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Sample records for acid suppressive therapy

  1. The use of long-term acid-suppression therapy.

    PubMed

    Rubin, G P; Contractor, B; Bramble, M G

    1995-01-01

    Drug therapy to suppress gastric acid secretion is commonly used in the management of dyspepsia, many patients taking such therapy over long periods of time. An audit of patients on long-term (> 12 months) acid-suppression therapy was carried out in the two practices providing primary healthcare to a town in Northeast England. Patients on continuous therapy (> 10 months' supply in the previous year) and intermittent therapy (6-10 months' supply in the previous year) were identified through computerised prescribing records. Their written and computer records were scrutinised to determine diagnosis, duration of therapy, use of NSAIDs and other features. A total of 365 patients were identified (208 men, 157 women): 132 were on intermittent and 233 on continuous therapy. Of the total, 83% were over 45 years and one-fifth were taking NSAIDs. Of the 310 patients investigated for their dyspepsia, only 250 had a positive diagnosis, of which duodenal ulcer (154) was the most common. PMID:7779658

  2. MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy.

    PubMed

    Aslam, Muhammad N; McClintock, Shannon; Khan, Shazli P; Perone, Patricia; Allen, Ronald; Ouillette, Peter D; Dame, Michael K; Cheng, Jason X; Kunkel, Steven L; Varani, James

    2015-08-01

    MDI 301 is a novel 9-cis retinoic acid derivative in which the terminal carboxylic acid group has been replaced by a picolinate ester. MDI 301, a retinoic acid receptor-α - agonist, suppressed the growth of several human myeloid leukemia cell lines (HL60, NB4, OCI-M2, and K562) in vitro and induced cell-substrate adhesion in conjunction with upregulation of CD11b. Tumor growth in HL60-injected athymic nude mice was reduced. In vitro, MDI 301 was comparable to all-trans retinoic acid (ATRA) whereas in vivo, MDI 301 was slightly more efficacious than ATRA. Most importantly, unlike what was found with ATRA treatment, MDI 301 did not induce a cytokine response in the treated animals and the severe inflammatory changes and systemic toxicity seen with ATRA did not occur. A retinoid with these characteristics might be valuable in the treatment of promyelocytic leukemia, or, perhaps, other forms of myeloid leukemia. PMID:26010252

  3. HIV-1 Reservoirs During Suppressive Therapy.

    PubMed

    Barton, Kirston; Winckelmann, Anni; Palmer, Sarah

    2016-05-01

    The introduction of antiretroviral therapy (ART) 20 years ago has dramatically reduced morbidity and mortality associated with HIV-1. Initially there was hope that ART would be curative, but it quickly became clear that even though ART was able to restore CD4(+) T cell counts and suppress viral loads below levels of detection, discontinuation of treatment resulted in a rapid rebound of infection. This is due to persistence of a small reservoir of latently infected cells with a long half-life, which necessitates life-long ART. Over the past few years, significant progress has been made in defining and characterizing the latent reservoir of HIV-1, and here we review how understanding the latent reservoir during suppressive therapy will lead to significant advances in curative approaches for HIV-1. PMID:26875617

  4. 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

  5. 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

  6. 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

  7. 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...

  8. Suppression of Acid Sphingomyelinase Protects the Retina from Ischemic Injury

    PubMed Central

    Fan, Jie; Wu, Bill X.; Crosson, Craig E.

    2016-01-01

    Purpose Acid sphingomyelinase (ASMase) catalyzes the hydrolysis of sphingomyelin to ceramide and mediates multiple responses involved in inflammatory and apoptotic signaling. However, the role ASMase plays in ischemic retinal injury has not been investigated. The purpose of this study was to investigate how reduced ASMase expression impacts retinal ischemic injury. Methods Changes in ceramide levels and ASMase activity were determined by high performance liquid chromatography-tandem mass spectrometry analysis and ASMase activity. Retinal function and morphology were assessed by electroretinography (ERG) and morphometric analyses. Levels of TNF-α were determined by ELISA. Activation of p38 MAP kinase was assessed by Western blot analysis. Results In wild-type mice, ischemia produced a significant increase in retinal ASMase activity and ceramide levels. These increases were associated with functional deficits as measured by ERG analysis and significant structural degeneration in most retinal layers. In ASMase+/− mice, retinal ischemia did not significantly alter ASMase activity, and the rise in ceramide levels were significantly reduced compared to levels in retinas from wild-type mice. In ASMase+/− mice, functional and morphometric analyses of ischemic eyes revealed significantly less retinal degeneration than in injured retinas from wild-type mice. The ischemia-induced increase in retinal TNF-α levels was suppressed by the administration of the ASMase inhibitor desipramine, or by reducing ASMase expression. Conclusions Our results demonstrate that reducing ASMase expression provides partial protection from ischemic injury. Hence, the production of ceramide and subsequent mediators plays a role in the development of ischemic retinal injury. Modulating ASMase may present new opportunities for adjunctive therapies when treating retinal ischemic disorders. PMID:27571014

  9. Bile acid dissolution therapy of gallbladder stones.

    PubMed

    Fromm, H; Malavolti, M

    1992-11-01

    Oral cholelitholytic bile acid therapy has become established treatment for selected patients with cholesterol gallstones. The treatment finds its clinical application both alone and in combination with ESWL. UDCA alone or, less commonly, a combination of this bile acid with CDCA is used. Optimal results can be expected only in carefully selected patients. Bile acid dissolution therapy is most successful in patients with radiolucent gallstones which are < or = 0.5 cm in diameter or are shown by OCG to be floating. Dissolution is seldom seen when the stones are > 1 cm in size. Cholelitholytic treatment in combination with ESWL yields optimal results in single radiolucent gallstones which are not greater than 2 cm. ESWL thus makes it possible to use medical treatment effectively in single 1-2 cm gallstones when bile acids alone would not be successful. Bile acid treatment is extremely safe, especially if UDCA is given without the addition of CDCA. PMID:1486209

  10. Effect of gastric acid suppressants on human gastric motility

    PubMed Central

    Parkman, H; Urbain, J; Knight, L; Brown, K; Trate, D; Miller, M; Maurer, A; Fisher, R

    1998-01-01

    Background—The effect of histamine H2 receptor antagonists on gastric emptying is controversial. 
Aims—To determine the effects of ranitidine, famotidine, and omeprazole on gastric motility and emptying. 
Patients and methods—Fifteen normal subjects underwent simultaneous antroduodenal manometry, electrogastrography (EGG), and gastric emptying with dynamic antral scintigraphy (DAS). After 30 minutes of fasting manometry and EGG recording, subjects received either intravenous saline, ranitidine, or famotidine, followed by another 30 minutes recording and then three hours of postprandial recording after ingestion of a radiolabelled meal. Images were obtained every 10-15 minutes for three hours to measure gastric emptying and assess antral contractility. Similar testing was performed after omeprazole 20 mg daily for one week. 
Results—Fasting antral phase III migrating motor complexes (MMCs) were more common after ranitidine (9/15 subjects, 60%), famotidine (12/15, 80%), and omeprazole (8/12, 67%) compared with placebo (4/14, 29%; p<0.05). Postprandially, ranitidine, famotidine, and omeprazole slowed gastric emptying, increased the amplitude of DAS contractions, increased the EGG power, and increased the antral manometric motility index. 
Conclusions—Suppression of gastric acid secretion with therapeutic doses of gastric acid suppressants is associated with delayed gastric emptying but increased antral motility. 

 Keywords: gastric motility; gastric emptying; histamine H2 receptor antagonists; proton pump inhibitors; gastric acid secretion; scintigraphy PMID:9536950

  11. Saturated fatty-acids regulate retinoic acid signaling and suppress tumorigenesis by targeting fatty-acid-binding protein 5

    PubMed Central

    Levi, Liraz; Wang, Zeneng; Doud, Mary Kathryn; Hazen, Stanley L.; Noy, Noa

    2015-01-01

    Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes, and precursors for signalling molecules. Here we show that these biological compounds also regulate gene expression and that they do so by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARβ/δ. The data indicate that these activities of LCFA are mediated by FABP5 which delivers ligands from the cytosol to nuclear PPARβ/δ. Both saturated and unsaturated LCFA (SLCFA, ULCFA) bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARβ/δ pathway. We show further that, by concomitantly promoting activation of RAR and inhibiting the activation of PPARβ/δ, SLCFA suppress the oncogenic properties of FABP5-expressing carcinoma cells in cultured cells and in vivo. The observations suggest that compounds that inhibit FABP5 may constitute a new class of drugs for therapy of certain types of cancer. PMID:26592976

  12. Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5.

    PubMed

    Levi, Liraz; Wang, Zeneng; Doud, Mary Kathryn; Hazen, Stanley L; Noy, Noa

    2015-01-01

    Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes and precursors for signalling molecules. Here we show that these biological compounds also regulate gene expression and that they do so by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARβ/δ. The data indicate that these activities of LCFA are mediated by FABP5, which delivers ligands from the cytosol to nuclear PPARβ/δ. Both saturated and unsaturated LCFA (SLCFA, ULCFA) bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARβ/δ pathway. We show further that, by concomitantly promoting the activation of RAR and inhibiting the activation of PPARβ/δ, SLCFA suppress the oncogenic properties of FABP5-expressing carcinoma cells in cultured cells and in vivo. The observations suggest that compounds that inhibit FABP5 may constitute a new class of drugs for therapy of certain types of cancer. PMID:26592976

  13. Uric acid lowering therapy in cardiovascular diseases.

    PubMed

    Volterrani, Maurizio; Iellamo, Ferdinando; Sposato, Barbara; Romeo, Franco

    2016-06-15

    Recent evidence would indicate that high serum uric acid (SUA) levels can be a significant and independent risk factor for hypertension and cardiovascular diseases, such as ischemic heart disease and heart failure. In the last few years an independent risk relationship between hyperuricemia, cardiovascular disease and mortality has also been reported. Hyperuricemia has been shown as an independent risk factor for acute myocardial infarction and an independent and conjoint association of either gout and SUA with total and cardiovascular mortality has been reported, with mortality impact in gout patients increasing with rising SUA concentrations, even for SUA levels in the normal to high range. These findings prompted a growing research interest on the possible benefits of uric acid lowering drugs in cardiovascular diseases. Indeed, clinical studies have reported on the beneficial effects of uric acid lowering drugs, in particular of xanthine oxidase inhibitors, in hypertension, ischemic heart disease and heart failure. Two main mechanisms have been claimed to explain the dangerous effects of hyperuricemia and, as a consequence, the benefits of uric acid lowering therapy: endothelial dysfunction and systemic inflammation. This brief review aims to summarize current evidence from human studies on the role of acid uric lowering therapy in cardiovascular diseases for practical and clinical purposes. The possible mechanisms underlying the benefits of acid uric lowering therapy are also addressed. PMID:26386814

  14. Lipoic acid suppression of neutrophil respiratory burst: effect of NADPH.

    PubMed

    O'Neill, Heidi C; Rancourt, Raymond C; White, Carl W

    2008-02-01

    Lipoic acid (LA) and its reduced product dihydrolipoic acid (DHLA) are potent antioxidants with capacity to scavenge reactive oxygen species (ROS) and recycle endogenous antioxidants. LA may increase cellular glutathione (GSH), an antioxidant lacking in the lung's epithelial lining fluid in lung disorders such as idiopathic pulmonary fibrosis (IPF). Neutrophils (PMN) are key innate responders and are pivotal in clearing bacterial infection, therefore it is crucial to understand the impact LA may have on their function. Circulating neutrophils were isolated from healthy volunteers and pretreated with LA or diluent. Cells were subsequently activated with phorbol 12-myristate 13-acetate (PMA, 100 ng/ml) to induce ROS production. SOD-inhibitable reduction of acetylated cytochrome c demonstrated the PMA-dependent respiratory burst was suppressed by LA. Oxygen consumption also was diminished when PMA-stimulated cells were pretreated with LA. PMN respiratory burst was partially restored by addition of NADPH but not other pyridine nucleotides. LA did not inhibit glucose-6-phosphate dehydrogenase activity of PMN. These data together suggest that the reduction of LA to DHLA using cellular NADPH may limit the capacity of the PMN NADPH oxidase to produce superoxide. Further studies will be required to determine if LA can diminish excessive superoxide produced by PMN and/or alveolar macrophages in IPF or relevant disease models in vivo. PMID:18158760

  15. Suppression of Autophagic Flux by Bile Acids in Hepatocytes

    PubMed Central

    Kong, Bo; Guo, Grace; Ding, Wen-Xing

    2014-01-01

    Retention of bile acids (BAs) in the liver during cholestasis plays an important role in the development of cholestatic liver injury. Several studies have reported that high concentrations of certain BAs induce cell death and inflammatory response in the liver, and BAs may promote liver tumorigenesis. Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation process that regulates organelle and protein homeostasis and serves as a cell survival mechanism under a variety of stress conditions. However, it is not known if BAs modulate autophagy in hepatocytes. In the present study, we determined autophagic flux in livers of farnesoid X receptor (FXR) knockout (KO) mice that have increased concentrations of hepatic BAs and in primary cultured mouse hepatocytes treated with BAs. The results showed that autophagic flux was impaired in livers of FXR KO mice and in BA-treated primary mouse hepatocytes. Mechanistically, BAs did not affect the activities of cathepsin or the proteasome, but impaired autophagosomal-lysosomal fusion likely due to reduction of Rab7 protein expression and targeting to autophagosomes. In conclusion, BAs suppress autophagic flux in hepatocytes by impairing autophagosomal-lysosomal fusion, which may be implicated in bile acid-induced liver tumor promotion observed in FXR KO mice. PMID:24189133

  16. Risk of Spontaneous Bacterial Peritonitis Associated With Gastric Acid Suppression

    PubMed Central

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

    2015-01-01

    Abstract 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. PMID:26039135

  17. Dietary eritadenine suppresses guanidinoacetic Acid-induced hyperhomocysteinemia in rats.

    PubMed

    Fukada, Shin-ichiro; Setoue, Minoru; Morita, Tatsuya; Sugiyama, Kimio

    2006-11-01

    We assessed the effect of eritadenine, a hypocholesterolemic factor isolated from the edible mushroom Lentinus edodes, on plasma homocysteine concentration using methyl-group acceptor-induced hyperhomocysteinemic rats. Male Wistar rats were fed a control diet or diets supplemented with a methyl-group acceptor or a precursor of methyl-group acceptor. Diets were supplemented with guanidinoacetic acid (GAA) at 2.5, 5, 7.5, and 10 g/kg, nicotinic acid (NiA) or ethanolamine (EA) at 5 and 10 g/kg, or glycine at 25 and 50 g/kg, and the rats were fed for 10 d (Expt. 1). Plasma total homocysteine concentration was increased 255 and 421% by 5 and 10 g/kg GAA, respectively, and 39 and 58% by 5 and 10 g/kg NiA, respectively, but not by EA or glycine. GAA supplementation dose-dependently decreased the hepatic S-adenosylmethionine (SAM) concentration and the activity of cystathionine beta-synthase (CBS) and increased the hepatic S-adenosylhomocysteine (SAH) and homocysteine concentrations. In another study in which rats were fed 5 g/kg GAA-supplemented diet for 1-10 d, plasma homocysteine and the other variables affected in Expt. 1 were affected in rats fed the GAA-supplemented diet (Expt. 2). We investigated the effect of supplementation of 5 g/kg GAA-supplemented diet with eritadenine (50 mg/kg) on plasma homocysteine concentration (Expt. 3). Eritadenine supplementation significantly suppressed the GAA-induced increase in plasma homocysteine concentration. Eritadenine also restored the decreased SAM concentration and CBS activity in the liver, whereas it further increased hepatic SAH concentration, suggesting that eritadenine might elicit its effect by both slowing homocysteine production and increasing cystathionine formation. The results confirm that GAA is a useful compound to induce experimental hyperhomocysteinemia and indicate that eritadenine can effectively counteract the hyperhomocysteinemic effect of GAA. PMID:17056803

  18. Glycolic acid peel therapy - a current review.

    PubMed

    Sharad, Jaishree

    2013-01-01

    Chemical peels have been time-tested and are here to stay. Alpha-hydroxy peels are highly popular in the dermatologist's arsenal of procedures. Glycolic acid peel is the most common alpha-hydroxy acid peel, also known as fruit peel. It is simple, inexpensive, and has no downtime. This review talks about various studies of glycolic acid peels for various indications, such as acne, acne scars, melasma, postinflammatory hyperpigmentation, photoaging, and seborrhea. Combination therapies and treatment procedure are also discussed. Careful review of medical history, examination of the skin, and pre-peel priming of skin are important before every peel. Proper patient selection, peel timing, and neutralization on-time will ensure good results, with no side effects. Depth of the glycolic acid peel depends on the concentration of the acid used, the number of coats applied, and the time for which it is applied. Hence, it can be used as a very superficial peel, or even a medium depth peel. It has been found to be very safe with Fitzpatrick skin types I-IV. All in all, it is a peel that is here to stay. PMID:24399880

  19. 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.

  20. 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

  1. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

    PubMed

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Divan, Ali; Grant, Stephanie; Patel, Nisha; Newell-Rogers, Karen; DeMorrow, Sharon

    2015-12-01

    Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease. PMID:26431088

  2. Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of caco-2 cells.

    PubMed

    Ogawa, N; Satsu, H; Watanabe, H; Fukaya, M; Tsukamoto, Y; Miyamoto, Y; Shimizu, M

    2000-03-01

    To understand how blood glucose level is lowered by oral administration of vinegar, we examined effects of acetic acid on glucose transport and disaccharidase activity in Caco-2 cells. Cells were cultured for 15 d in a medium containing 5 mmol/L of acetic acid. This chronic treatment did not affect cell growth or viability, and furthermore, apoptotic cell death was not observed. Glucose transport, evaluated with a nonmetabolizable substrate, 3-O-methyl glucose, also was not affected. However, the increase of sucrase activity observed in control cells (no acetic acid) was significantly suppressed by acetic acid (P < 0.01). Acetic acid suppressed sucrase activity in concentration- and time-dependent manners. Similar treatments (5 mmol/L and 15 d) with other organic acids such as citric, succinic, L-maric, L-lactic, L-tartaric and itaconic acids, did not suppress the increase in sucrase activity. Acetic acid treatment (5 mmol/L and 15 d) significantly decreased the activities of disaccharidases (sucrase, maltase, trehalase and lactase) and angiotensin-I-converting enzyme, whereas the activities of other hydrolases (alkaline phosphatase, aminopeptidase-N, dipeptidylpeptidase-IV and gamma-glutamyltranspeptidase) were not affected. To understand mechanisms underlying the suppression of disaccharidase activity by acetic acid, Northern and Western analyses of the sucrase-isomaltase complex were performed. Acetic acid did not affect the de novo synthesis of this complex at either the transcriptional or translational levels. The antihyperglycemic effect of acetic acid may be partially due to the suppression of disaccharidase activity. This suppression seems to occur during the post-translational processing. PMID:10702577

  3. Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

    PubMed Central

    Figg, William D; Cook, Katherine; Clarke, Robert

    2014-01-01

    The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. 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. PMID:25535893

  4. Ultraviolet-irradiated urocanic acid suppresses delayed-type hypersensitivity to herpes simplex virus in mice

    SciTech Connect

    Ross, J.A.; Howie, S.E.; Norval, M.; Maingay, J.; Simpson, T.J.

    1986-11-01

    Ultraviolet radiation is known to induce a transient defect in epidermal antigen presentation which leads to the generation of antigen-specific suppression of the delayed-type hypersensitivity (DTH) response. The putative receptor in skin for the primary event in UV-suppression is urocanic acid (UCA) which may then interact locally, or systemically, with antigen presenting cells or initiate a cascade of events resulting in suppression. We present the first direct evidence that UCA, when irradiated with a dose (96 mJ/cm2) of UVB radiation known to suppress the DTH response to herpes simplex virus, type 1 (HSV-1) in mice, can induce suppression following epidermal application or s.c. injection of the irradiated substance. This suppression is transferable with nylon wool-passed spleen cells.

  5. In-office Painless Aminolevulinic Acid Photodynamic Therapy

    PubMed Central

    2016-01-01

    Objective: To evaluate the efficacy, safety, and pain of in-office “painless” aminolevulinic acid photodynamic therapy aimed at decreasing treatment-associated pain in patients undergoing removal of actinic keratoses. Design: Prospective split-face study comparing short aminolevulinic acid incubation times of 15 minutes followed by extended exposure (60 minutes) of continuous blue light versus conventional aminolevulinic acid photodynamic therapy. Prospective assessment of pain in patients undergoing in-office “painless” aminolevulinic acid photodynamic therapy. Setting: Clinical practice office. Participants: Three patients with actinic keratoses participated in the split-face study and 101 in the pain assessment study. Measurements: Evaluations in the split-face study included removal of actinic keratoses, skin temperature, and pain measured on a 10-point visual analog scale. Pain was assessed using the visual analog scale in the pain assessment study. Results: In the split-face study, in-office “painless” aminolevulinic acid photodynamic therapy resulted in a 52-percent reduction in lesions versus 44 percent for conventional aminolevulinic acid photodynamic therapy. Maximum pain scores of in-office “painless” aminolevulinic acid photodynamic therapy were all 0 at each time point, and the average score for conventional aminolevulinic acid photodynamic therapy was 7. Baseline skin temperatures increased from a baseline of 29 to 32°C to 34 to 35°C by minute 10 of blue light activation on both sides of the face. Results from the pain assessment study indicated no or minimal (scores 0-2) pain in nearly all patients who received in-office “painless” aminolevulinic acid photodynamic therapy as monotherapy or in combination with 5-fluoruacil or imiquimod used as pretreatments. Conclusions: In-office “painless” aminolevulinic acid photodynamic therapy appears to be effective for removing actinic keratoses and is associated with little or no pain

  6. Effects of Levothyroxine Replacement or Suppressive Therapy on Energy Expenditure and Body Composition

    PubMed Central

    Kolobova, Irina; Smeraglio, Anne; Peters, Dawn; Purnell, Jonathan Q.; Schuff, Kathryn G.

    2016-01-01

    Background: Thyrotropin (TSH)-suppressive doses of levothyroxine (LT4) have adverse effects on bone and cardiac function, but it is unclear whether metabolic function is also affected. The objective of this study was to determine whether women receiving TSH-suppressive LT4 doses have alterations in energy expenditure or body composition. Methods: This study was a cross-sectional comparison between three groups of women: 26 women receiving chronic TSH-suppressive LT4 doses, 80 women receiving chronic replacement LT4 doses, and 16 untreated euthyroid control women. Subjects underwent measurements of resting energy expenditure (REE), substrate oxidation, and thermic effect of food by indirect calorimetry; physical activity energy expenditure by accelerometer; caloric intake by 24-hour diet recall; and body composition by dual X-ray absorptiometry. Results: REE per kilogram lean body mass in the LT4 euthyroid women was 6% lower than that of the LT4-suppressed group, and 4% lower than that of the healthy control group (p = 0.04). Free triiodothyronine (fT3) levels were directly correlated with REE, and were 10% lower in the LT4 euthyroid women compared with the other two groups (p = 0.007). The groups of subjects did not differ in other measures of energy expenditure, caloric intake, or body composition. Conclusions: LT4 suppression therapy does not adversely affect energy expenditure or body composition in women. However, LT4 replacement therapy is associated with a lower REE, despite TSH levels within the reference range. This may be due to lower fT3 levels, suggesting relative tissue hypothyroidism may contribute to impaired energy expenditure in LT4 therapy. PMID:26700485

  7. 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.

  8. 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.

  9. 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.

  10. Rapid HIV Viral Load Suppression in those Initiating Antiretroviral Therapy at First Visit after HIV Diagnosis.

    PubMed

    Hoenigl, Martin; Chaillon, Antoine; Moore, David J; Morris, Sheldon R; Mehta, Sanjay R; Gianella, Sara; Amico, K Rivet; Little, Susan J

    2016-01-01

    Expert guidelines for antiretroviral therapy (ART) now recommend ART as soon as possible in all HIV infected persons to reduce the risk of disease progression and prevent transmission. The goal of this observational study was to evaluate the impact of very early ART initiation and regimen type on time to viral suppression. We evaluated time to viral suppression among 86 persons with newly-diagnosed HIV infection who initiated ART within 30 days of diagnosis. A total of 36 (42%) had acute, 27 (31%) early, and 23 (27%) had established HIV infection. The median time from an offer of immediate ART to starting ART was 8 days. A total of 56/86 (65%) initiated an integrase inhibitor-based regimen and 30/86 (35%) a protease inhibitor-based regimen. The time to viral suppression was significantly shorter in those receiving an integrase inhibitor- versus a protease inhibitor-based regimen (p = 0.022). Twenty-two (26%) initiated ART at their HIV care intake visit and 79% of these participants achieved viral suppression at week 12, 82% at week 24 and 88% at week 48. ART initiated at the intake visit led to rapid and reliable viral suppression in acute, early and chronic HIV infection, in particular when integrase inhibitor-based regimens were used. PMID:27597312

  11. Rapid HIV Viral Load Suppression in those Initiating Antiretroviral Therapy at First Visit after HIV Diagnosis

    PubMed Central

    Hoenigl, Martin; Chaillon, Antoine; Moore, David J.; Morris, Sheldon R.; Mehta, Sanjay R.; Gianella, Sara; Amico, K. Rivet; Little, Susan J.

    2016-01-01

    Expert guidelines for antiretroviral therapy (ART) now recommend ART as soon as possible in all HIV infected persons to reduce the risk of disease progression and prevent transmission. The goal of this observational study was to evaluate the impact of very early ART initiation and regimen type on time to viral suppression. We evaluated time to viral suppression among 86 persons with newly-diagnosed HIV infection who initiated ART within 30 days of diagnosis. A total of 36 (42%) had acute, 27 (31%) early, and 23 (27%) had established HIV infection. The median time from an offer of immediate ART to starting ART was 8 days. A total of 56/86 (65%) initiated an integrase inhibitor-based regimen and 30/86 (35%) a protease inhibitor-based regimen. The time to viral suppression was significantly shorter in those receiving an integrase inhibitor- versus a protease inhibitor-based regimen (p = 0.022). Twenty-two (26%) initiated ART at their HIV care intake visit and 79% of these participants achieved viral suppression at week 12, 82% at week 24 and 88% at week 48. ART initiated at the intake visit led to rapid and reliable viral suppression in acute, early and chronic HIV infection, in particular when integrase inhibitor-based regimens were used. PMID:27597312

  12. Suppression of adipose lipolysis by long-chain fatty acid analogs.

    PubMed

    Kalderon, Bella; Azazmeh, Narmen; Azulay, Nili; Vissler, Noam; Valitsky, Michael; Bar-Tana, Jacob

    2012-05-01

    Agonist-induced lipolysis of adipose fat is robustly inhibited by insulin or by feedback inhibition by the long-chain fatty acids (LCFA) produced during lipolysis. However, the mode of action of LCFA in suppressing adipose lipolysis is not clear. β,β'-Tetramethyl hexadecanedioic acid (Mββ/ EDICA16) is a synthetic LCFA that is neither esterified into lipids nor β-oxidized, and therefore, it was exploited for suppressing agonist-induced lipolysis in analogy to natural LCFA. Mββ is shown here to suppress isoproterenol-induced lipolysis in the rat in vivo as well as in 3T3-L1 adipocytes. Inhibition of isoproterenol-induced lipolysis is due to decrease in isoproterenol-induced cAMP with concomitant inhibition of the phosphorylation of hormone-sensitive lipase and perilipin by protein kinase A. Suppression of cellular cAMP levels is accounted for by inhibition of the adenylate cyclase due to suppression of Raf1 expression by Mββ-activated AMPK. Suppression of Raf1 is further complemented by induction of components of the unfolded-protein-response by Mββ. Our findings imply genuine inhibition of agonist-induced adipose lipolysis by LCFA, independent of their β-oxidation or reesterification. Mββ suppression of agonist-induced lipolysis and cellular cAMP levels independent of the insulin transduction pathway may indicate that synthetic LCFA could serve as insulin mimetics in the lipolysis context under conditions of insulin resistance. PMID:22338010

  13. Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells

    PubMed Central

    Lu, Yong; Jiang, Feng; Jiang, Hao; Wu, Kalina; Zheng, Xuguang; Cai, Yizhong; Katakowski, Mark; Chopp, Michael; To, Shing-Shun Tony

    2010-01-01

    Gallic acid, an organic acid, also known as 3,4,5-trihydroxybenzoic acid, is cytotoxic against certain cancer cells, without harming normal cells. The objective of this study is to evaluate whether gallic acid can inhibit glioma cell viability, proliferation, invasion and reduce glioma cell mediated angiogenesis. Treatment of U87 and U251n glioma cells with gallic acid inhibited cell viability in a dose- and time-dependent manner. BrdU and tube formation assays indicated that gallic acid significantly decreased glioma cell proliferation and tube formation in mouse brain endothelial cells, respectively. In addition, gallic acid decreased U87 cell invasion in vitro. Western blot analysis showed that expression of ADAM17, p-Akt and p-Erk was suppressed by gallic acid in both U87 and U251n cell lines. These data suggest that suppression of ADAM17 and downregulation of PI3K/Akt and Ras/MAPK signaling pathways may contribute to gallic acid-induced decrease of invasiveness. Gallic acid may be a valuable candidate for treatment of brain tumor. PMID:20553913

  14. 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...

  15. 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. he background conductance of I-octanesulfonic acid, hexane sulfonic acid and sulfuric acid at varying concentrations was determined. sing 0.2 MM I-octanesulfonic acid as a mobile p...

  16. 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.

  17. Suppression of the primary IgM response by environmental teichoic acid.

    PubMed

    Oldfather, J W; Chorpenning, F W

    1981-05-01

    It has been shown previously that ingestion of glycerol teichoic acid (GTA) in the conventional laboratory diet (8 mg/kg) is the stimulus for natural background responses to GTA in rats. Since injected GTA suppresses responses to sheep red blood cells (SRBC), it was suspected that dietary GTA also might be acting suppressively. A comparison of rats fed the conventional diet with rats fed a GTA-free diet showed that ingested GTA markedly suppressed immune and background direct plaque-forming cell (PFC) responses to SRBC. It appeared that a direct causal relationship existed between the degree of suppression and the amount of GTA exposure. When GTA-deprived rats were force-fed varying doses of GTA or when conventional animals were injected (i.p.) with GTA, increasing the total GTA dose resulted in decreased direct PFC responses to SRBC. Suppression was also observed when GTA-deprived rats were force-fed GTA-containing Bacillus sp. ATCC 29726. The phenomenon of suppression by dietary GTA was not restricted to responses to SRBC, as similar results were obtained with chicken erythrocytes. When IgG PFC were measured, no difference between conventional and GTA-deprived groups was observed. Thus, an IgM-IgG shift does not seem to play a role in the mechanism of suppression by GTA. PMID:7021168

  18. Hyaluronic acid reagent suppressed endometriotic lesion formation in a mouse model.

    PubMed

    Hasegawa, Akiko; Yoshino, Osamu; Osuga, Yutaka; Kodama, Ako; Takamura, Masashi; Nishii, Osamu; Taketani, Yuji

    2010-05-15

    In an animal endometriosis model, the administration of hyaluronic acid (HA) reagent significantly suppressed the formation of endometriotic lesions in both number and weight. This effect was found when HA treatment was conducted at the time of endometrial fragment inoculation. PMID:20356589

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  20. Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth.

    PubMed

    Zhao, Yong; Tu, Mei-Juan; Yu, Yi-Feng; Wang, Wei-Peng; Chen, Qiu-Xia; Qiu, Jing-Xin; Yu, Ai-Xi; Yu, Ai-Ming

    2015-12-15

    Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent. PMID:26518752

  1. 5-Caffeoylquinic acid and caffeic acid orally administered suppresses P-selectin expression on mouse platelets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Caffeic acid and 5-caffeoylquinic acid are a naturally occurring phenolic acid and its ester found in human diets. In this paper, potential effects of caffeic acid and 5-caffeoylquinic acid found in coffee and other plant sources on platelet activation were studied via investigating P-selectin expre...

  2. G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer.

    PubMed

    Tang, Yong; Chen, Yakun; Jiang, Hongmei; Robbins, Gregory T; Nie, Daotai

    2011-02-15

    GPR43 is a G-protein-coupled receptor for short-chain fatty acids (SCFAs). Expression of GPR43 is detected in hematopoietic tissues and the large intestine. SCFAs are derived from bacterial fermentation and metabolism of undigested dietary fibers and have been recognized for their cancer prevention activities in the colon. The role of SCFAs, particularly butyrate, in colon cancer therapy has been extensively studied, and its tumor suppressive functions are believed to be due to their intracellular actions, notably inhibition of histone deacetylase. In our study, we show that SCFAs also exert their antitumor effects via receptor GPR43 and that GPR43 is frequently lost in colon cancer cells. Immunohistostaining revealed that GPR43 immunoreactivity was high in normal colon tissues (N = 31) but was markedly reduced or completely lost in most colorectal adenocarcinoma tissues (N = 70) and their corresponding lymph node metastatic adenocarcinomas (N = 38). RT-PCR analysis detected the presence of full length GPR43 mRNA in only one (HT-29) of nine established human colon cancer cell lines. Restoration of GPR43 expression in HCT8 human colonic adenocarcinoma cells induced G0/G1 cell cycle arrest and activated caspases, leading to increased apoptotic cell death after propionate/butyrate treatment. Restored GPR43 expression, coupled with propionate treatment, induced an upregulation of p21 and a decrease in the levels of cyclin D3 and cyclin-dependent kinases (CDKs) 1 and 2, while the CDK4 and CDK6 levels remained unchanged. Our results suggest that GPR43 functions as a tumor suppressor by mediating SCFA-induced cell proliferation inhibition and apoptotic cell death in colon cancer. PMID:20979106

  3. Long-term suppression of wetland methane flux following a pulse of simulated acid rain

    NASA Astrophysics Data System (ADS)

    Gauci, Vincent; Dise, Nancy; Blake, Stephen

    2005-06-01

    Wetlands are a potent source of the radiatively important gas methane (CH4). Recent findings have demonstrated that sulfate (SO42-) deposition via acid rain suppresses CH4 emissions by stimulating competitive exclusion of methanogens by sulfate-reducing microbial populations. Here we report data from a field experiment showing that a finite pulse of simulated acid rain SO42- deposition, as would be expected from a large Icelandic volcanic eruption, continues to suppress CH4 emissions from wetlands long after the pollution event has ceased. Our analysis of the stoichiometries suggests that 5 years is a minimum CH4 emission recovery period, with 10 years being a reasonable upper limit. Our findings highlight the long-term impact of acid rain on biospheric output of CH4 which, for discrete polluting events such as volcanic eruptions, outlives the relatively short-term SO42- aerosol radiative cooling effect.

  4. Suppression of Acid Diffusion in Chemical Amplification Resists by Molecular Control of Base Matrix Polymers

    NASA Astrophysics Data System (ADS)

    Yoshimura, Toshiyuki; Shiraishi, Hiroshi; Okazaki, Shinji

    1995-12-01

    Suppression of acid diffusion during post-exposure baking (PEB) of chemical amplification resists is investigated from the standpoint of molecular control of base matrix polymers. Negative-type chemical amplification resists composed of cresol novolak-based matrix polymers, acid-catalyzed crosslinkers of melamine resins, and acid generators of onium salts are prepared. The molecular weight distributions of the base matrix polymers are controlled by means of a precipitation method. The resists are exposed with electron beams in isolated lines to evaluate the acid diffusion characteristics. Dependence of pattern sizes on the PEB time clearly shows that acid diffusion determines the resist pattern sizes based on Fick's law. The diffusion coefficients of resists with base matrix polymers with small polydispersities are smaller than those of resists with base matrix polymers with large polydispersities. Acid diffusion can still be suppressed by applying base matrix polymers with small weight-average molecular weights and small polydispersities. Diffusion coefficients can be further decreased by using base matrix polymers with more p-cresol components. A diffusion mechanism is proposed based on acid diffusion channels composed of active OH-groups and vacancies in the base matrix polymers.

