conditions. These results suggest that a microgravity environment modifies the expression levels of certain class III peroxidase genes in rice shoots, that the resultant reduction of CW-PRX activity may be involved in suppressing DFA formation and lignin polymerization, and that this suppression may cause a decrease in cross-linkages within the cell wall architecture. The reduction in intra-network structures may contribute to keeping the cell wall loose under microgravity conditions. PMID:26378793

  14. Intragastric acid control in non-steroidal anti-inflammatory drug users: comparison of esomeprazole, lansoprazole and pantoprazole.

    PubMed

    Goldstein, J L; Miner, P B; Schlesinger, P K; Liu, S; Silberg, D G

    2006-04-15

    Studies to date have not directly compared the pharmacodynamic efficacies of different proton pump inhibitors in controlling intragastric acidity in patients treated with non-steroidal anti-inflammatory drugs. To compare acid suppression with once-daily esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg in patients receiving non-selective or cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drug therapy. In this multicentre, open-label, comparative, three-way crossover study, adult patients (n = 90) receiving non-steroidal anti-inflammatory drugs were randomized to one of six treatment sequences. At the study site, patients were administered esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg for 5 days each, with a washout period of > or =10 days between each treatment. Twenty-four-hour pH testing was performed on day 5 of each dosing period. The mean percentage of time during the 24-h pH monitoring period that gastric pH was >4.0 was significantly greater with esomeprazole (74.2%) compared with lansoprazole (66.5%; P < 0.001) and pantoprazole (60.8%; P < 0.001), and significantly greater with esomeprazole (P < 0.05) than with the comparators regardless of whether using non-selective vs. cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs. At the doses studied, esomeprazole treatment provides significantly greater gastric acid suppression than lansoprazole or pantoprazole in patients receiving non-selective or cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs.

  15. Dietary n-3 long chain polyunsaturated fatty acids in allergy prevention and asthma treatment.

    PubMed

    Willemsen, Linette E M

    2016-08-15

    The rise in non-communicable diseases, such as allergies, in westernized countries links to changes in lifestyle and diet. N-3 long chain polyunsaturated fatty acids (LCPUFA) present in marine oils facilitate a favorable milieu for immune maturation and may contribute to allergy prevention. N-3 LCPUFA can suppress innate and adaptive immune activation and induce epigenetic changes. Murine studies convincingly show protective effects of fish oil, a source of n-3 LCPUFA, in food allergy and asthma models. Observational studies in human indicate that high dietary intake of n-3 LCPUFA and low intake of n-6 PUFA may protect against the development of allergic disease early in life. High n-6 PUFA intake is also associated with an increased asthma risk while n-3 LCPUFA may be protective and reduce symptoms. The quality of the marine oil used has impact on efficacy of allergy prevention and several observations link in particular n-3 LCPUFA DHA to allergy suppression. Randomized controlled trials indicate that optimal timing, duration and dosage of n-3 LC-PUFA is required to exert an allergy protective effect. Supplementation during early pregnancy and lactation has shown promising results regarding allergy prevention. However these findings should be confirmed in a larger cohort. Although clinical trials in asthma patients reveal no consistent clinical benefits of n-3 LCPUFA supplementation on lung function, it can suppress airway inflammation. Future food-pharma approaches may reveal whether adjunct therapy with dietary n-3 LCPUFA can improve allergy prevention or immunotherapy via support of allergen specific oral tolerance induction or contribute to the efficacy of drug therapy for asthma patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Interruption of antiretroviral therapy is associated with increased plasma cystatin C.

    PubMed

    Mocroft, Amanda; Wyatt, Christina; Szczech, Lynda; Neuhaus, Jacquie; El-Sadr, Wafaa; Tracy, Russell; Kuller, Lewis; Shlipak, Michael; Angus, Brian; Klinker, Harting; Ross, Michael

    2009-01-02

    Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4 cell count (drug conservation) had altered cystatin C levels compared with those randomized to continuous antiretroviral therapy (viral suppression) in the Strategies for Management of Antiretroviral Therapy trial, and to identify factors associated with increased cystatin C. Cystatin C was measured in plasma collected at randomization, 1, 2, 4, 8 and 12 months after randomization in a random sample of 249 and 250 participants in the drug conservation and viral suppression groups, respectively. Logistic regression was used to model the odds of at least 0.15 mg/dl increase in cystatin C (1 SD) in the first month after randomization, adjusting for demographic and clinical characteristics. At randomization, mean (SD) cystatin C level was 0.99 (0.26 mg/dl) and 1.01 (0.28 mg/dl) in the drug conservation and viral suppression arms, respectively (P = 0.29). In the first month after randomization, 21.8 and 10.6% had at least 0.15 mg/dl increase in cystatin C in the drug conservation and viral suppression arms, respectively (P = 0.0008). The difference in cystatin C between the treatment arms was maintained through 1 year after randomization. After adjustment, participants in the viral suppression arm had significantly reduced odds of at least 0.15 mg/dl increase in cystatin C in the first month (odds ratio 0.42; 95% confidence interval 0.23-0.74, P = 0.0023). These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function.

  17. Lipoic acid suppresses portal endotoxemia-induced steatohepatitis and pancreatic inflammation in rats

    PubMed Central

    Tian, Yu-Feng; He, Chih-Tsueng; Chen, Yu-Ting; Hsieh, Po-Shiuan

    2013-01-01

    AIM: To examine the effect of α-lipoic acid (LA) on mild portal endotoxemia-induced steatohepatitis and associated pancreatic abnormalities in fructose-fed rats. METHODS: Rats were randomly assigned into two groups with a regular or 60% fructose-enriched diet for 8 wk. After fructose feeding for 4 wk, rats were further divided into four subgroups: with intraportal saline (FPV), with intraportal saline plus administration of LA (FPV + LA), with lipopolysaccharide (LPS) infusion (FPLPS), and with LPS infusion plus administration of LA (FPLPS + LA). Rats were treated with LPS using intraportal infusion while LA was administered orally. Metabolite levels, superoxide levels, inflammatory markers, malondialdehyde content, glutathione content and toll-like receptor 4 (TLR4) gene expression were all measured using standard biochemical techniques. Pancreatic insulin secretion was evaluated by a hyperglycemic clamp technique. Histology of liver and pancreas tissues were evaluated using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Fructose-induced elevation in plasma C-reactive protein, amylase, superoxide, white blood cell count as well as in hepatic and pancreatic contents of malondialdehyde, tumor necrosis factor alpha and interleukin-6 were increased in animals treated with LPS and reversed with LA administration. The augmented hepatic gene expression of TLR4 in fructose-fed rats was further increased in those with intraportal LPS infusion, which was partially reversed by LA administration. Pathological examination showed inflammatory changes and leukocyte infiltration in hepatic and pancreatic islets of animals treated with LPS but were rarely observed in those with LA treatment. In addition to affects on the liver, impaired pancreatic insulin secretion seen in fructose-fed rats was deteriorated in with LPS treatment and partially reversed with LA administration. CONCLUSION: These data suggest LA could significantly suppress mild portal

  18. Nickel Inhibits Mitochondrial Fatty Acid Oxidation

    PubMed Central

    Uppala, Radha; McKinney, Richard W.; Brant, Kelly A.; Fabisiak, James P.; Goetzman, Eric S.

    2015-01-01

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation—the pathway by which fatty acids are catabolized for energy—in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with L-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 hr), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

  19. Suppression of IL-1beta-induced COX-2 expression by trichostatin A (TSA) in human endometrial stromal cells.

    PubMed

    Wu, Yan; Guo, Sun-Wei

    2007-11-01

    Over-production of cyclooxygenase-2 (COX-2) plays an important role in the positive feedback loop that leads to proliferation and inflammation in endometriosis. Following our observation that histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and valproic acid (VPA) can suppress proliferation of endometrial stromal cells, we sought to determine whether TSA suppresses IL-1beta-induced COX-2 expression in endometrial stromal cells. In vitro study using a recently established immortalized endometrial stromal cell line. The stromal cells were pretreated with TSA before stimulation with IL-1beta, and COX-2 gene and protein expression was measured by real-time quantitative RT-PCR and Western blot analysis, respectively. IL-1beta stimulated COX-2 expression in a concentration-dependent manner in endometrial stromal cells. The induced COX-2 gene and protein expression were suppressed by TSA pretreatment. TSA suppresses IL-1beta-induced COX-2 gene and protein expression in endometrial stromal cells. This finding, coupled with the findings that TSA and another HDACI, valproic acid, suppress proliferation and induce cell cycle arrest, suggests that HDACIs are a promising class of compound that has therapeutic potential for endometriosis.

  20. Suppression of glycosaminoglycan synthesis by articular cartilage, but not of hyaluronic acid synthesis by synovium, after exposure to radiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hugenberg, S.T.; Myers, S.L.; Brandt, K.D.

    1989-04-01

    We recently found that injection of 2 mCi of yttrium 90 (90Y; approximately 23,000 rads) into normal canine knees stimulated glycosaminoglycan (GAG) synthesis by femoral condylar cartilage. The present investigation was conducted to determine whether radiation affects cartilage metabolism directly. Rates of GAG synthesis and degradation in normal canine articular cartilage were studied following irradiation. Cultured synovium from the same knees was treated similarly, to determine the effects of irradiation on hyaluronic acid synthesis. Twenty-four hours after exposure to 1,000 rads, 10,000 rads, or 50,000 rads, 35S-GAG synthesis by the cartilage was 93%, 69%, and 37%, respectively, of that inmore » control, nonirradiated cartilage. The effect was not rapidly reversible: 120 hours after exposure to 50,000 rads, GAG synthesis remained at only 28% of the control level. Autoradiography showed marked suppression of 35S uptake by chondrocytes after irradiation. Cartilage GAG degradation was also increased following irradiation: 4 hours and 8 hours after exposure to 50,000 rads, the cartilage GAG concentration was only 66% and 54%, respectively, of that at time 0, while corresponding values for control, nonirradiated cartilage were 90% and 87%. In contrast to its effects on cartilage GAG metabolism, radiation at these levels had no effect on synovial hyaluronic acid synthesis.« less

  1. Antagonism between abscisic acid and gibberellins is partially mediated by ascorbic acid during seed germination in rice.

    PubMed

    Ye, Nenghui; Zhang, Jianhua

    2012-05-01

    The antagonism between abscisic acid (ABA) and gibberellin (GA) plays a key role in controlling seed germination, but the mechanism of antagonism during this process is not known. In the associated study, we investigated the relationship among ABA, reactive oxygen species (ROS), ascorbic acid (ASC) and GA during rice seed germination. ROS production is reduced by ABA, which hence results in decreasing ASC accumulation during imbibition. GA accumulation was also suppressed by a reduced ROS and ASC level, whereas application of exogenous ASC can partially rescue seed germination from ABA treatment. Further results show that production of ASC, which acts as a substrate in GA biosynthesis, was significantly inhibited by lycorine which thus suppressed the accumulation of GA. Consequently, expression of GA biosynthesis genes was suppressed by the low levels of ROS and ASC in ABA-treated seeds. These studies reveal a new role for ASC in mediating the antagonism between ABA and GA during seed germination in rice.

  2. An in vivo invertebrate evaluation system for identifying substances that suppress sucrose-induced postprandial hyperglycemia

    PubMed Central

    Matsumoto, Yasuhiko; Ishii, Masaki; Sekimizu, Kazuhisa

    2016-01-01

    Sucrose is a major sweetener added to various foods and beverages. Excessive intake of sucrose leads to increases in blood glucose levels, which can result in the development and exacerbation of lifestyle-related diseases such as obesity and diabetes. In this study, we established an in vivo evaluation system using silkworms to explore substances that suppress the increase in blood glucose levels caused by dietary intake of sucrose. Silkworm hemolymph glucose levels rapidly increased after intake of a sucrose-containing diet. Addition of acarbose or voglibose, α-glycosidase inhibitors clinically used for diabetic patients, suppressed the dietary sucrose-induced increase in the silkworm hemolymph glucose levels. Screening performed using the sucrose-induced postprandial hyperglycemic silkworm model allowed us to identify some lactic acid bacteria that inhibit the increase in silkworm hemolymph glucose levels caused by dietary intake of sucrose. The inhibitory effects of the Lactococcus lactis #Ll-1 bacterial strain were significantly greater than those of different strains of lactic acid bacteria. No effect of the Lactococcus lactis #Ll-1 strain was observed in silkworms fed a glucose diet. These results suggest that the sucrose diet-induced postprandial hyperglycemic silkworm is a useful model for evaluating chemicals and lactic acid bacteria that suppress increases in blood glucose levels. PMID:27194587

  3. An in vivo invertebrate evaluation system for identifying substances that suppress sucrose-induced postprandial hyperglycemia.

    PubMed

    Matsumoto, Yasuhiko; Ishii, Masaki; Sekimizu, Kazuhisa

    2016-05-19

    Sucrose is a major sweetener added to various foods and beverages. Excessive intake of sucrose leads to increases in blood glucose levels, which can result in the development and exacerbation of lifestyle-related diseases such as obesity and diabetes. In this study, we established an in vivo evaluation system using silkworms to explore substances that suppress the increase in blood glucose levels caused by dietary intake of sucrose. Silkworm hemolymph glucose levels rapidly increased after intake of a sucrose-containing diet. Addition of acarbose or voglibose, α-glycosidase inhibitors clinically used for diabetic patients, suppressed the dietary sucrose-induced increase in the silkworm hemolymph glucose levels. Screening performed using the sucrose-induced postprandial hyperglycemic silkworm model allowed us to identify some lactic acid bacteria that inhibit the increase in silkworm hemolymph glucose levels caused by dietary intake of sucrose. The inhibitory effects of the Lactococcus lactis #Ll-1 bacterial strain were significantly greater than those of different strains of lactic acid bacteria. No effect of the Lactococcus lactis #Ll-1 strain was observed in silkworms fed a glucose diet. These results suggest that the sucrose diet-induced postprandial hyperglycemic silkworm is a useful model for evaluating chemicals and lactic acid bacteria that suppress increases in blood glucose levels.

  4. Acid-producing capacity from sugars and sugar alcohols among Lactobacillus isolates collected in connection with radiation therapy.