  5. Bile Acid diarrhea: prevalence, pathogenesis, and therapy.

    PubMed

    Camilleri, Michael

    2015-05-23

    Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as (75)selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD. PMID:25918262

  6. Bile Acid Diarrhea: Prevalence, Pathogenesis, and Therapy

    PubMed Central

    Camilleri, Michael

    2015-01-01

    Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn’s disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD. PMID:25918262

  7. Early versus deferred androgen suppression therapy for patients with lymph node-positive prostate cancer after local therapy with curative intent: a systematic review

    PubMed Central

    2013-01-01

    Background There is currently no consensus regarding the optimal timing for androgen suppression therapy in patients with prostate cancer that have undergone local therapy with curative intent but are proven to have node-positive disease without signs of distant metastases at the time of local therapy. The objective of this systematic review was to determine the benefits and harms of early (at the time of local therapy) versus deferred (at the time of clinical disease progression) androgen suppression therapy for patients with node-positive prostate cancer after local therapy. Methods The protocol was registered prospectively (CRD42011001221; http://www.crd.york.ac.uk/PROSPERO). We searched the MEDLINE, EMBASE, and CENTRAL databases, as well as reference lists, the abstracts of three major conferences, and three trial registers, to identify randomized controlled trials (search update 04/08/2012). Two authors independently screened the identified articles, assessed trial quality, and extracted data. Results Four studies including 398 patients were identified for inclusion. Early androgen suppression therapy lead to a significant decrease in overall mortality (HR 0.62, 95% CI 0.46-0.84), cancer-specific mortality (HR 0.34, 95% CI 0.18-0.64), and clinical progression at 3 or 9 years (RR 0.29, 95% CI 0.16-0.52 at 3 years and RR 0.49, 95% CI 0.36-0.67 at 9 years). One study showed an increase of adverse effects with early androgen suppression therapy. All trials had substantial methodological limitations. Conclusions The data available suggest an improvement in survival and delayed disease progression but increased adverse events for patients with node-positive prostate cancer after local therapy treated with early androgen suppression therapy versus deferred androgen suppression therapy. However, quality of data is low. Randomized controlled trials with blinding of outcome assessment, planned to determine the timing of androgen suppression therapy in node

  8. Nucleic Acid Aptamers: an Emerging Frontier in Cancer Therapy

    PubMed Central

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

    2013-01-01

    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. PMID:22951893

  9. Folic acid conjugated ferritins as photosensitizer carriers for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Zhen, Zipeng; Tang, Wei; Zhang, Weizhong; Xie, Jin

    2015-06-01

    We coupled folic acid as a tumour targeting ligand to the surface of ferritins and loaded them with ZnF16Pc. The resulting nanoconjugates can efficiently hone in on 4T1 tumours in vivo, and, with photoirradiation, leading to suppressed tumour growth and tumour metastasis.We coupled folic acid as a tumour targeting ligand to the surface of ferritins and loaded them with ZnF16Pc. The resulting nanoconjugates can efficiently hone in on 4T1 tumours in vivo, and, with photoirradiation, leading to suppressed tumour growth and tumour metastasis. Electronic supplementary information (ESI) available: Details of experiments and ex vivo imaging results. See DOI: 10.1039/c5nr01833a

  10. 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. PMID:25034231

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

    PubMed

    Fang, Zhong-Ze; Zhang, Dunfang; Cao, Yun-Feng; Xie, Cen; Lu, Dan; Sun, Dong-Xue; Tanaka, Naoki; Jiang, Changtao; Chen, Qianming; Chen, Yu; Wang, Haina; Gonzalez, Frank J

    2016-01-15

    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 showed 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(+) 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. PMID:26706406

  12. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2

    PubMed Central

    Ye, Jiangbin; Palm, Wilhelm; Peng, Min; King, Bryan; Lindsten, Tullia; Li, Ming O.; Koumenis, Constantinos; Thompson, Craig B.

    2015-01-01

    Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression. PMID:26543160

  13. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2.

    PubMed

    Ye, Jiangbin; Palm, Wilhelm; Peng, Min; King, Bryan; Lindsten, Tullia; Li, Ming O; Koumenis, Constantinos; Thompson, Craig B

    2015-11-15

    Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression. PMID:26543160

  14. 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

  15. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis.

    PubMed

    Wright, Graham P; Notley, Clare A; Xue, Shao-An; Bendle, Gavin M; Holler, Angelika; Schumacher, Ton N; Ehrenstein, Michael R; Stauss, Hans J

    2009-11-10

    Regulatory T cells (Tregs) can suppress a wide range of immune cells, making them an ideal candidate for the treatment of autoimmunity. The potential clinical translation of targeted therapy with antigen-specific Tregs is hampered by the difficulties of isolating rare specificities from the natural polyclonal T cell repertoire. Moreover, the initiating antigen is often unknown in autoimmune disease. Here we tested the ability of antigen-specific Tregs generated by retroviral gene transfer to ameliorate arthritis through linked suppression and therefore without cognate recognition of the disease-initiating antigen. We explored two distinct strategies: T cell receptor (TCR) gene transfer into purified CD4+CD25+ T cells was used to redirect the specificity of naturally occurring Tregs; and co-transfer of FoxP3 and TCR genes served to convert conventional CD4(+) T cells into antigen-specific regulators. Following adoptive transfer into recipient mice, the gene-modified T cells engrafted efficiently and retained TCR and FoxP3 expression. Using an established arthritis model, we demonstrate antigen-driven accumulation of the gene modified T cells at the site of joint inflammation, which resulted in a local reduction in the number of inflammatory Th17 cells and a significant decrease in arthritic bone destruction. Together, we describe a robust strategy to rapidly generate antigen-specific regulatory T cells capable of highly targeted inhibition of tissue damage in the absence of systemic immune suppression. This opens the possibility to target Tregs to tissue-specific antigens for the treatment of autoimmune tissue damage without the knowledge of the disease-causing autoantigens recognized by pathogenic T cells. PMID:19884493

  16. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor.

    PubMed

    Gough, Michael J; Ruby, Carl E; Redmond, William L; Dhungel, Birat; Brown, Alexis; Weinberg, Andrew D

    2008-07-01

    Acquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-beta. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor. PMID:18593921

  17. 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. PMID:25903506

  18. 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

  19. [Use of organic acids in acne and skin discolorations therapy].

    PubMed

    Kapuścińska, Alicja; Nowak, Izabela

    2015-01-01

    Acne is one of the most frequent skin disorders that occurs in puberty, but often adults also have acne. The most important factors responsible for acne are elevated production of sebum by hyperactive sebaceous glands and blockage of the follicle because of hyperkeratosis [14]. The third etiopathogenic factor of acne is excessive microflora reproduction [8]. The most significant bacterium that is responsible for formation of skin lesions is Propionibacterium acnes, a rod-shaped Gram-positive and aerotolerant anaerobic bacterium. It is estimated that P. acnes is responsible for acne in approximately 80% of people aged 11 to 30 [27,40]. Even healed skin lesions can often cause skin discolorations and scar formation [51]. Exfoliating chemical substances that are commonly used in dermatology and cosmetology are organic acids. Exfoliating treatment using organic acids is called "chemical peeling" and consists of controlled application of those substances on the skin [38]. The depth of exfoliation depends on organic acid concentration, type of substance and contact time with the skin [41]. Using exfoliating agents seems to be helpful in excessive keratinization - one of several factors responsible for acne. Moreover, epidermis exfoliation is a popular method of removing skin discoloration [22]. Considering chemical structure, exfoliating substances that are most often used in cosmetology contain alpha-hydroxyacids (glycolic acid, lactic acid, mandelic acid and citric acid), beta-hydroxyacids (salicylic acid) and other organic acids, such as trichloroacetic acid and pyruvic acid [47]. In this article, a literature review of use of organic acids in acne and skin discoloration therapy is presented. PMID:25811473

  20. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort.

    PubMed

    Lewis, J M; Stott, K E; Monnery, D; Seden, K; Beeching, N J; Chaponda, M; Khoo, S; Beadsworth, M B J

    2016-02-01

    Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. PMID:25721922

  1. 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. PMID:27073325

  2. 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

  3. Mechanism of Shope Fibroma Virus-Induced Suppression of Host Deoxyribonucleic Acid Synthesis

    PubMed Central

    Chan, James C.; Hodes, M. E.

    1973-01-01

    The effects of treatment with live or inactivated Shope fibroma virus on host cell deoxyribonucleic acid (DNA) synthesis were determined. The incorporation of 3H-thymidine into nuclear DNA was suppressed by both active and inactivated virus, although live virus was more effective. During the early phase of infection, stimulation of host nuclear DNA synthesis of up to 240% of control value was observed in cells infected with active virus. Inhibition of DNA synthesis began at about the 8th h and was maximal by 12 h postinfection. Virus inactivated by ultraviolet-irradiation or heat treatment did not induce viral DNA synthesis but was, nevertheless, able to suppress host DNA synthesis. PMID:4202660

  4. The Lactic Acid Bacterium Pediococcus acidilactici Suppresses Autoimmune Encephalomyelitis by Inducing IL-10-Producing Regulatory T Cells

    PubMed Central

    Takata, Kazushiro; Kinoshita, Makoto; Okuno, Tatsusada; Moriya, Masayuki; Kohda, Tohru; Honorat, Josephe A.; Sugimoto, Tomoyuki; Kumanogoh, Atsushi; Kayama, Hisako; Takeda, Kiyoshi; Sakoda, Saburo; Nakatsuji, Yuji

    2011-01-01

    Background Certain intestinal microflora are thought to regulate the systemic immune response. Lactic acid bacteria are one of the most studied bacteria in terms of their beneficial effects on health and autoimmune diseases; one of which is Multiple sclerosis (MS) which affects the central nervous system. We investigated whether the lactic acid bacterium Pediococcus acidilactici, which comprises human commensal bacteria, has beneficial effects on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Methodology/Principal Findings P. acidilactici R037 was orally administered to EAE mice to investigate the effects of R037. R037 treatment suppressed clinical EAE severity as prophylaxis and therapy. The antigen-specific production of inflammatory cytokines was inhibited in R037-treated mice. A significant increase in the number of CD4+ Interleukin (IL)-10-producing cells was observed in the mesenteric lymph nodes (MLNs) and spleens isolated from R037-treated naive mice, while no increase was observed in the number of these cells in the lamina propria. Because only a slight increase in the CD4+Foxp3+ cells was observed in MLNs, R037 may primarily induce Foxp3− IL10-producing T regulatory type 1 (Tr1) cells in MLNs, which contribute to the beneficial effect of R037 on EAE. Conclusions/Significance An orally administered single strain of P. acidilactici R037 ameliorates EAE by inducing IL10-producing Tr1 cells. Our findings indicate the therapeutic potential of the oral administration of R037 for treating multiple sclerosis. PMID:22110705

  5. Propionic acid and its esterified derivative suppress the growth of methicillin-resistant Staphylococcus aureus USA300.

    PubMed

    Wang, Y; Dai, A; Huang, S; Kuo, S; Shu, M; Tapia, C P; Yu, J; Two, A; Zhang, H; Gallo, R L; Huang, C-M

    2014-06-01

    Previously, we demonstrated that Propionibacterium acnes, a human skin commensal bacterium, ferments glycerol into short-chain fatty acids, including propionic acid. Propionic acid suppressed the growth of Staphylococcus aureus USA300, a community-acquired methicillin-resistant bacterium, in vitro and in vivo. In this study, it is demonstrated that the anti-USA300 activity of propionic acid persisted after buffering the acid with 4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid. This suggests that the growth suppression of USA300 mainly resulted from the antimicrobial activity of propionic acid per se and not from the acidity of the medium. In addition, proprionic acid significantly reduced the intracellular pH of USA300 and exhibited broad-spectrum antimicrobial activity against Escherichia coli and Candida albicans. P. acnes showed a higher tolerance to propionic acid. Next, an esterified derivative of propionic acid was synthesised. Propionic acid and the esterified derivative were equivalent in their efficacy to suppress the growth of USA300 in vitro. The esterified derivative thus provides an alternative to propionic acid as an antimicrobial agent against S. aureus. PMID:24686580

  6. 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

  7. 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.

  8. Recurrent neonatal herpes simplex virus infection with central nervous system disease after completion of a 6-month course of suppressive therapy: Case report.

    PubMed

    Kato, Koji; Hara, Shinya; Kawada, Jun-Ichi; Ito, Yoshinori

    2015-12-01

    A boy at 12 days of age developed neonatal herpes simplex virus (HSV) type 2 infection with central nervous system (CNS) disease. After a 21-day course of high-dose intravenous acyclovir, the patient recovered with negative results for HSV DNA in serum and cerebrospinal fluid. Two weeks after a 6-month course of oral valacyclovir suppressive therapy with negative virological assessment, the disease recurred. Another 21-day course of intravenous acyclovir and subsequent 1-year course of oral suppressive therapy were completed. He showed mild developmental delay in language-social skills at 18 months of age. Although recurrences of neonatal HSV infection with CNS disease after suppressive therapy are uncommon, both clinical and virological assessments at the end of the suppressive therapy may be required. Administration of extended long-term suppressive ACV therapy should be considered to reduce the rate of recurrence. PMID:26390826

  9. Suppression of rice methane emission by sulfate deposition in simulated acid rain

    NASA Astrophysics Data System (ADS)

    Gauci, Vincent; Dise, Nancy B.; Howell, Graham; Jenkins, Meaghan E.

    2008-09-01

    Sulfate in acid rain is known to suppress methane (CH4) emissions from natural freshwater wetlands. Here we examine the possibility that CH4 emissions from rice agriculture may be similarly affected by acid rain, a major and increasing pollution problem in Asia. Our findings suggest that acid rain rates of SO42- deposition may help to reduce CH4 emissions from rice agriculture. Emissions from rice plants treated with simulated acid rain at levels of SO42- consistent with the range of deposition in Asia were reduced by 24% during the grain filling and ripening stage of the rice season which accounts for 50% of the overall CH4 that is normally emitted in a rice season. A single application of SO42- at a comparable level reduced CH4 emission by 43%. We hypothesize that the reduction in CH4 emission may be due to a combination of effects. The first mechanism is that the low rates of SO42- may be sufficient to boost yields of rice and, in so doing, may cause a reduction in root exudates to the rhizosphere, a key substrate source for methanogenesis. Decreasing a major substrate source for methanogens is also likely to intensify competition with sulfate-reducing microorganisms for whom prior SO42- limitation had been lifted by the simulated acid rain S deposition.

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

    PubMed

    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

  12. -Therapy with ursodeoxycholic acid in primary biliary cirrhosis in pregnancy-.

    PubMed

    Rudi, J; Schönig, T; Stremmel, W

    1996-03-01

    Pregnancy is very uncommon in patients with primary biliary cirrhosis (PBC) and only few reports exist about pregnancy and PBC. However, no data are available on therapy and potential risks of treatment with ursodeoxycholic acid (UDCA) in PBC, especially in the first trimester of pregnancy. Furthermore, it is not known, whether UDCA is secreted into the breast milk during lactation. We report a 41 year old patient with the diagnosis of PBC stage III, who had been treated with UDCA (750 mg/day) for three years. At the time of diagnosis of pregnancy (5th gestational week), UDCA was withdrawn. Within nine days, severe pruritus developed, alkaline phosphatase and gamma-glutamyltransferase increased. UDCA was administered again (750 mg/day). The pruritus disappeared completely within one week. Liver enzymes decreased to baseline values and remained stable throughout the remainder of the pregnancy. No drug-related side effects were observed. Caesarean section for placental insufficiency unrelated to PBC was performed at the 34th week of pregnancy. The newborn thrived normally during a follow-up period of six months. When the patient's breast milk was analyzed by high pressure liquid chromatography, cholic acid, deoxycholic acid and lithocholic acid, but not UDCA were detected in trace amounts. It is concluded that UDCA therapy in PBC may be continued in the early pregnancy and during the breast feeding period. UDCA may be effective for the prevention of cholestasis in PBC during pregnancy. PMID:8650973

  13. Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2.

    PubMed

    Ogura, Masato; Kikuchi, Haruhisa; Suzuki, Toshiyuki; Yamaki, Junko; Homma, Miwako K; Oshima, Yoshiteru; Homma, Yoshimi

    2016-04-01

    Development of new immunosuppressing agents is necessary in organ transplantation or immune diseases. Because Ppc-1 exhibits a suppressing effect on interleukin-2 (IL2) production in Jurkat cells, we synthesized and screened Ppc-1 derivatives that preserve prenylated quinolinecarboxylic acid (PQA) structure, and identified compound 18 (PQA-18) as a novel molecule with immunosuppressing effect. PQA-18 suppressed not only IL2 but also IL4, IL6, and tumor necrosis factor-α production in human peripheral lymphocytes without affecting cell viability. Two-dimensional gel electrophoresis analysis and in vitro kinase assay revealed that PQA-18 inhibits kinase activity of p21-activated kinase 2 (PAK2). Administration of PQA-18 by intraperitoneal injection suppressed the population of a subset of regulatory T cells and the immunoglobulin (Ig) production against T cell-dependent antigens in mice. Treatment with the PQA-18 ointment on Nc/Nga mice, a model of human atopic dermatitis, improved skin lesions and serum IgE levels. These results suggest that PQA-18 is a unique PAK2 inhibitor with potent immunosuppressing effects in vitro and in vivo. PQA-18 may be a valuable lead for the development of novel immunosuppressants. PMID:26827943

  14. Characterization of bacteria that suppress rhizoctonia damping-off in bark compost media by analysis of Fatty Acid biomarkers.

    PubMed

    Tunlid, A; Hoitink, H A; Low, C; White, D C

    1989-06-01

    Examination of cucumber roots (Cucumis sativus L.) grown in bark compost media and of the surrounding edaphic substrate showed profiles of polar lipid fatty acids commonly found in bacteria. The composition of fatty acids in these profiles differed significantly between roots grown in a medium naturally suppressive to Rhizoctonia damping-off and roots from a conducive medium. Cucumber roots from the suppressive medium had higher proportions of cis-vaccenic acid (18:1 omega 7c) and the iso-branched monoenoic fatty acid i17:1 omega 8 but lower proportions of several iso- and anteiso-branched fatty acids compared with roots from the conducive medium. The concentrations of the bacterial fatty acids were significantly lower in the surrounding media. However, the suppressive and conducive growth substrates had differences in the composition of the bacterial fatty acids similar to those found between the cucumber roots proper. These results suggest major differences in bacterial community composition between suppressive and conducive systems. Fatty acid analyses were also utilized to examine the effects on bacterial community composition of root colonization by Flavobacterium balustinum 299, a biocontrol agent. The concentration of the most prominent fatty acid in this bacterium, i17:1 omega 8, was increased on roots produced from inoculated seeds in a medium rendered suppressive by the treatment. This change was concomitant with a significant increase in the concentration of 18:1 omega 7c, not present in the lipids of the antagonist, indicating a shift in the microflora from a conducive to a suppressive bacterial community. PMID:16347930

  15. Phytic acid suppresses ischemia-induced hydroxyl radical generation in rat myocardium.

    PubMed

    Obata, Toshio; Nakashima, Michiko

    2016-03-01

    The present study examined whether ischemia-reperfusion-induced hydroxyl radical (·OH) generation was attenuated by myo-inositol hexaphosphoric acid (phytic acid). A flexibly mounted microdialysis technique was used to detect the generation of ·OH in in vivo rat hearts. To measure the level of ·OH, sodium salicylate in Ringer's solution (0.5mM or 0.5 nmol/μl/min) was infused directly through a microdialysis probe to detect the generation of ·OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA). To confirm the generation of ·OH by Fenton-type reaction, iron(II) was infused through a microdialysis probe. A positive linear correlation between iron(II) and the formation of 2,3-DHBA (R(2)=0.983) was observed. However, the level of 2,3-DHBA in norepinephrine (100 μM) plus phytic acid (100 μM) treated group were significantly lower than those observed in norepinephrine-only-treated group (n=6, *p<0.05). To examine the effect of phytic acid on ischemia-reperfusion-induced ·OH generation, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, the normal elevation of 2,3-DHBA in the heart dialysate was not observed in animals pretreated with phytic acid. These results suggest that phytic acid is associated with antioxidant effect due to the suppression of iron-induced ·OH generation. PMID:26724394

  16. Suppression of ricinoleic acid toxicity by ptl2 overexpression in fission yeast Schizosaccharomyces pombe.

    PubMed

    Yazawa, Hisashi; Ogiso, Masayo; Kumagai, Hiromichi; Uemura, Hiroshi

    2014-11-01

    We previously succeeded to obtain a high content of ricinoleic acid (RA), a hydroxylated fatty acid with great values as a petrochemical replacement, in fission yeast Schizosaccharomyces pombe by introducing Claviceps purpurea oleate Δ12-hydroxylase gene (CpFAH12). Although the production was toxic to S. pombe cells, we identified plg7, encoding phospholipase A2, as a multicopy suppressor that restored the growth defect by removing RA from phospholipids and induced secretion of a part of the released free RA into culture media. In this study, we extended our analysis and examined the effect of triglyceride (TG) lipase overexpression on the tolerance to RA toxicity and RA productivity. S. pombe has three TG lipase genes, ptl1, ptl2, and ptl3, which have high protein sequence similarities to each other and to Saccharomyces cerevisiae counterparts TGL3, TGL4, and TGL5, but only ptl2 overexpression suppressed the growth defect induced by RA production, and the culture grown at 20 °C secreted free RA into media like plg7 overexpression. Suppression by ptl2 was independent of plg7, and a large amount of free RA was accumulated in the cells concomitant with the decrease in RA moieties in phospholipids. Furthermore, the suppression by ptl2 was attenuated by bromoenol lactone (BEL), a phospholipase A2 specific inhibitor, suggesting that Ptl2p may have phospholipase activity. Simultaneous overexpression of ptl2 and plg7 in the FAH12 integrant increased secretion and intracellular accumulation of RA 1.2- and 1.3-fold, respectively, compared to those with single overexpression of plg7 on day 10 at 20 °C. PMID:25109267

  17. Dietary histidine increases mouse skin urocanic acid levels and enhances UVB-induced immune suppression of contact hypersensitivity.

    PubMed

    Reilly, S K; De Fabo, E C

    1991-04-01

    Urocanic Acid (UCA) exists in mammalian skin primarily as the trans isomer and is photoisomerized to cis UCA upon UVB absorption. Our previous studies indicated that the photoisomerization of UCA is the initiating event in UBV-induced suppression of cell-mediated immunity (tUCA----cUCA----immune suppression). The purpose of this study was to verify the role of UCA in UV-induced immune suppression of contact hypersensitivity (CHS) in BALB/c mice. Since UCA is a metabolite of the amino acid L-histidine, we reasoned that increased dietary levels of histidine should raise skin tUCA levels. If skin tUCA is the UVB photoreceptor for immune suppression, this increase should enhance UV-induced suppression of CHS. HPLC analysis of skin from BALB/c mice given a histidine-rich diet (10%) showed that the total amount of UCA is significantly higher in these animals than in mice fed a normal diet. Further, levels of suppression of CHS of 3% and 49% in control fed mice, induced by 4.8 and 7.2 kJ/m2 UVB were significantly increased to 21% and 71% respectively in histidine-fed animals at these same UVB doses. These findings provide additional support for the UCA model for immune suppression, and provide the first evidence that UV-induced immune suppression can be enhanced by a dietary component, L-histidine. PMID:1857737

  18. Amino acids suppress apoptosis induced by sodium laurate, an absorption enhancer.

    PubMed

    Takayama, Chie; Mukaizawa, Fuyuki; Fujita, Takuya; Ogawara, Ken-ichi; Higaki, Kazutaka; Kimura, Toshikiro

    2009-12-01

    The formulation containing sodium laurate (C12), an absorption enhancer, and several amino acids such as taurine (Tau) and L-glutamine (L-Gln) is a promising preparation that can safely improve the intestinal absorption of poorly absorbable drugs. The safety for intestinal mucosa is achieved because the amino acids prevent C12 from causing mucosal damages via several mechanisms. In the present study, the possible involvement of apoptosis, programmed cell death, in mucosal damages caused by C12 and cytoprotection by amino acids was examined. C12 induced DNA fragmentation, a typical phenomenon of apoptosis, in rat large-intestinal epithelial cells while the addition of amino acids significantly attenuated it. C12 alone significantly increased the release of cytochrome C, an apoptosis-inducing factor, from mitochondria, which could be via the decrease in the level of Bcl-2, an inhibiting factor of cytochrome C release. The enhancement of cytochrome C release by C12 led to the activation of caspase 9, an initiator enzyme, and the subsequent activation of caspase 3, an effector enzyme. On the other hand, Tau or L-Gln significantly suppressed the release of cytochrome C from mitochondria and attenuated the activities of both caspases, which could be attributed to the maintenance of Bcl-2 expression. PMID:19630065

  19. Nucleic Acid Bioconjugates in Cancer Detection and Therapy.

    PubMed

    Patel, Pradeepkumar L; Rana, Niki K; Patel, Mayurbhai R; Kozuch, Stephen D; Sabatino, David

    2016-02-01

    Nucleoside- and nucleotide-based chemotherapeutics have been used to treat cancer for more than 50 years. However, their inherent cytotoxicities and the emergent resistance of tumors against treatment has inspired a new wave of compounds in which the overall pharmacological profile of the bioactive nucleic acid component is improved by conjugation with delivery vectors, small-molecule drugs, and/or imaging modalities. In this manner, nucleic acid bioconjugates have the potential for targeting and effecting multiple biological processes in tumors, leading to synergistic antitumor effects. Consequently, tumor resistance and recurrence is mitigated, leading to more effective forms of cancer therapy. Bioorthogonal chemistry has led to the development of new nucleoside bioconjugates, which have served to improve treatment efficacy en route towards FDA approval. Similarly, oligonucleotide bioconjugates have shown encouraging preclinical and clinical results. The modified oligonucleotides and their pharmaceutically active formulations have addressed many weaknesses of oligonucleotide-based drugs. They have also paved the way for important advancements in cancer diagnosis and treatment. Cancer-targeting ligands such as small-molecules, peptides, and monoclonal antibody fragments have all been successfully applied in oligonucleotide bioconjugation and have shown promising anticancer effects in vitro and in vivo. Thus, the application of bioorthogonal chemistry will, in all likelihood, continue to supply a promising pipeline of nucleic acid bioconjugates for applications in cancer detection and therapy. PMID:26663095

  20. Glycolic acid peel therapy – a current review

    PubMed Central

    Sharad, Jaishree

    2013-01-01

    Chemical peels have been time-tested and are here to stay. Alpha-hydroxy peels are highly popular in the dermatologist’s arsenal of procedures. Glycolic acid peel is the most common alpha-hydroxy acid peel, also known as fruit peel. It is simple, inexpensive, and has no downtime. This review talks about various studies of glycolic acid peels for various indications, such as acne, acne scars, melasma, postinflammatory hyperpigmentation, photoaging, and seborrhea. Combination therapies and treatment procedure are also discussed. Careful review of medical history, examination of the skin, and pre-peel priming of skin are important before every peel. Proper patient selection, peel timing, and neutralization on-time will ensure good results, with no side effects. Depth of the glycolic acid peel depends on the concentration of the acid used, the number of coats applied, and the time for which it is applied. Hence, it can be used as a very superficial peel, or even a medium depth peel. It has been found to be very safe with Fitzpatrick skin types I–IV. All in all, it is a peel that is here to stay. PMID:24399880

  1. Polyunsaturated fatty acid supplementation reverses cystic fibrosis-related fatty acid abnormalities in CFTR-/- mice by suppressing fatty acid desaturases.

    PubMed

    Njoroge, Sarah W; Laposata, Michael; Boyd, Kelli L; Seegmiller, Adam C

    2015-01-01

    Cystic fibrosis patients and model systems exhibit consistent abnormalities in metabolism of polyunsaturated fatty acids that appear to play a role in disease pathophysiology. Recent in vitro studies have suggested that these changes are due to overexpression of fatty acid desaturases that can be reversed by supplementation with the long-chain polyunsaturated fatty acids docosahexaenoate and eicosapentaenoate. However, these findings have not been tested in vivo. The current study aimed to test these results in an in vivo model system, the CFTR(-/-) knockout mouse. When compared with wild-type mice, the knockout mice exhibited fatty acid abnormalities similar to those seen in cystic fibrosis patients and other model systems. The abnormalities were confined to lung, ileum and pancreas, tissues that are affected by the disease. Similar to in vitro models, these fatty acid changes correlated with increased expression of Δ5- and Δ6-desaturases and elongase 5. Dietary supplementation with high-dose free docosahexaenoate or a combination of lower-dose docosahexaenoate and eicosapentaenoate in triglyceride form corrected the fatty acid abnormalities and reduced expression of the desaturase and elongase genes in the ileum and liver of knockout mice. Only the high-dose docosahexaenoate reduced histologic evidence of disease, reducing mucus accumulation in ileal sections. These results provide in vivo support for the hypothesis that fatty acid abnormalities in cystic fibrosis result from abnormal expression and activity of metabolic enzymes in affected cell types. They further demonstrate that these changes can be reversed by dietary n-3 fatty acid supplementation, highlighting the potential therapeutic benefit for cystic fibrosis patients. PMID:25448610

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

    PubMed

    Heemstra, K A; Hamdy, N A T; Romijn, J A; Smit, J W A

    2006-06-01

    Patients with differentiated thyroid carcinoma (DTC) are commonly treated long-term with thyrotropin (TSH)- suppressive thyroxine replacement therapy resolving in a state of subclinical hyperthyroidism. The relationship between subclinical hyperthyroidism and osteoporosis is not clear. In this review, we systematically selected and analyzed 21 studies addressing this issue. Although multiple methodological differences between studies prevented a structured meta-analysis, our data suggest that postmenopausal women with subclinical hyperthyroidism are most at risk, whereas no increased risk was observed in men and premenopausal women. Based on these findings we believe that measurement of bone mineral density is recommended in postmenopausal women with DTC starting TSH suppressive therapy. This should be subsequently regularly measured to enable timely intervention with bone protective agents. PMID:16839260

  3. Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of AMPK and Akt signaling networks

    PubMed Central

    Chuu, Chih-Pin; Lin, Hui-Ping; Ciaccio, Mark F.; Kokontis, John M.; Hause, Ronald J.; Hiipakka, Richard A.; Liao, Shutsung; Jones, Richard Baker

    2016-01-01

    Caffeic acid phenethyl ester (CAPE) is a bioactive component derived from honeybee hive propolis. CAPE has been shown to have anti-mitogenic, anti-carcinogenic, and other beneficial medicinal properties. Many of its effects have been shown to be mediated through its inhibition of NF-κB signaling pathways. We took a systematic approach to uncover CAPE’s effects from hours to days on the signaling networks in human prostate cancer cells. We observed that CAPE dosage-dependently suppressed the proliferation of LNCaP, DU-145, and PC-3 human prostate cancer cells. Administration of CAPE by gavage significantly inhibited the tumor growth of LNCaP xenografts in nude mice. Using LNCaP cells as a model system, we examined CAPE’s effect on gene expression, protein signaling, and transcriptional regulatory networks using Micro-Western Arrays and PCR arrays. We built a model of CAPE’s impact on cell signaling which suggested that it acted through inhibition of Akt-related protein signaling networks. Over-expression of Akt1 or cMyc, a downstream target of Akt signaling, significantly blocked the anti-proliferative effects of CAPE. In summary, our results suggest that CAPE administration may be useful as an adjuvant therapy for prostate and potentially other types of cancers that are driven by the AMPK and Akt signaling networks. PMID:22562408

  4. Apoptotic effect of gambogic acid in esophageal squamous cell carcinoma cells via suppression of the NF-κB pathway

    PubMed Central

    LIU, WEN-YUE; WU, XU; LIAO, CHENG-QUAN; SHEN, JIE; LI, JUN

    2016-01-01

    Despite extensive investigations of therapeutic improvements for surgical techniques, chemotherapy and chemoradiotherapy, esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive forms of cancer, and the prognosis for patients with advanced ESCC remains poor. Therefore, effective therapies are urgently required in order to improve the prognosis of patients with ESCC. TE-1 cells were treated with gambogic acid (GA), and then subjected to western blot analysis, TUNEL assay and caspase activity analysis. GA significantly induced apoptosis in ESCC TE-1 cells. In addition, the antitumor activity of GA was accompanied by the decreased expression of phosphorylated-protein kinase B (p-AKT) and nuclear factor of κ light polypeptide gene enhancer in B-cells 1 (NF-κB). The inhibition of protein kinase B (AKT) and NF-κB activation by chemical inhibitors augmented the apoptotic effect responses to GA in the TE-1 cells. The pan-caspase inhibitor z-VAD-fmk (zVAD) decreased GA-induced apoptosis. Furthermore, zVAD attenuated GA-induced growth inhibition in TE-1 cells. GA induced apoptosis in ESCC TE-1 via suppression of NF-κB pathway. The findings of the present study may provide a novel insight into ESCC treatment. PMID:27284372

  5. Parameter estimation and optimal scheduling algorithm for a mathematical model of intermittent androgen suppression therapy for prostate cancer

    NASA Astrophysics Data System (ADS)

    Guo, Qian; Lu, Zhichang; Hirata, Yoshito; Aihara, Kazuyuki

    2013-12-01

    We propose an algorithm based on cross-entropy to determine parameters of a piecewise linear model, which describes intermittent androgen suppression therapy for prostate cancer. By comparing with clinical data, the parameter estimation for the switched system shows good fitting accuracy and efficiency. We further optimize switching time points for the piecewise linear model to obtain a feasible therapeutic schedule. The simulation results of therapeutic effect are superior to those of previous strategy.

  6. Inhibition of Large Neutral Amino Acid Transporters Suppresses Kynurenic Acid Production Via Inhibition of Kynurenine Uptake in Rodent Brain.

    PubMed

    Sekine, Airi; Kuroki, Yusuke; Urata, Tomomi; Mori, Noriyuki; Fukuwatari, Tsutomu

    2016-09-01

    The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor and N-methyl-D-aspartic acid receptor at endogenous brain concentrations. Recent studies have suggested that increases of brain KYNA levels are involved in psychiatric disorders such as schizophrenia and depression, and regulation of KYNA production has become a new target for treatment of these diseases. Kynurenine (KYN), the immediate precursor of KYNA, is transported into astrocytes via large neutral amino acid transporters (LATs). In the present study, the effect of LATs regulation on KYN uptake and KYNA production was investigated in vitro and in vivo using an LATs inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). In the in vitro study, cortical slices of rat brain were incubated with a physiological concentration of KYN and 3 µmol/L-3 mmol/L BCH. BCH inhibited KYNA production and KYN uptake in a dose-dependent manner, and their IC50 values were 90.7 and 97.4 µmol/L, respectively. In the in vivo study, mice were administered KYN (50 mg/kg BW) orally and BCH (200 mg/kg BW) intravenously. Administration of KYN increased brain KYN and KYNA levels compared with the mice treated with vehicle, whereas additional administration of BCH suppressed KYN-induced elevations in KYN and KYNA levels to 50 and 70 % in the brain. These results suggest that inhibition of LATs prevented the increase of KYNA production via blockade of KYN uptake in the brain in vitro and in vivo. LATs can be a target to modulate brain function by regulation of KYNA production in the brain. PMID:27161376

  7. Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy.

    PubMed

    Del Prete, Gregory Q; Oswald, Kelli; Lara, Abigail; Shoemaker, Rebecca; Smedley, Jeremy; Macallister, Rhonda; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Li, Yuan; Fast, Randy; Kiser, Rebecca; Lu, Bing; Zheng, Jim; Alvord, W Gregory; Trubey, Charles M; Piatak, Michael; Deleage, Claire; Keele, Brandon F; Estes, Jacob D; Hesselgesser, Joseph; Geleziunas, Romas; Lifson, Jeffrey D

    2016-03-01

    Replication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination antiretroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (<30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n = 5) or saline (n = 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4(+) T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy. PMID:26711758

  8. Suppression of renal cell carcinoma growth and metastasis with sustained antiangiogenic gene therapy.

    PubMed

    Mellon, Matthew J; Bae, Kyung-Hee; Steding, Catherine E; Jiménez, Juan A; Kao, Chinghai; Gardner, Thomas A

    2008-05-01

    Renal cell carcinoma (RCC) is the third most common urologic neoplasm. This aggressive malignancy has proven refractory to conventional treatment options. Antiangiogenic agents have shown early success in treating metastatic disease. The highly vascular nature of RCC appears particularly susceptible to this approach. This study investigates the potential of sustained expression of an endostatin-angiostatin fusion protein in an early-stage model of RCC to inhibit tumor growth and metastasis. Subcutaneous RCC-29 tumors were induced in athymic nude mice. Once tumors reached volumes of 10 and 25 mm(3), subjects received intratumoral injections of a nonreplicating adenoviral vector every 20 days until the conclusion of the trial. The mice were randomly assigned to three treatment groups: saline control, viral Ad-GFP control, and Ad-EndoAngio. Tumor volumes were measured twice weekly for 80 days. During days 40-50 of the trial, subjects underwent dual-photon optical imaging of the tumor vasculature to ascertain angiogenic changes. All animals underwent postmortem histopathological analysis to assess for metastatic disease in the kidney, lung, liver, brain, and spleen. Results indicate that tumors treated with Ad-EndoAngio displayed 97% growth reduction compared with controls (p < 0.001). Further, in vivo tumor vascular imaging illustrated a reduction in blood vessel number and lumen diameter size. Kaplan-Meier analysis suggested dramatic survival advantage with Ad-EndoAngio treatment. Importantly, histopathological examination demonstrated marked lung and liver metastasis suppression in the treatment arms. These results suggest that sustained EndoAngio gene therapy has effective antiangiogenic action against human RCC tumors and possesses potential as a novel treatment for metastatic renal cell carcinoma. PMID:18507514

  9. Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules.

    PubMed

    Mohiuddin, M A; Pursnani, K G; Katzka, D A; Gideon, R M; Castell, J A; Castell, D O

    1997-04-01

    Omeprazole is inactivated by exposure to gastric acid and is formulated as a gelatin capsule containing enteric-coated granules that release the drug in alkaline medium. In clinical situations where patients are unable to take the capsule orally, the optimum means of administration is uncertain. Eleven normal volunteers were given omeprazole 20 mg every day for one week before breakfast in random order as either a 20-mg capsule with water or free enteric-coated granules with either 8 oz of orange juice, 8 oz of water with 2 Alka-Seltzer antacid tablets (aspirin free), or 1 teaspoon of apple sauce. On day 7 of each regimen, an 8-hr intragastric pH study was performed following omeprazole 20 mg and standard breakfast. The median percentage of time of gastric acid pH > 4 after an omeprazole capsule was 68.5 (25-100); after granules with orange juice 59 (43-100); after granules in Alka-Seltzer solution 63 (31-100), and after granules in apple sauce 65 (30-99), with no significant differences (ANOVA). The time for the gastric pH to reach <4' after having been above was also similar for all four regimens (ANOVA). Omeprazole granules administered orally in a variety of ways achieve gastric acid suppression as effectively as the intact capsule. PMID:9125637

  10. 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.

  11. Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa.