    PubMed

    Almståhl, Annica; Rudbäck, Helena; Basic, Amina; Carlén, Anette; Alstad, Torgny

    2017-12-01

    To investigate the acid-producing capacity from sugars and sugar alcohols of oral Lactobacillus collected in connection with radiation therapy (RT) to the head and neck region. Lactobacillus were collected from the tongue, buccal mucosa and supragingival plaque in 24 patients before, during, and after RT. The acid-producing capacity of Lactobacillus isolates (n=211) was analyzed using a colorimetric fermentation test in microtiter plates. Solutions containing 2% sugars (sucrose, glucose, fructose, lactose) or sugar-alcohols (sorbitol and xylitol) were used. After 24h of incubation, bacterial acid-producing capacity was determined as strong (pH<5), weak (pH  ≥5-≤ 6) or low/absent (pH>6). Data regarding intake frequency of sugar-rich products and products with sugar-alcohols was collected. The highest acid-producing capacity using the sugars was seen for isolates collected during RT. Sorbitol was fermented to a higher extent during and post RT, especially among isolates from plaque. Lactobacillus fermenting xylitol showed the highest acid-producing capacity during RT (p<0.05). No statistically significant correlations between stimulated whole salivary secretion rate and acid-producing capacity, or between the intake frequency of sugar-rich products or sugar-alcohol containing products and Lactobacillus acid-producing capacity, were found. The results suggest that Lactobacillus isolates, collected from the tongue, buccal mucosa and supragingival plaque, have a higher acid-producing capacity using sugars and sugar-alcohols during RT than one year post RT. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Influence of Liver Triglycerides on Suppression of Glucose Production by Insulin in Men

    PubMed Central

    Szuszkiewicz-Garcia, Magdalene; Browning, Jeffrey D.; Baxter, Jeannie D.; Abate, Nicola; Malloy, Craig R.

    2015-01-01

    Context: The ability of insulin to suppress hepatic glucose production is impaired among subjects with increased intrahepatic triglycerides (IHTG). However, little is known about the roles of insulin on the supporting fluxes of glucose production among patients with fatty liver. Objective: To evaluate the effects of insulin on fluxes through the three potential sources of plasma glucose (glycerol, the citric acid cycle, and glycogen) among patients with fatty liver. Design, Settings, Participants, and Intervention: Nineteen men with a range of IHTG (∼0.5% to 23%) were studied after an overnight fast and during hyperinsulinemia using magnetic resonance spectroscopy and stable isotope tracers. Main Outcome Measures: IHTG, gluconeogenesis from glycerol, gluconeogenesis from the citric acid cycle, glycogenolysis, and 13C-labeled glucose produced from the citric acid cycle during hyperinsulinemia were measured. Results: Men with high IHTG had higher fluxes through all pathways contributing to glucose production during hyperinsulinemia, compared to men with low IHTG, but they had similar fluxes after the fast. Consequently, men with fatty liver had impaired insulin efficiency in suppressing total glucose production as well as fluxes through all three biochemical pathways contributing to glucose. The detection of glucose isotopomers with 13C arising from [U-13C3]propionate ingested during hyperinsulinemia demonstrated continuous gluconeogenesis from the citric acid cycle in all subjects. Conclusions: These findings challenge the concept that individual glucose production pathways are selectively dysregulated during hepatic insulin resistance. Overproduction of glucose during hyperinsulinemia in men with fatty liver results from inadequate suppression of all the supporting fluxes of glucose production in response to insulin. PMID:25250633

  6. Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17

    PubMed Central

    Guinea-Viniegra, Juan; Zenz, Rainer; Scheuch, Harald; Jiménez, María; Bakiri, Latifa; Petzelbauer, Peter; Wagner, Erwin F.

    2012-01-01

    Squamous cell carcinomas (SCCs) are heterogeneous and aggressive skin tumors for which innovative, targeted therapies are needed. Here, we identify a p53/TACE pathway that is negatively regulated by FOS and show that the FOS/p53/TACE axis suppresses SCC by inducing differentiation. We found that epidermal Fos deletion in mouse tumor models or pharmacological FOS/AP-1 inhibition in human SCC cell lines induced p53 expression. Epidermal cell differentiation and skin tumor suppression were caused by a p53-dependent transcriptional activation of the metalloprotease TACE/ADAM17 (TNF-α–converting enzyme), a previously unknown p53 target gene that was required for NOTCH1 activation. Although half of cutaneous human SCCs display p53-inactivating mutations, restoring p53/TACE activity in mouse and human skin SCCs induced tumor cell differentiation independently of the p53 status. We propose FOS/AP-1 inhibition or p53/TACE reactivating strategies as differentiation-inducing therapies for SCCs. PMID:22772468

  7. Extreme Suppression of Lateral Floret Development by a Single Amino Acid Change in the VRS1 Transcription Factor1[OPEN

    PubMed Central

    Lundqvist, Udda; Kakei, Yusuke; Suzuki, Takako; Hori, Kiyosumi; Wu, Jianzhong; Shimada, Yukihisa; Thomas, William T.B.; Komatsuda, Takao

    2017-01-01

    Increasing grain yield is an endless challenge for cereal crop breeding. In barley (Hordeum vulgare), grain number is controlled mainly by Six-rowed spike 1 (Vrs1), which encodes a homeodomain leucine zipper class I transcription factor. However, little is known about the genetic basis of grain size. Here, we show that extreme suppression of lateral florets contributes to enlarged grains in deficiens barley. Through a combination of fine-mapping and resequencing of deficiens mutants, we have identified that a single amino acid substitution at a putative phosphorylation site in VRS1 is responsible for the deficiens phenotype. deficiens mutant alleles confer an increase in grain size, a reduction in plant height, and a significant increase in thousand grain weight in contemporary cultivated germplasm. Haplotype analysis revealed that barley carrying the deficiens allele (Vrs1.t1) originated from two-rowed types carrying the Vrs1.b2 allele, predominantly found in germplasm from northern Africa. In situ hybridization of histone H4, a marker for cell cycle or proliferation, showed weaker expression in the lateral spikelets compared with central spikelets in deficiens. Transcriptome analysis revealed that a number of histone superfamily genes were up-regulated in the deficiens mutant, suggesting that enhanced cell proliferation in the central spikelet may contribute to larger grains. Our data suggest that grain yield can be improved by suppressing the development of specific organs that are not positively involved in sink/source relationships. PMID:29101279

  8. NITRIC ACID RECPVERY FROM WASTE COLUTIONS

    DOEpatents

    Wilson, A.S.

    1959-04-14

    The recovery of nitric acid from aqueous nitrate solutions containing fission products as impurities is described. It is desirable to subject such solutions to concentration by evaporation since nitric acid is regenerated thereby. A difficulty, however, is that the highly radioactive fission product ruthenium is volatilized together with the nitric acid. It has been found that by adding nitrous acids ruthenium volatilization is suppressed and reduced to a negligible degree so that the distillate obtained is practically free of rutheniuim.

  9. Nitric acid recovery from waste solutions

    DOEpatents

    Wilson, A. S.

    1959-04-14

    The recovery of nitric acid from aqueous nitrate solutions containing fission products as impurities is described. It is desirable to subject such solutions to concentration by evaporation since nitric acid is regenerated thereby. A difficulty, however, is that the highly radioactive fission product ruthenium is volatilized together with the nitric acid. It has been found that by adding nitrous acid, ruthenium volatilization is suppressed and reduced to a negligible degree so that the distillate obtained is practically free of ruthenium.

  10. Impact of the branched-chain amino acid to tyrosine ratio and branched-chain amino acid granule therapy in patients with hepatocellular carcinoma: A propensity score analysis.