    PubMed

    Millington-Ward, Sophia; Chadderton, Naomi; O'Reilly, Mary; Palfi, Arpad; Goldmann, Tobias; Kilty, Claire; Humphries, Marian; Wolfrum, Uwe; Bennett, Jean; Humphries, Peter; Kenna, Paul F; Farrar, G Jane

    2011-04-01

    For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in the rhodopsin gene. Validation of a mutation-independent suppression and replacement gene therapy for this disorder has been undertaken. The therapy provides a means of correcting the genetic defect in a mutation-independent manner thereby circumventing the mutational diversity. Separate adeno-associated virus (AAV) vectors were used to deliver an RNA interference (RNAi)-based rhodopsin suppressor and a codon-modified rhodopsin replacement gene resistant to suppression due to nucleotide alterations at degenerate positions over the RNAi target site. Viruses were subretinally coinjected into P347S mice, a model of dominant rhodopsin-linked retinitis pigmentosa. Benefit in retinal function and structure detected by electroretinography (ERG) and histology, respectively, was observed for at least 5 months. Notably, the photoreceptor cell layer, absent in 5-month-old untreated retinas, contained 3-4 layers of nuclei, whereas photoreceptor ultrastructure, assessed by transmission electron microscopy (TEM) improved significantly. The study provides compelling evidence that codelivered suppression and replacement is beneficial, representing a significant step toward the clinic. Additionally, dual-vector delivery of combined therapeutics represents an exciting approach, which is potentially applicable to other inherited disorders. PMID:21224835

  12. Role of acid suppressants in patients with Zollinger-Ellison syndrome.

    PubMed

    Maton, P N

    1991-01-01

    Virtually all symptoms in patients with Zollinger-Ellison syndrome are due to acid hypersecretion, thus the control of acid secretion is the first and most important step in the management of patients with this syndrome. Antisecretory medication is prescribed as soon as the diagnosis of Zollinger-Ellison syndrome is made, as patients may bleed or perforate with little warning. Acid output is reduced to less than 10 mmol/h to heal mucosal lesions, but in patients with a Billroth I or II gastrectomy and those with severe oesophagitis and stricture formation, acid output is reduced to less than 5 or less than 1 mmol/h. Acid output and not symptomatic response is a reliable guide of the adequacy of therapy. In sufficient doses, all H2-receptor antagonists are useful; however, side effects associated with cimetidine therapy limit its use. The ratio of potencies of cimetidine:ranitidine:famotidine is 1:4:32. Ranitidine given as a 50-mg intravenous bolus, followed by a continuous infusion of 0.5 mg.kg/h, controls acid hypersecretion acutely in patients with Zollinger-Ellison syndrome. Acid output is checked after 4 h, and the dose increased until acid output is less than 10 mmol/h. In 70% of patients with Zollinger-Ellison syndrome, 1 mg.kg/h reduces acid output to less than 10 mmol/h; however, doses up to 4 mg.kg/h have been used. When patients are switched to oral ranitidine, a useful dosage conversion is to administer 1.5 times the total daily intravenous dose in four equal doses every 6 h. Four doses of oral drug are given before the infusion is stopped. Six hours after the first/last oral dose, acid output is checked. In our patients, the mean dose of ranitidine was 2100 mg/day (range, 450-9200 mg/day). No serious toxicity was observed. Omeprazole, which has a long duration of action and is a potent inhibitor of gastric acid secretion, has simplified management. Once-daily dosing is sufficient in most patients, and a reasonable starting dose is 60 mg daily. The dose

  13. Ingestion of theanine, an amino acid in tea, suppresses psychosocial stress in mice.

    PubMed

    Unno, Keiko; Iguchi, Kazuaki; Tanida, Naoki; Fujitani, Keisuke; Takamori, Nina; Yamamoto, Hiroyuki; Ishii, Naoto; Nagano, Hiroko; Nagashima, Takashi; Hara, Ayane; Shimoi, Kayoko; Hoshino, Minoru

    2013-01-01

    The antistress effect of theanine (γ-glutamylethylamide), an amino acid in tea, was investigated using mice that were psychosocially stressed from a conflict among male mice in conditions of confrontational housing. Two male mice were housed in the same cage separated by a partition to establish a territorial imperative. When the partition was removed, the mice were co-housed confrontationally. As a marker for the stress response, changes in the adrenal gland were studied in comparison to group-housed control mice (six mice in a cage). Significant adrenal hypertrophy was observed in mice during confrontational housing, which was developed within 24 h and persisted for at least 1 week. The size of cells in the zona fasciculata of the adrenal gland, from which glucocorticoid is mainly secreted, increased (∼1.11-fold) in mice during confrontational housing, which was accompanied by a flattened diurnal rhythm of corticosterone and ACTH in blood. The ingestion of theanine (>5 μg ml(-1)) prior to confrontational housing significantly suppressed adrenal hypertrophy. An antidepressant, paroxetin, suppressed adrenal hypertrophy in a similar manner in mice during confrontational housing. In mice that ingested theanine, behavioural depression was also suppressed, and a diurnal rhythm of corticosterone and ACTH was observed, even in mice that were undergoing confrontational housing. Furthermore, the daily dose of theanine (40 μg ml(-1)) blocked the counteracting effects of caffeine (30 μg ml(-1)) and catechin (200 μg ml(-1)). The present study demonstrated that theanine prevents and relieves psychosocial stress through the modulation of hypothalamic-pituitary-adrenal axis activity. PMID:22707502

  14. 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. PMID:18603787

  15. Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress.

    PubMed

    Si, Pei-Pei; Zhen, Jun-Li; Cai, Yun-Lei; Wang, Wen-Jing; Wang, Wei-Ping

    2016-04-01

    There are numerous mechanisms by which the brain generates seizures. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Salidroside (SDS) extracted from Rhodiola rosea L. shows multiple bioactive properties, such as neuroprotection and antioxidant activity in vitro and in vivo. This study explored the role of SDS in kainic acid (KA)-induced SE and investigated the underlying mechanism. Latency to SE increased in the SDS-pretreated mice compared to the KA group, while the percentage of incidence of SE was significantly reduced. These results suggested that pretreatment with SDS not only delayed SE, but it also decreased the incidence of SE induced by KA. KA increased MDA level and reduced the production of SOD and GSH at multiple timepoints after KA administration. SDS inhibited the change of MDA, SOD and GSH induced by KA prior to SE onset, indicating that SDS protects against KA-induced SE via suppressing oxidative stress. Based on these results, we investigated the possible molecular mechanism of SDS. Pretreatment with SDS reversed the KA-induced decrease in AMP-activated protein kinase (AMPK); increased the sirtuin 1 (SIRT1) deacetylase activity in KA-treated mice, which had no demonstrable effect on SIRT1 mRNA and protein; and suppressed the KA-induced increase in Ace-FoxO1. These results showed that AMPK/SIRT1/FoxO1 signaling is possibly the molecular mechanism of neuroprotection by SDS. PMID:26940236

  16. 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

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

    PubMed

    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

  18. 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

  19. Might the use of acid-suppressive medications predispose to the development of eosinophilic esophagitis?

    PubMed

    Merwat, Shehzad Nawaz; Spechler, Stuart Jon

    2009-08-01

    The prevalence of eosinophilic esophagitis, a manifestation of food allergy, has increased in recent years for reasons that are not clear. The gastrointestinal mucosa is regularly exposed to food antigens with the potential to evoke immunological reactions. Studies have shown that some food allergens that ordinarily would be degraded by peptic digestion are not degraded when the pH of gastric fluid is raised to levels commonly found in the stomachs of patients treated with proton pump inhibitors (PPIs). Other studies have shown that PPIs increase gastrointestinal mucosal permeability, which might facilitate the uptake of undegraded peptide allergens. Mice treated with antisecretory medications while being fed a diet of caviar have been found to develop caviar-specific immunoglobulin E (IgE) antibodies, T-cell reactivity, and gastric eosinophilia. Adult patients treated with antisecretory medications for 3 months have been found to develop a rise in their IgE antibody levels and new, food-specific IgE antibodies. These data establish a plausible mechanism whereby acid-suppressive medications, by interfering with the peptic digestion of food allergens and increasing mucosal permeability, might lead to the development of food allergy. The time course of the introduction and subsequent widespread usage of PPIs with the emergence of eosinophilic esophagitis fits well with the hypothesis that PPIs may play an etiological role. Although the mere demonstration of a plausible association does not establish cause and effect, further studies on the role of acid suppression in the development of eosinophilic esophagitis clearly are warranted. PMID:19661930

  20. Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice

    PubMed Central

    Su, Jin; Sherman, Alexandra; Doerfler, Phillip A.; Byrne, Barry J.; Herzog, Roland W.; Daniell, Henry

    2015-01-01

    Summary Deficiency of acid alpha glucosidase (GAA) causes Pompe disease in which the patients systemically accumulate lysosomal glycogen in muscles and nervous systems, often resulting in infant mortality. Although enzyme replacement therapy (ERT) is effective in treating patients with Pompe disease, formation of antibodies against rhGAA complicates treatment. In this report, we investigated induction of tolerance by oral administration of GAA expressed in chloroplasts. Because full-length GAA could not be expressed, N-terminal 410-amino acids of GAA (as determined by T-cell epitope mapping) were fused with the transmucosal carrier CTB. Tobacco transplastomic lines expressing CTB-GAA were generated through site-specific integration of transgenes into the chloroplast genome. Homoplasmic lines were confirmed by Southern blot analysis. Despite low-level expression of CTB-GAA in chloroplasts, yellow or albino phenotype of transplastomic lines was observed due to binding of GAA to a chloroplast protein that has homology to mannose-6 phosphate receptor. Oral administration of the plant-made CTB-GAA fusion protein even at 330-fold lower dose (1.5 μg) significantly suppressed immunoglobulin formation against GAA in Pompe mice injected with 500 μg rhGAA per dose, with several-fold lower titre of GAA-specific IgG1 and IgG2a. Lyophilization increased CTB-GAA concentration by 30-fold (up to 190 μg per g of freeze-dried leaf material), facilitating long-term storage at room temperature and higher dosage in future investigations. This study provides the first evidence that oral delivery of plant cells is effective in reducing antibody responses in ERT for lysosomal storage disorders facilitating further advances in clinical investigations using plant cell culture system or in vitro propagation. PMID:26053072

  1. Self-reported non-adherence to immune-suppressant therapy in liver transplant recipients: demographic, interpersonal, and intrapersonal factors.

    PubMed

    Lamba, Sangeeta; Nagurka, Roxanne; Desai, Kunj K; Chun, Shaun J; Holland, Bart; Koneru, Baburao

    2012-01-01

    Adherence to immune suppressants and follow-up care regimen is important in achieving optimal long-term outcomes after organ transplantation. To identify patients most at risk for non-adherence, this cross-sectional, descriptive study explores the prevalence and correlates of non-adherence to immune-suppressant therapy among liver recipients. Anonymous questionnaires mailed consisted of the domains: (i) adherence barriers to immune suppressants, (ii) immune suppressants knowledge, (iii) demographics, (iv) social support, (v) medical co-morbidities, and (vi) healthcare locus of control and other beliefs. Overall response was 49% (281/572). Data analyzed for those transplanted within 10 yr of study reveal 50% (119/237) recipients or 9.2/100 person years reporting non-adherence. Non-adherence was reported highest in the 2-5 yr post-transplant phase (69/123, 56%). The highest immune-suppressant non-adherence rates were in recipients who are: divorced (26/34, 76%, p=0.0093), have a history of substance or alcohol use (42/69, 61%, p=0.0354), have mental health needs (50/84, 60%, p=0.0336), those who missed clinic appointments (25/30, 83%, p<0.0001), and did not maintain medication logs (71/122, 58%, p=0.0168). Respondents who were non-adherent with physician appointments were more than four and a half times as likely (OR 4.7, 95% CI 1.5-14.7, p=0.008) to be non-adherent with immune suppressants. In conclusion, half of our respondents report non-adherence to immune suppressants. Factors identified may assist clinicians to gauge patients' non-adherence risk and target resources. PMID:21955028

  2. Cholera Toxin B Subunit Linked to Glutamic Acid Decarboxylase Suppresses Dendritic Cell Maturation and Function

    PubMed Central

    Odumosu, Oludare; Nicholas, Dequina; Payne, Kimberly; Langridge, William

    2012-01-01

    Dendritic cells are the largest population of antigen presenting cells in the body. One of their main functions is to regulate the delicate balance between immunity and tolerance responsible for maintenance of immunological homeostasis. Disruption of this delicate balance often results in chronic inflammation responsible for initiation of organ specific autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and type I diabetes. The cholera toxin B subunit (CTB) is a weak mucosal adjuvant known for its ability to stimulate immunity to antigenic proteins. However, conjugation of CTB to many autoantigens can induce immunological tolerance resulting in suppression of autoimmunity. In this study, we examined whether linkage of CTB to a 5 kDa C-terminal protein fragment of the major diabetes autoantigen glutamic acid decarboxylase (GAD35), can block dendritic cell (DC) functions such as biosynthesis of co-stimulatory factor proteins CD86, CD83, CD80 and CD40 and secretion of inflammatory cytokines. The results of human umbilical cord blood monocyte-derived DC - GAD35 autoantigen incubation experiments showed that inoculation of immature DCs (iDCs), with CTB-GAD35 protein dramatically suppressed levels of CD86, CD83, CD80 and CD40 co-stimulatory factor protein biosynthesis in comparison with GAD35 alone inoculated iDCs. Surprisingly, incubation of iDCs in the presence of the CTB-autoantigen and the strong immunostimulatory molecules PMA and Ionomycin revealed that CTB-GAD35 was capable of arresting PMA + Ionomycin induced DC maturation. Consistant with this finding, CTB-GAD35 mediated suppression of DC maturation was accompanied by a dramatic decrease in the secretion of the pro-inflammatory cytokines IL-12/23p40 and IL-6 and a significant increase in secretion of the immunosuppressive cytokine IL-10. Taken together, our experimental data suggest that linkage of the weak adjuvant CTB to the dominant type 1 diabetes autoantigen GAD strongly inhibits DC

  3. Compost-induced suppression of Pythium damping-off is mediated by fatty-acid-metabolizing seed-colonizing microbial communities.

    PubMed

    McKellar, Mary E; Nelson, Eric B

    2003-01-01

    Leaf composts were studied for their suppressive effects on Pythium ultimum sporangium germination, cottonseed colonization, and the severity of Pythium damping-off of cotton. A focus of the work was to assess the role of fatty-acid-metabolizing microbial communities in disease suppression. Suppressiveness was expressed within the first few hours of seed germination as revealed by reduced P. ultimum sporangium germination, reduced seed colonization, and reduced damping-off in transplant experiments. These reductions were not observed when cottonseeds were sown in a conducive leaf compost. Microbial consortia recovered from the surface of cottonseeds during the first few hours of germination in suppressive compost (suppressive consortia) induced significant levels of damping-off suppression, whereas no suppression was induced by microbial consortia recovered from cottonseeds germinated in conducive compost (conducive consortia). Suppressive consortia rapidly metabolized linoleic acid, whereas conducive consortia did not. Furthermore, populations of fatty-acid-metabolizing bacteria and actinobacteria were higher in suppressive consortia than in conducive consortia. Individual bacterial isolates varied in their ability to metabolize linoleic acid and protect seedlings from damping-off. Results indicate that communities of compost-inhabiting microorganisms colonizing cottonseeds within the first few hours after sowing in a Pythium-suppressive compost play a major role in the suppression of P. ultimum sporangium germination, seed colonization, and damping-off. Results further indicate that fatty acid metabolism by these seed-colonizing bacterial consortia can explain the Pythium suppression observed. PMID:12514027

  4. Fatty acid competition as a mechanism by which Enterobacter cloacae suppresses Pythium ultimum sporangium germination and damping-off.

    PubMed

    van Dijk, K; Nelson, E B

    2000-12-01

    Interactions between plant-associated microorganisms play important roles in suppressing plant diseases and enhancing plant growth and development. While competition between plant-associated bacteria and plant pathogens has long been thought to be an important means of suppressing plant diseases microbiologically, unequivocal evidence supporting such a mechanism has been lacking. We present evidence here that competition for plant-derived unsaturated long-chain fatty acids between the biological control bacterium Enterobacter cloacae and the seed-rotting oomycete, Pythium ultimum, results in disease suppression. Since fatty acids from seeds and roots are required to elicit germination responses of P. ultimum, we generated mutants of E. cloacae to evaluate the role of E. cloacae fatty acid metabolism on the suppression of Pythium sporangium germination and subsequent plant infection. Two mutants of E. cloacae EcCT-501R3, Ec31 (fadB) and EcL1 (fadL), were reduced in beta-oxidation and fatty acid uptake, respectively. Both strains failed to metabolize linoleic acid, to inactivate the germination-stimulating activity of cottonseed exudate and linoleic acid, and to suppress Pythium seed rot in cotton seedling bioassays. Subclones containing fadBA or fadL complemented each of these phenotypes in Ec31 and EcL1, respectively. These data provide strong evidence for a competitive exclusion mechanism for the biological control of P. ultimum-incited seed infections by E. cloacae where E. cloacae prevents the germination of P. ultimum sporangia by the efficient metabolism of fatty acid components of seed exudate and thus prevents seed infections. PMID:11097912

  5. Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis, in close correlation with depressive-like behavior.

    PubMed

    Hu, Pu; Wang, Yu; Liu, Ji; Meng, Fan-Tao; Qi, Xin-Rui; Chen, Lin; van Dam, Anne-Marie; Joëls, Marian; Lucassen, Paul J; Zhou, Jiang-Ning

    2016-07-01

    Clinical studies have highlighted an association between retinoid treatment and depressive symptoms. As we had shown before that chronic application of all-trans retinoic acid (RA) potently activated the hypothalamus-pituitary-adrenal (HPA) stress axis, we here questioned whether RA also induced changes in adult hippocampal neurogenesis, a form of structural plasticity sensitive to stress and implicated in aspects of depression and hippocampal function. RA was applied intracerebroventricularly (i.c.v.) to adult rats for 19 days after which animals were subjected to tests for depressive-like behavior (sucrose preference) and spatial learning and memory (water maze) performance. On day 27, adult hippocampal neurogenesis and astrogliosis was quantified using BrdU (newborn cell survival), PCNA (proliferation), doublecortin (DCX; neuronal differentiation), and GFAP (astrocytes) as markers. RA was found to increase retinoic acid receptor-α (RAR-α) protein expression in the hippocampus, suggesting an activation of RA-induced signaling mechanisms. RA further potently suppressed cell proliferation, newborn cell survival as well as neurogenesis, but not astrogliosis. These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA-induced impairments in hippocampal neurogenesis correlate with depression-like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA-associated mood disorders. © 2016 Wiley Periodicals, Inc. PMID:26860546

  6. 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. PMID:26232092

  7. Ginkgolic acid suppresses the development of pancreatic cancer by inhibiting pathways driving lipogenesis.

    PubMed

    Ma, Jiguang; Duan, Wanxing; Han, Suxia; Lei, Jianjun; Xu, Qinhong; Chen, Xin; Jiang, Zhengdong; Nan, Ligang; Li, Jiahui; Chen, Ke; Han, Liang; Wang, Zheng; Li, Xuqi; Wu, Erxi; Huo, Xiongwei

    2015-08-28

    Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. with a wide range of bioactive properties, including anti-tumor effect. However, whether GA has antitumor effect on pancreatic cancer cells and the underlying mechanisms have yet to be investigated. In this study, we show that GA suppressed the viability of cancer cells but has little toxicity on normal cells, e.g, HUVEC cells. Furthermore, treatment of GA resulted in impaired colony formation, migration, and invasion ability and increased apoptosis of cancer cells. In addition, GA inhibited the de novo lipogenesis of cancer cells through inducing activation of AMP-activated protein kinase (AMPK) signaling and downregulated the expression of key enzymes (e.g. acetyl-CoA carboxylase [ACC], fatty acid synthase [FASN]) involved in lipogenesis. Moreover, the in vivo experiment showed that GA reduced the expression of the key enzymes involved in lipogenesis and restrained the tumor growth. Taken together, our results suggest that GA may serve as a new candidate against tumor growth of pancreatic cancer partially through targeting pathway driving lipogenesis. PMID:25895130

  8. Intracoronary photodynamic therapy reduces neointimal growth without suppressing re‐endothelialisation in a porcine model

    PubMed Central

    Waksman, R; Leitch, I M; Roessler, J; Yazdi, H; Seabron, R; Tio, F; Scott, R W; Grove, R I; Rychnovsky, S; Robinson, B; Pakala, R; Cheneau, E

    2006-01-01

    Objective To examine the effects of intracoronary PhotoPoint photodynamic therapy (PDT) with a new photosensitiser, MV0611, in the overstretch balloon and stent porcine models of restenosis. Methods 28 pigs were injected with 3 mg/kg of MV0611 systemically 4 h before the procedure. Animals were divided into either the balloon overstretch injury (BI) group (n  =  19) or the stented group (n  =  9). After BI, a centred delivery catheter was positioned in the artery to cover the injured area, and light (532 nm, 125 J/cm2) was applied to activate the drug (n  =  10). Control arteries (n  =  9) were not activated by light. In the stented group, the drug was light activated before stent deployment. Serial sections of vessels were processed 14 days after treatment in the BI group and 30 days after treatment in the stented group for histomorphometric or immunohistochemical analysis. Results Intracoronary PDT significantly reduced intimal thickness in both BI and stented arteries (about 65%: 0.22 (SEM 0.05) mm v 0.62 (0.05) mm, p < 0.01; and about 26%: 0.40 (0.04) mm v 0.54 (0.04) mm, p < 0.01, respectively). PDT increased luminal area by ⩽ 60% and 50% within BI and stented arteries (3.43 (0.27) mm2v 5.51 (0.52) mm2, p < 0.05; 4.0 (0.02) mm2v 6.0 (0.16) mm2, p < 0.01), respectively. Complete re‐endothelialisation was observed by immunohistochemical and gross histological analyses in all PDT and control arteries. There were no cases of aneurysm formation or thrombosis. Conclusion Intracoronary PhotoPoint PDT with MV0611 reduces intimal proliferation without suppressing re‐endothelialisation in a porcine model of restenosis. PMID:16399853

  9. Theranostic nanoparticles based on PEGylated hyaluronic acid for the diagnosis, therapy and monitoring of colon cancer

    PubMed Central

    Choi, Ki Young; Jeon, Eun Jung; Yoon, Hong Yeol; Lee, Beom Suk; Na, Jin Hee; Min, Kyung Hyun; Kim, Sang Yoon; Myung, Seung-Jae; Lee, Seulki; Chen, Xiaoyuan; Kwon, Ick Chan; Choi, Kuiwon; Jeong, Seo Young; Kim, Kwangmeyung; Park, Jae Hyung

    2013-01-01

    Colon cancer is the second leading cause of cancer-related death in the United States. The considerable mortality from colon cancer is due to metastasis to other organs, mainly the liver. In the management of colon cancer, early detection and targeted therapy are crucial. In this study, we aimed to establish a versatile theranostic system for early tumor detection and targeted tumor therapy by using poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) which can selectively accumulate in tumor tissue. For the diagnostic application, a near-infrared fluorescence (NIRF) imaging dye (Cy 5.5) was chemically conjugated onto the HA backbone of P-HA-NPs. After intravenous injection of Cy5.5-P-HA-NPs into the tumor-bearing mice, small-sized colon tumors as well as liver-implanted colon tumors were effectively visualized using the NIRF imaging technique. For targeted therapy, we physically encapsulated the anticancer drug, irinotecan (IRT), into the hydrophobic cores of P-HA-NPs. Owing to their notable tumor targeting capability, IRT-P-HA-NPs exhibited an excellent antitumor activity while showing a reduction in undesirable systemic toxicity. Importantly, we demonstrated the theranostic application using Cy5.5-P-HA-NPs and IRT-P-HA-NPs in orthotopic colon cancer models. Following the systemic administration of Cy5.5-P-HA-NPs, neoplasia was clearly visualized, and the tumor growth was effectively suppressed by intravenous injection of IRT-P-HA-NPs. It should be emphasized that the therapeutic responses could be simultaneously monitored by Cy5.5-P-HA-NPs. Our results suggest that P-HA-NPs can be used as a versatile theranostic system for the early detection, targeted therapy, and therapeutic monitoring of colon cancer. PMID:22687759

  10. 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. PMID:21691101

  11. Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts

    PubMed Central

    KOMATSU, YUKO; IBI, MIHO; CHOSA, NAOYUKI; KYAKUMOTO, SEIKO; KAMO, MASAHARU; SHIBATA, TOSHIYUKI; SUGIYAMA, YOSHIKI; ISHISAKI, AKIRA

    2016-01-01

    Bisphosphonates (BPs) are analogues of pyro-phosphate 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. PMID:27176567

  12. Tolfenamic Acid Suppresses Inflammatory Stimuli-Mediated Activation of NF-κB Signaling

    PubMed Central

    Shao, Hong Jun; Lou, Zhiyuan; Jeong, Jin Boo; Kim, Kui Jin; Lee, Jihye; Lee, Seong-Ho

    2015-01-01

    Tolfenamic acid (TA) is a traditional non-steroid anti-inflammatory drug (NSAID) and has been broadly used for the treatment of migraines. Nuclear factor kappa B (NF-κB) is a sequence-specific transcription factor and plays a key role in the development and progression of inflammation and cancer. We performed the current study to investigate the underlying mechanisms by which TA suppresses inflammation focusing on NF-κB pathway in TNF-α stimulated human normal and cancer cell lines and lipopolysaccharide (LPS)-stimulated mouse macrophages. Different types of human cells (HCT116, HT-29 and HEK293) and mouse macrophages (RAW264.7) were pre-treated with different concentrations of TA and then exposed to inflammatory stimuli such as TNF-α and LPS. Transcriptional activity of NF-κB, IκB-α-degradation, p65 translocation and mitogen-activated protein kinase (MAPK) activations were measured using luciferase assay and Western blots. Pre-treatment of TA repressed TNF-α- or LPS-stimulated NF-κB transactivation in a dose-dependent manner. TA treatment reduced degradation of IκB-α and subsequent translocation of p65 into nucleus. TA significantly down-regulated the phosphorylation of c-Jun N-terminal kinase (JNK). However, TA had no effect on NF-κB signaling and JNK phosphorylation in HT-29 human colorectal cancer cells. TA possesses anti-inflammatory activities through suppression of JNK/NF-κB pathway in different types of cells. PMID:25593642

  13. Differential effects of rapamycin and retinoic acid on expansion, stability and suppressive qualities of human CD4+CD25+FOXP3+ T regulatory cell subpopulations

    PubMed Central

    Scottà, Cristiano; Esposito, Marianna; Fazekasova, Henrieta; Fanelli, Giorgia; Edozie, Francis C.; Ali, Niwa; Xiao, Fang; Peakman, Mark; Afzali, Behdad; Sagoo, Pervinder; Lechler, Robert I.; Lombardi, Giovanna

    2013-01-01

    Adoptive transfer of ex vivo expanded CD4+CD25+FOXP3+ regulatory T cells is a successful therapy for autoimmune diseases and transplant rejection in experimental models. In man, equivalent manipulations in bone marrow transplant recipients appear safe, but questions regarding the stability of the transferred regulatory T cells during inflammation remain unresolved. In this study, protocols for the expansion of clinically useful numbers of functionally suppressive and stable human regulatory T cells were investigated. Regulatory T cells were expanded in vitro with rapamycin and/or all-trans retinoic acid and then characterized under inflammatory conditions in vitro and in vivo in a humanized mouse model of graft-versus-host disease. Addition of rapamycin to regulatory T-cell cultures confirms the generation of high numbers of suppressive regulatory T cells. Their stability was demonstrated in vitro and substantiated in vivo. In contrast, all-trans retinoic acid treatment generates regulatory T cells that retain the capacity to secrete IL-17. However, combined use of rapamycin and all-trans retinoic acid abolishes IL-17 production and confers a specific chemokine receptor homing profile upon regulatory T cells. The use of purified regulatory T-cell subpopulations provided direct evidence that rapamycin can confer an early selective advantage to CD45RA+ regulatory T cells, while all-trans retinoic acid favors CD45RA− regulatory T-cell subset. Expansion of regulatory T cells using rapamycin and all-trans retinoic acid drug combinations provides a new and refined approach for large-scale generation of functionally potent and phenotypically stable human regulatory T cells, rendering them safe for clinical use in settings associated with inflammation. PMID:23242600

  14. Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy

    PubMed Central

    Lokeshwar, Vinata B.; Mirza, Summan; Jordan, Andre

    2016-01-01

    Hyaluronic acid or hyaluronan (HA) is perhaps one of the most uncomplicated large polymers that regulates several normal physiological processes and, at the same time, contributes to the manifestation of a variety of chronic and acute diseases, including cancer. Members of the HA signaling pathway (HA synthases, HA receptors, and HYAL-1 hyaluronidase) have been experimentally shown to promote tumor growth, metastasis, and angiogenesis, and hence each of them is a potential target for cancer therapy. Furthermore, as these members are also overexpressed in a variety of carcinomas, targeting of the HA family is clinically relevant. A variety of targeted approaches have been developed to target various HA family members, including small-molecule inhibitors and antibody and vaccine therapies. These treatment approaches inhibit HA-mediated intracellular signaling that promotes tumor cell proliferation, motility, and invasion, as well as induction of endothelial cell functions. Being nontoxic, nonimmunogenic, and versatile for modifications, HA has been used in nanoparticle preparations for the targeted delivery of chemotherapy drugs and other anticancer compounds to tumor cells through interaction with cell-surface HA receptors. This review discusses basic and clinical translational aspects of targeting each HA family member and respective treatment approaches that have been described in the literature. PMID:25081525

  15. Gene therapy for aromatic L-amino acid decarboxylase deficiency.

    PubMed

    Hwu, Wuh-Liang; Muramatsu, Shin-ichi; Tseng, Sheng-Hong; Tzen, Kai-Yuan; Lee, Ni-Chung; Chien, Yin-Hsiu; Snyder, Richard O; Byrne, Barry J; Tai, Chun-Hwei; Wu, Ruey-Meei

    2012-05-16

    Aromatic L-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector-mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[(18)F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function. PMID:22593174

  16. Rosmarinic acid and arbutin suppress osteoclast differentiation by inhibiting superoxide and NFATc1 downregulation in RAW 264.7 cells

    PubMed Central

    OMORI, AKINA; YOSHIMURA, YOSHITAKA; DEYAMA, YOSHIAKI; SUZUKI, KUNIAKI

    2015-01-01

    The present study investigated the effect of the natural polyphenols, rosmarinic acid and arbutin, on osteoclast differentiation in RAW 264.7 cells. Rosmarinic acid and arbutin suppressed osteoclast differentiation and had no cytotoxic effect on osteoclast precursor cells. Rosmarinic acid and arbutin inhibited superoxide production in a dose-dependent manner. mRNA expression of the master regulator of osteoclastogenesis, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and the osteoclast marker genes, matrix metalloproteinase-9, tartrate-resistant acid phosphatase and cathepsin-K, decreased following treatments with rosmarinic acid and arbutin. Furthermore, resorption activity decreased with the number of osteoclasts. These results suggest that rosmarinic acid and arbutin may be useful for the prevention and treatment of bone diseases, such as osteoporosis, through mechanisms involving inhibition of superoxide and downregulation of NFATc1. PMID:26171153

  17. Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance

    PubMed Central

    YOSHIJI, HITOSHI; NOGUCHI, RYUICHI; NAMISAKI, TADASHI; MORIYA, KEI; KITADE, MITSUTERU; AIHARA, YOSUKE; DOUHARA, AKITOSHI; YAMAO, JUNICHI; FUJIMOTO, MASAO; TOYOHARA, MASAHISA; MITORO, AKIRA; SAWAI, MASAYOSHI; YOSHIDA, MOTOYUKI; MORIOKA, CHIE; UEJIMA, MASAKAZU; UEMURA, MASAHITO; FUKUI, HIROSHI

    2013-01-01

    Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI) >15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS) >110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions. PMID:23708326

  18. Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance.

    PubMed

    Yoshiji, Hitoshi; Noguchi, Ryuichi; Namisaki, Tadashi; Moriya, Kei; Kitade, Mitsuteru; Aihara, Yosuke; Douhara, Akitoshi; Yamao, Junichi; Fujimoto, Masao; Toyohara, Masahisa; Mitoro, Akira; Sawai, Masayoshi; Yoshida, Motoyuki; Morioka, Chie; Uejima, Masakazu; Uemura, Masahito; Fukui, Hiroshi

    2013-08-01

    Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI)>15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS)>110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions. PMID:23708326

  19. Alpha-lipoic acid supplementation: a tool for obesity therapy?

    PubMed

    Carbonelli, M G; Di Renzo, L; Bigioni, M; Di Daniele, N; De Lorenzo, A; Fusco, M A

    2010-01-01

    Lipid peroxidation has supposed as the major biochemical alteration underling oxidant-induced cell injury in stress including numerous diseases. One of the natural molecules know to prevent or retard oxidation is alpha-lipoic acid (LA) and, therefore, the lipoic acid/dihydrolipoic acid (LA/DHLA) redox couple has received considerable attention. Recent studies have highlighted the potential of free LA and DHLA as powerful metabolic antioxidants that are able to scavenge the reactive oxygen species, to recycle other antioxidants. Our aim was to investigate the beneficial effects of LA in the treatment of Italian pre-obese and obese subjects. We screened 1612 subjects for enrollment; of these, 1127 subjects (445 men and 682 women, 18-60 age) met enrolment criteria and were enrolled in the study. According to body mass index (BMI) the 53% was obese and the 43% was pre-obese. The subjects were treated for 4 month with 800 mg/day of LA. In pre-obese subject significant reduction (p<0.001) of weight (8%, both gender), BMI (2 points), blood pressure, and abdominal circumference (female 6 cm, male 7 cm) were observed. In obese subjects significant reductions (p<0.001) of weight (9%, both gender), BMI (female 3 point, male 4 point), blood pressure and abdominal circumference (female 9 cm, male 11 cm) were observed. Our study indicated that LA is an ideal antioxidant candidate for the therapy of obesity related diseases. Further clinical studies should be considered to highlight the role and efficacy of LA treatment. PMID:20388095

  20. CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

    PubMed Central

    Wang, Xingxu; Ni, Li; Yang, Lei; Duan, Quanlu; Chen, Chen; Edin, Matthew L.; Zeldin, Darryl C.

    2014-01-01

    Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca2+. These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca2+ homeostasis and SERCA2a expression and activity. PMID:24145329

  1. CYP2J2-derived epoxyeicosatrienoic acids suppress endoplasmic reticulum stress in heart failure.

    PubMed

    Wang, Xingxu; Ni, Li; Yang, Lei; Duan, Quanlu; Chen, Chen; Edin, Matthew L; Zeldin, Darryl C; Wang, Dao Wen

    2014-01-01

    Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca(2+). These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca(2+) homeostasis and SERCA2a expression and activity. PMID:24145329

  2. Resistance training suppresses intra-abdominal fatty acid synthesis in ovariectomized rats.

    PubMed

    Stotzer, U S; Rodrigues, M F C; Domingos, M M; Silva, G H G; Duarte, F O; Gatto, C V G; Duarte, A C G O; Shiguemoto, G E; Perez, S E A; Selistre-de-Araujo, H S

    2015-03-01

    Ovarian hormone loss is associated with a shift in fat distribution to intra-abdomin al adipose tissue (intra-AAT) depots and with lipid metabolism disorders, which predisposes individuals to developing insulin resistance. Resistance training (RT) prevents increases in intra-AAT after ovarian hormone loss. However, the molecular mechanisms underlying these changes remain unclear. We investigated the effects of ovariectomy and RT on gene expression related to lipogenesis and fat oxidation in the intra-AAT of ovariectomized rats. Sprague-Dawley rats (n=6/group) were divided into the groups: sham-sedentary, ovariectomized-sedentary, sham-RT and ovariectomized-RT. RT groups performed a 10-week climbing program on a ladder with progressive overload. Intra-AAT was subjected to morphometric and mRNA analysis. Ovariectomized-sedentary group had larger adipocytes and higher expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), sterol regulatory element-binding protein-1c (SREBP-1c), stearoyl-CoA desaturase-1 (SCD-1), acetyl-CoA carboxylase (ACC), hormone-sensitive lipase (HSL) and lower expression of the oxidative carnitinepalmitoyltransferase-I (CPT-1). RT counteracted OVX-induced increases in PPAR-γ and SCD-1 and decreased SREBP-1c. ACC and HSL were downregulated in ovariectomized-RT compared with the ovariectomized-sedentary group. Ovariectomized-RT group had the highest CPT-1 gene expression. Adipocyte size decreased in ovariectomized-RT group. Results suggest that RT reduces intra-AAT adipocyte size in ovariectomized rats by suppressing intra-AAT fatty acid synthesis and enhancing fatty acid β-oxidation. PMID:25415388

  3. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins.

    PubMed

    Göbel, Andy; Browne, Andrew J; Thiele, Stefanie; Rauner, Martina; Hofbauer, Lorenz C; Rachner, Tilman D

    2015-12-01

    The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50% reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25% compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation. PMID:26515701

  4. DNA/polyethyleneimine/hyaluronic acid small complex particles and tumor suppression in mice.

    PubMed

    Ito, Tomoko; Yoshihara, Chieko; Hamada, Katsuyuki; Koyama, Yoshiyuki

    2010-04-01

    The highest barriers for non-viral vectors to an efficient in vivo gene transfection would be (1) non-specific interaction with biological molecules, and (2) large size of the DNA complex particles. Protective coating of the DNA/polyethyleneimine (PEI) complexes by hyaluronic acid (HA) effectively diminished the adverse interactions with biological molecules. Here we found HA also protected the DNA/PEI complexes against aggregation and inactivation through lyophilization-and-rehydration procedures. It allows us to prepare the concentrated very small DNA complex particles (<70 nm) suspension by preparing the complexes at highly diluted conditions, followed by lyophilized-and-rehydrated to a small volume. In vivo gene expression efficiency of the small complex was examined with mice subcutaneously inoculated with B16 melanoma cells. These formulations showed high reporter-gene expression level in tumor after intravenous injection into tumor-bearing mice. Small complex was then made of the plasmid encoding GM-CSF gene, and injected into the mice bearing subcutaneous solid B16 tumor. After intravenous injection, it induced apparent tumor growth suppression in 50% of the mice. Notably, significant therapeutic effect was detected in the mice that received intratumoral injection, and 75% of the mice were completely cured with disappearance of tumor. PMID:20047759

  5. Omega-3 Fatty Acid Intervention Suppresses Lipopolysaccharide-Induced Inflammation and Weight Loss in Mice

    PubMed Central

    Liu, Ying-Hua; Li, Xiang-Yong; Chen, Chih-Yu; Zhang, Hong-Man; Kang, Jing X.

    2015-01-01

    Bacterial endotoxin lipopolysaccharide (LPS)-induced sepsis is a critical medical condition, characterized by a severe systemic inflammation and rapid loss of muscle mass. Preventive and therapeutic strategies for this complex disease are still lacking. Here, we evaluated the effect of omega-3 (n-3) polyunsaturated fatty acid (PUFA) intervention on LPS-challenged mice with respect to inflammation, body weight and the expression of Toll-like receptor 4 (TLR4) pathway components. LPS administration induced a dramatic loss of body weight within two days. Treatment with n-3 PUFA not only stopped loss of body weight but also gradually reversed it back to baseline levels within one week. Accordingly, the animals treated with n-3 PUFA exhibited markedly lower levels of inflammatory cytokines or markers in plasma and tissues, as well as down-regulation of TLR4 pathway components compared to animals without n-3 PUFA treatment or those treated with omega-6 PUFA. Our data demonstrate that n-3 PUFA intervention can suppress LPS-induced inflammation and weight loss via, at least in part, down-regulation of pro-inflammatory targets of the TLR4 signaling pathway, and highlight the therapeutic potential of n-3 PUFA in the management of sepsis. PMID:25689565

  6. Valproic acid suppresses the self-renewal and proliferation of head and neck cancer stem cells.

    PubMed

    Lee, Sang Hyuk; Nam, Hyo Jung; Kang, Hyun Jung; Samuels, Tina L; Johnston, Nikki; Lim, Young Chang

    2015-10-01

    Emerging evidence suggests that cancer cells present profound epigenetic alterations in addition to featuring classic genetic mutations. Valproic acid (VPA), a histone deacetylase inhibitor, can potently inhibit tumor growth and induce differentiation. However, the effect and underlying mechanism of VPA on head and neck squamous cell carcinoma (HNSCC) cancer stem cells (CSCs) remain unclear. In the present study we investigated the effects of VPA on the characteristics of HNSCC CSCs in vitro and in vivo. As a result, VPA inhibited the self-renewal abilities of HNSCC CSCs during two serial passages and decreased the expression of stem cell markers, such as Oct4, Sox2 and CD44. VPA also potentiated the cytotoxic effect of cisplatin by suppressing the ABCC2 and ABCC6 transporters as well as by inducing caspase-mediated apoptosis. In addition, the combination of VPA and cisplatin attenuated tumor growth and induced apoptosis in a xenograft model. Our results suggest that VPA might be a potential therapeutic strategy in combination with conventional cisplatin for HNSCC patients by elimination of CSC traits. PMID:26239260

  7. Suppression of Adult Neurogenesis Increases the Acute Effects of Kainic Acid

    PubMed Central

    Iyengar, Sloka S.; LaFrancois, John J.; Friedman, Daniel; Drew, Liam J.; Denny, Christine A.; Burghardt, Nesha S.; Wu, Melody V.; Hsieh, Jenny; Hen, René; Scharfman, Helen E.

    2016-01-01

    Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4 hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21 hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30 min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA. PMID:25476494

  8. Endogenous central suppressive mechanisms regulating cough as potential targets for novel antitussive therapies.

    PubMed

    Mazzone, Stuart B; McGovern, Alice E; Farrell, Michael J

    2015-06-01

    Cough and the accompanying sensation known as the urge-to-cough are complex neurobiological phenomena dependent on sensory and motor neural processing at many levels of the neuraxis. In addition to the excitatory neural circuits that provide the positive drive for inducing cough and the urge-to-cough, recent studies have highlighted the existence of likely inhibitory central neural processes that can be engaged to suppress cough sensorimotor processing. In many respects, the balance between excitatory and inhibitory central cough control may be a critical determinant of cough in health and disease which argues for the importance of understanding the biology of these putative central inhibitory processes. This brief review summarises the current knowledge of the central circuits that govern voluntary and involuntary cough suppression and posits the notion of targeting central suppressive mechanisms as a treatment for disordered cough in disease. PMID:25704497

  9. Viral protein suppresses oxidative burst and salicylic acid-dependent autophagy and facilitates bacterial growth on virus-infected plants.

    PubMed

    Zvereva, Anna S; Golyaev, Victor; Turco, Silvia; Gubaeva, Ekaterina G; Rajeswaran, Rajendran; Schepetilnikov, Mikhail V; Srour, Ola; Ryabova, Lyubov A; Boller, Thomas; Pooggin, Mikhail M

    2016-08-01

    Virus interactions with plant silencing and innate immunity pathways can potentially alter the susceptibility of virus-infected plants to secondary infections with nonviral pathogens. We found that Arabidopsis plants infected with Cauliflower mosaic virus (CaMV) or transgenic for CaMV silencing suppressor P6 exhibit increased susceptibility to Pseudomonas syringae pv. tomato (Pst) and allow robust growth of the Pst mutant hrcC-, which cannot deploy effectors to suppress innate immunity. The impaired antibacterial defense correlated with the suppressed oxidative burst, reduced accumulation of the defense hormone salicylic acid (SA) and diminished SA-dependent autophagy. The viral protein domain required for suppression of these plant defense responses is dispensable for silencing suppression but essential for binding and activation of the plant target-of-rapamycin (TOR) kinase which, in its active state, blocks cellular autophagy and promotes CaMV translation. Our findings imply that CaMV P6 is a versatile viral effector suppressing both silencing and innate immunity. P6-mediated suppression of oxidative burst and SA-dependent autophagy may predispose CaMV-infected plants to bacterial infection. PMID:27120694

  10. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

    PubMed Central

    Sim, Geok Choo; Martin-Orozco, Natalia; Jin, Lei; Yang, Yan; Wu, Sheng; Washington, Edwina; Sanders, Deborah; Lacey, Carol; Wang, Yijun; Vence, Luis; Hwu, Patrick; Radvanyi, Laszlo

    2013-01-01

    High-dose (HD) IL-2 therapy in patients with cancer increases the general population of Tregs, which are positive for CD4, CD25, and the Treg-specific marker Foxp3. It is unknown whether specific subsets of Tregs are activated and expanded during HD IL-2 therapy or whether activation of any particular Treg subset correlates with clinical outcome. Here, we evaluated Treg population subsets that were induced in patients with melanoma following HD IL-2 therapy. We identified a Treg population that was positive for CD4, CD25, Foxp3, and the inducible T cell costimulator (ICOS). This Treg population increased more than any other lymphocyte subset during HD IL-2 therapy and had an activated Treg phenotype, as indicated by high levels of CD39, CD73, and TGF-β. ICOS+ Tregs were the most proliferative lymphocyte population in the blood after IL-2 therapy. Patients with melanoma with enhanced expansion of ICOS+ Tregs in blood following the first cycle of HD IL-2 therapy had worse clinical outcomes than patients with fewer ICOS+ Tregs. However, there was no difference in total Treg expansion between HD IL-2 responders and nonresponders. These data suggest that increased expansion of the ICOS+ Treg population following the first cycle of HD IL-2 therapy may be predictive of clinical outcome. PMID:24292706

  11. 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. PMID:27176567

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

    PubMed Central

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

    2016-01-01

    Objective 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. Methods 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. Results Pre-ART high-sensitivity C-reactive protein (hsCRP) values of men were in the high-risk cardiovascular disease category (>3.0mg/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. Conclusion 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. PMID:26372272

  13. [Antibiotics, azelaic acid and benzoyl peroxide in topical acne therapy].

    PubMed

    Fluhr, Joachim W; Degitz, Klaus

    2010-03-01

    Benzoyl peroxide was introduced as a basic treatment already in acne therapy 1934. The mechanism of action is the reduction of anaerobe bacteria by strong oxidation processes. No resistancies have been ever reported. BPO is available in 2.5, 5 and 10 % formulations. Its efficacy is slightly related to the strength of concentrations, but the side effect profile with burning, erythema and desquamation is increasing with concentrations. BPO 5% mostly is efficient enough to control acne of grades I to II according to the Kligman & Plewig classification. BPO my bleach clothes and hair. It is the most costeffective topical drug in acne of grades I-II. Inflammatory acne of the papular-pustular type I-II can also be treated by topical antibiotics such as erythromycin, clindamycin, and, less frequent and today not anymore recommended tetracyclines. Mechanism of action is not alone an antibacterial but anti inflammatory effect. The efficacy and penetration of the topical antibiotics between the groups are similar. Randomized studies have shown that concentrations of 2-4% are equivalent to oral tetracycline and minocycline in mild to moderate acne. Combinatory formulations with BPO and with retinoids enhance the efficacy significantly. Topical antibiotics plus BPO show less bacterial resistancies as topical antibiotics alone. Antibiotics should therefore not be used as monotherapy. Moreover gram negative folliculitis may develop. Azelaic acid is acting as an antimicrobial and can also reduce comedones. It can also be used in pregnancy and during the lactation period. PMID:20482689

  14. Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis

    PubMed Central

    Parajuli, Keshab R; Zhang, Qiuyang; Liu, Sen; Patel, Neil K; Lu, Hua; Zeng, Shelya X; Wang, Guangdi; Zhang, Changde; You, Zongbing

    2014-01-01

    Methoxyacetic acid (MAA) is a primary metabolite of ester phthalates that are used in production of consumer products and pharmaceutical products. MAA causes embryo malformation and spermatocyte death through inhibition of histone deacetylases (HDACs). Little is known about MAA’s effects on cancer cells. In this study, two immortalized human normal prostatic epithelial cell lines (RWPE-1 and pRNS-1-1) and four human prostate cancer cell lines (LNCaP, C4-2B, PC-3, and DU-145) were treated with MAA at different doses and for different time periods. Cell viability, apoptosis, and cell cycle analysis were performed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR, Western blot, and chromatin immunoprecipitation analyses. We found that MAA dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. MAA-induced apoptosis was due to down-regulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, also named cIAP1), leading to activation of caspases 7 and 3 and turning on the downstream apoptotic events. MAA-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and CDK2 expression at the late time. MAA up-regulated p21 expression through inhibition of HDAC activities, independently of p53/p63/p73. These findings demonstrate that MAA suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which suggests that MAA could be used as a potential therapeutic drug for prostate cancer. PMID:25606576

  15. NFX1-LIKE2 (NFXL2) Suppresses Abscisic Acid Accumulation and Stomatal Closure in Arabidopsis thaliana

    PubMed Central

    Lisso, Janina; Schröder, Florian; Fisahn, Joachim; Müssig, Carsten

    2011-01-01

    The NFX1-LIKE1 (NFXL1) and NFXL2 genes were identified as regulators of salt stress responses. The NFXL1 protein is a nuclear factor that positively affects adaptation to salt stress. The nfxl1-1 loss-of-function mutant displayed reduced survival rates under salt and high light stress. In contrast, the nfxl2-1 mutant, defective in the NFXL2 gene, and NFXL2-antisense plants exhibited enhanced survival under these conditions. We show here that the loss of NFXL2 function results in abscisic acid (ABA) overaccumulation, reduced stomatal conductance, and enhanced survival under drought stress. The nfxl2-1 mutant displayed reduced stomatal aperture under all conditions tested. Fusicoccin treatment, exposition to increasing light intensities, and supply of decreasing CO2 concentrations demonstrated full opening capacity of nfxl2-1 stomata. Reduced stomatal opening presumably is a consequence of elevated ABA levels. Furthermore, seedling growth, root growth, and stomatal closure were hypersensitive to exogenous ABA. The enhanced ABA responses may contribute to the improved drought stress resistance of the mutant. Three NFXL2 splice variants were cloned and named NFXL2-78, NFXL2-97, and NFXL2-100 according to the molecular weight of the putative proteins. Translational fusions to the green fluorescent protein suggest nuclear localisation of the NFXL2 proteins. Stable expression of the NFXL2-78 splice variant in nfxl2-1 plants largely complemented the mutant phenotype. Our data show that NFXL2 controls ABA levels and suppresses ABA responses. NFXL2 may prevent unnecessary and costly stress adaptation under favourable conditions. PMID:22073231

  16. Structured triacylglycerol containing behenic and oleic acids suppresses triacylglycerol absorption and prevents obesity in rats

    PubMed Central

    2010-01-01

    Background Dietary 1(3)-behenoyl-2,3(1)-dioleoyl-rac-glycerol (BOO) has been reported to inhibit pancreatic lipase activity in vitro and suppress postprandial hypertriacylglycerolemia in humans. In the present study, the anti-obesity activities of BOO and its inhibitory effects on lymphatic triacylglycerol (TAG) absorption were investigated in rats. Methods In Experiment 1, rats were fed either BOO or soybean oil (SO) diet for 6 weeks. In the BOO diet, 20% of SO was replaced with an experimental oil rich in BOO. In Experiments 2 and 3, rats cannulated in the thoracic duct were administered an emulsions containing trioleoylglycerol (OOO) or an oil mixture (OOO:BOO, 9:1). Tri[1-14C]oleoylglycerol (14C-OOO) was added to the emulsions administered in Experiment 3. Results No observable differences were detected in food intake or body weight gain between the BOO and SO groups in Experiment 1. Plasma and liver TAG concentrations and visceral fat weights were significantly lower in the BOO group than in the SO group. The apparent absorption rate of fat was significantly lower in the BOO group than in the SO group. In Experiment 2, the lymphatic recovery of oleic and behenic acids was significantly lower at 5 and 6 h after BOO administration than after OOO administration. In Experiment 3, the lymphatic recovery of 14C-OOO was significantly lower at 5 and 6 h after BOO administration than after OOO administration. Conclusions These results suggest that BOO prevents deposition of visceral fat and hepatic TAG by lowering and delaying intestinal absorption of TAG. PMID:20653972

  17. [Acne therapy with topical benzoyl peroxide, antibiotics and azelaic acid].

    PubMed

    Worret, Wolf-Ingo; Fluhr, Joachim W

    2006-04-01

    Benzoyl peroxide (BPO) was introduced in the treatment of acne in 1934. Despite the fact that only few randomized trials have been published, BPO is considered the standard in topical acne treatment. Anaerobic bacteria are reduced by oxidative mechanisms and the induction of resistant strains is reduced. Topical formulations are available at concentrations of 2.5, 5, 10 and 20 %. The effect is dose-dependent, but the irritation increases with higher concentrations. Usually 5 % BPO is sufficient to control acne grade I-II. Due to its strong oxidative potential, patients should be advised that BPO may bleach colored and dark clothing, bedding and even hair. BPO is safe for use in pregnant and lactating females because it is degraded to benzoic acid. It is a cost-effective treatment for acne grade I-II. Patients with papulopustular acne grade I-II, particularly with marked inflammation, show satisfactory improvement with topical antibiotic treatment. The following compounds are available and effective: erythromycin, clindamycin and tetracycline (the latter being less frequently used). A review in 1990 suggested that topical tetracycline was ineffective in the treatment of acne. Along with eliminating Propionibacterium acnes, the main mechanism of topical antibiotics is their antiinflammatory effect. All three penetrate the epidermal barrier well and are similarly efficacious. Randomized trials have shown that in concentrations of 2-4 %, their effects are comparable to oral tetracycline and minocycline. Combination therapy with retinoids or benzoyl peroxide (BPO) increases efficacy. Retinoids increase penetration and reduce comedones, while topical antibiotics primarily address inflammation. One side effect of topical antibacterial treatment is an increase in drug-resistant resident skin flora with gram-negative microorganisms prevailing, which can lead to gram-negative folliculitis. All three antibiotics fluoresce under black light which may produce interesting

  18. Alpha-linolenic acid suppresses dopaminergic neurodegeneration induced by 6-OHDA in C. elegans.

    PubMed

    Shashikumar, S; Pradeep, H; Chinnu, Salim; Rajini, P S; Rajanikant, G K

    2015-11-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the specific and massive loss of dopamine (DA) containing neurons in the substantia nigra pars compacta (SNpc) and aggregation of protein α-synuclein. There are a few animal studies, which indirectly implicate the neuroprotective action of omega-3 polyunsaturated fatty acids in neurodegenerative diseases. In this study, we exposed Caenorhabditis elegans (both wild type N2, and transgenic strain, UA44) to 6-hydroxydopamine (6-OHDA, the model neurotoxicant) and evaluated the extent of protection offered by alpha-linolenic acid (ALA). Larval stage worms (L1/L2) of N2 and transgenic strains were exposed to 6-OHDA (25 mM) with or without ALA (10, 50 and 100 μM) for 48 h at 20 °C. After 48 h, while the N2 worms were assessed for their responses in terms of locomotion, pharyngeal pumping, lifespan and AChE activity, the transgenic worms were monitored for dopaminergic neuronal degeneration. Worms exposed to 6-OHDA exhibited a significant reduction (48%) in the locomotion rate. Interestingly, supplementation with ALA increased the locomotion rate in 6-OHDA treated worms. A marked decrease (45%) in thrashing was evident in worms exposed to 6-OHDA while thrashing was slightly improved in worms co-exposed to 6-OHDA and higher concentrations of ALA. Interestingly, worms co-exposed to 6-OHDA with ALA (100 μM) exhibited a significant increase in thrashing (66 ± 1.80 thrashes/30s). The pharyngeal pumping rate declined significantly in the case of worms exposed to 6-OHDA (35%). However, the worms co-treated with ALA exhibited significant recovery in pharyngeal pumping. The mean survival for the control worms was 26 days, while the worms exposed to 6-OHDA, showed a marked reduction in survival (21 days). Worms co-exposed to 6-OHDA and ALA showed a concentration-dependent increase in lifespan compared to those exposed to 6-OHDA alone (23, 25 and 26 days respectively). Transgenic worms

  19. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    SciTech Connect

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai; Bai, Xianyong

    2013-11-01

    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 the 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 may

  20. Myristoleic acid inhibits osteoclast formation and bone resorption by suppressing the RANKL activation of Src and Pyk2.

    PubMed

    Kwon, Jun-Oh; Jin, Won Jong; Kim, Bongjun; Kim, Hong-Hee; Lee, Zang Hee

    2015-12-01

    Cytoskeletal changes in osteoclasts such as formation of actin ring is required for bone-resorbing activity. The tyrosine kinase Src is a key player in massive cytoskeletal change of osteoclasts, thereby in bone destruction. In order for Src to be activated, trafficking to the inner plasma membrane via myristoylation is of importance. A previous study reported that myristoleic acid derived from myristic acid, inhibited N-myristoyl-transferase, an essential enzyme for myristoylation process. This prompted us to investigate whether myristoleic acid could affect osteoclastogenesis. Indeed, we observed that myristoleic acid inhibited RANKL-induced osteoclast formation in vitro, especially, at later stages of differentiation. Myristoleic acid attenuated the tyrosine phosphorylation of c-Src and Pyk2, which associates with Src, by RANKL. When myristoleic acid was co-administered with soluble RANKL into mice, RANKL-induced bone loss was substantially prevented. Bone dissection clearly revealed that the number of multinucleated osteoclasts was significantly diminished by myristoleic acid. On the other hand, myristoleic acid treatment had little or no influence on early osteoclast differentiation markers, such as c-Fos and NFATc1, and proteins related to cytoskeletal rearrangement, including DC-STAMP, integrin αv and integrin β3 in vitro. Taken together, our data suggest that myristoleic acid is capable of blocking the formation of large multinucleated osteoclasts and bone resorption likely through suppressing activation of Src and Pyk2. PMID:26528796

  1. Epigenetic suppression of the antitumor cytotoxicity of NK cells by histone deacetylase inhibitor valproic acid

    PubMed Central

    Shi, Xiumin; Li, Min; Cui, Meizi; Niu, Chao; Xu, Jianting; Zhou, Lei; Li, Wei; Gao, Yushun; Kong, Weisheng; Cui, Jiuwei; Hu, Jifan; Jin, Haofan

    2016-01-01

    Natural killer (NK) cells play an essential role in the fight against tumor development. The therapeutic use of autologous NK cells has been exploited to treat human malignancies, yet only limited antitumor activity is observed in cancer patients. In this study, we sought to augment the antitumor activity of NK cells using epigenetic approaches. Four small molecules that have been known to promote epigenetic reprogramming were tested for their ability to enhance the activity of NK cells. Using a tumor cell lysis assay, we found that the DNA demethylating agent 5-azacytidine and vitamin C did not significantly affect the tumor killing ability of NK cells. The thyroid hormone triiodothyronine (T3) slightly increased the activity of NK cells. The histone deacetylase inhibitor valproic acid (VPA), however, inhibited NK cell lytic activity against leukemic cells in a dose-dependent manner. Pretreatment using VPA reduced IFNγ secretion, impaired CD107a degranulation, and induced apoptosis by activating the PD-1/PD-L1 pathway. VPA downregulated the expression of the activating receptor NKG2D (natural-killer group 2, member D) by inducing histone K9 hypermethylation and DNA methylation in the gene promoter. Histone deacetylase inhibitors have been developed as anticancer agents for use as monotherapies or in combination with other anticancer therapies. Our data suggest that the activity of histone deacetylase inhibitors on NK cell activity should be considered in drug development. PMID:27152238

  2. Salvianolic acid B ameliorates CNS autoimmunity by suppressing Th1 responses.

    PubMed

    Dong, Zhihui; Ma, Dihui; Gong, Ye; Yu, Tingmin; Yao, Gang

    2016-04-21

    Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is a Th1 and Th17 cell-mediated CNS autoimmune disease. Therefore, immune regulation is a key target for therapy. Salvianolic acid B (Sal B) is a major water-soluble bioactive component of the famous traditional Chinese medicine Salvia miltiorrhiza, which is notable for its anti-oxidative and anti-inflammatory effects. Thus Sal B, by impairing Th1 or Th17 responses in EAE/MS, might ameliorate the crippling symptoms. Here we show that the intraperitoneal administration of 30mg/kg Sal B daily for 14 days after the onset of MOG-induced EAE in mice effectively reduced its severity. Additionally, Sal B treatment downgraded the infiltration of inflammatory cells, limited astrogliosis and blocked Th1 responses other than that of Th17. These results indicated that Sal B may serve as an effective therapeutic agent for MS/EAE by inhibiting Th1 cell responses. PMID:26777627

  3. Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility

    PubMed Central

    Ennis, Irene L.; Li, Ronald A.; Murphy, Anne M.; Marbán, Eduardo; Nuss, H. Bradley

    2002-01-01

    Heart failure is characterized by depressed contractility and delayed repolarization. The latter feature predisposes the failing heart to ventricular arrhythmias and represents a logical target for gene therapy. Unfortunately, unopposed correction of the delay in repolarization will decrease the time available for calcium cycling during each heartbeat, potentially aggravating the depression of contractility. Here we describe the development and application of a novel gene therapy strategy designed to abbreviate excitation without depressing contraction. The calcium ATPase SERCA1 was coexpressed with the potassium channel Kir2.1 in guinea pig hearts. Myocytes from the hearts had bigger calcium transients and shorter action potentials. In vivo, repolarization was abbreviated, but contractile function remained unimpaired. Dual gene therapy of the sort described here can be generalized to exploit opposing or synergistic therapeutic principles to achieve a tailored phenotype. PMID:11827999

  4. Tumor growth suppression by gadolinium-neutron capture therapy using gadolinium-entrapped liposome as gadolinium delivery agent.

    PubMed

    Dewi, Novriana; Yanagie, Hironobu; Zhu, Haito; Demachi, Kazuyuki; Shinohara, Atsuko; Yokoyama, Kazuhito; Sekino, Masaki; Sakurai, Yuriko; Morishita, Yasuyuki; Iyomoto, Naoko; Nagasaki, Takeshi; Horiguchi, Yukichi; Nagasaki, Yukio; Nakajima, Jun; Ono, Minoru; Kakimi, Kazuhiro; Takahashi, Hiroyuki

    2013-07-01

    Neutron capture therapy (NCT) is a promising non-invasive cancer therapy approach and some recent NCT research has focused on using compounds containing gadolinium as an alternative to currently used boron-10 considering several advantages that gadolinium offers compared to those of boron. In this study, we evaluated gadolinium-entrapped liposome compound as neutron capture therapy agent by in vivo experiment on colon-26 tumor-bearing mice. Gadolinium compound were injected intravenously via tail vein and allowed to accumulate into tumor site. Tumor samples were taken for quantitative analysis by ICP-MS at 2, 12, and 24 h after gadolinium compound injection. Highest gadolinium concentration was observed at about 2 h after gadolinium compound injection with an average of 40.3 μg/g of wet tumor tissue. We performed neutron irradiation at JRR-4 reactor facility of Japan Atomic Energy Research Institute in Tokaimura with average neutron fluence of 2×10¹² n/cm². The experimental results showed that the tumor growth suppression of gadolinium-injected irradiated group was revealed until about four times higher compared to the control group, and no significant weight loss were observed after treatment suggesting low systemic toxicity of this compound. The gadolinium-entrapped liposome will become one of the candidates for Gd delivery system on NCT. PMID:23743325

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

    SciTech Connect

    Zhai, Yingying; Chen, Xi; Yu, Dehai; Li, Tao; Cui, Jiuwei; Wang, Guanjun; Hu, Ji-Fan; Li, Wei

    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 phase 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.

  6. 5-Aminolevulinic Acid Photodynamic Therapy combined with CO2 laser therapy in treatment of laryngeal papilloma: Case report.

    PubMed

    Zhang, Yunjie; Yang, Yuguang; Zou, Xianbiao; Huang, Zheng

    2016-06-01

    This article describes the case of 5-Aminolevulinic Acid Photodynamic Therapy (ALA-PDT) via self-retaining laryngoscope under general anesthesia combined with CO2 Laser Therapy in the treatment of three patients with juvenile laryngeal papilloma. Laryngeal papilloma Clinically, it features rapid growth, multi-focus, frequent recurrence and possibility of spreading to the lower respiratory tract. ALA-PDT via self-retaining laryngoscope under general anesthesia combined with CO2 Laser Therapy is safe and effective for clearing laryngeal papilloma, laryngeal papilloma was fully removed from the three patients, with no recurrence during the 6-24 months of follow-up medical examination. 5-Aminolevulinic Acid Photodynamic Therapy (ALA-PDT) via self-retaining laryngoscope under general anesthesia combined with CO2 Laser can be used for treating laryngeal papilloma. PMID:27045601

  7. Does Prolonged Therapy with a Long-Acting Stimulant Suppress Growth in Children with ADHD?

    ERIC Educational Resources Information Center

    Spencer, Thomas J.; Faraone, Stephen V.; Biederman, Joseph; Lerner, Marc; Cooper, Kimberly M.; Zimmerman, Brenda

    2006-01-01

    Objective: To investigate whether prolonged therapy with a long-acting stimulant affects growth in children with attention-deficit/hyperactivity disorder (ADHD). Method: One hundred seventy-eight children ages 6 to 13 years received OROS methylphenidate (OROS MPH, CONCERTA) for at least 21 months. Height and weight were measured monthly during the…

  8. Sphingomyelins suppress the targeted disruption of lysosomes/endosomes by the photosensitizer NPe6 during photodynamic therapy.

    PubMed

    Caruso, Joseph A; Mathieu, Patricia A; Reiners, John J

    2005-12-01

    Recent studies have described a biochemical pathway whereby lysosome disruption and the released proteases initiate the intrinsic apoptotic pathway. Irradiation of murine hepatoma 1c1c7 cells preloaded with the lysosomal photosensitizer NPe6 (N-aspartyl chlorin e6) caused a rapid loss of Acridine Orange staining of acidic organelles, release of cathepsin D from late endosomes/lysosomes and the activation of procaspase-3. Pretreatment of NPe6-loaded cultures with 10-50 microM 3-O-MeSM (3-O-methylsphingomyelin) caused a concentration-dependent suppression of apoptosis following irradiation. This suppression reflected a stabilization of lysosomes/endosomes, as opposed to an inhibition of the accumulation of photosensitizer in these organelles. Exogenously added sphingomyelin, at comparable concentrations, offered some protection, but less than 3-O-MeSM. Fluorescence microscopy showed that 3-O-MeSM competed with NBD-C6-sphingomyelin (6-{[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl} sphingosyl phosphocholine) for co-localization with LysoTracker Red in acidic organelles. Pre-treatment of 1c1c7 cultures with 3-O-MeSM also suppressed the induction of apoptosis by TNFalpha (tumour necrosis factor alpha), but offered no protection against HA14-1 [ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate], staurosporine, tunicamycin or thapsigargin. These results suggest that exogenously added 3-O-MeSM is trafficked to and stabilizes late endosomes/lysosomes against oxidant-induced damage, and further implicate a role for lysosomal proteases in the apoptotic processes initiated by TNFalpha and lysosomal photosensitizers. PMID:15943580

  9. Sphingomyelins suppress the targeted disruption of lysosomes/endosomes by the photosensitizer NPe6 during photodynamic therapy

    PubMed Central

    2005-01-01

    Recent studies have described a biochemical pathway whereby lysosome disruption and the released proteases initiate the intrinsic apoptotic pathway. Irradiation of murine hepatoma 1c1c7 cells preloaded with the lysosomal photosensitizer NPe6 (N-aspartyl chlorin e6) caused a rapid loss of Acridine Orange staining of acidic organelles, release of cathepsin D from late endosomes/lysosomes and the activation of procaspase-3. Pretreatment of NPe6-loaded cultures with 10–50 μM 3-O-MeSM (3-O-methylsphingomyelin) caused a concentration-dependent suppression of apoptosis following irradiation. This suppression reflected a stabilization of lysosomes/endosomes, as opposed to an inhibition of the accumulation of photosensitizer in these organelles. Exogenously added sphingomyelin, at comparable concentrations, offered some protection, but less than 3-O-MeSM. Fluorescence microscopy showed that 3-O-MeSM competed with NBD-C6-sphingomyelin (6-{[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl} sphingosyl phosphocholine) for co-localization with LysoTracker Red in acidic organelles. Pre-treatment of 1c1c7 cultures with 3-O-MeSM also suppressed the induction of apoptosis by TNFα (tumour necrosis factor α), but offered no protection against HA14-1 [ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate], staurosporine, tunicamycin or thapsigargin. These results suggest that exogenously added 3-O-MeSM is trafficked to and stabilizes late endosomes/lysosomes against oxidant-induced damage, and further implicate a role for lysosomal proteases in the apoptotic processes initiated by TNFα and lysosomal photosensitizers. PMID:15943580

  10. Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

    PubMed Central

    Chang, Li-Yuan; Lin, Yung-Chang; Chiang, Jy-Ming; Mahalingam, Jayashri; Su, Shih-Huan; Huang, Ching-Tai; Chen, Wei-Ting; Huang, Chien-Hao; Jeng, Wen-Juei; Chen, Yi-Cheng; Lin, Shi-Ming; Sheen, I-Shyan; Lin, Chun-Yen

    2015-01-01

    Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8+ T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-α in both tissue and serum were also demonstrated. Interestingly, TNF-α could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8+ T cells. Furthermore, targeting TNFR2 signaling with a TNF-α inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-α could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-α inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion. PMID:26451304

  11. Increased IL-37 in Atherosclerotic Disease could be Suppressed by Atorvastatin Therapy.

    PubMed

    Shaoyuan, C; Ming, D; Yulang, H; Hongcheng, F

    2015-10-01

    Recently, the evidence showed that interleukin-37 (IL-37) was expressed in the foam-like cells of atherosclerotic coronary and carotid artery plaques in IL-37-transgenic mice, suggesting that interleukin-37 is involved in atherosclerosis-related diseases. The purpose of this study was to determine the change of IL-37 in atherosclerotic plaque, the effect of atorvastatin on IL-37 and the association between IL-37 and Smad3 in atherosclerotic disease. Rabbits were subjected to atherosclerosis by the immunologic injury composite with balloon injury (BI). Some rabbits received atorvastatin treatment from 6 weeks to 12 weeks. Serum levels of IL-37 were assessed at baseline, 6 weeks and 12 weeks in normal, atherosclerotic and atorvastatin groups. Protein and RNA levels of IL-37 atherosclerotic plaque from abdominal aorta were processed at 12 weeks. Abdominal aorta including atherosclerotic plaque was immunostained with IL-37 and Smad3. Serum IL-37 significantly increased in atherosclerotic disease, and this increase could be reduced by the atorvastatin treatment. IL-37 and Smad3 were accumulated in the macrophage-derived foam cells in the plaque and significantly increased in protein and RNA levels. Atorvastatin treatment could significantly suppress the increase of both IL-37 and Smad3. Plasma level of IL-37 and the IL-37 expression of the plaque were significantly increased in atherosclerotic disease. This increase could be suppressed by the atorvastatin treatment. In addition, Smad3 might be required for IL-37 activity during the atherosclerotic physiologic process. PMID:26074195

  12. Inhibition of Hyaluronic Acid Synthesis Suppresses Angiogenesis in Developing Endometriotic Lesions

    PubMed Central

    Olivares, Carla N.; Alaniz, Laura D.; Menger, Michael D.; Barañao, Rosa I.; Laschke, Matthias W.; Meresman, Gabriela F.

    2016-01-01

    Background The development and long-term survival of endometriotic lesions is crucially dependent on an adequate vascularization. Hyaluronic acid (HA) through its receptor CD44 has been described to be involved in the process of angiogenesis. Objective To study the effect of HA synthesis inhibition using non-toxic doses of 4-methylumbelliferone (4-MU) on endometriosis-related angiogenesis. Materials and Methods The cytotoxicity of different in vitro doses of 4-MU on endothelial cells was firstly tested by means of a lactate dehydrogenase assay. The anti-angiogenic action of non-cytotoxic doses of 4-MU was then assessed by a rat aortic ring assay. In addition, endometriotic lesions were induced in dorsal skinfold chambers of female BALB/c mice, which were daily treated with an intraperitoneal injection of 0.9% NaCl (vehicle group; n = 6), 20mg/kg 4-MU (n = 8) or 80mg/kg 4-MU (n = 7) throughout an observation period of 14 days. The effect of 4-MU on their vascularization, survival and growth were studied by intravital fluorescence microscopy, histology and immunohistochemistry. Main Results Non-cytotoxic doses of 4-MU effectively inhibited vascular sprout formation in the rat aortic ring assay. Endometriotic lesions in dorsal skinfold chambers of 4-MU-treated mice dose-dependently exhibited a significantly smaller vascularized area and lower functional microvessel density when compared to vehicle-treated controls. Histological analyses revealed a downregulation of HA expression in 4-MU-treated lesions. This was associated with a reduced density of CD31-positive microvessels within the lesions. In contrast, numbers of PCNA-positive proliferating and cleaved caspase-3-positive apoptotic cells did not differ between 4-MU-treated and control lesions. Conclusions The present study demonstrates for the first time that targeting the synthesis of HA suppresses angiogenesis in developing endometriotic lesions. Further studies have to clarify now whether in the future this

  13. Antiretroviral Therapy and Viral Suppression Among Foreign-Born HIV-Infected Persons Receiving Medical Care in the United States

    PubMed Central

    Myers, Tanya R.; Lin, Xia; Skarbinski, Jacek

    2016-01-01

    Abstract Immigrants to the United States are more likely to be diagnosed with human immunodeficiency virus (HIV) infection compared with native-born persons. Navigating access to healthcare in the United States can be challenging for foreign-born persons, and HIV treatment outcomes may be suboptimal for these persons. We compared characteristics of and assessed disparities in clinical outcomes of foreign-born persons in care for HIV in the United States. The Medical Monitoring Project is a complex sample, cross-sectional survey designed to be nationally representative of HIV-infected adults receiving medical care in the United States. Using data from 2009, 2010, and 2011, we conducted descriptive analyses and multivariable logistic regression to assess associations between foreign-born status and antiretroviral therapy (ART) prescription, and between foreign-born status and viral suppression. In all, 13.4% of HIV-infected persons were self-identified as foreign-born; the most common regions of birth were Central America and Mexico (45.4%) and the Caribbean (16.0%). Nearly 90% of foreign-born persons were diagnosed with HIV after entry into the United States. Compared with US-born persons, foreign-born persons were more likely to be younger, Hispanic, less educated, and uninsured. The prevalence of ART prescription (prevalence ratio 1.00; 95% confidence interval 0.98–1.02) was not significantly different between foreign-born and US-born persons. A higher percentage of foreign-born persons achieved viral suppression compared with US-born persons (prevalence ratio 1.05; 95% confidence interval 1.00–1.09). No major disparities in ART prescription and viral suppression were found between foreign-born and US-born HIV-infected persons receiving medical care, despite higher percentages being uninsured. PMID:26986128

  14. Influence of Genes Suppressing Interferon Effects in Peripheral Blood Mononuclear Cells during Triple Antiviral Therapy for Chronic Hepatitis C

    PubMed Central

    Iijima, Sayuki; Matsuura, Kentaro; Watanabe, Tsunamasa; Onomoto, Koji; Fujita, Takashi; Ito, Kyoko; Iio, Etsuko; Miyaki, Tomokatsu; Fujiwara, Kei; Shinkai, Noboru; Kusakabe, Atsunori; Endo, Mio; Nojiri, Shunsuke; Joh, Takashi; Tanaka, Yasuhito

    2015-01-01

    The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (IL28B) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-λs) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-λs were evaluated by real-time PCR. All 31 patients with a favorable IL28B genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for A20, SOCS1, and SOCS3, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as IRF1 were significantly higher at 8 h in patients with an unfavorable IL28B genotype than in those with a favorable one (P = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of IRF1 at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable IL28B genotype (P = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to IL28B genotypes, paralleling treatment efficacy. PMID:25706116

  15. Slimming and Appetite-Suppressing Effects of Caraway Aqueous Extract as a Natural Therapy in Physically Active Women.