    PubMed

    Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori; Kiriyama, Seiki; Tanikawa, Makoto; Hisanaga, Yasuhiro; Kanamori, Akira; Kitabatake, Shusuke; Yama, Tsuyoki

    2015-09-01

    It has been reported that the branched-chain amino acid (BCAA) to tyrosine ratio (BTR) is a useful indicator of liver function and BCAA therapy is associated with a decreased incidence of hepatocellular carcinoma (HCC). However, there has not been sufficient research on the relationship between BTR and the effects of BCAA therapy after initial treatment of HCC. We investigated the impact of BTR and BCAA therapy on survival in patients with HCC. A total of 315 patients with HCC who were treated (n = 66) or not treated (n = 249) with BCAA were enrolled; of these, 66 were selected from each group using propensity score matching. Survival from liver-related mortality was analyzed. In patients who did not receive BCAA therapy (n = 249), multivariate analysis for factors associated with survival indicated that low BTR (≤ 4.4) was independently associated with poor prognosis in patients with HCC (hazard ratio, 1.880; 95% confidence interval, 1.125-3.143; P = 0.016). In addition, among patients selected by propensity score matching (n = 132), multivariate analysis indicated that BCAA therapy was independently associated with good prognosis in patients with HCC (hazard ratio, 0.524; 95% confidence interval, 0.282-0.973; P = 0.041). BTR was not significantly associated with survival. Intervention involving BCAA therapy improved survival in patients with HCC versus untreated controls, regardless of BTR. In addition, low BTR was associated with poor prognosis in patients who did not receive BCAA therapy. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  11. Potential Suppressive Effects of Two C60 Fullerene Derivatives on Acquired Immunity

    NASA Astrophysics Data System (ADS)

    Hirai, Toshiro; Yoshioka, Yasuo; Udaka, Asako; Uemura, Eiichiro; Ohe, Tomoyuki; Aoshima, Hisae; Gao, Jian-Qing; Kokubo, Ken; Oshima, Takumi; Nagano, Kazuya; Higashisaka, Kazuma; Mashino, Tadahiko; Tsutsumi, Yasuo

    2016-10-01

    The therapeutic effects of fullerene derivatives on many models of inflammatory disease have been demonstrated. The anti-inflammatory mechanisms of these nanoparticles remain to be elucidated, though their beneficial roles in allergy and autoimmune diseases suggest their suppressive potential in acquired immunity. Here, we evaluated the effects of C60 pyrrolidine tris-acid (C60-P) and polyhydroxylated fullerene (C60(OH)36) on the acquired immune response in vitro and in vivo. In vitro, both C60 derivatives had dose-dependent suppressive effects on T cell receptor-mediated activation of T cells and antibody production by B cells under anti-CD40/IL-4 stimulation, similar to the actions of the antioxidant N-acetylcysteine. In addition, C60-P suppressed ovalbumin-specific antibody production and ovalbumin-specific T cell responses in vivo, although T cell-independent antibodies responses were not affected by C60-P. Together, our data suggest that fullerene derivatives can suppress acquired immune responses that require T cells.

  12. Reward enhances tic suppression in children within months of tic disorder onset.

    PubMed

    Greene, Deanna J; Koller, Jonathan M; Robichaux-Viehoever, Amy; Bihun, Emily C; Schlaggar, Bradley L; Black, Kevin J

    2015-02-01

    Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress tics, particularly when an immediate, contingent reward is given for successful tic suppression. As a diagnosis of TS/CTD requires tics to be present for at least one year, children in these tic suppression studies had been living with tics for quite some time. Thus, it is unclear whether the ability to inhibit tics is learned over time or present at tic onset. Resolving that issue would inform theories of how tics develop and how behavior therapy for tics works. We investigated tic suppression in school-age children as close to the time of tic onset as possible, and no later than six months after onset. Children were asked to suppress their tics both in the presence and absence of a contingent reward. Results demonstrated that these children, like children with TS/CTD, have some capacity to suppress tics, and that immediate reward enhances that capacity. These findings demonstrate that the modulating effect of reward on inhibitory control of tics is present within months of tic onset, before tics have become chronic. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. A Reproducible Immunopotency Assay to Measure Mesenchymal Stromal Cell Mediated T cell Suppression

    PubMed Central

    Bloom, Debra D.; Centanni, John M.; Bhatia, Neehar; Emler, Carol A.; Drier, Diana; Leverson, Glen E.; McKenna, David H.; Gee, Adrian P.; Lindblad, Robert; Hei, Derek J.; Hematti, Peiman

    2014-01-01

    Background The T cell suppressive property of bone marrow derived mesenchymal stromal cells (MSCs) has been considered a major mode of action and basis for their utilization in a number of human clinical trials. However, there is no well-established reproducible assay to measure MSC-mediated T cell suppression. Methods At the University of Wisconsin-Madison Production Assistance for Cellular Therapy (PACT) Center we developed an in vitro quality control T cell suppression immunopotency assay (IPA) which utilizes anti-CD3 and anti-CD28 antibodies to stimulate T cell proliferation. We measured MSC-induced suppression of CD4+ T cell proliferation at various effector to target cell ratios using defined peripheral blood mononuclear cells and in parallel compared to a reference standard MSC product. We calculated an IPA value for suppression of CD4+ T cells for each MSC product. Results Eleven MSC products generated at three independent PACT centers were evaluated for cell surface phenotypic markers and T cell suppressive properties. Flow cytometry results demonstrated typical MSC cell surface marker profiles. There was significant variability in the level of suppression of T cell proliferation with IPA values ranging from 27% to 88%. However, MSC suppression did not correlate with HLA-DR expression. Discussion We have developed a reproducible immunopotency assay to measure allogeneic MSC-mediated suppression of CD4+ T cells. Additional studies may be warranted to determine how these in vitro assay results may correlate with other immunomodulatory properties of MSCs, in addition to evaluating the ability of this assay to predict in vivo efficacy. PMID:25455739

  14. Antiretroviral Therapy Use, Medication Adherence, and Viral Suppression among PLWHA with Panic Symptoms

    PubMed Central

    Sam, Tanyka S; Hutton, Heidi E; Lau, Bryan; McCaul, Mary E; Keruly, Jeanne; Moore, Richard; Chander, Geetanjali

    2015-01-01

    Panic symptoms are prevalent among PLWHAs, yet few studies have examined their relationship with HIV outcomes. Using data from an observational cohort study in Baltimore, MD, we examined the association between panic symptoms and ART use, medication adherence, and viral suppression. Data were analyzed using GEE and adjusted for age, sex, race/ethnicity, cocaine and/or heroin use, clinic enrollment time, alcohol use, and depressive symptoms. Between June 2010 and September 2012, 1195 individuals participated in 2080 audio computer assisted interviews; 9.9% (n=118) of individuals endorsed current panic symptoms. In multivariate analysis, panic symptoms were associated with decreased ART use (IRR 0.94; p = 0.05). Panic symptoms were neither associated with medication adherence nor viral suppression. These findings were independent of depressive symptoms and substance use. Panic symptoms are under-recognized in primary care settings and present an important barrier to ART use. Further studies investigating the reasons for this association are needed. PMID:25903506

  15. Suppressing effects of glucan on micronuclei induced by Co60 in mice.

    PubMed

    Chorvatovicová, D

    1991-10-01

    The effects of glucan on the frequency of micronuclei in polychromatic erythrocytes of A/Ph mouse bone marrow induced by Co60 irradiation were examined. Suppressing effect of three glucan derivatives was statistically significant (P less than 0.01) by intravenous application of glucan one hour after irradiation. The most expressive effect was obvious by K3 substituent (DS 0.89). Intraperitoneal application of glucan has to be done earlier than one hour after irradiation. The suppressive effects of glucans can be explained by their ability to trap OH radicals and so decrease the clastogenic effect of irradiation. The results may be useful for therapeutic application of glucan with radiation therapy.

  16. Potent Anti-Inflammatory Activity of Ursolic Acid, a Triterpenoid Antioxidant, Is Mediated through Suppression of NF-κB, AP-1 and NF-AT

    PubMed Central

    Checker, Rahul; Sandur, Santosh K.; Sharma, Deepak; Patwardhan, Raghavendra S.; Jayakumar, S.; Kohli, Vineet; Sethi, Gautam; Aggarwal, Bharat B.; Sainis, Krishna B.

    2012-01-01

    Background Ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, is the major component of many plants including apples, basil, cranberries, peppermint, rosemary, oregano and prunes and has been reported to possess antioxidant and anti-tumor properties. These properties of UA have been attributed to its ability to suppress NF-κB (nuclear factor kappa B) activation. Since NF-κB, in co-ordination with NF-AT (nuclear factor of activated T cells) and AP-1(activator protein-1), is known to regulate inflammatory genes, we hypothesized that UA might exhibit potent anti-inflammatory effects. Methodology/Principal Findings The anti-inflammatory effects of UA were assessed in activated T cells, B cells and macrophages. Effects of UA on ERK, JNK, NF-κB, AP-1 and NF-AT were studied to elucidate its mechanism of action. In vivo efficacy of UA was studied using mouse model of graft-versus-host disease. UA inhibited activation, proliferation and cytokine secretion in T cells, B cells and macrophages. UA inhibited mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells. It inhibited mitogen-induced phosphorylation of ERK and JNK and suppressed the activation of immunoregulatory transcription factors NF-κB, NF-AT and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and also significantly reduced the serum levels of pro-inflammatory cytokines IL-6 and IFN-γ. UA treatment inhibited T cell activation even when added post-mitogenic stimulation demonstrating its therapeutic utility as an anti-inflammatory agent. Conclusions/Significance The present study describes the detailed mechanism of anti-inflammatory activity of UA. Further, UA may find application in the treatment of inflammatory disorders. PMID:22363615

  17. Bile acid malabsorption after pelvic and prostate intensity modulated radiation therapy: an uncommon but treatable condition.

    PubMed

    Harris, Victoria; Benton, Barbara; Sohaib, Aslam; Dearnaley, David; Andreyev, H Jervoise N

    2012-12-01

    Intensity modulated radiation therapy (IMRT) is a significant therapeutic advance in prostate cancer, allowing increased tumor dose delivery and increased sparing of normal tissues. IMRT planning uses strict dose constraints to nearby organs to limit toxicity. Bile acid malabsorption (BAM) is a treatable disorder of the terminal ileum (TI) that presents with symptoms similar to radiation therapy toxicity. It has not been described in patients receiving RT for prostate cancer in the contemporary era. We describe new-onset BAM in men after IMRT for prostate cancer. Diagnosis of new-onset BAM was established after typical symptoms developed, selenium-75 homocholic acid taurine (SeHCAT) scanning showed 7-day retention of <15%, and patients' symptoms unequivocally responded to a bile acid sequestrant. The TI was identified on the original radiation therapy plan, and the radiation dose delivered was calculated and compared with accepted dose-volume constraints. Five of 423 men treated in a prospective series of high-dose prostate and pelvic IMRT were identified with new onset BAM (median age, 65 years old). All reported having normal bowel habits before RT. The volume of TI ranged from 26-141 cc. The radiation dose received by the TI varied between 11.4 Gy and 62.1 Gy (uncorrected). Three of 5 patients had TI treated in excess of 45 Gy (equivalent dose calculated in 2-Gy fractions, using an α/β ratio of 3) with volumes ranging from 1.6 cc-49.0 cc. One patient had mild BAM (SeHCAT retention, 10%-15%), 2 had moderate BAM (SeHCAT retention, 5%-10%), and 2 had severe BAM (SeHCAT retention, <5%). The 3 patients whose TI received ≥45 Gy developed moderate to severe BAM, whereas those whose TI received <45 Gy had only mild to moderate BAM. Radiation delivered to the TI during IMRT may cause BAM. Identification of the TI from unenhanced RT planning computed tomography scans is difficult and may impede accurate dosimetric evaluation. Thorough toxicity assessment and close

  18. Magnaporthe oryzae Induces the Expression of a MicroRNA to Suppress the Immune Response in Rice.

    PubMed

    Zhang, Xin; Bao, Yalin; Shan, Deqi; Wang, Zhihui; Song, Xiaoning; Wang, Zhaoyun; Wang, Jiansheng; He, Liqiang; Wu, Liang; Zhang, Zhengguang; Niu, Dongdong; Jin, Hailing; Zhao, Hongwei

    2018-05-01

    MicroRNAs play crucial roles in plant responses to pathogen infections. The rice blast disease, caused by the fungus Magnaporthe oryzae , is the most important disease of rice ( Oryza sativa ). To explore the microRNA species that participate in rice immunity against the rice blast disease, we compared the expression of small RNAs between mock- and M. oryzae -treated rice. We found that infection by M. oryzae strain Guy11 specifically induced the expression of rice miR319 and, consequently, suppressed its target gene TEOSINTE BRANCHED/CYCLOIDEA/PROLIFERATING CELL FACTOR1 ( OsTCP21 ), which encodes a transcription factor. Using transgenic rice that overexpresses miR319b (OE) or expresses OsTCP21 -Res (which is resistant to miR319-mediated silencing), we found that OsTCP21 is a positive regulator of the rice defense response against the blast disease. When wild-type and miR319b-OE rice were infected by Guy11, multiple jasmonic acid (JA) synthetic and signaling components were suppressed, indicating that Guy11 suppresses JA signaling through inducing miR319. In particular, we found that LIPOXYGENASE2 ( LOX2 ) and LOX5 were specifically suppressed by miR319 overexpression or by Guy11 infection. LOXs are the key enzymes of JA synthesis, which catalyze the conversion of α-linoleic acid to hydroperoxy-octadecadienoic acid. The application of α-linoleic acid rescued disease symptoms on the OsTCP21 -Res rice but not wild-type rice, supporting our hypothesis that OsLOX2 and OsLOX5 are the key JA synthesis genes hijacked by Guy11 to subvert host immunity and facilitate pathogenicity. We propose that induced expression of OsLOX2/5 may improve resistance to the rice blast disease. © 2018 American Society of Plant Biologists. All Rights Reserved.