    PubMed

    Kazemipoor, Mahnaz; Hamzah, Sareena; Hajifaraji, Majid; Radzi, Che Wan Jasimah Bt Wan Mohamed; Cordell, Geoffrey A

    2016-06-01

    Following the current 'Globesity' trend, there is an increasing demand for alternative natural therapies for weight management. Numerous phytoconstituents reduce body weight through suppressing appetite and reducing food intake. Caraway (Carum carvi L.) is one of the medicinal plants that is traditionally used for weight loss. In this study, the appetite-suppressing effects of caraway aqueous extract (CAE) on 70 aerobically trained, overweight, and obese women were examined in a triple-blind, placebo-controlled, clinical study. Subjects were randomly allocated into placebo and experimental groups and consumed either 30 mL/day of CAE or placebo without changing their diet or physical activity over a period of 90 days. Calorie and macronutrient intake and anthropometric indices were measured before and after the intervention. In addition, appetite changes were assessed through a visual analog scale and an ad libitum pizza test. After the intervention, the results showed a significant reduction in appetite levels and carbohydrate intake of the experimental group compared with the placebo group. All of the anthropometric indices were reduced significantly in CAE compared with placebo group (p < 0.01). These preliminary outcomes suggest that a dietary CAE might be effective in weight management of physically active, adult females, reducing their body size and hunger level. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26988309

  16. 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. PMID:25250392

  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. Management of thyroid nodules: scanning techniques, thyroid suppressive therapy, and fine needle aspiration

    SciTech Connect

    Ashcraft, M.W.; Van Herle, A.J.

    1981-03-01

    For the differentiation of benign from malignant thyroidal disease, ultrasound displays anatomic but not histologic features. Other visualization techniques can be used including isotope scanning (radioiodine, 99m technetium, 241 americium fluorescence, 131 cesium, 67 gallium, 75 selenomethionine, 201 thallium, 32 phosphorus, 99m Tc-bleomycin, 197 mercury, 133 xenon), thermography, x-ray techniques (plain films, computed tomographic scan, xeroradiography, chest x-ray barium swallow, lymphography, angiography), and thyroid hormone suppression. Needle biopsy can be done by core biopsy (Vim-Silverman and drill biopsy), large needle biopsy for histologic processing and fine needle aspiration for cytologic interpretation. The latter is the safest, most reliable, and most cost-effective technique currently available to differentiate between benign and malignant thyroidal disease and has great promise for the future.

  19. Opiate-Induced Suppression of Rat Hypoglossal Motoneuron Activity and Its Reversal by Ampakine Therapy

    PubMed Central

    Lorier, Amanda R.; Funk, Gregory D.; Greer, John J.

    2010-01-01

    Background Hypoglossal (XII) motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of μ-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s). We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity. Methodology/Principal Findings A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the μ-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717) alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons. Conclusions/Significance The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract μ-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron

  20. Induced Pluripotent Stem Cell Therapy Ameliorates Hyperoxia-Augmented Ventilator-Induced Lung Injury through Suppressing the Src Pathway

    PubMed Central

    Liu, Yung-Yang; Fu, Jui-Ying; Kao, Kuo-Chin; Huang, Chung-Chi; Chien, Yueh; Liao, Yi-Wen; Chiou, Shih-Hwa

    2014-01-01

    Background High tidal volume (VT) mechanical ventilation (MV) can induce the recruitment of neutrophils, release of inflammatory cytokines and free radicals, and disruption of alveolar epithelial and endothelial barriers. It is proposed to be the triggering factor that initiates ventilator-induced lung injury (VILI) and concomitant hyperoxia further aggravates the progression of VILI. The Src protein tyrosine kinase (PTK) family is one of the most critical families to intracellular signal transduction related to acute inflammatory responses. The anti-inflammatory abilities of induced pluripotent stem cells (iPSCs) have been shown to improve acute lung injuries (ALIs); however, the mechanisms regulating the interactions between MV, hyperoxia, and iPSCs have not been fully elucidated. In this study, we hypothesize that Src PTK plays a critical role in the regulation of oxidants and inflammation-induced VILI during hyperoxia. iPSC therapy can ameliorate acute hyperoxic VILI by suppressing the Src pathway. Methods Male C57BL/6 mice, either wild-type or Src-deficient, aged between 2 and 3 months were exposed to high VT (30 mL/kg) ventilation with or without hyperoxia for 1 to 4 h after the administration of Oct4/Sox2/Parp1 iPSCs at a dose of 5×107 cells/kg of mouse. Nonventilated mice were used for the control groups. Results High VT ventilation during hyperoxia further aggravated VILI, as demonstrated by the increases in microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 (MIP-2) and plasminogen activator inhibitor-1 (PAI-1) production, Src activation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and malaldehyde (MDA) level. Administering iPSCs attenuated ALI induced by MV during hyperoxia, which benefited from the suppression of Src activation, oxidative stress, acute inflammation, and apoptosis, as indicated by the Src-deficient mice. Conclusion The data suggest that iPSC-based therapy is capable of

  1. Polyunsaturated fatty acid-enriched diet therapy for a child with epilepsy.

    PubMed

    Yoon, Jung-Rim; Lee, Eun Joo; Kim, Heung Dong; Lee, Jae Hwan; Kang, Hoon-Chul

    2014-02-01

    The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with an established efficacy for treating medically refractory epilepsy in children. Fatty acids are the most important constituent of the KD in all aspects of efficacy and complications. Among fatty acids, polyunsaturated fatty acids (PUFAs) increase anticonvulsant properties and reduce the complications associated with the high-fat diet. Here, we report a 7-year-old boy with Lennox-Gastaut syndrome combined with mitochondrial respiratory chain complex I deficiency, whose medically intractable seizures have been successfully controlled with a PUFA-enriched modified Atkins diet without any significant adverse events. The diet consists of canola oil and diverse menu items like fish and nuts instead of olive oil and has an ideal 1:2.8 ratio of omega-3 to omega-6. In addition, fractionation of this boy's plasma showed normal levels of fatty acids, including omega-3 (alpha-linoleic acid, eicosapentaenoic acid) and omega-6 (linoleic acid, arachidonic acid) as well as monounsaturated fatty acids (oleic acid). Plasma docosahexanoic acid remained low after PUFA-enriched diet therapy. PUFA-enriched diet therapy is likely to increase the efficacy of diet therapy and reduce complications of a high-fat diet in children with refractory epilepsy. PMID:23465587

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

    PubMed

    Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng

    2015-10-15

    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-suppressive 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. PMID:26253462

  3. Hyperbaric Oxygen Therapy Suppresses Apoptosis and Promotes Renal Tubular Regeneration After Renal Ischemia/Reperfusion Injury in Rats

    PubMed Central

    Migita, Heihachi; Yoshitake, Shigenori; Tange, Yoshihiro; Choijookhuu, Narantsog; Hishikawa, Yoshitaka

    2016-01-01

    Background: Renal ischemia/reperfusion (I/R) injury remains a major cause of acute kidney injury (AKI), in addition to I/R injury-induced tissue inflammation, necrosis and apoptosis. Hyperbaric oxygen therapy (HBO) is defined as a treatment in which a patient is intermittently exposed to 100% oxygen pressurized to a pressure above sea level (> 2.0 atmospheres absolute (ATA), 1.0 ATA = 760 mmHg). It has been used in a number of medical conditions with a proven efficacy in a limited number of disorders. However, the effects of HBO therapy on apoptosis and proliferative activity after I/R injury have not been fully understood. Objectives: We studied the possible beneficial effects of HBO therapy on apoptosis and tubular cell regeneration after renal I/R injury in rats. Materials and Methods: Sprague-Dawley (SD) rats were randomized into three groups: Sham (Sham-operated rats); I/R (animals submitted to I/R); and I/R + HBO (I/R rats exposed to HBO). Tubular cell apoptosis was confirmed by DNA laddering and the terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay. Cellular proliferation activity was determined using the anti-Ki-67 antibody. Results: A significant decrease in apoptotic cells and increase in proliferative reaction were observed in the I/R + HBO group compared to the I/R group. Conclusions: We demonstrated that HBO suppressed apoptosis, which caused inflammation after renal I/R, and promoted tubular cell regeneration. HBO has protective effects against AKI caused by renal I/R through the inhibition of apoptosis. PMID:26981502

  4. Hyaluronic Acid Suppresses the Expression of Metalloproteinases in Osteoarthritic Cartilage Stimulated Simultaneously by Interleukin 1β and Mechanical Load

    PubMed Central

    Pohlig, Florian; Guell, Florian; Lenze, Ulrich; Lenze, Florian W.; Mühlhofer, Heinrich M. L.; Schauwecker, Johannes; Toepfer, Andreas; Mayer-Kuckuk, Philipp; von Eisenhart-Rothe, Rüdiger; Burgkart, Rainer; Salzmann, Gian M.

    2016-01-01

    Purpose In patients with osteoarthritis (OA), intraarticular injection of hyaluronic acid (HA) frequently results in reduced pain and improved function for prolonged periods of time, i.e. more than 6 months. However, the mechanisms underlying these effects are not fully understood. Our underlying hypothesis is that HA modifies the enzymatic breakdown of joint tissues. Methods To test this hypothesis, we examined osteochondral cylinders from 12 OA patients. In a bioreactor, these samples were stimulated by interleukin 1β (Il1ß) (2 ng/ml) plus mechanical load (2.0 Mpa at 0.5 Hz horizontal and 0.1 Hz vertical rotation), thus the experimental setup recapitulated both catabolic and anabolic clues of the OA joint. Results Upon addition of HA at either 1 or 3 mg/ml, we observed a significant suppression of expression of metalloproteinase (MMP)-13. A more detailed analysis based on the Kellgren and Lawrence (K&L) OA grade, showed a much greater degree of suppression of MMP-13 expression in grade IV as compared to grade II OA. In contrast to the observed MMP-13 suppression, treatment with HA resulted in a suppression of MMP-1 expression only at 1 mg/ml HA, while MMP-2 expression was not significantly affected by either HA concentration. Conclusion Together, these data suggest that under concurrent catabolic and anabolic stimulation, HA exhibits a pronounced suppressive effect on MMP-13. In the long-run these findings may benefit the development of treatment strategies aimed at blocking tissue degradation in OA patients. PMID:26934732

  5. Plasma and cerebrosponal fluid amino acid levels in diabetic ketoacidosis before and after corrective therapy.

    PubMed

    Aoki, T T; Assal J-P; Manzano, F M; Kozak, G P; Cahill, G F

    1975-05-01

    To evaluate the effect of insulin-saline-bicarbonate therapy on amino acid metabolism in diabetic ketoacidosis, arterial and venous blood samples as well as cerebrospinal fluid (CSF) were obtained from six patients before and after initiation of corrective therapy. Levels of CSF glutamine were decreased while alanine alpha-amino-n-butyrate, valine, isoleucine and leucine were increased significantly compared to a control group composed of six normal, postabsorptive adults free of any neurologic disease. Following therapy, CSF levels of alanine, alpha-amino-n-butyrate, valine, isoleucine, and leucine declined while glutamine levels did not change. Admission arterial plasma levels of the glycogenic amino acids were lower than normal while the branched-chain amino acids were elevated. Plasma alanine and glutamine arterio-venous (A-V) differences across forearm tissue were larger. After four hours of corrective therapy, arterial plasma levels of most of the amino acids had declined sharply and A-V differences for glutamine and alanine were markedly reduced (p smaller than.025 and p smaller than.01, paired t, respectively). Coincident with the decrease in A-V amino acid differences, plasma glucagon and free fatty acid levels declined significantly. These data suggest that the effect exerted by insulin-saline-bicarbonate therapy on amino acid metabolism is manifested by diminished A-V plasma alanine and glutamine differences across forearm tissue. Thus, the role played by the splanchnic bed both before and following corrective measures may be secondary to substrate availability. PMID:805076

  6. When Proteins Start to Make Sense: Fine-tuning Aminoglycosides for PTC Suppression Therapy

    PubMed Central

    Shalev, Moran; Baasov, Timor

    2014-01-01

    Aminoglycosides (AGs) are highly potent antibacterial agents, which are known to exert their deleterious effects on bacterial cells by interfering with the translation process, leading to aberrant protein synthesis that usually results in cell death. Nearly 45 years ago, AGs were shown to induce read-through activity in prokaryotic systems by selectively encoding tRNA molecules at premature termination codon (PTC) positions; resulting in the generation of full length functional proteins. However, only in the last 20 years this ability has been demonstrated in eukaryotic systems, highlighting their potential as therapeutic agents to treat PTC induced genetic disorders. Despite the great potential, AGs use in these manners is quite restricted due to relatively high toxicity values observed upon their administration. Over the last few years several synthetic derivatives were developed to overcome some of the enhanced toxicity issues, while in parallel showed significantly improved PTC suppression activity in various in-vitro, ex-vivo and in-vivo models of a variety of different diseases models underling by PTC mutations. Although these derivatives hold great promise to serve as therapeutic candidates they also demonstrate the necessity to further understand the molecular mechanisms of which AGs confer their biological activity in eukaryotic cells for further rational drug design. Recent achievements in structural research shed light on AGs mechanism of action and opened a new avenue in the development of new and improved therapeutic derivatives. The following manuscript highlights these accomplishments and summarizes their contributions to the state of art rational drug design. PMID:25147726

  7. Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy

    PubMed Central

    Sherman, Mara H.; Yu, Ruth T.; Engle, Dannielle D.; Ding, Ning; Atkins, Annette R.; Tiriac, Herve; Collisson, Eric A.; Connor, Frances; Van Dyke, Terry; Kozlov, Serguei; Martin, Philip; Tseng, Tiffany W.; Dawson, David W.; Donahue, Timothy R.; Masamune, Atsushi; Shimosegawa, Tooru; Apte, Minoti V.; Wilson, Jeremy S.; Ng, Beverly; Lau, Sue Lynn; Gunton, Jenny E.; Wahl, Geoffrey M.; Hunter, Tony; Drebin, Jeffrey A.; O’Dwyer, Peter J.; Liddle, Christopher; Tuveson, David A.; Downes, Michael; Evans, Ronald M.

    2014-01-01

    Summary The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests Vitamin D priming as an adjunct in PDA therapy. PMID:25259922

  8. Bile Acid Signaling in Metabolic Disease and Drug Therapy

    PubMed Central

    Li, Tiangang

    2014-01-01

    Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

  9. Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice.

    PubMed

    Verma, Rajeev; Chopra, Avijeet; Giardina, Charles; Sabbisetti, Venkata; Smyth, Joan A; Hightower, Lawrence E; Perdrizet, George A

    2015-05-01

    The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from

  10. Disruption of a Nuclear NFATc2 Protein Stabilization Loop Confers Breast and Pancreatic Cancer Growth Suppression by Zoledronic Acid*

    PubMed Central

    Singh, Shiv K.; Baumgart, Sandra; Singh, Garima; König, Alexander O.; Reutlinger, Kristina; Hofbauer, Lorenz C.; Barth, Peter; Gress, Thomas M.; Lomberk, Gwen; Urrutia, Raul; Fernandez-Zapico, Martin E.; Ellenrieder, Volker

    2011-01-01

    The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3β-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid. PMID:21628454

  11. Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor α expression by releasing cytokines.

    PubMed

    Fang, Xuemei; Zou, Shanshan; Zhao, Yuanyuan; Cui, Ruina; Zhang, Wei; Hu, Jiayue; Dai, Jiayin

    2012-10-01

    Kupffer cells (KCs) have been demonstrated to play a role in the regulation of intra-hepatic lipid metabolism through the synthesis and secretion of biologically active products. The involvement of KCs in the disturbance of lipid metabolism that induced by perfluorononanoic acid (PFNA), a known agonist of the peroxisome proliferator-activated receptor alpha (PPARα), was investigated in this study. Rats were exposed to PFNA or PFNA combined with gadolinium chloride, an inhibitor of KCs, for 14 days. PFNA exposure dose-dependently increased absolute and relative liver weights, induced triglyceride accumulation, up-regulated the expression of both SERBP-1c and PPARα, and stimulated the release of TNFα and IL-1β. Inactivation of KCs markedly lowered TNFα and IL-1β level, enhanced PFNA-induced expression of PPARα and its target genes, and reduced liver triglyceride levels. In vitro, PFNA-induced expression of PPARα in primary cultured hepatocytes was suppressed by recombinant rat TNFα and IL-1β. However, inhibition of the NF-κB pathway prevented this. Transient transfection and promoter analysis further revealed that these two cytokines and NF-κB were coordinately involved in the suppression of PPARα promoter activity. Our data demonstrate that TNFα and IL-1β released from KCs following PFNA exposure can suppress the expression of PPARα via NF-κB pathway, which partially contribute to the evident accumulation of triglycerides in rat liver. PMID:22648072

  12. 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

    2015-01-01

    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. PMID:26329786

  13. Controls on suppression of methane flux from a peat bog subjected to simulated acid rain sulfate deposition

    NASA Astrophysics Data System (ADS)

    Gauci, Vincent; Dise, Nancy; Fowler, David

    2002-01-01

    The effect of acid rain SO42- deposition on peatland CH4 emissions was examined by manipulating SO42- inputs to a pristine raised peat bog in northern Scotland. Weekly pulses of dissolved Na2SO4 were applied to the bog over two years in doses of 25, 50, and 100 kg S ha-1 yr-1, reflecting the range of pollutant S deposition loads experienced in acid rain-impacted regions of the world. CH4 fluxes were measured at regular intervals using a static chamber/gas chromatographic flame ionization detector method. Total emissions of CH4 were reduced by between 21 and 42% relative to controls, although no significant differences were observed between treatments. Estimated total annual fluxes during the second year of the experiment were 16.6 g m-2 from the controls and (in order of increasing SO42- dose size) 10.7, 13.2, and 9.8 g m-2 from the three SO42- treatments, respectively. The relative extent of CH4 flux suppression varied with changes in both peat temperature and peat water table with the largest suppression during cool periods and episodes of falling water table. Our findings suggest that low doses of SO42- at deposition rates commonly experienced in areas impacted by acid rain, may significantly affect CH4 emissions from wetlands in affected areas. We propose that SO42- from acid rain can stimulate sulfate-reducing bacteria into a population capable of outcompeting methanogens for substrates. We further propose that this microbially mediated interaction may have a significant current and future effect on the contribution of northern peatlands to the global methane budget.

  14. Abscisic Acid Determines Basal Susceptibility of Tomato to Botrytis cinerea and Suppresses Salicylic Acid-Dependent Signaling Mechanisms1

    PubMed Central

    Audenaert, Kris; De Meyer, Geert B.; Höfte, Monica M.

    2002-01-01

    Abscisic acid (ABA) is one of the plant hormones involved in the interaction between plants and pathogens. In this work, we show that tomato (Lycopersicon esculentum Mill. cv Moneymaker) mutants with reduced ABA levels (sitiens plants) are much more resistant to the necrotrophic fungus Botrytis cinerea than wild-type (WT) plants. Exogenous application of ABA restored susceptibility to B. cinerea in sitiens plants and increased susceptibility in WT plants. These results indicate that ABA plays a major role in the susceptibility of tomato to B. cinerea. ABA appeared to interact with a functional plant defense response against B. cinerea. Experiments with transgenic NahG tomato plants and benzo(1,2,3)thiadiazole-7-carbothioic acid demonstrated the importance of salicylic acid in the tomato-B. cinerea interaction. In addition, upon infection with B. cinerea, sitiens plants showed a clear increase in phenylalanine ammonia lyase activity, which was not observed in infected WT plants, indicating that the ABA levels in healthy WT tomato plants partly repress phenylalanine ammonia lyase activity. In addition, sitiens plants became more sensitive to benzo(1,2,3)thiadiazole-7-carbothioic acid root treatment. The threshold values for PR1a gene expression declined with a factor 10 to 100 in sitiens compared with WT plants. Thus, ABA appears to negatively modulate the salicylic acid-dependent defense pathway in tomato, which may be one of the mechanisms by which ABA levels determine susceptibility to B. cinerea. PMID:11842153

  15. 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

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

    PubMed

    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

  17. Biocontrol agents-mediated suppression of oxalic acid induced cell death during Sclerotinia sclerotiorum-pea interaction.

    PubMed

    Jain, Akansha; Singh, Akanksha; Singh, Surendra; Sarma, Birinchi Kumar; Singh, Harikesh Bahadur

    2015-05-01

    Oxalic acid (OA) is an important pathogenic factor during early Sclerotinia sclerotiorum-host interaction and might work by reducing hydrogen peroxide production (H2 O2 ). In the present investigation, oxalic acid-induced cell death in pea was studied. Pea plants treated with biocontrol agents (BCAs) viz., Pseudomonas aeruginosa PJHU15, Bacillus subtilis BHHU100, and Trichoderma harzianum TNHU27 either singly and/or in consortium acted on S. sclerotiorum indirectly by enabling plants to inhibit the OA-mediated suppression of oxidative burst via induction of H2 O2 . Our results showed that BCA treated plants upon treatment with culture filtrate of the pathogen, conferred the resistance via. significantly decreasing relative cell death of pea against S. sclerotiorum compared to control plants without BCA treatment but treated with the culture filtrate of the pathogen. The results obtained from the present study indicate that the microbes especially in consortia play significant role in protection against S. sclerotiorum by modulating oxidative burst and partially enhancing tolerance by increasing the H2 O2 generation, which is otherwise suppressed by OA produced by the pathogen. PMID:24920251

  18. Lovastatin suppresses the aberrant tau phosphorylation from FTDP-17 mutation and okadaic acid-induction in rat primary neurons.

    PubMed

    Li, R; Xu, D-E; Ma, T

    2015-05-21

    Statins are a class of cholesterol-lowering drugs and have been suggested therapeutic use for neurodegenerative diseases including Alzheimer's disease (AD). Our recent studies revealed a neuronal protective effect of lovastatin (LOV) from N-methyl-d-aspartic acid (NMDA) excitotoxicity. The neuroprotective mechanism of statins, however, is far unknown. Here we demonstrated that LOV suppressed the aberrant tau phosphorylation both from frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) mutation and okadaic acid (OA) induction in cultured rat primary neurons. The protective effect of LOV occurred at multiple pathological sites of tau protein, including Tyr181, Tyr231 Ser202/Tyr205, Tyr212/Ser214 and Ser396/Ser404. Further analysis revealed that the potential mechanism of the suppressive effect of LOV resulted from two aspects, activating OA-inhibited protein phosphatase 2A (PP2A) activity and attenuating OA-induced activity of tau kinases CDK5/P25 and CDK2/4, but not glycogen synthase kinase 3β (GSK3β). These findings give new insights into the molecular mechanism of LOV-mediated neuroprotective effect and provide experimental evidence for its therapeutic use in AD. PMID:25770969

  19. Enhancing the performance of LC-MS for intact protein analysis by counteracting the signal suppression effects of trifluoroacetic acid during electrospray.

    PubMed

    Chen, Jin; Liu, Zheyi; Wang, Fangjun; Mao, Jiawei; Zhou, Ye; Liu, Jing; Zou, Hanfa; Zhang, Yukui

    2015-10-11

    We develop an acidic vapor assisted electrospray ionization strategy within an enclosed electrospray ionization source to counteract the ion suppression effects caused by trifluoroacetic acid. The mass spectrometry signal intensity of intact proteins was improved 10 times and the number of valid signals for E. coli intact protein samples was improved 96% by using this strategy. PMID:26295950

  20. Omega-3 Fatty Acids and Cancer Cell Cytotoxicity: Implications for Multi-Targeted Cancer Therapy

    PubMed Central

    D’Eliseo, Donatella; Velotti, Francesca

    2016-01-01

    Cancer is a major disease worldwide. Despite progress in cancer therapy, conventional cytotoxic therapies lead to unsatisfactory long-term survival, mainly related to development of drug resistance by tumor cells and toxicity towards normal cells. n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can exert anti-neoplastic activity by inducing apoptotic cell death in human cancer cells either alone or in combination with conventional therapies. Indeed, n-3 PUFAs potentially increase the sensitivity of tumor cells to conventional therapies, possibly improving their efficacy especially against cancers resistant to treatment. Moreover, in contrast to traditional therapies, n-3 PUFAs appear to cause selective cytotoxicity towards cancer cells with little or no toxicity on normal cells. This review focuses on studies investigating the cytotoxic activity of n-3 PUFAs against cancer cells via apoptosis, analyzing the molecular mechanisms underlying this effective and selective activity. Here, we highlight the multiple molecules potentially targeted by n-3 PUFAs to trigger cancer cell apoptosis. This analysis can allow a better comprehension of the potential cytotoxic therapeutic role of n-3 PUFAs against cancer, providing specific information and support to design future pre-clinical and clinical studies for a better use of n-3 PUFAs in cancer therapy, mainly combinational therapy. PMID:26821053

  1. Influence of disease-suppressive strains of Streptomyces on the native Streptomyces community in soil as determined by the analysis of cellular fatty acids.

    PubMed

    Bowers, J H; Kinkel, L L; Jones, R K

    1996-01-01

    Analysis of cellular fatty acid profiles was used to distinguish among introduced pathogen- suppressive strains and indigenous strains of Streptomyces spp. isolated from soil of field plots established to test the efficacy of Streptomyces strains PonSSII and PonR in the biological control of potato scab. Reference libraries of fatty acid profiles were developed for a collection of known pathogenic strains and the introduced suppressive strains. Population densities of pathogen-related, suppressive, and saprophytic Streptomyces strains were determined from the relationship of field isolates to mean library profiles using cluster analysis and the unweighted pair-group method using arithmetic averages. Community diversity was similarly determined. Streptomyces strains PonSSII and PonR were distinguished from each other and from the pathogen group (which clustered together) based on fatty acid profiles. The introduced, suppressive strains successfully colonized the soil and represented 2-19% of the isolates sampled over 2 years. The introduction of the suppressive strains inhibited the population of strains related to the pathogen library at each sample date; the pathogen population was substantially lower in soil from treatments where the suppressive strains were introduced compared with the nonamended control. At harvest, the pathogen-related population was suppressed 85-93 and 36-44% in 1991 and 1992, respectively, in treatments with the suppressive strains compared with the nonamended control. Diversity of the community was not affected by the introduced strains, and diversity and equitability indices were similar among treatments at any sample time. The inhibition of the pathogen-related population was correlated with a reduction of scab symptoms observed in the field plots into which the suppressive strains were introduced. Implications of a fundamental shift in the pathogen-related population in response to the introduction of the suppressive strains for long

  2. Amphipathic β2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae

    PubMed Central

    Tiirola, Terttu M.; Strøm, Morten B.; Vuorela, Pia M.

    2016-01-01

    We demonstrate in the current work that small cationic antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 μM, i.e. < 3.4 μg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the β2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these β2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic β2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen. PMID:27280777

  3. Structural Determinants of Antiretroviral Therapy Use, HIV Care Attendance, and Viral Suppression among Adolescents and Young Adults Living with HIV

    PubMed Central

    Kahana, Shoshana Y.; Jenkins, Richard A.; Bruce, Douglas; Fernandez, Maria I.; Hightow-Weidman, Lisa B.; Bauermeister, Jose A.

    2016-01-01

    Background The authors examined associations between structural characteristics and HIV disease management among a geographically diverse sample of behaviorally and perinatally HIV-infected adolescents and young adults in the United States. Methods The sample included 1891 adolescents and young adults living with HIV (27.8% perinatally infected; 72.2% behaviorally infected) who were linked to care through 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions Units. All completed audio computer–assisted self-interview surveys. Chart abstraction or blood draw provided viral load data. Geographic-level variables were extracted from the United States Census Bureau (e.g., socioeconomic disadvantage, percent of Black and Latino households, percent rural) and Esri Crime (e.g., global crime index) databases as Zip Code Tabulation Areas. AIDSVu data (e.g., prevalence of HIV among youth) were extracted at the county-level. Using HLM v.7, the authors conducted means-as-outcomes random effects multi-level models to examine the association between structural-level and individual-level factors and (1) being on antiretroviral therapy (ART) currently; (2) being on ART for at least 6 months; (3) missed HIV care appointments (not having missed any vs. having missed one or more appointments) over the past 12 months; and (4) viral suppression (defined by the corresponding assay cutoff for the lower limit of viral load at each participating site which denoted nondetectability vs. detectability). Results Frequencies for the 4 primary outcomes were as follows: current ART use (n = 1120, 59.23%); ART use for ≥6 months (n = 861, 45.53%); at least one missed HIV care appointment (n = 936, 49.50); and viral suppression (n = 577, 30.51%). After adjusting for individual-level factors, youth living in more disadvantaged areas (defined by a composite score derived from 2010 Census indicators including percent poverty, percent receiving public assistance, percent of female, single

  4. 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

  5. Suppression of muscle protein turnover and amino acid degradation by dietary protein deficiency

    NASA Technical Reports Server (NTRS)

    Tawa, N. E. Jr; Goldberg, A. L.

    1992-01-01

    To define the adaptations that conserve amino acids and muscle protein when dietary protein intake is inadequate, rats (60-70 g final wt) were fed a normal or protein-deficient (PD) diet (18 or 1% lactalbumin), and their muscles were studied in vitro. After 7 days on the PD diet, both protein degradation and synthesis fell 30-40% in skeletal muscles and atria. This fall in proteolysis did not result from reduced amino acid supply to the muscle and preceded any clear decrease in plasma amino acids. Oxidation of branched-chain amino acids, glutamine and alanine synthesis, and uptake of alpha-aminoisobutyrate also fell by 30-50% in muscles and adipose tissue of PD rats. After 1 day on the PD diet, muscle protein synthesis and amino acid uptake decreased by 25-40%, and after 3 days proteolysis and leucine oxidation fell 30-45%. Upon refeeding with the normal diet, protein synthesis also rose more rapidly (+30% by 1 day) than proteolysis, which increased significantly after 3 days (+60%). These different time courses suggest distinct endocrine signals for these responses. The high rate of protein synthesis and low rate of proteolysis during the first 3 days of refeeding a normal diet to PD rats contributes to the rapid weight gain ("catch-up growth") of such animals.

  6. Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenac: suppressing the rearrangement pathway in aqueous media.

    PubMed

    Ribeiro, Lina; Silva, Nuno; Iley, Jim; Rautio, Jarkko; Järvinen, Tomi; Mota-Filipe, Hélder; Moreira, Rui; Mendes, Eduarda

    2007-01-01

    Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an O-->N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37 degrees C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility. PMID:17206608

  7. Hyaluronic acid-tagged silica nanoparticles in colon cancer therapy: therapeutic efficacy evaluation

    PubMed Central

    Liu, Kai; Wang, Zhi-qi; Wang, Shi-jiang; Liu, Ping; Qin, Yue-hong; Ma, Yan; Li, Xiao-Chen; Huo, Zhi-Jun

    2015-01-01

    Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 µg/mL compared with ~2.8 µg/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer

  8. Suppression of tricarboxylic acid cycle in Escherichia coli exposed to sub-MICs of aminoglycosides.

    PubMed Central

    Cavallero, A; Eftimiadi, C; Radin, L; Schito, G C

    1990-01-01

    The metabolic activity of Escherichia coli ATCC 25922 challenged with sub-MICs of aminoglycosides was analyzed with a batch calorimeter. High-performance and gas-liquid chromatographic techniques were utilized to evaluate the concentrations of metabolic reactants, intermediates, and end products. The data reported indicate that aminoglycosides inhibit or delay bacterial catabolism of carboxylic acids, with the following relative degrees of activity: amikacin greater than gentamicin greater than sisomicin greater than netilmicin greater than kanamycin. The decrease in total biomass production was proportional to the degree of tricarboxylic acid cycle inhibition. PMID:2183717

  9. Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We recently showed that the developing gut is a significant site of methionine transmethylation to homocysteine and transsulfuration to cysteine. We hypothesized that sulfur amino acid (SAA) deficiency would preferentially reduce mucosal growth and antioxidant function in neonatal pigs. Neonatal pi...

  10. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43.

    PubMed

    Kimura, Ikuo; Ozawa, Kentaro; Inoue, Daisuke; Imamura, Takeshi; Kimura, Kumi; Maeda, Takeshi; Terasawa, Kazuya; Kashihara, Daiji; Hirano, Kanako; Tani, Taeko; Takahashi, Tomoyuki; Miyauchi, Satoshi; Shioi, Go; Inoue, Hiroshi; Tsujimoto, Gozoh

    2013-01-01

    The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis. PMID:23652017

  11. Six Tissue Transcriptomics Reveals Specific Immune Suppression in Spleen by Dietary Polyunsaturated Fatty Acids

    PubMed Central

    Gabrielsson, Britt G.; Peris, Eduard; Nookaew, Intawat; Grahnemo, Louise; Sandberg, Ann-Sofie; Wernstedt Asterholm, Ingrid; Jansson, John-Olov; Nielsen, Jens

    2016-01-01

    Dietary polyunsaturated fatty acids (PUFA) are suggested to modulate immune function, but the effects of dietary fatty acids composition on gene expression patterns in immune organs have not been fully characterized. In the current study we investigated how dietary fatty acids composition affects the total transcriptome profile, and especially, immune related genes in two immune organs, spleen (SPL) and bone marrow cells (BMC). Four tissues with metabolic function, skeletal muscle (SKM), white adipose tissue (WAT), brown adipose tissue (BAT), and liver (LIV), were investigated as a comparison. Following 8 weeks on low fat diet (LFD), high fat diet (HFD) rich in saturated fatty acids (HFD-S), or HFD rich in PUFA (HFD-P), tissue transcriptomics were analyzed by microarray and metabolic health assessed by fasting blood glucose level, HOMA-IR index, oral glucose tolerance test as well as quantification of crown-like structures in WAT. HFD-P corrected the metabolic phenotype induced by HFD-S. Interestingly, SKM and BMC were relatively inert to the diets, whereas the two adipose tissues (WAT and BAT) were mainly affected by HFD per se (both HFD-S and HFD-P). In particular, WAT gene expression was driven closer to that of the immune organs SPL and BMC by HFDs. The LIV exhibited different responses to both of the HFDs. Surprisingly, the spleen showed a major response to HFD-P (82 genes differed from LFD, mostly immune genes), while it was not affected at all by HFD-S (0 genes differed from LFD). In conclusion, the quantity and composition of dietary fatty acids affected the transcriptome in distinct manners in different organs. Remarkably, dietary PUFA, but not saturated fat, prompted a specific regulation of immune related genes in the spleen, opening the possibility that PUFA can regulate immune function by influencing gene expression in this organ. PMID:27166587

  12. Six Tissue Transcriptomics Reveals Specific Immune Suppression in Spleen by Dietary Polyunsaturated Fatty Acids.

    PubMed

    Svahn, Sara L; Väremo, Leif; Gabrielsson, Britt G; Peris, Eduard; Nookaew, Intawat; Grahnemo, Louise; Sandberg, Ann-Sofie; Wernstedt Asterholm, Ingrid; Jansson, John-Olov; Nielsen, Jens; Johansson, Maria E

    2016-01-01

    Dietary polyunsaturated fatty acids (PUFA) are suggested to modulate immune function, but the effects of dietary fatty acids composition on gene expression patterns in immune organs have not been fully characterized. In the current study we investigated how dietary fatty acids composition affects the total transcriptome profile, and especially, immune related genes in two immune organs, spleen (SPL) and bone marrow cells (BMC). Four tissues with metabolic function, skeletal muscle (SKM), white adipose tissue (WAT), brown adipose tissue (BAT), and liver (LIV), were investigated as a comparison. Following 8 weeks on low fat diet (LFD), high fat diet (HFD) rich in saturated fatty acids (HFD-S), or HFD rich in PUFA (HFD-P), tissue transcriptomics were analyzed by microarray and metabolic health assessed by fasting blood glucose level, HOMA-IR index, oral glucose tolerance test as well as quantification of crown-like structures in WAT. HFD-P corrected the metabolic phenotype induced by HFD-S. Interestingly, SKM and BMC were relatively inert to the diets, whereas the two adipose tissues (WAT and BAT) were mainly affected by HFD per se (both HFD-S and HFD-P). In particular, WAT gene expression was driven closer to that of the immune organs SPL and BMC by HFDs. The LIV exhibited different responses to both of the HFDs. Surprisingly, the spleen showed a major response to HFD-P (82 genes differed from LFD, mostly immune genes), while it was not affected at all by HFD-S (0 genes differed from LFD). In conclusion, the quantity and composition of dietary fatty acids affected the transcriptome in distinct manners in different organs. Remarkably, dietary PUFA, but not saturated fat, prompted a specific regulation of immune related genes in the spleen, opening the possibility that PUFA can regulate immune function by influencing gene expression in this organ. PMID:27166587

  13. Suppression of IL-12p40-related regulatory cytokines by suberoylanilide hydroxamic acid an inhibitor of histone deacetylases.

    PubMed

    Dobreva, Zlatka Georgieva; Grigorov, Boncho Grigorov; Stanilova, Spaska Angelova

    2016-08-01

    Small molecule inhibitors of histone deacetylases (HDACs) are a new class drugs used in clinical trials for the treatment of various malignancies. Emerging evidence suggest that HDAC inhibitors may also have anti-inflammatory properties, although the molecular mechanisms remain poorly defined. Our study investigates the effect of the HDACs inhibitor suberoylanilide hydroxamic acid (SAHA) on the expression of IL-12p40-related cytokines. For this purpose, human peripheral blood mononuclear cells (PBMC) were stimulated with LPS and C3bgp with or without SAHA. IL-12p40, IL-12p35 and IL-23p19 mRNA was determined at 6 h by qRT-PCR. Cytokine levels were determined in culture supernatants at 6 and 24 h, by ELISA. SAHA significantly inhibited IL-12p40 and IL-23p19 mRNA synthesis and did not change IL-12p35 mRNA transcription. Early at 6 h, we detected significantly decreased IL-12p40 and IL-23, but not IL-12p70 protein production in cultures treated with SAHA. Results also showed that the suppression of IL-12p40-related cytokines was clearly defined at 24 h. However, this suppression was less pronounced regarding IL-12p70. The present study showed that SAHA suppressed the gene expression of IL-23p19 stronger than the expression of IL-12p35, as well as the synthesis of IL-23 compared to that of IL-12p70. We suggest that this inhibitory effect of SAHA may be beneficial during treatment of inflammatory and autoimmune diseases mediated by Th17 immune response. PMID:27240992

  14. Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

    PubMed Central

    Xia, Qinghua; Zheng, Yi; Jiang, Wei; Huang, Zhongxian; Wang, Muwen; Rodriguez, Ronald; Jin, Xunbo

    2016-01-01

    Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition. PMID:27588130

  15. Uric Acid as a Target of Therapy in CKD

    PubMed Central

    Jalal, Diana I.; Chonchol, Michel; Chen, Wei; Targher, Giovanni

    2012-01-01

    The prevalence of chronic kidney disease (CKD) has risen and will continue to rise in the United States and worldwide. This is alarming considering that CKD remains an irreversible condition and patients who progress to chronic kidney failure suffer reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have revealed several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this manuscript we offer a critical review of the experimental evidence linking hyperuricemia to CKD, we highlight the gaps in our knowledge on the topic as it stands today, and we review the observational and interventional studies that have examined the potential nephro-protective effect of lowering uric acid in CKD patients . While uric acid may also be linked to cardiovascular disease and mortality in patients with CKD, this review will focus only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression. PMID:23058478

  16. High-casein diet suppresses guanidinoacetic acid-induced hyperhomocysteinemia and potentiates the hypohomocysteinemic effect of serine in rats.

    PubMed

    Ohuchi, Seiya; Matsumoto, Yuko; Morita, Tatsuya; Sugiyama, Kimio

    2008-12-01

    To determine the effect of dietary protein level on experimental hyperhomocysteinemia, rats were fed 10% casein (10C) and 40% casein (40C) diets with or without 0.5% guanidinoacetic acid (GAA) for 14 d. In addition, rats were fed 10C + 0.75% methionine (10CM) and 40C + 0.75% methionine (40CM) diets with or without 2.5% serine for 14 d to determine the relationship between the dietary protein level and intensity of the hypohomocysteinemic effect of serine. GAA supplementation markedly increased the plasma homocysteine concentration in rats fed with the 10C diet, whereas it did not increase the plasma homocysteine concentration in rats fed with the 40C diet. Although serine supplementation significantly suppressed the methionine-induced enhancement of plasma homocysteine concentration, the decreased plasma homocysteine concentration was significantly lower in rats fed with the 40CM diet than in rats fed with the 10CM diet. The hepatic cystathionine beta-synthase and betaine-homocysteine S-methyltransferase activities were significantly higher in rats fed with the 40C or 40CM diet than in rats fed with the 10C or 10CM diet, irrespective of supplementation with GAA and serine. These results indicate that the high-casein diet was effective for both suppressing GAA-induced hyperhomocysteinemia and potentiating the hypohomocysteinemic effect of serine, probably through the enhanced activity of homocysteine-metabolizing enzymes. PMID:19060401

  17. Oleanolic acid inhibits colorectal cancer angiogenesis in vivo and in vitro via suppression of STAT3 and Hedgehog pathways.

    PubMed

    Li, Li; Lin, Jiumao; Sun, Guodong; Wei, Lihui; Shen, Aling; Zhang, Mingyue; Peng, Jun

    2016-06-01

    Angiogenesis is an essential process of cancer progression and is regulated by multiple intracellular signaling pathways, including signal transducer and activator of transcription 3 (STAT3) and sonic hedgehog (SHH). Thus, these pathways have become a promising target for anti‑cancer therapeutic strategies. Oleanolic acid (OA) is an active compound present in various herbal medicines, which have been used historically for the clinical treatment of various types of human malignancies, including colorectal cancer (CRC). The present study used a CRC mouse xenograft model and human umbilical vein endothelial cells (HUVECs) to evaluate the effect of OA on tumor angiogenesis and on the activation of the STAT3 and SHH signaling pathways. It was determined that OA treatment significantly inhibited tumor growth and reduced intratumoral microvessel density (MVD) in CRC mice. In addition, OA treatment inhibited the proliferation, migration and tube formation in HUVECs, in a dose and time-dependent manner. Furthermore, OA markedly suppressed the activation of the STAT3 and SHH signaling pathways and inhibited the expression of the pro‑angiogenic vascular endothelial growth factor A and basic fibroblast growth factor, two important target genes of the aforementioned signaling pathways. Therefore it is suggested that inhibition of tumor angiogenesis via the suppression of multiple signaling pathways may be one of the underlying mechanisms by which OA exerts its anti-cancer effect. PMID:27108756

  18. Gambogenic acid inhibits LPS-simulated inflammatory response by suppressing NF-κB and MAPK in macrophages.

    PubMed

    Yu, Xianjun; Zhao, Qun; Zhang, Haiwei; Fan, Cunxian; Zhang, Xixi; Xie, Qun; Xu, Chengxian; Liu, Yongbo; Wu, Xiaoxia; Han, Quanbin; Zhang, Haibing

    2016-05-01

    Inflammation is a response of body tissues to injury and infection. Compounds that can inhibit inflammation have been shown to have potential therapeutic clinical application. Gambogenic acid (GEA) has potent antitumor and anti-inflammatory activities. Herein, the molecular mechanisms of GEA's anti-inflammatory effect were investigated in lipopolysaccharide (LPS)-stimulated macrophage cells. The results showed that pretreatment with GEA could markedly inhibit interleukin (IL)-1α, IL-1β, tumor necrosis factor-α, IFN-β, IL-12b, and IL-23a production in a dose-dependent manner in LPS-induced model. Furthermore, this drug significantly reduced the release of nitric oxide (NO), and impaired the protein level of inducible NO synthase and the cyclooxygenase 2. The finding also showed that the effect of GEA may be related to the suppression of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway. These results indicate that GEA could suppress LPS-simulated inflammatory response partially by attenuating NO synthesis and NF-κB and MAPK activation, suggesting that it may become a potent therapeutic agent for the treatment of inflammatory diseases. PMID:27025602

  19. CD4+ T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa

    PubMed Central

    Geng, Elvin H; Neilands, Torsten B; Thièbaut, Rodolphe; Bosco Bwana, Mwebesa; Nash, Denis; Moore, Richard D; Wood, Robin; Marcel Zannou, Djimon; Althoff, Keri N; Lian Lim, Poh; Nachega, Jean B; Easterbrook, Philippa J; Kambugu, Andrew; Little, Francesca; Nakigozi, Gertrude; Nakanjako, Damalie; Kiggundu, Valerian; Chung Ki Li, Patrick; Bangsberg, David R; Fox, Matthew P; Prozesky, Hans W; Hunt, Peter W; Davies, Mary-Ann; Reynolds, Steven J; Egger, Matthias; Yiannoutsos, Constantin T; Vittinghoff, Eric V; Deeks, Steven G; Martin, Jeffrey N

    2015-01-01

    Background: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally. Methods: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitor-based regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/µl in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years. Results: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150/µl was 529/µl [95% confidence interval (CI): 517–541] in North America, 494/µl (95% CI: 429–559) in West Africa, 515/µl (95% CI: 508–522) in Southern Africa, 503/µl (95% CI: 478–528) in Asia and 437/µl (95% CI: 425–449) in East Africa. Conclusions: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional level. PMID:25859596

  20. Acetyl Eburicoic Acid from Laetiporus sulphureus var. miniatus Suppresses Inflammation in Murine Macrophage RAW 264.7 Cells

    PubMed Central

    Saba, Evelyn; Son, Youngmin; Jeon, Bo Ra; Kim, Seong-Eun; Lee, In-Kyoung

    2015-01-01

    The basidiomycete Laetiporus sulphureus var. miniatus belongs to the Aphyllophorales, Polyporaceae, and grows on the needleleaf tree. The fruiting bodies of Laetiporus species are known to produce N-methylated tyramine derivatives, polysaccharides, and various lanostane triterpenoids. As part of our ongoing effort to discover biologically active compounds from wood-rotting fungi, an anti-inflammatory triterpene, LSM-H7, has been isolated from the fruiting body of L. sulphureus var. miniatus and identified as acetyl eburicoic acid. LSM-H7 dose-dependently inhibited the NO production in RAW 264.7 cells without any cytotoxicity at the tested concentrations. Furthermore it suppressed the production of proinflammatory cytokines, mainly inducible nitric oxide synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6 and tumor necrosis factor α, when compared with glyceraldehyde 3-phosphate dehydrogenase. These data suggest that LSM-H7 is a crucial component for the anti-inflammatory activity of L. sulphureus var. miniatus. PMID:26190920

  1. Carboranyl amino acids for the specific neutron capture therapy of malignant melanoma

    SciTech Connect

    Kahl, S.B.

    1991-01-15

    We are pleased to summarize the very significant progress made since our last report dated April 6, 1990. Significant progress has been made toward our twin objectives of both the steroselective and non-steroselective synthesis of carborane-containing amino acids for boron neutron capture therapy of malignant melanoma. Additionally, we have developed a new, general procedure for the synthesis of a variety of {alpha}-amino acids which may find wide applicability in this area. 8 refs., 5 figs., 1 tab.

  2. Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

    PubMed Central

    Solomon, Ajantha; Ghneim, Khader; Ahlers, Jeffrey; Cameron, Mark J.; Smith, Miranda Z.; Spelman, Tim; McMahon, James; Velayudham, Pushparaj; Brown, Gregor; Roney, Janine; Watson, Jo; Prince, Miles H.; Hoy, Jennifer F.; Chomont, Nicolas; Fromentin, Rémi; Procopio, Francesco A.; Zeidan, Joumana; Palmer, Sarah; Odevall, Lina; Johnstone, Ricky W.; Martin, Ben P.; Sinclair, Elizabeth; Deeks, Steven G.; Hazuda, Daria J.; Cameron, Paul U.; Sékaly, Rafick-Pierre; Lewin, Sharon R.

    2014-01-01

    Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. Trial Registration ClinicalTrials.gov NCT01365065 PMID:25393648

  3. Comprehensive Suppression of All Apoptosis-Induced Proliferation Pathways as a Proposed Approach to Colorectal Cancer Prevention and Therapy

    PubMed Central

    Bordonaro, Michael; Drago, Eric; Atamna, Wafa; Lazarova, Darina L.

    2014-01-01

    Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs), and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1) the signaling heterogeneity of CRC cell populations, and (2) the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents. We explored the strategy of augmenting CRC cell death by inhibiting all survival pathways induced by the pro-apoptotic agent LBH589, a histone deacetylase inhibitor: AKT, JAK/STAT, and ERK signaling. The apoptosis-enhancing ability of a cocktail of synthetic inhibitors of proliferation was compared to the effects of the natural product propolis. We utilized colorectal adenoma, drug-sensitive and drug-resistant colorectal carcinoma cells to evaluate the apoptotic potential of the combination treatments. The results suggest that an effective approach to CRC combination therapy is to combine apoptosis-inducing drugs (e.g., histone deacetylase inhibitors, such as LBH589) with agents that suppress all compensatory survival pathways induced during apoptosis (such as the cocktail of inhibitors of apoptosis-associated proliferation). The same paradigm can be applied to a CRC prevention approach, as the apoptotic effect of butyrate, a diet-derived histone deacetylase inhibitor, is augmented by other dietary agents that modulate survival pathways (e.g., propolis and coffee extract). Thus, dietary supplements composed by fermentable fiber, propolis, and coffee extract may effectively counteract neoplastic growth in the colon. PMID:25500581

  4. Elucidation of the mechanism of suppressed steroidogenesis during androgen deprivation therapy of prostate cancer patients using a mouse model.

    PubMed

    Taniguchi, H; Katano, T; Nishida, K; Kinoshita, H; Matsuda, T; Ito, S

    2016-09-01

    Androgen deprivation therapy (ADT) is the standard medical approach to the management of prostate cancer. Patients switched from a GnRH antagonist to a GnRH agonist, did not experience a testosterone surge in spite of the occurrence of luteinizing hormone (LH) surge in our protocol of clinical study. To clarify this observation, male mice pre-treated with two different doses of the GnRH antagonist degarelix for 28 days were further administered the GnRH agonist leuprolide or chorionic gonadotropin, and testosterone production of the mice was studied. Serum LH and testosterone levels, the size of Leydig cells, and expression level of steroidogenesis-related genes in the testis were analyzed. Treatment of mice with a high dose of degarelix (0.1 μg/mouse; HDG), but not a low dose (0.05 μg/mouse; LDG), for 28 days reproduced declined steroidogenesis observed in prostate cancer patients during ADT switched from a GnRH antagonist to a GnRH agonist. The size of the Leydig cells in the HDG mice was not significantly different from that in naive mice. Although expression levels of StAR, P450scc, and 17β HSD increased significantly in the LDH testis, those in the HDG testis did not change. Treatment of mice with a high dose of degarelix for 28 days reproduced the decline in steroidogenesis observed in prostate cancer patients during ADT. In this animal model, we demonstrated that initial ADT may inhibit the ability of Leydig cells to produce testosterone by suppressing the expression of genes involved in steroidogenesis, such as StAR, P450scc, and 17βHSD. PMID:27230983

  5. Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression

    PubMed Central

    Osawa, Yosuke; Seki, Ekihiro; Kodama, Yuzo; Suetsugu, Atsushi; Miura, Kouichi; Adachi, Masayuki; Ito, Hiroyasu; Shiratori, Yoshimune; Banno, Yoshiko; Olefsky, Jerrold M.; Nagaki, Masahito; Moriwaki, Hisataka; Brenner, David A.; Seishima, Mitsuru

    2011-01-01

    Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine-1-phosphate (S1P). Because sphingolipids regulate AKT activation, we investigated the role of ASM in hepatic glucose and lipid metabolism. Initially, we overexpressed ASM in the livers of wild-type and diabetic db/db mice by adenovirus vector (Ad5ASM). In these mice, glucose tolerance was improved, and glycogen and lipid accumulation in the liver were increased. Using primary cultured hepatocytes, we confirmed that ASM increased glucose uptake, glycogen deposition, and lipid accumulation through activation of AKT and glycogen synthase kinase-3β. In addition, ASM induced up-regulation of glucose transporter 2 accompanied by suppression of AMP-activated protein kinase (AMPK) phosphorylation. Loss of sphingosine kinase-1 (SphK1) diminished ASM-mediated AKT phosphorylation, but exogenous S1P induced AKT activation in hepatocytes. In contrast, SphK1 deficiency did not affect AMPK activation. These results suggest that the SphK/S1P pathway is required for ASM-mediated AKT activation but not for AMPK inactivation. Finally, we found that treatment with high-dose glucose increased glycogen deposition and lipid accumulation in wild-type hepatocytes but not in ASM−/− cells. This result is consistent with glucose intolerance in ASM−/− mice. In conclusion, ASM modulates AKT activation and AMPK inactivation, thus regulating glucose and lipid metabolism in the liver.—Osawa, Y., Seki, E., Kodama, Y., Suetsugu, A., Miura, K., Adachi, M., Ito, H., Shiratori, Y., Banno, Y., Olefsky, J. M., Nagaki, M., Moriwaki, H., Brenner, D. A., Seishima, M. Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression. PMID:21163859

  6. Tauroursodeoxycholic acid suppresses endoplasmic reticulum stress in the chondrocytes of patients with osteoarthritis.

    PubMed

    Liu, Chao; Cao, Yongping; Yang, Xin; Shan, Pengcheng; Liu, Heng

    2015-10-01

    The main pathogenic events in osteoarthritis (OA) include loss and abnormal remodeling of cartilage extracellular matrix. The present study aimed to evaluate the protective effect of tauroursodeoxycholic acid on chondrocyte apoptosis induced by endoplasmic reticulum (ER) stress. Articular cartilage tissues were collected from 18 patients who underwent total knee arthroplasty and were analyzed histologically. Subsequently, chondrocyte apoptosis was assessed by TUNEL. Quantitative polymerase chain reaction and western blot analysis were employed to evaluate gene and protein expression, respectively, of ER stress markers, including glucose‑regulated protein 78 (GRP78), growth arrest and DNA‑damage‑inducible gene 153 (GADD153) and caspase‑12 along with type II collagen. Chondrocytes obtained from osteoarthritis patients at different stages were cultured in three conditions including: No treatment (CON group), tunicamycin treatment to induce ER stress (ERS group) and tauroursodeoxycholic acid treatment after 4 h of tunicamycin (TDA group); and cell proliferation, apoptosis, function and ER stress level were assessed. Degradation of cartilage resulted in histological damage with more apoptotic cartilage cells observed. Of note, GRP78, GADD153 and caspase‑12 mRNA and protein expression increased gradually from grade I to III cartilage tissue, while type II collagen expression decreased. Tunicamycin induced ER stress, as shown by a high expression of ER stress markers, reduced cell proliferation, increased apoptosis and decreased synthesis of type II collagen. Notably, tauroursodeoxycholic acid treatment resulted in the improvement of tunicamycin‑induced ER stress. These results indicated that ER stress is highly involved in the tunicamycin‑induced apoptosis in chondrocytes, which can be prevented by tauroursodeoxycholic acid. PMID:26238983

  7. Corosolic acid suppresses the expression of inflammatory marker genes in CCL4-induced-hepatotoxic rats.

    PubMed

    Balakrishnan, Aristatile; Al-Assaf, Abdullah Hassan

    2016-07-01

    The aim of the study was to asses the anti-inflammatory effects of corosolic acid on the carbon tetrachloride (CCL4) toxicity in rats. Liver toxicity was induced by administered CCL4 (single dose (1:1 in liquid paraffin) orally at 1.25 ml/kg. Rats were pretreated with CRA for 7 days before made CCL(4) toxicity at 20 mg/kg BW. The mRNA levels of TNF-α, IL-6, iNOS, COX-2 and NF-kB were assayed by reverse transcriptase PCR analysis. The mRNA levels of proinflammatory cytokines such as TNF-α, IL-6, and the inflammatory markers such as iNOS, COX-2 and NF-kB were significantly up regulated in CCl(4) induced rats and treatment with corosolic acid significantly reduced the expression of the above indicators. Our results suggest that the inhibition of TNF-α, IL-6, iNOS, COX-2 and NF-κB by corosolic acid, a potential candidate could possess anti-inflammatory activity besides its hepatoprotective effect in CCl4 liver toxicity in rats. PMID:27393448

  8. Mechanism of Tissue-specific Farnesoid X Receptor in Suppressing the Expression of Genes in Bile-acid Synthesis in Mice

    PubMed Central

    Kong, Bo; Wang, Li; Chiang, John Y. L.; Zhang, Youcai; Klaassen, Curtis D.; Guo, Grace L.

    2012-01-01

    Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing bile-acid synthesis by reducing the expression levels of genes encoding key bile-acid synthetic enzymes, CYP7A1/Cyp7a1 and CYP8B1/Cyp8b1. FXR-mediated induction of hepatic small heterodimer partner (SHP/Shp, Nr0b2) and intestinal fibroblast growth factor 15 (Fgf15, FGF19 in human) has been shown to be responsible for this suppression. However, the exact contribution of Shp/Fgf15 to this suppression and the associated cell signaling pathway is unclear. By using novel genetically modified mice, the current study showed that the intestinal Fxr/Fgf15 pathway was critical for suppressing both Cyp7a1 and Cyp8b1 gene expression, but the liver Fxr/Shp pathway was important for suppressing Cyp8b1 gene expression and had a minor role in suppressing Cyp7a1 gene expression. Furthermore, in vivo administration of Fgf15 protein to mice led to a strong activation of ERK, and to a smaller degree, JNK, in the liver. In addition, deficiency of either the ERK or JNK pathway in mouse livers reduced the basal, but not the Fgf15-mediated suppression, of Cyp7a1 and Cyp8b1 gene expression. However, deficiency of both ERK and JNK pathways prevented Fgf15-mediated suppression of Cyp7a1 and Cyp8b1 gene expression. Conclusion the current study clearly elucidates the underlying molecular mechanism of hepatic vs. intestinal Fxr in regulating the expression of genes critical for bile-acid synthesis and hydrophobicity in the liver. PMID:22467244

  9. 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. PMID:27149247

  10. Systemic Cytokine Levels Do Not Predict CD4(+) T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection.

    PubMed

    Norris, Philip J; Zhang, Jinbing; Worlock, Andrew; Nair, Sangeetha V; Anastos, Kathryn; Minkoff, Howard L; Villacres, Maria C; Young, Mary; Greenblatt, Ruth M; Desai, Seema; Landay, Alan L; Gange, Stephen J; Nugent, C Thomas; Golub, Elizabeth T; Keating, Sheila M

    2016-01-01

    Background.  Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4(+) T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4(+) T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status. Methods.  A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression. Results.  There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3β levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects. Conclusions.  These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects. PMID:26966697

  11. Systemic Cytokine Levels Do Not Predict CD4+ T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection

    PubMed Central

    Norris, Philip J.; Zhang, Jinbing; Worlock, Andrew; Nair, Sangeetha V.; Anastos, Kathryn; Minkoff, Howard L.; Villacres, Maria C.; Young, Mary; Greenblatt, Ruth M.; Desai, Seema; Landay, Alan L.; Gange, Stephen J.; Nugent, C. Thomas; Golub, Elizabeth T.; Keating, Sheila M.

    2016-01-01

    Background. Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4+ T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4+ T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status. Methods. A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression. Results. There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3β levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects. Conclusions. These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects. PMID:26966697

  12. Dual pH-responsive 5-aminolevulinic acid pseudopolyrotaxane prodrug micelles for enhanced photodynamic therapy.

    PubMed

    Tong, Hongxin; Wang, Yin; Li, Huan; Jin, Qiao; Ji, Jian

    2016-03-11

    Novel 5-aminolevulinic acid (ALA) pseudopolyrotaxane prodrug micelles with dual pH-responsive properties were prepared by the host-guest interaction of α-cyclodextrin (α-CD) and poly(ethylene glycol) (PEG). The micelles exhibited pH dependent cellular uptake and pH-sensitive ALA release, enabling enhanced photodynamic therapy. PMID:26882232

  13. An acid-cleavable phthalocyanine tetramer as an activatable photosensitiser for photodynamic therapy.

    PubMed

    Chow, Sun Y S; Lo, Pui-Chi; Ng, Dennis K P

    2016-08-16

    An acetal-linked self-quenched zinc(ii) phthalocyanine tetramer has been prepared. In an acidic environment in phosphate buffered saline or inside tumour cells, the phthalocyanine units of the tetramer are separated thereby restoring the fluorescence emission and singlet oxygen production. This response enables this compound to serve as a promising activatable photosensitiser for photodynamic therapy. PMID:27396392

  14. Abscisic Acid Promotes Susceptibility to the Rice Leaf Blight Pathogen Xanthomonas oryzae pv oryzae by Suppressing Salicylic Acid-Mediated Defenses

    PubMed Central

    Xu, Jing; Audenaert, Kris

    2013-01-01

    The plant hormone abscisic acid (ABA) is involved in a wide variety of plant processes, including the initiation of stress-adaptive responses to various environmental cues. Recently, ABA also emerged as a central factor in the regulation and integration of plant immune responses, although little is known about the underlying mechanisms. Aiming to advance our understanding of ABA-modulated disease resistance, we have analyzed the impact, dynamics and interrelationship of ABA and the classic defense hormone salicylic acid (SA) during progression of rice infection by the leaf blight pathogen Xanthomonas oryzae pv. oryzae (Xoo). Consistent with ABA negatively regulating resistance to Xoo, we found that exogenously administered ABA renders rice hypersusceptible to infection, whereas chemical and genetic disruption of ABA biosynthesis and signaling, respectively, led to enhanced Xoo resistance. In addition, we found successful Xoo infection to be associated with extensive reprogramming of ABA biosynthesis and response genes, suggesting that ABA functions as a virulence factor for Xoo. Interestingly, several lines of evidence indicate that this immune-suppressive effect of ABA is due at least in part to suppression of SA-mediated defenses that normally serve to limit pathogen growth. Resistance induced by the ABA biosynthesis inhibitor fluridone, however, appears to operate in a SA-independent manner and is likely due to induction of non-specific physiological stress. Collectively, our findings favor a scenario whereby virulent Xoo hijacks the rice ABA machinery to cause disease and highlight the importance of ABA and its crosstalk with SA in shaping the outcome of rice-Xoo interactions. PMID:23826294

  15. Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling

    PubMed Central

    Mu, Da-Wei; Guo, He-Qing; Zhou, Gao-Biao; Li, Jian-Ye; Su, Bin

    2015-01-01

    Oleanolic acid has significant pharmacological activities, such as anti-tumor, regulating blood sugar level and liver protection, which are more effective compared with free aglyconeoleanolic acid. However, it is still unknown if oleanolic acid affects the proliferation of human bladder cancer. We utilized T24 cells to study the effect of oleanolic acid on the proliferation and apoptosis of human bladder cancer. In this study, we found that the anti-cancer effect of oleanolic acid significantly suppressed cell proliferation and increased apoptosis and caspase-3 activity of T24 cells. Furthermore, Akt, mTOR and S6K protein expression was greatly inhibited in T24 cells under oleanolic acid treatment. Meanwhile, ERK1/2 of phosphorylation protein expression was significantly promoted by oleanolic acid treatment. Taken together, we provided evidences that oleanolic acid was Akt/mTOR/S6K and ERK1/2 signaling-targeting anti-tumor agent. These findings represent new evidences that oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling, and oleanolic acid may be used to prevent human bladder cancer. PMID:26823699

  16. Retinoic acid receptors: from molecular mechanisms to cancer therapy.

    PubMed

    di Masi, Alessandra; Leboffe, Loris; De Marinis, Elisabetta; Pagano, Francesca; Cicconi, Laura; Rochette-Egly, Cécile; Lo-Coco, Francesco; Ascenzi, Paolo; Nervi, Clara

    2015-02-01

    Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported. PMID:25543955

  17. Suppression of glycosaminoglycan synthesis by articular cartilage, but not of hyaluronic acid synthesis by synovium, after exposure to radiation

    SciTech Connect

    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 in 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.

  18. Change of Bone Mineral Density and Biochemical Markers of Bone Turnover in Patients on Suppressive Levothyroxine Therapy for Differentiated Thyroid Carcinoma

    PubMed Central

    Kim, Chei Won; Hong, Seokbo; Oh, Se Hwan; Lee, Jung Jin; Han, Joo Young; Kim, So Hun; Nam, Moonsuk; Kim, Yong Seong

    2015-01-01

    Untreated hyperthyroidism and high-dose thyroid hormone are associated with osteoporosis, and increased bone mineral density (BMD) has been demonstrated in postmenopausal females with hypoparathyroidism. Studies on the effect of suppressive levothyroxine (LT4) therapy on BMD and bone metabolism after total thyroidectomy in patients with differentiated thyroid carcinoma have presented conflicting results, and few studies in relation to the status of hypoparathyroidism have been studied. One hundred postmenopausal women and 24 premenopausal women on LT4 suppression therapy were included in this study. BMD of lumbar spine and femur and bone turnover markers were measured at the baseline and during the follow-up period up to 18 months using dual energy X-ray absorptiometry. Biochemical marker of bone resorption was measured by urine deoxypyridinoline and bone formation by serum osteocalcin. The age ranged from 36 to 64 years old. Thyroid stimulating hormone (TSH) was suppressed during the study. The results showed that BMD of femur and lumbar spine were not significantly changed in both pre- and postmenopausal women except femur neck in postmenopausal women without hypoparathyroidism. Patients with hypoparathyroidism had higher BMD gain than those without hypoparathyroidism in total hip (1.25 vs. -1.18%, P=0.015). Biochemical markers of bone turnover, serum osteocalcin, and urine deoxypyridinoline did not show significant change. In conclusion, patients with well differentiated thyroid carcinoma are not at a great risk of bone loss after LT4 suppressive therapy. The state of hypoparathyroidism is associated with increased BMD, particularly in postmenopausal women. PMID:26389089

  19. Auxin promotes susceptibility to Pseudomonas syringae via a mechanism independent of suppression of salicylic acid-mediated defenses.

    PubMed

    Mutka, Andrew M; Fawley, Stephen; Tsao, Tiffany; Kunkel, Barbara N

    2013-06-01

    Auxin is a key plant growth regulator that also impacts plant-pathogen interactions. Several lines of evidence suggest that the bacterial plant pathogen Pseudomonas syringae manipulates auxin physiology in Arabidopsis thaliana to promote pathogenesis. Pseudomonas syringae strategies to alter host auxin biology include synthesis of the auxin indole-3-acetic acid (IAA) and production of virulence factors that alter auxin responses in host cells. The application of exogenous auxin enhances disease caused by P. syringae strain DC3000. This is hypothesized to result from antagonism between auxin and salicylic acid (SA), a major regulator of plant defenses, but this hypothesis has not been tested in the context of infected plants. We further investigated the role of auxin during pathogenesis by examining the interaction of auxin and SA in the context of infection in plants with elevated endogenous levels of auxin. We demonstrated that elevated IAA biosynthesis in transgenic plants overexpressing the YUCCA 1 (YUC1) auxin biosynthesis gene led to enhanced susceptibility to DC3000. Elevated IAA levels did not interfere significantly with host defenses, as effector-triggered immunity was active in YUC1-overexpressing plants, and we observed only minor effects on SA levels and SA-mediated responses. Furthermore, a plant line carrying both the YUC1-overexpression transgene and the salicylic acid induction deficient 2 (sid2) mutation, which impairs SA synthesis, exhibited additive effects of enhanced susceptibility from both elevated auxin levels and impaired SA-mediated defenses. Thus, in IAA overproducing plants, the promotion of pathogen growth occurs independently of suppression of SA-mediated defenses. PMID:23521356

  20. Gene Therapy With Mitochondrial Heat Shock Protein 70 Suppresses Visual Loss and Optic Atrophy in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Talla, Venu; Porciatti, Vittorio; Chiodo, Vince; Boye, Sanford L.; Hauswirth, William W.; Guy, John

    2014-01-01

    Purpose. To rescue visual loss and optic neuropathy in experimental autoimmune encephalomyelitis (EAE). Methods. Encephalomyelitis was induced in mice that received intravitreal injections of AAV2-mtHSP70Flag or AAV2-Cox8-mCherry. Additional mice were injected with AAV2-Cox8-mCherry, but not sensitized for EAE. Visual function was assessed by pattern electroretinograms (PERG) at 1, 3, and 6 months post injection (MPI). Optical coherence tomography (OCT) evaluated the thickness of the inner plexiform layer + nerve fiber layers at 1, 3, and 6 MPI. Retinas and optic nerves (ONs) of mice euthanized 6 MPI were processed for light and electron microscopy. Expression of mtHSP70Flag in the retina and ONs was evaluated by RT-PCR, immunofluorescence, and Western blotting. The activities of respiratory complexes I and III, as well as mitochondrial protein import were quantitated. Results. Expression: immunofluorescence revealed punctate and perinuclear expression of mtHSP70Flag that colocalized with mitochondrial porin in thy1.2 labeled retinal ganglion cells (RGCs). Immunoblotting and RT-PCR confirmed mtHSP70Flag expression in the retina and ON. Rescue: treatment with mtHSP70Flag resulted in a 44% increase in PERG amplitude and less delays in latency relative to the EAE-mCherry group that also showed progressive inner retinal thinning. At 6 MPI, the almost 50% loss of RGCs and optic nerve axons in EAE mice was suppressed by mtHSP70Flag. In addition, retinas of EAE-mtHSP70Flag mice showed nearly complete rescue of complex I and III activities that was reduced by one-third in the EAE-mCherry retinas. Lastly, reductions in import of COX8-mCherry into mitochondria of mice sensitized for EAE improved by 30% with mtHSP70Flag gene therapy. Conclusions. Mitochondrial HSP70 ameliorates mitochondrial dysfunction that culminates in irreversible visual loss and atrophy of the optic nerve in EAE suggesting that it may be useful to prevent irreversible disability in patients with optic

  1. 18β-Glycyrrhetinic acid suppresses cell proliferation through inhibiting thromboxane synthase in non-small cell lung cancer.

    PubMed

    Huang, Run-Yue; Chu, Yong-Liang; Huang, Qing-Chun; Chen, Xiu-Min; Jiang, Ze-Bo; Zhang, Xian; Zeng, Xing

    2014-01-01

    18β-Glycyrrhetinic acid (18β-GA) is a bioactive component of licorice. The anti-cancer activity of 18β-GA has been studied in many cancer types, whereas its effects in lung cancer remain largely unknown. We first showed that 18β-GA effectively suppressed cell proliferation and inhibited expression as well as activity of thromboxane synthase (TxAS) in non-small cell lung cancer (NSCLC) cells A549 and NCI-H460. In addition, the administration of 18β-GA did not have any additional inhibitory effect on the decrease of cell proliferation induced by transfection with TxAS small interference RNA (siRNA). Moreover, 18β-GA failed to inhibit cell proliferation in the immortalized human bronchial epithelial cells 16HBE-T and another NSCLC cell line NCI-H23, both of which expressed minimal level of TxAS as compared to A549 and NCI-H460. However, 18β-GA abolished the enhancement of cell proliferation induced by transfection of NCI-H23 with pCMV6-TxAS plasmid. Further study found that the activation of both extracellular signal-regulated kinase (ERK)1/2 and cyclic adenosine monophosphate response element binding protein (CREB) induced by TxAS cDNA transfection could be totally blocked by 18β-GA. Altogether, we have delineated that, through inhibiting TxAS and its initiated ERK/CREB signaling, 18β-GA suppresses NSCLC cell proliferation. Our study has highlighted the significance of 18β-GA with respect to prevention and treatment of NSCLC. PMID:24695790

  2. Tousled kinase activator, gallic acid, promotes homologous recombinational repair and suppresses radiation cytotoxicity in salivary gland cells.

    PubMed

    Timiri Shanmugam, Prakash Srinivasan; Nair, Renjith Parameshwaran; De Benedetti, Arrigo; Caldito, Gloria; Abreo, Fleurette; Sunavala-Dossabhoy, Gulshan

    2016-04-01

    Accidental or medical radiation exposure of the salivary glands can gravely impact oral health. Previous studies have shown the importance of Tousled-like kinase 1 (TLK1) and its alternate start variant TLK1B in cell survival against genotoxic stresses. Through a high-throughput library screening of natural compounds, the phenolic phytochemical, gallic acid (GA), was identified as a modulator of TLK1/1B. This small molecule possesses anti-oxidant and free radical scavenging properties, but in this study, we report that in vitro it promotes survival of human salivary acinar cells, NS-SV-AC, through repair of ionizing radiation damage. Irradiated cells treated with GA show improved clonogenic survival compared to untreated controls. And, analyses of DNA repair kinetics by alkaline single-cell gel electrophoresis and γ-H2AX foci immunofluorescence indicate rapid resolution of DNA breaks in drug-treated cells. Study of DR-GFP transgene repair indicates GA facilitates homologous recombinational repair to establish a functional GFP gene. In contrast, inactivation of TLK1 or its shRNA knockdown suppressed resolution of radiation-induced DNA tails in NS-SV-AC, and homology directed repair in DR-GFP cells. Consistent with our results in culture, animals treated with GA after exposure to fractionated radiation showed better preservation of salivary function compared to saline-treated animals. Our results suggest that GA-mediated transient modulation of TLK1 activity promotes DNA repair and suppresses radiation cytoxicity in salivary gland cells. PMID:26855419

  3. Pyridoxine supplementation protects mice from suppression of contact hypersensitivity induced by 2-acetyl-4-tetrahydroxybutylimidazole (THI), ultraviolet B radiation (280-320 nm), or cis-urocanic acid.

    PubMed

    Reeve, V E; Bosnic, M; Boehm-Wilcox, C; Cope, R B

    1995-03-01

    Evidence exists implicating the epidermal ultraviolet B (UVB) photoproduct cis-urocanic acid as an immunogenic mediator of the systemic suppression of T cell-mediated immunity by UVB exposure. Cis-urocanic acid appears to act via histamine receptor pathways, and histamine receptor antagonists and other imidazole ring compounds may modify its immune suppressing action. A component of the food coloring substance ammonia caramel, 2-acetyl-4-tetrahydroxybutylimidazole (THI), which is known to cause lymphopenia in rats, appears to suppress immunity by a similar pathway when the contact hypersensitivity reaction has been the immune function assay in mice. The induction of lymphopenia in rats by THI is inhibited by the vitamin pyridoxine. This study demonstrates that the suppression of contact hypersensitivity in mice by UVB radiation, cis-urocanic acid, or THI is strongly inhibited by supplemental pyridoxine, fed at 30 mg/kg diet, in comparison with the normal diet, which supplies 7 mg pyridoxine/kg diet. These results suggest that pyridoxine competes with cis-urocanic acid and THI for the same binding site or receptor, which we postulate to be a histamine-like T lymphocyte receptor, and that a role may exist for the control of photoimmunosuppression by this vitamin. PMID:7872221

  4. 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...

  5. 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...