  19. The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway.

    PubMed

    Su, Ke; Wang, Chun-Fang; Zhang, Ying; Cai, Yu-Jie; Zhang, Yan-Yan; Zhao, Qian

    2016-08-01

    Cervical cancer has been the fourth most common cancer killing many women across the world. Carnosic acid (CA), as a phenolic diterpene, has been suggested to against cancer, exerting protective effects associated with inflammatory cytokines. It is aimed to demonstrate the therapeutic role of carnosic acid against cervical cancer and indicate its underlying molecular mechanisms. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was performed to assess the possible anti-proliferative effects of carnosic acid. And also, colony formation was used to further estimate carnosic acid's ability in suppressing cervical cancer cells proliferation. Flow cytometry assays were performed here to indicate the alterations of cervical cancer cells cycle and the development of apoptosis. Western blot assays and RT-PCR were also applied to clarify the apoptosis-associated signaling pathways affected by reactive oxygen species (ROS) generation. And immunofluorescence was used to detect ROS-positive cells. In vivo experiments, CaSki xenograft model samples of nude mice were involved to further elucidate the effects of carnosic acid. In our results, we found that carnosic acid exerted anti-tumor ability in vitro supported by up-regulation of apoptosis and ROS production in cervical cancer cells. Also, acceleration of ROS led to the phospharylation of (c-Jun N-terminal kinase (JNK) and its-related signals, as well as activation of Endoplasmic Reticulum (ER) stress, promoting the progression of apoptosis via stimulating Caspase3 expression. The development and growth of xenograft tumors in nude mice were found to be inhibited by the administration of carnosic acid for five weeks. And the suppressed role of carnosic acid in proliferation of cervical cancer cells and apoptosis of nude mice with tumor tissues were observed in our study. Taken together, our data indicated that carnosic acid resulted in apoptosis both in vitro and vivo experiments via promoting ROS and

  20. Factors associated with reduction in use of neoadjuvant androgen suppression therapy before radical prostatectomy.

    PubMed

    O'Shaughnessy, Matthew J; Jarosek, Stephanie L; Virnig, Beth A; Konety, Badrinath R; Elliott, Sean P

    2013-04-01

    To determine whether the prescribing patterns for nonindicated androgen suppression therapy (AST), using neoadjuvant AST as the model, changed according to the prevailing clinical evidence, changes in reimbursement, or evidence of increased harm from treatment. We identified 34,976 men with prostate cancer who had undergone radical prostatectomy within 12 months of diagnosis from the Surveillance, Epidemiology, and End Results-Medicare data set (1992-2007), and their clinical and demographic parameters were assessed. We measured the Medicare claims for receipt of AST before radical prostatectomy and calculated the annual rates of neoadjuvant AST, which were adjusted for confounding variables using multivariate logistic regression analysis, and compared them with the prevailing published clinical data on the outcomes of neoadjuvant AST, changes in reimbursement, or published data on clinical harm from treatment. The use of neoadjuvant AST increased from 7.8% in 1992 to a peak of 17.6% in 1996 and then decreased steadily to 4.6% in 2007. This rate change was significant on multivariate regression analysis, with a single join point in 1996 (P <.001), and corresponded to published data showing improved surgical margin rates and pathologic downstaging in the early 1990s and data showing no improvement in disease recurrence or overall survival beginning in 1997. Changes in reimbursement and evidence of harm from AST were not associated with the decreased use of neoadjuvant AST. Using neoadjuvant AST as the model for the nonindicated use of AST, physicians reduced AST use in response to high-level evidence showing a lack of benefit, despite the high reimbursement. This suggests that physicians adapt to emerging evidence and use evidence-based practice. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Coagulation imbalance and neurocognitive functioning in older HIV-positive adults on suppressive antiretroviral therapy.

    PubMed

    Montoya, Jessica L; Iudicello, Jennifer; Oppenheim, Hannah A; Fazeli, Pariya L; Potter, Michael; Ma, Qing; Mills, Paul J; Ellis, Ronald J; Grant, Igor; Letendre, Scott L; Moore, David J

    2017-03-27

    The aim of this study was to compare plasma biomarkers of coagulation between HIV-infected individuals and HIV-uninfected controls and to assess the impact of disturbances in coagulation on neurocognitive functioning in HIV. A cross-sectional study of 66 antiretroviral therapy treated, virally suppressed, HIV-infected and 34 HIV-uninfected older (≥50 years of age) adults. Participants completed standardized neurobehavioral and neuromedical assessments. Neurocognitive functioning was evaluated using a well validated comprehensive neuropsychological battery. Plasma biomarkers associated with procoagulation (fibrinogen, p-selectin, tissue factor and von Willebrand factor), anticoagulation (antithrombin, protein C and thrombomodulin), fibrinolysis (d-dimer, plasminogen activator inhibitor-1 and plasminogen) were collected. Multivariable linear regression was used to test the interaction of HIV and coagulation on neurocognitive functioning. Most participants were male (78.0%) and non-Hispanic white (73.0%) with a mean age of 57.8 years. Among HIV-infected participants, mean estimated duration of HIV infection was 19.4 years and median current CD4 cell count was 654 cells/μl. Levels of soluble biomarkers of procoagulation, anticoagulation and fibrinolysis were comparable between the HIV serostatus groups. Coagulation and HIV had an interacting effect on neurocognitive functioning, such that greater coagulation imbalance was associated with poorer neurocognitive functioning among the HIV-infected participants. The moderating effect of coagulation on neurocognition was driven by procoagulant but not anticoagulant or fibrinolytic biomarkers. Elevated levels of procoagulants may exert a particularly detrimental effect on neurocognitive functioning among older HIV-infected persons. A better understanding of the specific role of coagulation in the cause of HIV-associated neurocognitive disorders may lead to treatments aimed at reducing coagulopathy, thereby improving

  2. Phosphite, an analog of phosphate, suppresses the coordinated expression of genes under phosphate starvation.

    PubMed

    Varadarajan, Deepa K; Karthikeyan, Athikkattuvalasu S; Matilda, Paino Durzo; Raghothama, Kashchandra G

    2002-07-01

    Phosphate (Pi) and its analog phosphite (Phi) are acquired by plants via Pi transporters. Although the uptake and mobility of Phi and Pi are similar, there is no evidence suggesting that plants can utilize Phi as a sole source of phosphorus. Phi is also known to interfere with many of the Pi starvation responses in plants and yeast (Saccharomyces cerevisiae). In this study, effects of Phi on plant growth and coordinated expression of genes induced by Pi starvation were analyzed. Phi suppressed many of the Pi starvation responses that are commonly observed in plants. Enhanced root growth and root to shoot ratio, a hallmark of Pi stress response, was strongly inhibited by Phi. The negative effects of Phi were not obvious in plants supplemented with Pi. The expression of Pi starvation-induced genes such as LePT1, LePT2, AtPT1, and AtPT2 (high-affinity Pi transporters); LePS2 (a novel acid phosphatase); LePS3 and TPSI1 (novel genes); and PAP1 (purple acid phosphatase) was suppressed by Phi in plants and cell cultures. Expression of luciferase reporter gene driven by the Pi starvation-induced AtPT2 promoter was also suppressed by Phi. These analyses showed that suppression of Pi starvation-induced genes is an early response to addition of Phi. These data also provide evidence that Phi interferes with gene expression at the level of transcription. Synchronized suppression of multiple Pi starvation-induced genes by Phi points to its action on the early molecular events, probably signal transduction, in Pi starvation response.

  3. Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling.

    PubMed

    Moon, Seungtae; Lee, Yong-Kyu; Lee, Sang-Wang; Um, Soo-Jong

    2017-10-07

    BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Suppression of umami aftertaste by polysaccharides in soy sauce.

    PubMed

    Imamura, Miho; Matsushima, Kenichiro

    2013-08-01

    Umami is one of 5 basic tastes that make foods savory and palatable. The umami aftertaste is a long-lasting taste sensation that is important for Japanese broth (dashi) utilized for various Japanese foods. Soy sauce is usually added when making dashi-based dishes; however, different soy sauces produce distinct effects on the umami aftertaste. In this study, we attempted to identify the substances that cause the suppression of the umami aftertaste in soy sauce by combining sensory analysis, size fractionation, chemical analysis, and enzymatic treatment. The suppressive substance was revealed to be polysaccharides with molecular weights between 44900 and 49700. The results of acid hydrolysis and enzymatic treatment suggested that the polysaccharides were cellulose. These results indicate that a type of water-soluble cellulose derived from soybean, wheat, or microorganisms has a suppressive effect on the umami aftertaste of soy sauce. Future studies should focus on developing a strategy that regulates the amount of these polysaccharides generated during soy sauce production, to maintain or enhance the umami aftertaste. © 2013 Institute of Food Technologists®

  5. Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase.