  6. Ascorbic acid repletion: A possible therapy for diabetic macular edema?

    PubMed

    May, James M

    2016-05-01

    Macular edema poses a significant risk for visual loss in persons with diabetic retinopathy. It occurs when plasma constituents and fluid leak out of damaged retinal microvasculature in the area of the macula, causing loss of central vision. Apoptotic loss of pericytes surrounding capillaries is perhaps the earliest feature of diabetic vascular damage in the macula, which is also associated with dysfunction of the endothelium and loss of the otherwise very tight endothelial permeability barrier. Increased oxidative stress is a key feature of damage to both cell types, mediated by excess superoxide from glucose-induced increases in mitochondrial metabolism, as well as by activation of the receptor for advanced glycation end products (RAGE). The latter in turn activates multiple pathways, some of which lead to increased oxidative stress, such as those involving NF-ĸB, NADPH oxidase, and endothelial nitric oxide synthase. Such cellular oxidative stress is associated with low cellular and plasma ascorbic acid levels in many subjects with diabetes in poor glycemic control. Whether repletion of low ascorbate in retinal endothelium and pericytes might help to prevent diabetic macular edema is unknown. However, cell culture studies show that the vitamin prevents high-glucose and RAGE-induced apoptosis in both cell types, that it preserves nitric oxide generated by endothelial cells, and that it tightens the leaky endothelial permeability barrier. Although these findings need to be confirmed in pre-clinical animal studies, it is worth considering clinical trials to determine whether adequate ascorbate repletion is possible and whether it might help to delay or even reverse early diabetic macular edema. PMID:26898503

  7. Folic acid supplementation of pregnant mice suppresses heat-induced neural tube defects in the offspring.

    PubMed

    Shin, J H; Shiota, K

    1999-11-01

    Neural tube defects (NTD) are a group of malformations that result from the failure of the neural tube to close early in embryonic development and among the most common congenital malformations in humans. It has been reported that a substantial proportion of NTD in humans can be prevented by folic acid (FA) supplementation prior to conception and during the first months of pregnancy, and myo-inositol (MI) was shown to reduce the incidence of NTD in curly tail mice which are not prevented by FA. Brief maternal hyperthermia (HT) early in pregnancy has been implicated in NTD both in humans and laboratory animals, and anterior NTD including exencephaly and anencephaly are induced frequently when pregnant mice are exposed to HT. We examined the effect of FA or MI supplementation of pregnant mice on the occurrence of heat-induced NTD in the offspring. When pregnant mice were treated with FA (3 mg/kg) daily from gestational day (GD) 0.5 through GD 9.5 and heated at GD 8.5, the prevalence of NTD in the fetuses (26.6%) was significantly lower than the corresponding figure in the HT alone group (38.6%; P < 0.05). However we failed to detect the preventive effect of MI (500 mg/kg). The results of this study suggest that prenatal FA supplementation decreases HT-induced NTD in mice and sufficient FA intake during early pregnancy may be recommended to avoid the birth of malformed children. PMID:10539786

  8. Suppression of Fusarium solani f. sp. phaseoli on Bean by Aluminum in Acid Soils.

    PubMed

    Furuya, H; Takahashi, T; Matsumoto, T

    1999-01-01

    ABSTRACT The severity of bean root rot caused by Fusarium solani f. sp. phaseoli in vitro was studied with regard to exchangeable soil aluminum for 25 soil samples collected from northeastern Honshyu island, Japan. Of these, 24 were Andosols, typically acidic and of volcanic ash origin. Disease severity was assessed based on the number of lesions produced by the pathogen on a 6-cm section of bean stem buried and incubated for 8 days at 25 degrees C in artificially infested soil samples. The number of lesions differed considerably among soil samples. In all soils in which disease incidence was very low, macroconidial germination was strongly inhibited. The inhibition was observed in all soil samples with exchangeable aluminum contents of at least 0.4 meq/100 g of soil, although it is unclear if this concentration is the lowest limit for inhibition. When soil pH was 5.6 or lower, higher amounts of exchangeable aluminum were detected from soils in which the major clay mineralogy was chloritized 2:1 minerals, while no or limited amounts of aluminum were detected from soils in which the major clay mineralogy was allophane/imogolite. Macroconidial germination and disease incidence are thus closely related to clay mineralogy, which regulates the behavior of exchangeable aluminum. PMID:18944802

  9. A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy

    PubMed Central

    Hsu, Tsung-I; Chen, Ying-Jung; Hung, Chia-Yang; Wang, Yi-Chang; Lin, Sin-Jin; Su, Wu-Chou; Lai, Ming-Derg; Kim, Sang-Yong; Wang, Qiang; Qian, Keduo; Goto, Masuo; Zhao, Yu; Kashiwada, Yoshiki; Lee, Kuo-Hsiung; Chang, Wen-Chang; Hung, Jan-Jong

    2015-01-01

    Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer. PMID:25909174

  10. TSH/TSHR Signaling Suppresses Fatty Acid Synthase (FASN) Expression in Adipocytes.

    PubMed

    Chen, Jicui; Ren, Jianmin; Jing, Qingping; Lu, Sumei; Zhang, Yuchao; Liu, Yuantao; Yu, Cong; Gao, Peng; Zong, Chen; Li, Xia; Wang, Xiangdong

    2015-09-01

    TSH/TSHR signaling plays a role in the regulation of lipid metabolism in adipocytes. However, the precise mechanisms are not known. In the present study, we determined the effect of TSH on fatty acid synthase (FASN) expression, and explored the underlying mechanisms. In vitro, TSH reduced FASN expression in both mRNA and protein levels in mature adipocytes and was accompanied by protein kinase A (PKA) activation, cAMP-response element binding protein (CREB) phosphorylation, as well as extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2 -terminal kinase (JNK) activation. TSH-induced downregulation of FASN was partially abolished by inhibition of PKA and ERK, but not JNK. TSHR and FASN expression in visceral tissue was significantly increased in C57BL/6 mice with diet-induced obesity compared with control animals, whereas thyroid TSHR expression was normal. These findings suggest that activation of TSHR directly inhibits FASN expression in mature adipocytes, possibly mediated by PKA and ERK. In obese animals, this function of TSHR seems to be counteracted. The precise mechanisms need further investigation. PMID:25655684

  11. A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy.

    PubMed

    Hsu, Tsung-I; Chen, Ying-Jung; Hung, Chia-Yang; Wang, Yi-Chang; Lin, Sin-Jin; Su, Wu-Chou; Lai, Ming-Derg; Kim, Sang-Yong; Wang, Qiang; Qian, Keduo; Goto, Masuo; Zhao, Yu; Kashiwada, Yoshiki; Lee, Kuo-Hsiung; Chang, Wen-Chang; Hung, Jan-Jong

    2015-05-30

    Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer. PMID:25909174

  12. Lipoic acid suppresses compound 48/80-induced anaphylaxis-like reaction

    PubMed Central

    Choi, Yun Ho; Chai, Ok Hee; Han, Eui-Hyeog; Choi, Su-Young; Kim, Hyoung Tae

    2010-01-01

    Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor in metabolic reactions involved in energy utilization. LA improves glycemic control, reduces diabetic polyneuropathies, atherosclerosis, and allergic inflammation. The effects of LA on mast cell-mediated anaphylactic reactions, however, are unknown. LA dose-dependently inhibited systemic and passive cutaneous anaphylaxis-like reactions in mice induced by compound 48/80, a condensation product of N-methyl-p-methoxyphenethylamine and formaldehyde. Pretreatment with LA, prior to induction of the systemic anaphylaxis-like reaction with compound 48/80, reduced plasma histamine levels in a dose-dependent manner. In our in vitro study, LA decreased histamine release from rat peritoneal mast cells (RPMCs) triggered by compound 48/80. Moreover, an increase in calcium uptake activated by compound 48/80 was inhibited by LA. LA also significantly elevated intracellular cyclic adenosine-3',5' monophosphate (cAMP) levels in RPMCs. This inhibition of mediator release from RPMCs may be due to inhibition of calcium uptake and augmentation of intracellular cAMP levels. Based on these results, we suggest that LA may be a potential remedy for allergy-related diseases. PMID:21267406

  13. Subchronic exposure to ellagic acid impairs cytotoxic T-cell function and suppresses humoral immunity in mice.

    PubMed

    Allen, C T; Peden-Adams, M M; EuDaly, J; Keil, D E

    2003-08-01

    Ellagic acid (EA) is present in a variety of foods such as grapes, strawberries, raspberries, and nuts. It is a dietary plant phenol that has been shown to inhibit oxidative stress and chemical carcinogenesis. Although several studies have examined the protective mechanisms of dietary EA including the induction of detoxifying enzymes, regulation of cell cycle, chelation of nickel, and prevention of DNA methylation, none have addressed the role of EA in immunological surveillance. This study investigates the status of immune function in B6C3F1 mice exposed continuously to EA in drinking water at 0.5, 1.0, or 2.0 mg/kg/day for 28 days. Although this range of exposure is above the estimated human daily intake (approximately 940 microg/day for 70 kg person or 13.4 microg/kg/day), these levels would not be unreasonable if EA were used as a dietary supplement or as a chemotherapeutic agent. Previous reports have demonstrated the anticarcinogenic effects of EA at levels 10- to 250-fold greater than those applied in this study. Immunological parameters assessed included natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity, IgM antibody plaque forming cell (PFC) response, thymus, spleen, kidney, and liver mass, and total cellularity for the thymus and spleen. Subchronic exposure to EA for 28 days in drinking water caused significant suppression of specific IgM antibody responses in the 2.0 mg/kg EA treatment group and suppressed cytotoxic T-cell function in the 0.5 and 1.0 mg/kg EA treatment groups. All other immunological parameters were within normal ranges. Kidney and liver mass were not altered after treatment with EA. The results from this study indicate that EA suppressed both IgM antibody responses and CTLs. These observations suggest important implications on human health should EA be prescribed as a chemotherapeutic agent or a preventative dietary supplement for cancer. PMID:19180803

  14. Preclinical Evaluation of Bioabsorbable Polyglycolic Acid Spacer for Particle Therapy

    SciTech Connect

    Akasaka, Hiroaki; Sasaki, Ryohei; Miyawaki, Daisuke; Mukumoto, Naritoshi; Sulaiman, Nor Shazrina Binti; Nagata, Masaaki; Yamada, Shigeru; Murakami, Masao; Demizu, Yusuke; Fukumoto, Takumi

    2014-12-01

    Purpose: To evaluate the efficacy and safety of a polyglycolic acid (PGA) spacer through physical and animal experiments. Methods and Materials: The spacer was produced with surgical suture material made of PGA, forming a 3-dimensional nonwoven fabric. For evaluation or physical experiments, 150-MeV proton or 320-MeV carbon-ion beams were used to generate 60-mm width of spread-out Bragg peak. For animal experiments, the abdomens of C57BL/6 mice, with or without the inserted PGA spacers, were irradiated with 20 Gy of carbon-ion beam (290 MeV) using the spread-out Bragg peak. Body weight changes over time were scored, and radiation damage to the intestine was investigated using hematoxylin and eosin stain. Blood samples were also evaluated 24 days after the irradiation. Long-term thickness retention and safety were evaluated using crab-eating macaques. Results: No chemical or structural changes after 100 Gy of proton or carbon-ion irradiation were observed in the PGA spacer. Water equivalency of the PGA spacer was equal to the water thickness under wet condition. During 24 days' observation after 20 Gy of carbon-ion irradiation, the body weights of mice with the PGA spacer were relatively unchanged, whereas significant weight loss was observed in those mice without the PGA spacer (P<.05). In mice with the PGA spacer, villus and crypt structure were preserved after irradiation. No inflammatory reactions or liver or renal dysfunctions due to placement of the PGA spacer were observed. In the abdomen of crab-eating macaques, thickness of the PGA spacer was maintained 8 weeks after placement. Conclusions: The absorbable PGA spacer had water-equivalent, bio-compatible, and thickness-retaining properties. Although further evaluation is warranted in a clinical setting, the PGA spacer may be effective to stop proton or carbon-ion beams and to separate normal tissues from the radiation field.

  15. 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

  16. Autologous formalin-fixed tumor vaccine suppressed re-recurrence of HCV-related hepatocellular carcinoma following 29 unsuccessful treatments with extensive conventional therapy: a case report.

    PubMed

    Inui, Toshio; Ohno, Tadao

    2012-01-01

    Treatment of hepatocellular carcinoma (HCC) with autologous formalin-fixed tumor vaccine after primary resection has been shown to suppress the recurrence of hepatitis B virus-associated HCC, but the effect of this treatment on hepatitis C virus (HCV)-related disease has not yet been clarified. Here, we report a case of a patient with repeat recurrent HCC that was associated with HCV who had endured 29 episodes of HCC recurrence despite a variety of therapy using conventional methods. Finally, treatment with a single course of autologous formalin-fixed tumor vaccine resulted in suppression of potential further re-recurrence of HCC for more than 43 months without any additional treatment. PMID:22789008

  17. 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

  18. Systematic Review of HIV Transmission between Heterosexual Serodiscordant Couples where the HIV-Positive Partner Is Fully Suppressed on Antiretroviral Therapy

    PubMed Central

    Loutfy, Mona R.; Wu, Wei; Letchumanan, Michelle; Bondy, Lise; Antoniou, Tony; Margolese, Shari; Zhang, Yimeng; Rueda, Sergio; McGee, Frank; Peck, Ryan; Binder, Louise; Allard, Patricia; Rourke, Sean B.; Rochon, Paula A.

    2013-01-01

    Background The risk of sexual HIV transmission in serodiscordant couples when the HIV-positive partner has full virologic suppression on combination antiretroviral therapy (cART) is debated. This study aims to systematically review observational studies and randomized controlled trials (RCTs), evaluating rates of sexual HIV transmission between heterosexual serodiscordant couples when the HIV-positive partner has full suppression on cART. Methods and Findings We searched major bibliographic databases to November 2012 for relevant observational studies and RCTs without language restrictions. Conference proceedings, key journals and bibliographies were also searched. Studies reporting HIV transmission rates, cART histories and viral loads of the HIV-positive partners were included. Two reviewers extracted methodologic characteristics and outcomes. Of 20,252 citations, 3 studies met all eligibility criteria with confirmed full virologic suppression in the HIV-positive partner. We included 3 additional studies (2 cohort studies, 1 RCT) that did not confirm viral suppression in the HIV-positive partner at transmission in a secondary meta-analysis. Methodologic quality was reasonable. The rate of transmission in the 3 studies confirming virologic suppression was 0 per 100 person-years (95% CI = 0–0.05), with low heterogeneity (I2 = 0%). When we included the 3 studies that did not confirm virologic suppression, the rate of transmission was 0.14 per 100 person-years (95%CI = 0.04–0.31) (I2 = 0%). In a sensitivity analysis including all 6 studies, the rate of transmission was 0 per 100 person-years (95%CI = 0–0.01) after omitting all transmissions with known detectable or unconfirmed viral loads, as full suppression in these cases was unlikely. Limitations included lack of data on same-sex couples, type of sexual intercourse (vaginal vs. anal), direction of HIV transmission, exact viral load at the time of transmission, sexually transmitted

  19. Zoledronic acid suppresses metastasis of esophageal squamous cell carcinoma cells through upregulating the tight junction protein occludin.

    PubMed

    Lin, Canfeng; Xin, Shubo; Qin, Xin; Li, Haijun; Lin, Lianxing; You, Yanjie

    2016-08-01

    We have previously demonstrated the radio-sensitizing effect of zoledronic acid (ZOL), a third generation bisphosphonate, on human esophageal squamous cell carcinoma (ESCC) cells. Here we show that ZOL suppresses metastatic progression of ESCC cells mainly through up-regulating the tight junction protein occludin. Exposure to ZOL at lower concentrations dramatically reduced migration and invasion of ESCC cells. In addition, ZOL treatment decreased the expression of mesenchymal markers, vimentin and N-cadherin, while increased the expression of the tight junction protein occludin. Moreover, ectopic expression of Slug, a well-known transcriptional repressor of occludin, partially but significantly abrogated the effect of ZOL on occludin expression and subsequently rescued the malignant metastatic phenotype, suggesting that Slug is one of the mediators underlying the anti-metastatic effect of ZOL. The present study is the first to report the significance of ZOL on ESCC metastasis. These data are promising for the future application of this drug regimen in patients with ESCC. PMID:26204820

  20. Suppression of Jasmonic Acid-Mediated Defense by Viral-Inducible MicroRNA319 Facilitates Virus Infection in Rice.

    PubMed

    Zhang, Chao; Ding, Zuomei; Wu, Kangcheng; Yang, Liang; Li, Yang; Yang, Zhen; Shi, Shan; Liu, Xiaojuan; Zhao, Shanshan; Yang, Zhirui; Wang, Yu; Zheng, Luping; Wei, Juan; Du, Zhenguo; Zhang, Aihong; Miao, Hongqin; Li, Yi; Wu, Zujian; Wu, Jianguo

    2016-09-01

    MicroRNAs (miRNAs) are pivotal modulators of plant development and host-virus interactions. However, the roles and action modes of specific miRNAs involved in viral infection and host susceptibility remain largely unclear. In this study, we show that Rice ragged stunt virus (RRSV) infection caused increased accumulation of miR319 but decreased expression of miR319-regulated TCP (TEOSINTE BRANCHED/CYCLOIDEA/PCF) genes, especially TCP21, in rice plants. Transgenic rice plants overexpressing miR319 or downregulating TCP21 exhibited disease-like phenotypes and showed significantly higher susceptibility to RRSV in comparison with the wild-type plants. In contrast, only mild disease symptoms were observed in RRSV-infected lines overexpressing TCP21 and especially in the transgenic plants overexpressing miR319-resistant TCP21. Both RRSV infection and overexpression of miR319 caused the decreased endogenous jasmonic acid (JA) levels along with downregulated expression of JA biosynthesis and signaling-related genes in rice. However, treatment of rice plants with methyl jasmonate alleviated disease symptoms caused by RRSV and reduced virus accumulation. Taken together, our results suggest that the induction of miR319 by RRSV infection in rice suppresses JA-mediated defense to facilitate virus infection and symptom development. PMID:27381440

  1. Pomolic Acid Inhibits Invasion of Breast Cancer Cells Through the Suppression of CXC Chemokine Receptor Type 4 Expression.

    PubMed

    Kim, Buyun; Kim, Ji-Hun; Park, Byoungduck

    2016-06-01

    High mortality of cancer-mediated deaths is due to metastasis. CXC chemokine receptor type 4 (CXCR4) signaling has been demonstrated to be involved in migration of breast cancer. Thus, identification of CXCR4 inhibitor has been challenged constantly as an anticancer drug. This study is aimed to investigate the CXCR4 inhibitor that could inhibit tumor metastasis from natural products. We demonstrated that pomolic acid (PA), a component of Euscaphis japonica, could downregulate CXCR4 expression in breast cancer cells. Treatment with proteasomal and lysosomal inhibitors did not show significant effects on PA's ability. When we further explored the molecular mechanism, suppression of CXCR4 occurred at transcriptional level and was correlated with inhibition of nuclear factor-kappaB (NF-κB) activation. Downregulation of CXCR4 by PA was accompanied by the inhibition of CXC motif chemokine 12 (CXCL12)-induced invasion of breast cancer cells. Overall, our results indicate that PA, as a novel inhibitor of CXCR4, can be a promising therapeutic agent for treatment of cancer metastasis. J. Cell. Biochem. 117: 1296-1307, 2016. © 2015 Wiley Periodicals, Inc. PMID:26495998

  2. Glycyrrhizic acid pretreatment prevents sepsis-induced acute kidney injury via suppressing inflammation, apoptosis and oxidative stress.

    PubMed

    Zhao, Hongyu; Liu, Zhenning; Shen, Haitao; Jin, Shuai; Zhang, Shun

    2016-06-15

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. The aim of our study was to investigate the molecular mechanism involved in the protective effects of GA in lipopolysaccharide (LPS) stimulated rat mesangial cells (HBZY-1) and septic rats. Sepsis model was established by injection of 5mg/kg LPS in rats or incubation with 1μg/ml LPS for 24h in HBZY-1 cells. A variety of molecular biological experiments were carried out to assess the effects of GA on inflammation, apoptosis, and oxidative stress. First we found that GA alleviated sepsis-induced kidney injury in vivo. Furthermore, GA suppressed inflammatory response in vivo and in vitro. Additionally, GA inhibited cell apoptosis and the changes in expressions of apoptosis related proteins induced by LPS. Moreover, GA markedly inhibited oxidative stress induced by LPS via activation of ERK signaling pathway. Finally GA could inhibit the activation of NF-κ B induced by LPS. Our present study indicates that GA has a protective effect against sepsis-induced inflammatory response, apoptosis, and oxidative stress damage, which provides a molecular basis for a new medical treatment of septic acute kidney injury. PMID:27063444

  3. 5-aminolevulinic acid in photodynamic diagnosis and therapy of urological malignancies

    NASA Astrophysics Data System (ADS)

    Nelius, Thomas; de Riese, Werner T. W.

    2003-06-01

    Completeness and certainty of tumor detection are very important issues in clinical oncology. Recent technological developments in ultrasound, radiologic and magnetic resonance imaging diagnostics are very promising, but could not improve the detection rate of early stage malignancies. One of the most promising new approaches is the use of 5-aminolevulinic acid, a potent photosensitizer, in photodynamic diagnosis and therapy. 5-aminolevulinic acid is meanwhile a well-established tool in the photodynamic diagnosis of bladder cancer. It has been shown to improve the sensitivity of detection of superficial tumors and carcinoma in situ, which enables to reduce the risk of tumor recurrence related to undetected lesions or incomplete transurethral resection of the primary lesions. The use of 5-aminolevulinic acid is steadily expanding in diagnostics of urological malignancies. First clinical results are now reported in detection of urethral and ureteral lesions as well as in urine fluorescence cytology. Furthermore, due to the selective accumulation in transitional cell carcinoma of the bladder, 5-aminolevulinic acid may be an ideal candidate for photodynamic therapy in superficial bladder cancer. Summarizing the data of multiple clinical trials, 5-aminolevulinic acid is a promising agent in photodynamic diagnostics and treatment of superficial bladder cancer.

  4. 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. PMID:22146711

  5. Linoelaidic acid enhances adipogenic differentiation in adipose tissue-derived stromal cells through suppression of Wnt/β-catenin signaling pathway in vitro.

    PubMed

    Wang, Jihui; Liang, Yuan; Jian, Luyang; Zhang, Jingwei; Liang, Shuai; Xiao, Shan; Liu, Bingnan; Wang, Han

    2016-07-01

    Obesity has become a major health problem which is related with high-trans fatty acids diet. Adipogenic differentiation of adipose tissue-derived stromal cells (ADSCs) plays an important role in the development of adipose tissue. In order to determine the effect of trans fatty acids on adipogenic differentiation in ADSCs, cells were treated with linoelaidic acid, as well as linoleic acid and linolenic acid. We found that linoelaidic acid significantly increased the lipid droplet formation and triglyceride content compared with linoleic acid and linolenic acid. Linoelaidic acid also down-regulated the levels of β-catenin in cells and inhibited the accumulation of β-catenin in cell nuclei. Lithium chloride, an activator of Wnt/β-catenin pathway, antagonized the enhancement of linoelaidic acid on adipogenesis and up-regulated the levels of β-catenin in ADSCs. These results indicated that linoelaidic acid could enhance the adipogenic differentiation in ADSCs in vitro, which is partly due to the suppression of Wnt/β-catenin pathway. PMID:27255637

  6. Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009

    PubMed Central

    Hanna, David B.; Buchacz, Kate; Gebo, Kelly A.; Hessol, Nancy A.; Horberg, Michael A.; Jacobson, Lisa P.; Kirk, Gregory D.; Kitahata, Mari M.; Korthuis, P. Todd; Moore, Richard D.; Napravnik, Sonia; Patel, Pragna; Silverberg, Michael J.; Sterling, Timothy R.; Willig, James H.; Lau, Bryan; Althoff, Keri N.; Crane, Heidi M.; Collier, Ann C.; Samji, Hasina; Thorne, Jennifer E.; Gill, M. John; Klein, Marina B.; Martin, Jeffrey N.; Rodriguez, Benigno; Rourke, Sean B.; Gange, Stephen J.; Benson, A.; Bosch, Ronald J.; Collier, Ann C.; Boswell, Stephen; Grasso, Chris; Mayer, Ken; Hogg, Robert S.; Harrigan, Richard; Montaner, Julio; Cescon, Angela; Brooks, John T.; Buchacz, Kate; Gebo, Kelly A.; Moore, Richard D.; Rodriguez, Benigno; Horberg, Michael A.; Silverberg, Michael J.; Thorne, Jennifer E.; Goedert, James J.; Jacobson, Lisa P.; Klein, Marina B.; Rourke, Sean B.; Burchell, Ann; Rachlis, Anita R.; Hunter-Mellado, Robert F.; Mayor, Angel M.; Gill, M. John; Deeks, Steven G.; Martin, Jeffrey N.; Saag, Michael S.; Mugavero, Michael J.; Willig, James; Eron, Joseph J.; Napravnik, Sonia; Kitahata, Mari M.; Crane, Heidi M.; Justice, Amy C.; Dubrow, Robert; Fiellin, David; Sterling, Timothy R.; Haas, David; Bebawy, Sally; Turner, Megan; Gange, Stephen J.; Anastos, Kathryn; Moore, Richard D.; Saag, Michael S.; Gange, Stephen J.; Kitahata, Mari M.; McKaig, Rosemary G.; Justice, Amy C.; Freeman, Aimee M.; Moore, Richard D.; Freeman, Aimee M.; Lent, Carol; Platt, Aaron; Kitahata, Mari M.; Van Rompaey, Stephen E.; Crane, Heidi M.; Webster, Eric; Morton, Liz; Simon, Brenda; Gange, Stephen J.; Abraham, Alison G.; Lau, Bryan; Althoff, Keri N.; Zhang, Jinbing; Jing, Jerry; Golub, Elizabeth; Modur, Shari; Hanna, David B.; Rebeiro, Peter; Wong, Cherise; Mendes, Adell

    2013-01-01

    Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes. Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness. Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001). Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide. PMID:23315317

  7. Salicylic acid derivatives as potential anti asthmatic agents using disease responsive drug delivery system for prophylactic therapy of allergic asthma.

    PubMed

    Raju, Kalidhindi Rama Satyanarayana; Ambhore, Nilesh S; Mulukutla, Shashank; Gupta, Saurabh; Murthy, Vishakantha; Kumar, M N Kiran; Madhunapantula, Subba Rao V; Kuppuswamy, Gowthamarajan; Elango, Kannan

    2016-02-01

    Asthma is a multi-factorial and complicated lung disorder of the immune system which has expanded to a wider ambit unveiling its etiology to be omnipresent at both ends of the spectrum involving basic pharmacology and in-depth immunology. As asthma occurs through triggered activation of various immune cells due to different stimuli, it poses a great challenge to uncover specific targets for therapeutic interventions. Recent pharmacotherapeutic approaches for asthma have been focused on molecular targeting of transcription factors and their signaling pathways; mainly nucleus factor kappa B (NFκB) and its associated pathways which orchestrate the synthesis of pro-inflammatory cytokines (IL-1β, TNF-α, GM-CSF), chemokines (RANTES, MIP-1a, eotaxin), adhesion molecules (ICAM-1, VCAM-1) and inflammatory enzymes (cyclooxygenase-2 and iNOS). 5-aminosalicylic acid (5-ASA) and sodium salicylate are known to suppress NFκB activation by inhibiting inhibitor of kappa B kinase (IKκB). In order to target the transcription factor, a suitable carrier system for delivering the drug to the intracellular space is essential. 5-ASA and sodium salicylate loaded liposomes incorporated into PEG-4-acrylate and CCRGGC microgels (a polymer formed by crosslinking of trypsin sensitive peptide and PEG-4-acrylate) could probably suit the needs for developing a disease responsive drug delivery system which will serve as a prophylactic therapy for asthmatic patients. PMID:26643666

  8. Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo.

    PubMed

    Yue, Peibin; Lopez-Tapia, Francisco; Paladino, David; Li, Yifei; Chen, Chih-Hong; Namanja, Andrew T; Hilliard, Tyvette; Chen, Yuan; Tius, Marcus A; Turkson, James

    2016-02-01

    STAT3 offers an attractive target for cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src-transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, and survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA-binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3-inhibitory effects of SH4-54. Neither compound appreciably affected STAT1 or STAT5 DNA-binding activities, STAT3-independent gene transcription, or activation of a panel of oncogenic kinases in malignant cells. Each compound decreased the proliferation and viability of glioma, breast, and prostate cancer cells and v-Src-transformed murine fibroblasts harboring constitutively active STAT3. Further, in mouse xenograft models of glioma and breast cancer, administration of SH5-07 or SH4-54 effectively inhibited tumor growth. Our results offer preclinical proof of concept for SH5-07 and SH4-54 as candidates for further development as cancer therapeutics. PMID:26088127

  9. Persistently Elevated C-Reactive Protein Level in the First Year of Antiretroviral Therapy, Despite Virologic Suppression, Is Associated With HIV Disease Progression in Resource-Constrained Settings.

    PubMed

    Shivakoti, Rupak; Yang, Wei-Teng; Berendes, Sima; Mwelase, Noluthando; Kanyama, Cecilia; Pillay, Sandy; Samaneka, Wadzanai; Santos, Breno; Poongulali, Selvamuthu; Tripathy, Srikanth; Riviere, Cynthia; Lama, Javier R; Cardoso, Sandra W; Sugandhavesa, Patcharaphan; Balagopal, Ashwin; Gupte, Nikhil; Semba, Richard D; Campbell, Thomas B; Bollinger, Robert C; Gupta, Amita

    2016-04-01

    A case-cohort analysis of human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) was performed within a multicountry randomized trial (PEARLS) to assess the prevalence of persistently elevated C-reactive protein (CRP) levels, based on serial measurements of CRP levels, and their association with HIV clinical failure. A persistently elevated CRP level in plasma (defined as ≥ 5 mg/L at both baseline and 24 weeks after ART initiation) was observed in 50 of 205 individuals (24%). A persistently elevated CRP level but not an elevated CRP level only at a single time point was independently associated with increased clinical failure, compared with a persistently low CRP level, despite achievement of virologic suppression. Serial monitoring of CRP levels could identify individuals who are at highest risk of HIV progression and may benefit from future adjunct antiinflammatory therapies. PMID:26621909

  10. Removing perfluorooctane sulfonate and perfluorooctanoic acid from solid matrices, paper, fabrics, and sand by mineral acid suppression and supercritical carbon dioxide extraction.

    PubMed

    Chen, Hsiang-Yu; Liao, Weisheng; Wu, Ben-Zen; Nian, Hungchi; Chiu, KongHwa; Yak, Hwa-Kwang

    2012-09-01

    The removal of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) from solid matrices has received considerable attention because of the environmental persistence, bioaccumulation, and potential toxicity of these compounds. This study presents a simple method using concentrated HNO(3) as a suppression agent, and methanol-modified supercritical carbon dioxide (Sc-CO(2)) extraction for removing PFOS and PFOA from solid matrices. The optimal conditions were 16 M HNO(3) and 20% (v/v) methanol containing Sc-CO(2), under a pressure of 20.3 MPa and a temperature of 50 °C. Extraction time was set at 70 min (40 min for static and 30 min for dynamic extraction). PFOA and PFOS were identified and quantitated by liquid chromatography/mass spectrometry. The extraction efficiencies (with double extractions) were close to 100% for PFOA and 80% for PFOS for both paper and fabric matrices. The extraction efficiencies for sand were approximately 77% for PFOA and 59% for PFOS. The results show that this method is accurate, and effective, and that it provides a promising and convenient approach to remediate the environment of hazardous PFOA and PFOS contamination. PMID:22748389

  11. Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy-generated vaccine.

    PubMed

    Korbelik, Mladen; Banáth, Judit; Zhang, Wei; Saw, Kyi Min; Szulc, Zdzislaw M; Bielawska, Alicja; Separovic, Duska

    2016-09-15

    Acid ceramidase has been identified as a promising target for cancer therapy. One of its most effective inhibitors, LCL521, was examined as adjuvant to photodynamic therapy (PDT) using mouse squamous cell carcinoma SCCVII model of head and neck cancer. Lethal effects of PDT, assessed by colony forming ability of in vitro treated SCCVII cells, were greatly enhanced when combined with 10 µM LCL521 treatment particularly when preceding PDT. When PDT-treated SCCVII cells are used to vaccinate SCCVII tumor-bearing mice (PDT vaccine protocol), adjuvant LCL521 treatment (75 mg/kg) resulted in a marked retardation of tumor growth. This effect can be attributed to the capacity of LCL521 to effectively restrict the activity of two main immunoregulatory cell populations (Tregs and myeloid-derived suppressor cells, MDSCs) that are known to hinder the efficacy of PDT vaccines. The therapeutic benefit with adjuvant LCL521 was also achieved with SCCVII tumors treated with standard PDT when using immunocompetent mice but not with immunodeficient hosts. The interaction of LCL521 with PDT-based antitumor mechanisms is dominated by immune system contribution that includes overriding the effects of immunoregulatory cells, but could also include a tacit contribution from boosting direct tumor cell kill. PMID:27136745

  12. Safety & Efficacy of Cyclic Zoledronic Acid Therapy on Pediatric Secondary Osteoporosis

    PubMed Central

    Al-Agha, Abdulmoein E.; Shaikhain, Talal A.; Ashour, Abdullah A.

    2016-01-01

    Background/Aim: Osteoporosis is a systemic disease characterized by decreased bone density and increased tendency to develop fractures. Osteoporosis in children and adolescents is a rare disease usually secondary to Medical conditions or medications given to children. The condition affects normal bone growth and development and carries with it multiple morbidities (physical and psychological) if not corrected promptly. This study aims to share our experience with Zoledronic Acid Therapy in Pediatric patients with secondary osteoporosis. Method: A retrospective study which included 46 patients aged 3 to 18 years. All patients received specific doses of Zoledronic acid and were followed up at King Abdulaziz University Hospital (KAUH) in Jeddah, Saudi Arabia. Clinical and laboratory data were collected for each patient from their files. Adverse events were also recorded. Results: The use of Zoledronic Acid in children and adolescents appears to be statically significant reduce fracture rate (p=0.005), bone turnover markers (Osteocalcin p= 0.003, CTX p= 0.008) and pain frequency in symptomatic individuals (p=0.000). Careful selection of cases is required to provide maximum benefits compared to risks associated with therapy. Conclusion: This study demonstrates that Zoledronic acid has positive effects on clinical outcome and bone marker level as well as quality of life for Pediatric patients with Osteoporosis and their families, with no long-term side effects.

  13. Determination of threshold dose with delta-aminolevulinic acid-induced porphyrins for effective photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Fritsch, Clemens; Abels, Christoph; Bolsen, Klaus; Ruzicka, Thomas; Goetz, Alwin E.; Goerz, Guenter

    1995-03-01

    In this study the metabolism in tumors and various tissues of intravenously administered (delta) -aminolevulinic acid was investigated. Amelanotic melanoma (A-Mel-3) were implanted in the dorsal skin of Syrian golden hamsters. Distribution and metabolism of i.v. injected (delta) -aminolevulinic acid in blood was studied by determination of (delta) - aminolevulinic acid and protoporphyrin concentration in red blood cells. In addition extraction of various tissues, e.g. tumor, liver, kidney, and normal skin was performed, to verify fluorescence kinetic studies by determination of total porphyrin concentration by photometry and of distribution of the porphyrin metabolites by HPLC. In untreated animals the total porphyrin concentration in all tissues examined were comparably low. In red blood cells the maximal concentration of (delta) -aminolevulinic acid as well as protoporphyrin was detected 45 min after i.v. injection of (delta) -aminolevulinic acid. Porphyrins accumulated in melanoma reaching a maximum tumor:skin tissue ratio of 6.9:1 at 45 min after i.v. injection of (delta) -aminolevulinic acid. A second high tumor:skin tissue ratio of 5.7:1 could be measured at 24 h after injection, but at this point in time the protoporphyrin content in normal skin was higher than 45 min after injection. The kidney may not be strongly affected by i.v. administration of (delta) -aminolevulinic acid, whereas the liver reveals an accumulation of porphyrins, e.g. protoporphyrin. Concluding from these results in this experimental tumor model, i.v. administration of (delta) -aminolevulinic acid seems to be a promising modality to perform photodynamic therapy more effectively and more selectively by irradiation 45 - 180 min after injection of (delta) -aminolevulinic acid.

  14. Docosahexaenoic acid inhibited the Wnt/β-catenin pathway and suppressed breast cancer cells in vitro and in vivo.

    PubMed

    Xue, Meilan; Wang, Qing; Zhao, Jinglan; Dong, Liyan; Ge, Yinlin; Hou, Lin; Liu, Yongchao; Zheng, Zheng

    2014-02-01

    N-3 fatty acids (FAs) are essential FAs necessary for human health and are known to possess anticancer properties. However, the relationship between n-3 FAs and β-catenin, one of the key components of the Wnt signaling pathway, in mouse breast cancer remains poorly characterized. In this study, 4T1 mouse breast cancer cells were exposed to a representative n-3 FA, docosahexaenoic acid (DHA), to investigate the relationship between n-3 FAs and the Wnt/β-catenin signaling pathway in vivo and in vitro. In vitro studies showed that DHA strongly inhibited cell growth, and induced G1 cell cycle arrest both in 4T1 mouse breast cells and MCF-7 human breast cells. DHA reduced β-catenin expression and T cell factor/lymphoid-enhancing factor reporter activity in 4T1 mouse breast cells. In addition, DHA down-regulated the expression of downstream target genes such as c-myc and cyclinD1. In vivo, therapy experiments were conducted on Babl/c mice bearing breast cancer. We found that feeding mouse the 5% fish oil-supplemented diet for 30 days significantly reduced the growth of 4T1 mouse breast cancer in vivo through inhibition of cancer cell proliferation as well as induction of apoptosis. Feeding animals a 5% fish oil diet significantly induced down-regulation of β-catenin in tumor tissues with a notable increase in apoptosis. In addition, fish oil-supplemented diet decreased lung metastases of breast cancer. These observations suggested that DHA exerted its anticancer activity through down-regulation of Wnt/β-catenin signaling. Thus, our data call for further studies to assess the effectiveness of fish oil as a dietary supplement in the prevention and treatment of breast cancer. PMID:24290517

  15. Enterococcus faecalis lipoteichoic acid suppresses Aggregatibacter actinomycetemcomitans lipopolysaccharide-induced IL-8 expression in human periodontal ligament cells.