    PubMed

    Zigmond, Ehud; Ben Ya'acov, Ami; Lee, Hyunbeom; Lichtenstein, Yoav; Shalev, Zvi; Smith, Yoav; Zolotarov, Lidya; Ziv, Ehud; Kalman, Rony; Le, Hoang V; Lu, Hejun; Silverman, Richard B; Ilan, Yaron

    2015-08-13

    Hepatocellular carcinoma is the second leading cause of cancer death worldwide. DNA microarray analysis identified the ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by gabaculine (1), a neurotoxic natural product, which suppressed in vitro proliferation of two HCC cell lines. Alpha-fetoprotein (AFP) secretion, a biomarker for HCC, was suppressed by gabaculine in both cell lines, but not significantly. Because of the active site similarity between GABA aminotransferase (GABA-AT) and OAT, a library of 24 GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic acid (2) was found to be an inactivator of OAT that only weakly inhibits GABA-AT, l-aspartate aminotransferase, and l-alanine aminotransferase. In vitro administration of 2 significantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum levels and tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of suppression of HCC by an OAT inactivator.

  6. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO{sub 2}), carbon dioxide tension, pH, and themore » PaO{sub 2}/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22{sup phox} levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation

  7. The dual nature of retinoic acid in pemphigus and its therapeutic potential: Special focus on all-trans Retinoic Acid.

    PubMed

    Tavakolpour, Soheil; Daneshpazhooh, Maryam; Mahmoudi, Hamid Reza; Balighi, Kamran

    2016-07-01

    The efficient treatment of pemphigus with no certain side effect remained a controversial issue. Although there are various options for controlling disease severity, the majority of them may cause serious side effects. Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune functions. Effects of RA, especially all-trans-Retinoic Acid (ATRA) on different types of cells involved in immune responses were analyzed in vitro and in vivo. RAs could affect the differentiation of T helper (Th) cells, B cells responses, stabilization of both natural regulatory T cells (nTregs) and regulatory B cells (Bregs) populations, and regulating the expression of critical genes in immune responses. The role of RA, based on major immune cells involved in pemphigus has not been addressed so far. In this study, we sought to determine the possible effects of RA, with a special focus on ATRA in pemphigus. All the evidences of ATRA effects on the immune system were collected and their association with the pemphigus was analyzed. According to the previous results, ATRA causes a decline in Th17 populations; increase in CD4+ induced regulatory T cells (iTregs), stabilization of nTregs, and promotion of suppressive B cells, which are critical in the improvement of pemphigus. Nevertheless, it also causes shifting of the Th1:Th2 balance toward Th2 cells, which is not favorable for pemphigus patients. In conclusion, ATRA acts via different ways in pemphigus. Due to increase in the suppressive function via iTregs, nTregs, and Bregs, it is suggested that patients with pemphigus may benefit from systemic ATRA therapy. To clarify this issue, further studies, such as clinical trials are needed. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.

    PubMed

    Wang, Ronghao; Lin, Wanying; Lin, Changyi; Li, Lei; Sun, Yin; Chang, Chawnshang

    2016-08-28

    Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway.

    PubMed

    Nan, Yang; Guo, Liyun; Song, Yunpeng; Wang, Le; Yu, Kai; Huang, Qiang; Zhong, Yue

    2017-08-01

    Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo. In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method. The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone. Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.

  10. Gadolinium diethylenetriaminopentaacetic acid-loaded chitosan microspheres for gadolinium neutron-capture therapy.

    PubMed

    Saha, Tapan Kumar; Ichikawa, Hideki; Fukumori, Yoshinobu

    2006-12-11

    In order to provide a suitable device that would contain water-soluble drugs, highly water-soluble gadolinium diethylenetriaminopentaacetic acid-loaded chitosan microspheres (CMS-Gd-DTPA) were prepared by the emulsion method using glutaraldehyde as a cross-linker and Span 80 as a surfactant for gadolinium neutron-capture therapy of cancer. The gadolinium content and the mass median diameter of CMS-Gd-DTPA were estimated. The size and morphology of the CMS-Gd-DTPA were strongly influenced by the initial applied weight ratio of Gd-DTPA:chitosan. FTIR spectra showed that the electrostatic interaction between chitosan and Gd-DTPA accelerated the formation of gadolinium-enriched chitosan microspheres. Sufficient amounts of glutaraldehyde and Span 80 were necessary for producing discrete CMS-Gd-DTPA. The CMS-Gd-DTPA having a mass median diameter 11.7microm and 11.6% of gadolinium could be used in Gd-NCT following intratumoral injection.

  11. Nickel inhibits mitochondrial fatty acid oxidation.

    PubMed

    Uppala, Radha; McKinney, Richard W; Brant, Kelly A; Fabisiak, James P; Goetzman, Eric S

    2015-08-07

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Synthesis and in vitro evaluation of thiododecaborated α, α- cycloalkylamino acids for the treatment of malignant brain tumors by boron neutron capture therapy.

    PubMed

    Hattori, Yoshihide; Kusaka, Shintaro; Mukumoto, Mari; Ishimura, Miki; Ohta, Yoichiro; Takenaka, Hiroshi; Uehara, Kouki; Asano, Tomoyuki; Suzuki, Minoru; Masunaga, Shin-Ichiro; Ono, Koji; Tanimori, Shinji; Kirihata, Mitsunori

    2014-12-01

    Boron-neutron capture therapy (BNCT) is an attractive technique for cancer treatment. As such, α, α-cycloalkyl amino acids containing thiododecaborate ([B12H11](2-)-S-) units were designed and synthesized as novel boron delivery agents for BNCT. In the present study, new thiododecaborate α, α-cycloalkyl amino acids were synthesized, and biological evaluation of the boron compounds as boron carrier for BNCT was carried out.

  13. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma.

    PubMed

    Mehta, Amit K; Singh, Bhanu P; Arora, Naveen; Gaur, Shailendra N

    2010-07-01

    Asthma is a chronic immune inflammatory disease characterized by variable airflow obstruction and increased bronchial hyperreactivity (BHR). Therapeutic interventions reduce airway inflammation and relieve symptoms but associated with potential side effects that limit their usefulness. The present study was undertaken to assess the effect of choline on immune inflammation and BHR in asthma subjects. The patients of asthma (n=76) were recruited and treated with choline supplement (1500 mg twice) or standard pharmacotherapy for 6 months in two groups. The patients were evaluated by clinical, immunologic and biochemical parameters. The treatment with choline showed significant reduction in symptom/drug score and improvement in PC(20) FEV1 compared to baseline or standard pharmacotherapy (p<0.01). Choline therapy significantly reduced IL-4, IL-5 and TNF-alpha level as compared to baseline or standard pharmacotherapy after 6 months (p<0.01). Blood eosinophil count and total IgE levels were reduced in both the treatment groups. Cysteinyl leukotriene and leukotriene B4 were suppressed significantly by choline treatment (p<0.01). This was accompanied by decreased 8-isoprostanes, a biomarker for oxidative stress after choline treatment (p<0.01). Choline therapy modulates immune inflammation and suppresses oxidative stress in asthma patients. It can be used as an adjunct therapy for asthma patients. Copyright 2009 Elsevier GmbH. All rights reserved.

  14. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment.

    PubMed

    McLean, Leon P; Cross, Raymond K

    2014-03-01

    Crohn's disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered.

  15. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment

    PubMed Central

    McLean, Leon P; Cross, Raymond K

    2014-01-01

    Crohn’s disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered. PMID:24490595

  16. Ferulic Acid: A Hope for Alzheimer’s Disease Therapy from Plants

    PubMed Central

    Sgarbossa, Antonella; Giacomazza, Daniela; di Carlo, Marta

    2015-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the deposition of extracellular amyloid-beta peptide (Aβ) and intracellular neurofibrillar tangles, associated with loss of neurons in the brain and consequent learning and memory deficits. Aβ is the major component of the senile plaques and is believed to play a central role in the development and progress of AD both in oligomer and fibril forms. Inhibition of the formation of Aβ fibrils as well as the destabilization of preformed Aβ in the Central Nervous System (CNS) would be an attractive therapeutic target for the treatment of AD. Moreover, a large number of studies indicate that oxidative stress and mitochondrial dysfunction may play an important role in AD and their suppression or reduction via antioxidant use could be a promising preventive or therapeutic intervention for AD patients. Many antioxidant compounds have been demonstrated to protect the brain from Aβ neurotoxicity. Ferulic acid (FA) is an antioxidant naturally present in plant cell walls with anti-inflammatory activities and it is able to act as a free radical scavenger. Here we present the role of FA as inhibitor or disaggregating agent of amyloid structures as well as its effects on biological models. PMID:26184304

  17. Music therapy in pediatrics.

    PubMed

    Avers, Laura; Mathur, Ambika; Kamat, Deepak

    2007-09-01

    The soothing effects of music have been well described over the centuries and across cultures. In more recent times, studies have shown the beneficial effects of music in alleviating symptoms in a wide variety of clinical and psychologic conditions. Music therapy has been primarily used as an intervention to control emotional states, in pain management, cognitive processing, and stress management. Stress is associated with increased production of the stress hormone cortisol, which is known to suppress immune responses. Several studies in the past few decades have demonstrated a positive effect of music therapy on reducing stress or increasing immune responses, or both. Music therapy should therefore be considered as a valuable addition to standard pharmacologic therapeutic modalities in enhancing the immune response and lowering stress levels in such conditions. This article reviews the role of music as a therapeutic modality and the future for music therapy, particularly in pediatrics.

  18. Long-Term Response of Hirsutism and Other Hyperandrogenic Symptoms to Combination Therapy in Polycystic Ovary Syndrome.

    PubMed

    Ezeh, Uche; Huang, Andy; Landay, Melanie; Azziz, Ricardo

    2018-06-07

    Polycystic ovary syndrome (PCOS) affects 5%-15% of women and is the most common cause of hirsutism. Data on the time-course of improvement to suppressive therapy and predictors of that response in PCOS are lacking. The objectives of our study are to determine the long-term response and identify predictors of response in PCOS women treated with suppressive therapy, including spironolactone (SPL) + oral contraceptives (OCs). Retrospective cross-sectional analysis of 200 women with PCOS (1990 NIH criteria) treated with suppressive therapy in general, and a subgroup of 138 subjects treated with OCP+SPL who had been prospectively included in a biorepository. Main outcome measure included improvement rate per 100 person-month of follow-up for hirsutism, menstrual irregularity and acne measured qualitatively as "feeling better", and changes in the severity of hirsutism quantified by modified Ferriman-Gallwey [mF-G] score. During a mean follow-up of 34.2 months, 85.1%, 82.7%, and 79.3% of patients reported improvement in hirsutism, menstrual dysfunction, and acne, respectively. The modified Ferriman-Gallwey (mF-G) hirsutism score improved by 59.9%. The net reduction in mF-G score and the percent of patients reporting improvement in hirsutism were greater for OC+SPL than for either drug alone, with no difference in the percent of patients free of adverse effects. Among those treated with OC+SPL (n = 138), the initial mF-G and sex hormone-binding globulin (SHBG) independently predicted successful therapy for hirsutism. There is a high rate of patient satisfaction with suppressive therapy in PCOS. The efficacy of suppressive therapy for hirsutism was greater with OC+SPL than with either drug alone. Successful treatment of hirsutism with combination OC+SPL requires at least 6 months of therapy, with the proportion of satisfied patients continuing to increase with treatment duration. The probability of patient satisfaction with OC+SPL treatment for hirsutism can be

  19. Preliminary study of highly cross-linked hyaluronic acid-based combination therapy for management of knee osteoarthritis-related pain

    PubMed Central

    Palmieri, Beniamino; Rottigni, Valentina; Iannitti, Tommaso

    2013-01-01

    6-month follow-up. At 6-month follow-up, therapy with hyaluronic acid plus sodium clodronate was the most beneficial in terms of percentage improvement in VAS pain score. A significant improvement in ESR and CRP was observed at 6-month follow-up in each treatment group. No significant difference was observed when the percentage change from baseline related to these parameters was compared among the groups. No dropout was observed in any group. No serious adverse events were observed. Conclusion Further studies are necessary to determine the effect of a therapy based on hyaluronic acid combined with diclofenac sodium or sodium clodronate in larger cohorts of patients affected by knee osteoarthritis and in longer-term follow-up. PMID:23326188

  20. Acupuncture suppresses intravenous methamphetamine self-administration through GABA receptor's mediation.

    PubMed

    Choi, Yi Jeong; Kim, Nam Jun; Zhao, Rong Jie; Kim, Da Hye; Yang, Chae Ha; Kim, Hee Young; Gwak, Young S; Jang, Eun Young; Kim, Jae Su; Lee, Yun Kyu; Lee, Hyun Jong; Lee, Sang Nam; Lim, Sung Chul; Lee, Bong Hyo

    2018-01-01

    Methamphetamine is one of the widely abused drugs. In spite of a number of studies, there is still little successful therapy to suppress the methamphetamine abuse. Acupuncture has shown to attenuate the reinforcing effects of psychostimulant. Based on, the present study investigated if acupuncture could suppress intravenous methamphetamine self-administration behavior. In addition, a possible neuronal mechanism was investigated. Male Sprague-Dawley rats weighing 270-300g were trained to intake food pellet. After catheter implantation, animal was trained to self-administer methamphetamine (0.05mg/kg) intravenously using fixed ratio 1 schedule in daily 2h session during 3 weeks. After training, rats who established baseline (infusion variation less than 20% of the mean for 3 consecutive days) received acupuncture treatment on the next day. Acupuncture was performed at each acupoint manually. In the second experiment, the selective antagonists of GABA A or GABA B receptor were given before acupuncture to investigate the possible neuronal involvement of GABA receptor pathway in the acupuncture effects. C-Fos expression was examined in the nucleus accumbens to support behavioral data. Acupuncture at HT7, but not at control acupoint LI5, reduced the self-administration behavior significantly. Also, the effects of acupuncture were blocked by the GABA receptor antagonists. C-Fos expression was shown to be parallel with the behavioral data. Results of this study have shown that acupuncture at HT7 suppressed methamphetamine self-administration through GABA receptor system, suggesting that acupuncture at HT7 can be a useful therapy for the treatment of methamphetamine abuse. Copyright © 2017 Elsevier B.V. All rights reserved.