    PubMed

    Im, Jintaek; Baik, Jung Eun; Kim, Kyoung Whun; Kang, Seok-Seong; Jeon, Jun Ho; Park, Ok-Jin; Kim, Hyun Young; Kum, Kee-Yeon; Yun, Cheol-Heui; Han, Seung Hyun

    2015-08-01

    Periodontitis is caused by multi-bacterial infection and Aggregatibacter actinomycetemcomitans and Enterococcus faecalis are closely associated with inflammatory periodontal diseases. Although lipopolysaccharide (LPS) of A. actinomycetemcomitans (Aa.LPS) and lipoteichoic acid of E. faecalis (Ef.LTA) are considered to be major virulence factors evoking inflammatory responses, their combinatorial effect on the induction of chemokines has not been investigated. In this study, we investigated the interaction between Aa.LPS and Ef.LTA on IL-8 expression in human periodontal ligament (PDL) cells. Aa.LPS, but not Ef.LTA, substantially induced IL-8 expression at the protein and mRNA levels. Interestingly, Ef.LTA suppressed Aa.LPS-induced IL-8 expression without affecting the binding of Aa.LPS to Toll-like receptor (TLR) 4. Ef.LTA reduced Aa.LPS-induced phosphorylation of mitogen-activated protein kinases, including ERK, JNK and p38 kinase. Furthermore, Ef.LTA inhibited the Aa.LPS-induced transcriptional activities of the activating protein 1, CCAAT/enhancer-binding protein and nuclear factor-kappa B transcription factors, all of which are known to regulate IL-8 gene expression. Ef.LTA augmented the expression of IL-1 receptor-associated kinase-M (IRAK-M), a negative regulator of TLR intracellular signaling pathways, in the presence of Aa.LPS at both the mRNA and protein levels. Small interfering RNA silencing IRAK-M reversed the attenuation of Aa.LPS-induced IL-8 expression by Ef.LTA. Collectively, these results suggest that Ef.LTA down-regulates Aa.LPS-induced IL-8 expression in human PDL cells through up-regulation of the negative regulator IRAK-M. PMID:25840438

  16. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    SciTech Connect

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-11-15

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: Black-Right-Pointing-Pointer ATO and SAHA are therapeutic agents with different action modes. Black-Right-Pointing-Pointer Combination of ATO and SAHA synergistically inhibits tumor cell growth. Black-Right-Pointing-Pointer SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. Black-Right-Pointing-Pointer ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  17. Identification of differentially expressed genes in SHSY5Y cells exposed to okadaic acid by suppression subtractive hybridization

    PubMed Central

    2012-01-01

    Background Okadaic acid (OA), a toxin produced by several dinoflagellate species is responsible for frequent food poisonings associated to shellfish consumption. Although several studies have documented the OA effects on different processes such as cell transformation, apoptosis, DNA repair or embryogenesis, the molecular mechanistic basis for these and other effects is not completely understood and the number of controversial data on OA is increasing in the literature. Results In this study, we used suppression subtractive hybridization in SHSY5Y cells to identify genes that are differentially expressed after OA exposure for different times (3, 24 and 48 h). A total of 247 subtracted clones which shared high homology with known genes were isolated. Among these, 5 specific genes associated with cytoskeleton and neurotransmission processes (NEFM, TUBB, SEPT7, SYT4 and NPY) were selected to confirm their expression levels by real-time PCR. Significant down-regulation of these genes was obtained at the short term (3 and 24 h OA exposure), excepting for NEFM, but their expression was similar to the controls at 48 h. Conclusions From all the obtained genes, 114 genes were up-regulated and 133 were down-regulated. Based on the NCBI GenBank and Gene Ontology databases, most of these genes are involved in relevant cell functions such as metabolism, transport, translation, signal transduction and cell cycle. After quantitative PCR analysis, the observed underexpression of the selected genes could underlie the previously reported OA-induced cytoskeleton disruption, neurotransmission alterations and in vivo neurotoxic effects. The basal expression levels obtained at 48 h suggested that surviving cells were able to recover from OA-caused gene expression alterations. PMID:22284234

  18. Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV-induced suppression of delayed-type hypersensitivity.

    PubMed

    Kim, Tae-Hueng; Moodycliffe, Angus M; Yarosh, Daniel B; Norval, Mary; Kripke, Margaret L; Ullrich, Stephen E

    2003-09-01

    UV radiation suppresses the immune response, and UV-induced immune suppression contributes to UV-induced photocarcinogenesis. For UV-induced immune suppression to occur, electromagnetic energy (i.e. UV radiation) must be converted to a biological signal. Two photoreceptors have been identified in the skin that serves this purpose, epidermal DNA and trans-urocanic acid (UCA). Although compelling evidence exists to support a role for each pathway (UV-induced DNA damage or photoisomerization of UCA) in UV-induced immune suppression, it is not clear what determines which photoreceptor pathway is activated. To address this question, we injected UV-irradiated mice with a monoclonal antibody with specificity for cis-UCA or applied liposomes containing DNA repair enzymes to the skin of UV-irradiated mice. The effect that each had on UV-induced suppression of delayed-type hypersensitivity was measured. We asked whether the light source used (FS-40 sunlamps vs solar-simulated UV radiation) altered whichever pathway of immune suppression was activated. Different doses of UV radiation and the viability of the antigen were also considered. Neither the dose of UV nor the light source had any influence on determining which pathway was activated. Rather, we found that the viability of the antigen was the critical determinant. When live antigens were used, UV-induced immune suppression was blocked with monoclonal anti-cis-UCA but not with T4 endonuclease V-containing liposomes. The reverse was observed when formalin-fixed or killed antigens were used. Our findings indicate that antigen viability dictates which photoreceptor pathway predominates after UV exposure. PMID:14556308

  19. Identification of the domains of cauliflower mosaic virus protein P6 responsible for suppression of RNA silencing and salicylic acid signalling

    PubMed Central

    Laird, Janet; McInally, Carol; Carr, Craig; Doddiah, Sowjanya; Yates, Gary; Chrysanthou, Elina; Khattab, Ahmed; Love, Andrew J.; Geri, Chiara; Sadanandom, Ari; Smith, Brian O.; Kobayashi, Kappei

    2013-01-01

    Cauliflower mosaic virus (CaMV) encodes a 520 aa polypeptide, P6, which participates in several essential activities in the virus life cycle including suppressing RNA silencing and salicylic acid-responsive defence signalling. We infected Arabidopsis with CaMV mutants containing short in-frame deletions within the P6 ORF. A deletion in the distal end of domain D-I (the N-terminal 112 aa) of P6 did not affect virus replication but compromised symptom development and curtailed the ability to restore GFP fluorescence in a GFP-silenced transgenic Arabidopsis line. A deletion in the minimum transactivator domain was defective in virus replication but retained the capacity to suppress RNA silencing locally. Symptom expression in CaMV-infected plants is apparently linked to the ability to suppress RNA silencing. When transiently co-expressed with tomato bushy stunt virus P19, an elicitor of programmed cell death in Nicotiana tabacum, WT P6 suppressed the hypersensitive response, but three mutants, two with deletions within the distal end of domain D-I and one involving the N-terminal nuclear export signal (NES), were unable to do so. Deleting the N-terminal 20 aa also abolished the suppression of pathogen-associated molecular pattern-dependent PR1a expression following agroinfiltration. However, the two other deletions in domain D-I retained this activity, evidence that the mechanisms underlying these functions are not identical. The D-I domain of P6 when expressed alone failed to suppress either cell death or PR1a expression and is therefore necessary but not sufficient for all three defence suppression activities. Consequently, concerns about the biosafety of genetically modified crops carrying truncated ORFVI sequences appear unfounded. PMID:24088344

  20. Extracellular acidity, a "reappreciated" trait of tumor environment driving malignancy: perspectives in diagnosis and therapy.

    PubMed

    Peppicelli, Silvia; Bianchini, Francesca; Calorini, Lido

    2014-09-01

    Tumors are ecosystems which develop from stem cells endowed with unlimited self-renewal capability and genetic instability, under the effects of mutagenesis and natural selection imposed by environmental changes. Abnormal vascularization, reduced lymphatic network, uncontrolled cell growth frequently associated with hypoxia, and extracellular accumulation of glucose metabolites even in the presence of an adequate oxygen level are all factors contributing to reduce pH in the extracellular space of tumors. Evidence is accumulating that acidity is associated with a poor prognosis and participates actively to tumor progression. This review addresses some of the most experimental evidences providing that acidity of tumor environment facilitates local invasiveness and metastatic dissemination, independently from hypoxia, with which acidity is often but not always associated. Clinical investigations have also shown that tumors with acidic environment are associated with resistance to chemotherapy and radiation-induced apoptosis, suppression of cytotoxic lymphocytes, and natural killer cells tumoricidal activity. Therefore, new technologies for functional and molecular imaging as well as strategies directed to target low extracellular pH and low pH-adapted tumor cells might represent important issues in oncology. PMID:24984804

  1. Hyaluronic acid reagent functional chitosan-PEI conjugate with AQP2-siRNA suppressed endometriotic lesion formation

    PubMed Central

    Zhao, Meng-Dan; Cheng, Jin-Lin; Yan, Jing-Jing; Chen, Feng-Ying; Sheng, Jian-Zhong; Sun, Dong-Li; Chen, Jian; Miao, Jing; Zhang, Run-Ju; Zheng, Cai-Hong; Huang, He-Feng

    2016-01-01

    To identify a new drug candidate for treating endometriosis which has fewer side effects, a new polymeric nanoparticle gene delivery system consisting of polyethylenimine-grafted chitosan oligosaccharide (CSO-PEI) with hyaluronic acid (HA) and small interfering RNA (siRNA) was designed. There was no obvious difference in sizes observed between (CSO-PEI/siRNA)HA and CSO-PEI/siRNA, but the fluorescence accumulation in the endometriotic lesion was more significant for (CSO-PEI/siRNA)HA compared with CSO-PEI/siRNA due to the specific binding of HA to CD44. In addition, the (CSO-PEI/siRNA)HA nanoparticle gene therapy significantly decreased the endometriotic lesion sizes with atrophy and degeneration of the ectopic endometrium. The epithelial cells of ectopic endometrium from rat models of endometriosis showed a significantly lower CD44 expression than control after treatment with (CSO-PEI/siRNA)HA. Furthermore, observation under an electron microscope showed no obvious toxic effect on the reproductive organs. Therefore, (CSO-PEI/siRNA)HA gene delivery system can be used as an effective method for the treatment of endometriosis. PMID:27099493

  2. (1→3)-β-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy: A Cohort Study.

    PubMed

    Hoenigl, Martin; de Oliveira, Michelli Faria; Pérez-Santiago, Josué; Zhang, Yonglong; Morris, Sheldon; McCutchan, Allen J; Finkelman, Malcolm; Marcotte, Thomas D; Ellis, Ronald J; Gianella, Sara

    2016-03-01

    Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1→3)-β-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals. PMID:26986173

  3. (1→3)-β-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy

    PubMed Central

    Hoenigl, Martin; de Oliveira, Michelli Faria; Pérez-Santiago, Josué; Zhang, Yonglong; Morris, Sheldon; McCutchan, Allen J.; Finkelman, Malcolm; Marcotte, Thomas D.; Ellis, Ronald J.; Gianella, Sara

    2016-01-01

    Abstract Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1→3)-β-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals. PMID:26986173

  4. Effect of Insulin Sensitizer Therapy on Amino Acids and their Metabolites

    PubMed Central

    Irving, B.A.; Carter, R.E.; Soop, M.; Weymiller, A.; Syed, H.; Karakelides, H.; Bhagra, S.; Short, K.R.; Tatpati, L.; Barazzoni, R.; Nair, K.S.

    2015-01-01

    Aims Prior studies have reported that elevated concentrations of several plasma amino acids (AA) in plasma, 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. Methods We performed a secondary analysis of a randomized, double-blind, placebo, controlled study conducted in twenty five overweight/obese (BMI~30 kg/m2) adults with impaired fasting glucose or untreated diabetes. Participants were randomized to three months of pioglitazone (45 mg per day) plus metformin (1000 mg 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. Results 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. Conclusions 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. PMID:25733201

  5. Stability and effectiveness of linear polyacrylamide capillary coating to suppress EOF in acidic media in the presence of surfactants, ionic liquids and organic modifiers.

    PubMed

    Beneito-Cambra, Miriam; Anres, Philippe; Vial, Jérôme; Gareil, Pierre; Delaunay, Nathalie

    2016-04-01

    Because of its high hydrophilicity, linear polyacrylamide (LPA) has often been used as a coating to suppress electroosmotic flow (EOF) in capillary electrophoresis (CE); however, its stability and effectiveness in acidic media, with or without organic modifiers, surfactants or ionic liquids is not well documented. In this work, the adequacy of LPA coating to suppress EOF in those different conditions was studied. It was shown that electroosmotic mobilities (µEO) did not change for at least 70h of non-stopped operation in all the tested conditions and the coating was stable. It was also shown that LPA coating efficiently suppresses EOF in acidic media (pH 4.0, 3.1, and 2.3) with or without organic modifiers (50% methanol or acetonitrile, ACN), as measured µEO values were between 18 and 84 times lower than those obtained with bare fused-silica capillaries. In acidic media with anionic surfactant (50mM sodium dodecylsulfate, SDS), ionic liquid (25 mM dodecyldimethylimidazolium bromide) or both SDS and ACN (buffer pH 2.1/ACN (8:2, v/v)+50mM SDS) EOF was reduced to a magnitude lower than with bare fused-silica capillaries, even though slight adsorptions of these surfactants were observed. LPA showed its superiority to hydroxypropyl cellulose, for which marked adsorption occurred because of its lower hydrophilicity. PMID:26838442

  6. Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats.

    PubMed

    Tang, Quan Yong; Kukita, Toshio; Ushijima, Yuki; Kukita, Akiko; Nagata, Kengo; Sandra, Ferry; Watanabe, Toshiyuki; Toh, Kazuko; Okuma, Yutaka; Kawasaki, Sadamichi; Rasubala, Linda; Teramachi, Junpei; Miyamoto, Ichiko; Wu, Zhou; Iijima, Tadahiko

    2006-03-01

    Simon extracts are vitamin K(1)-rich food materials extracted from the leaves of the Simon sweet potato. Although vitamin K is known to stimulate bone formation, we postulated that Simon extracts also contain unknown biological compounds having the ability to regulate bone resorption. Here we prepared the vitamin K-free fraction from the Simon extracts and investigated the ability of this fraction on the differentiation of osteoclasts. A remarkable inhibitory effect of osteoclastogenesis was observed when osteoclast precursors were treated with this fraction in rat bone marrow culture systems as well as in a pure differentiation system using murine osteoclast precursor cell line. The vitamin K-free Simon extracts markedly suppressed severe bone destruction mediated by abundant osteoclasts associated with adjuvant-induced arthritis in rats. High performance liquid chromatography (HPLC) analysis revealed that the vitamin K-free Simon extracts contained three types of low molecular weight inhibitors for osteoclastogenesis; caffeic acid, chlorogenic acids and isochlorogenic acids. Among these substances, caffeic acid showed the most powerful inhibitory effects on osteoclastogenesis. Caffeic acid significantly suppressed expression of NFATc1, a key transcription factor for the induction of osteoclastogenesis. Our current study enlightened a high utility of the Simon extracts and their chemical components as effective regulators for bone resorption accompanied with inflammation and metabolic bone diseases. PMID:16205940

  7. Negative Pressure Wound Therapy of Chronically Infected Wounds Using 1% Acetic Acid Irrigation

    PubMed Central

    Lee, Byeong Ho; Lee, Hye Kyung; Kim, Hyoung Suk; Moon, Min Seon; Suh, In Suck

    2015-01-01

    Background Negative-pressure wound therapy (NPWT) induces angiogenesis and collagen synthesis to promote tissue healing. Although acetic acid soaks normalize alkali wound conditions to raise tissue oxygen saturation and deconstruct the biofilms of chronic wounds, frequent dressing changes are required. Methods Combined use of NPWT and acetic acid irrigation was assessed in the treatment of chronic wounds, instilling acetic acid solution (1%) beneath polyurethane membranes twice daily for three weeks under continuous pressure (125 mm Hg). Clinical photographs, pH levels, cultures, and debrided fragments of wounds were obtained pre- and posttreatment. Tissue immunostaining (CD31, Ki-67, and CD45) and reverse transcription-polymerase chain reaction (vascular endothelial growth factor [VEGF], vascular endothelial growth factor receptor [VEGFR]; procollagen; hypoxia-inducible factor 1 alpha [HIF-1-alpha]; matrix metalloproteinase [MMP]-1,-3,-9; and tissue inhibitor of metalloproteinase [TIMP]) were also performed. Results Wound sizes tended to diminish with the combined therapy, accompanied by drops in wound pH (weakly acidic or neutral) and less evidence of infection. CD31 and Ki-67 immunostaining increased (P<0.05) post-treatment, as did the levels of VEGFR, procollagen, and MMP-1 (P<0.05), whereas the VEGF, HIF-1-alpha, and MMP-9/TIMP levels declined (P<0.05). Conclusions By combining acetic acid irrigation with negative-pressure dressings, both the pH and the size of chronic wounds can be reduced and infections be controlled. This approach may enhance angiogenesis and collagen synthesis in wounds, restoring the extracellular matrix. PMID:25606491

  8. [Antithrombotic therapy after myocardial infarction: arguments for the use of acetylsalicylic acid and coumarin derivatives].

    PubMed

    Waskowsky, W M; Brouwer, A; Verheugt, F W A

    2005-01-01

    Patients who survived myocardial infarction and who are being treated with the current optimal therapy (antithrombotics, statins and beta-blockers), have a 10-20% chance of death, re-infarction and stroke within in the first year. A possible explanation for this could be an increased activation and generation ofthrombin for at least 6 months following the cardiovascular event preceding preventative therapy. Acetylsalicylic acid and clopidogrel do not affect activation by thrombin of the platelet aggregation and the clotting cascade. The additional use of cumarin derivatives could therefore reduce the chance of recurring thrombotic events, and subsequently improve prognosis. Since the nineteen-nineties several randomised trials have been conducted to study the clinical relevance ofcumarin derivatives both with and without acetylsalicylic acid, in patients who had had a myocardial infarction. The conclusions of these studies were not unambiguous. If the international normalized ratio (INR) was kept > 2 for a long period, by means of frequent check-ups and effective dosage adjustment, the chance of death, recurrent myocardial infarction or stroke was 30-50% lower than when acetylsalicylic acid only was used. The risk of bleeding was raised by 2-4 times, but there were no life-threatening episodes of bleeding. In view of the recent development of anticoagulant agents, for which monitoring seems to be becoming unnecessary, identification of patients who would benefit most from a combined antithrombotic strategy is warranted. PMID:15688836

  9. Catalytic nucleic acid enzymes for the study and development of therapies in the central nervous system

    PubMed Central

    Tritz, Richard; Habita, Cellia; Robbins, Joan M.; Gomez, German G.; Kruse, Carol A.

    2005-01-01

    Summary Nucleic acid enzymes have been used with great success for studying natural processes in the central nervous system (CNS). We first provide information on the structural and enzymatic differences of various ribozymes and DNAzymes. We then discuss how they have been used to explore new therapeutic approaches for treating diseases of the CNS. They have been tested in various systems modeling retinitis pigmentosum, proliferative vitreoretinopathy, Alzheimer's disease, and malignant brain tumors. For these models, effective targets for nucleic acid enzymes have been readily identified and the rules for selecting cleavage sites have been well established. The bulk of studies, including those from our laboratory, have emphasized their use for gliomas. With the availability of multiple excellent animal models to test glioma treatments, good progress has been made in the initial testing of nucleic acid enzymes for brain tumor therapy. However, opportunities still exist to significantly improve the delivery and efficacy of ribozymes to achieve effective treatment. The future holds significant potential for the molecular targeting and therapy of eye diseases, neurodegenerative disorders, and brain tumors with these unique treatment agents. PMID:16467915

  10. Carnitine palmitoyltransferase 1A prevents fatty acid-induced adipocyte dysfunction through suppression of c-Jun N-terminal kinase.

    PubMed

    Gao, Xuefei; Li, Kuai; Hui, Xiaoyan; Kong, Xiangping; Sweeney, Gary; Wang, Yu; Xu, Aimin; Teng, Maikun; Liu, Pentao; Wu, Donghai

    2011-05-01

    The adipocyte is the principal cell type for fat storage. CPT1 (carnitine palmitoyltransferase-1) is the rate-limiting enzyme for fatty acid β-oxidation, but the physiological role of CPT1 in adipocytes remains unclear. In the present study, we focused on the specific role of CPT1A in the normal functioning of adipocytes. Three 3T3-L1 adipocyte cell lines stably expressing hCPT1A (human CPT1A) cDNA, mouse CPT1A shRNA (short-hairpin RNA) or GFP (green fluorescent protein) were generated and the biological functions of these cell lines were characterized. Alteration in CPT1 activity, either by ectopic overexpression or pharmacological inhibition using etomoxir, did not affect adipocyte differentiation. However, overexpression of hCPT1A significantly reduced the content of intracellular NEFAs (non-esterified fatty acids) compared with the control cells when adipocytes were challenged with fatty acids. The changes were accompanied by an increase in fatty acid uptake and a decrease in fatty acid release. Interestingly, CPT1A protected against fatty acid-induced insulin resistance and expression of pro-inflammatory adipokines such as TNF-α (tumour necrosis factor-α) and IL-6 (interleukin-6) in adipocytes. Further studies demonstrated that JNK (c-Jun N terminal kinase) activity was substantially suppressed upon CPT1A overexpression, whereas knockdown or pharmacological inhibition of CPT1 caused a significant enhancement of JNK activity. The specific inhibitor of JNK SP600125 largely abolished the changes caused by the shRNA- and etomoxir-mediated decrease in CPT1 activity. Moreover, C2C12 myocytes co-cultured with adipocytes pre-treated with fatty acids displayed altered insulin sensitivity. Taken together, our findings have identified a favourable role for CPT1A in adipocytes to attenuate fatty acid-evoked insulin resistance and inflammation via suppression of JNK. PMID:21348853

  11. Construction of hyaluronic acid noisome as functional transdermal nanocarrier for tumor therapy.

    PubMed

    Kong, Ming; Park, Hyunjin; Feng, Chao; Hou, Lin; Cheng, Xiaojie; Chen, Xiguang

    2013-04-15

    To develop a functional nanosized transdermal drug delivery system for tumor therapy, amphiphilic hyaluronic acid (HA) based niosome was constructed combining transdermal and tumor targeting ability in one entity. HA esterified with monostearin, the conjugate labeled as HA-GMS self-assembled onto niosome surface and formed HA-niosome. The multilayer vesicle had small size (around 40 nm), good stability and desirable drug encapsulating efficacy, and well compatible with blood. It exhibited better endocytosis to mouse breast tumor cell (4T1) than the control chitosan nanoparticle, which was verified qualitatively and quantitatively. Skin permeation of HA-niosome was proven to be efficient using in vitro stratum corneum model and in vivo fluorescence observation. Histological section study confirmed the security and efficiency of transdermal permeation. The results evidence HA-niosome to be exciting and promising for tumor therapy through trandermal administration. PMID:23544584

  12. pH-Responsive Fe(III)-Gallic Acid Nanoparticles for In Vivo Photoacoustic-Imaging-Guided Photothermal Therapy.

    PubMed

    Zeng, Jianfeng; Cheng, Ming; Wang, Yong; Wen, Ling; Chen, Ling; Li, Zhen; Wu, Yongyou; Gao, Mingyuan; Chai, Zhifang

    2016-04-01

    pH-responsive biocompatible Fe(III)-gallic acid nanoparticles with strong near-infrared absorbance are very stable in mild acidic conditions, but easily decomposed in neutral conditions, which enables the nanoparticles to be stable in a tumor and easily metabolized in other organs, thus providing a safe nanoplatform for in vivo photoacoustic imaging/photothermal therapy theranostic applications. PMID:26845393

  13. Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer A systematic review with meta-analysis

    PubMed Central

    Kunath, Frank; Borgmann, Hendrik; Blümle, Anette; Keck, Bastian; Wullich, Bernd; Schmucker, Christine; Sikic, Danijel; Roelle, Catharina; Schmidt, Stefanie; Wahba, Amr; Meerpohl, Joerg J

    2015-01-01

    Objectives To evaluate efficacy and safety of gonadotropin-releasing hormone (GnRH) antagonists compared to standard androgen suppression therapy for advanced prostate cancer. Setting The international review team included methodologists of the German Cochrane Centre and clinical experts. Participants We searched CENTRAL, MEDLINE, Web of Science, EMBASE, trial registries and conference books for randomised controlled trials (RCT) for effectiveness data analysis, and randomised or non-randomised controlled studies (non-RCT) for safety data analysis (March 2015). Two authors independently screened identified articles, extracted data, evaluated risk of bias and rated quality of evidence according to GRADE. Results 13 studies (10 RCTs, 3 non-RCTs) were included. No study reported cancer-specific survival or clinical progression. There were no differences in overall mortality (RR 1.35, 95% CI 0.63 to 2.93), treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or prostate-specific antigen progression (RR 0.83, 95% CI 0.64 to 1.06). While there was no difference in quality of life related to urinary symptoms, improved quality of life regarding prostate symptoms, measured with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression therapy (mean score difference −0.40, 95% CI −0.94 to 0.14, and −1.84, 95% CI −3.00 to −0.69, respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less often by using GnRH antagonist. Available evidence is hampered by risk of bias, selective reporting and limited follow-up. Conclusions There is currently insufficient evidence to make firm conclusive statements on the efficacy of GnRH antagonist compared to standard androgen suppression therapy for advanced prostate cancer. There is need for further high-quality research on

  14. 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

    Prasad, Sahdeo; Yadav, Vivek R; Sung, Bokyung; Gupta, Subash C; Tyagi, Amit K; Aggarwal, Bharat B

    2016-03-15

    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

  15. 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

  16. Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I

    PubMed Central

    Park, Seung Bum; Seronello, Scott; Mayer, Wasima; Ojcius, David M.

    2016-01-01

    Hepatitis C virus (HCV) actively evades host interferon (IFN) responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I)-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP) from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP) and poly(IC). The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain) were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity. PMID:27404108

  17. Lack of deleterious effect on bone mineral density of long-term thyroxine suppressive therapy for differentiated thyroid carcinoma.

    PubMed

    Reverter, J L; Holgado, S; Alonso, N; Salinas, I; Granada, M L; Sanmartí, A

    2005-12-01

    The effect of subclinical hyperthyroidism on bone mineral density is controversial and could be significant in patients with differentiated thyroid carcinoma who receive suppressive doses of levothyroxine (LT4). To ascertain whether prolonged treatment with LT4 to suppress thyrotropin had a deleterious effect on bone mineral density and/or calcium metabolism in patients thyroidectomized for differentiated thyroid cancer we have performed a cross-sectional study in a group of 88 women (mean +/- SD age: 51 +/- 12 years) treated with LT4 after near-total thyroidectomy and in a control group of 88 healthy women (51 +/- 11 years) matched for body mass index and menopausal status. We determined calcium metabolism parameters, bone turnover marker N-telopeptide and bone mass density by dual-energy X-ray absorptiometry. No differences were found between patients and controls in calcium metabolism parameters or N-telopeptide except for PTH, which was significantly increased in controls. No differences were found between groups in bone mineral density in femoral neck (0.971 +/- 0.148 gr/cm(2) vs 0.956 +/- 0.130 gr/cm(2) in patients and controls respectively, P = 0.5). In lumbar spine, bone mineral density values were lower in controls than in patients (1.058 +/- 0.329 gr/cm(2) vs 1.155 +/- 0.224 gr/cm(2) respectively, P < 0.05). When premenopausal (n = 44) and postmenopausal (n = 44) patients were compared with their respective controls, bone mineral density was similar both in femoral neck and lumbar spine. The proportion of women with normal bone mass density, osteopenia and osteoporosis in patient and control groups was similar in pre- and postmenopausal women. In conclusion, long-term suppressive LT4 treatment does not appear to affect skeletal integrity in women with differentiated thyroid carcinoma. PMID:16322336

  18. Two phenotypically distinct T cells are involved in ultraviolet-irradiated urocanic acid-induced suppression of the efferent delayed-type hypersensitivity response to herpes simplex virus, type 1 in vivo

    SciTech Connect

    Ross, J.A.; Howie, S.E.; Norval, M.; Maingay, J.

    1987-09-01

    When UVB-irradiated urocanic acid, the putative photoreceptor/mediator for UVB suppression, is administered to mice it induces a dose-dependent suppression of the delayed-type hypersensitivity response to herpes simplex virus, type 1 (HSV-1), of similar magnitude to that induced by UV irradiation of mice. In this study, the efferent suppression of delayed-type hypersensitivity by UV-irradiated urocanic acid is demonstrated to be due to 2 phenotypically distinct T cells, (Thy1+, L3T4-, Ly2+) and (Thy1+, L3T4+, Ly2-). The suppression is specific for HSV-1. This situation parallels the generation of 2 distinct T-suppressor cells for HSV-1 by UV irradiation of mice and provides further evidence for the involvement of urocanic acid in the generation of UVB suppression.

  19. Effect of suppressor current intensity on the determination of glyphosate and aminomethylphosphonic acid by suppressed conductivity ion chromatography.

    PubMed

    Dimitrakopoulos, Ioannis K; Thomaidis, Nikolaos S; Megoulas, Nikolaos C; Koupparis, Michael A

    2010-05-28

    This paper presents the application of ion chromatography with electrolytic eluent generation and mobile phase suppression for the direct conductimetric detection of glyphosate and its degradation product aminomethylphosphonic acid (AMPA). The compounds were separated on a Dionex AS18 anion exchange column with a 12-40 mM KOH step gradient from 9 to 9.5 min. The effect of the suppressor current intensity on the electrostatic interaction of these amphoteric compounds with the suppressor cation exchange membranes was evaluated. A suppressor current gradient technique was proposed for the limitation of peak broadening and baseline noise, in order to improve method sensitivity and detectability. It was observed that residual sample carbonates co-eluted with AMPA when a large injection loop was installed for the low level determination of both compounds in natural waters. For this reason, glyphosate was isocratically eluted using 33 mM KOH in order to decrease analysis time within 10 min and a column clean up step using 100 mM KOH was used to ensure retention time reproducibility. The developed method was applied to the analysis of drinking and natural water and it was further successfully applied to orange samples with slight modifications. Instrumental LOD for glyphosate was 0.24 microg/L, while method LOD was 0.54 microg/L for spring waters and 0.01 mg/kg for oranges using a 1000 microL direct loop injection of the sample. Intra-day and inter-day precision (as %RSD) for water samples was 4.6% and 12% at a spiking level of 2 microg/L, and the recovery ranged from 64% to 88% depending on sample conductivity. For orange samples, the inter-day precision was 1.4% at a spiking level of 4.4 mg/kg, while overall recovery was 103%. The developed method is direct, fast, sensitive and relatively inexpensive, and could be used as an ideal fast screening tool for the monitoring of glyphosate residues in water and fruit samples. PMID:20399436

  20. Apigenin inhibits platelet adhesion and thrombus formation and synergizes with aspirin in the suppression of the arachidonic acid pathway.

    PubMed

    Navarro-Núñez, L; Lozano, M L; Palomo, M; Martínez, C; Vicente, V; Castillo, J; Benavente-García, O; Diaz-Ricart, M; Escolar, G; Rivera, J

    2008-05-14

    Previous studies using washed platelets demonstrated that certain flavonoids inhibit platelet function through several mechanisms including blockade of TxA(2) receptors (TPs). We aimed to analyze the binding capacity of flavonoids to TPs in platelet rich plasma (PRP), investigated their effect in flowing blood, and evaluated the ability of apigenin to improve the efficacy of aspirin in the inhibition of platelet aggregation. The binding of flavonoids to TPs in PRP was explored using binding assays and the TP antagonist [ (3)H]SQ29548. Effects of flavonoids on platelet adhesion were assessed using arterial subendothelium with annular plate perfusion chambers, and global evaluation of apigenin on high-shear-dependent platelet function was determined by the PFA-100. To evaluate the ability of apigenin to potentiate the effect of aspirin, arachidonic acid-induced platelet aggregation was measured prior to and after consumption of subaggregatory doses of aspirin in the presence or absence of apigenin. Binding assays revealed that apigenin was an efficient competitor of [ (3)H]SQ29548 binding to PRP ( K i = 155.3 +/- 65.4 microM), and perfusion studies showed that apigenin, genistein, and catechin significantly diminished thrombus formation when compared to control (26.2 +/- 3.8, 33.1 +/- 5.2, and 26.2 +/- 5.2 vs 76.6 +/- 2.6%, respectively; p < 0.05). Apigenin, similarly to the TP antagonist SQ29548, significantly prolonged collagen epinephrine-induced PFA-100 closure time in comparison to the control and, when added to platelets that had been exposed in vivo to aspirin, potentiated its inhibitory effect on platelet aggregation. The inhibitory effect of some flavonoids in the presence of plasma, particularly apigenin, might in part rely on TxA(2) receptor antagonism. There is a clear increase in the ex vivo antiplatelet effect of aspirin in the presence of apigenin, which encourages the idea of the combined use of aspirin and certain flavonoids in patients in which

  1. Anacardic acid sensitizes prostate cancer cells to radiation therapy by regulating H2AX expression

    PubMed Central

    Yao, Kun; Jiang, Xianzhen; He, leye; Tang, Yuxin; Yin, Guangming; Zeng, Qing; Jiang, Zhiqiang; Tan, Jing

    2015-01-01

    Anacardic acid (6-pentadecylsalicylic acid, AA), a natural compound isolated from the traditional medicine Amphipterygiumadstringens, has been reported as potential antitumor agents in various cancers including prostate cancer (PC). However, the effects and mechanism of AA on the radiosensitivity of prostate cancer remains unknown. The results indicated that AA exhibited strong antitumor activity in PC cell lines, either as a single agentor in combination with radiation. AA significantly induced the downregulation of H2AX and p-H2AX expression, increase of cell apoptosis and decreasing of cell invasion, which were reversed by overexpressed H2AX. These results suggest that AA sensitize prostate cancer cells to radiation therapy by repressing H2AX expression. PMID:26884865

  2. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients.

    PubMed

    Tassara, Michela; Döhner, Konstanze; Brossart, Peter; Held, Gerhard; Götze, Katharina; Horst, Heinz-A; Ringhoffer, Mark; Köhne, Claus-Henning; Kremers, Stephan; Raghavachar, Aruna; Wulf, Gerald; Kirchen, Heinz; Nachbaur, David; Derigs, Hans Günter; Wattad, Mohammed; Koller, Elisabeth; Brugger, Wolfram; Matzdorff, Axel; Greil, Richard; Heil, Gerhard; Paschka, Peter; Gaidzik, Verena I; Göttlicher, Martin; Döhner, Hartmut; Schlenk, Richard F

    2014-06-26

    The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255. PMID:24797300

  3. Bilateral atypical femoral subtrochanteric fractures in a premenopausal patient receiving prolonged bisphosphonate therapy: evidence of severely suppressed bone turnover

    PubMed Central

    Kondo, Naoki; Yoda, Takuya; Fujisawa, Junichi; Arai, Katsumitsu; Sakuma, Mayumi; Ninomiya, Hiroshi; Sano, Hiroshige; Endo, Naoto

    2015-01-01

    Summary We report a case of bilateral atypical femoral fractures that occurred in a patient who had been taking bisphosphonate long-term. A 36-year-old premenopausal female diagnosed with systemic lupus erythematosus and dermatomyositis had been treated with glucocorticoid and alendronate (5 mg/day) to prevent glucocorticoid-induced osteoporosis. She was taken to our hospital because she could not walk immediately after falling down from the standing position. A plain radiograph showed a subtrochanteric fracture of the left femur. Four months later, she fell again and sustained a contralateral subtrochanteric fracture. For each fracture, a femoral intramedullary nail was inserted. Delayed union was detected in both sides, and revision surgery with an iliac bone graft was required for implant breakage in the right side. Histomorphometric findings for the ilium revealed remarkably decreased osteoid volume with no osteoclasts and a minimally eroded surface, suggesting that bone turnover was severely suppressed. However, histology of the delayed union site revealed callus formation and some osteoclast appearance, suggesting that fracture healing was occurring. In total, it took 29 months (left) and 24 months (right) until fracture healing was achieved, showing delayed union. This case is extremely rare in that patient who presented with atypical femoral fractures in spite of her premenopausal status. The bone histomorphometric findings from this case suggest that severely suppressed bone turnover is associated with atypical femoral subtrochanteric fracture and can cause delayed union in patients treated with alendronate long-term. PMID:26811712

  4. Natural conception in HIV-serodiscordant couples with the infected partner in suppressive antiretroviral therapy: A prospective cohort study.

    PubMed

    Del Romero, Jorge; Baza, María Begoña; Río, Isabel; Jerónimo, Adrián; Vera, Mar; Hernando, Victoria; Rodríguez, Carmen; Castilla, Jesús

    2016-07-01

    The potential of antiretroviral treatment (ART) to prevent the sexual transmission of HIV has increased the number of serodiscordant couples who are considering natural conception. We aim to describe the results of a protocol for reproductive counseling aimed at HIV serodiscordant couples who desire natural conception, in which the infected partner, the index case, is receiving suppressive antiretroviral treatment.A prospective cohort included all HIV serodiscordant couples attended a counseling program in the period 2002 to 2013 who opted for natural conception and met the following criteria: index case on ART with persistent plasma viral suppression for at least the previous 6 months, ART compliance over 95%, preserved immune status, undetectable HIV viral and proviral load in semen in male index cases, and absence of genitourinary infections and fertility problems in both members of the couple.Of the 161 HIV serodiscordant couples included, 133 with male index cases, 66% achieved at least 1 pregnancy, 18% a second one, and 5% a third pregnancy. A total of 144 natural pregnancies occurred and 107 babies were born. The pregnancy rate was 1.9 for each 100 acts of vaginal intercourse, and the mean time to conception was 6.1 months, both independently of the sex of the index case. No case of sexual or vertical HIV transmission occurred.In the absence of fertility problems and under controlled conditions, natural conception might be a safe and effective reproductive method for those HIV serodiscordant couples who choose this reproductive option. PMID:27472733

  5. Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    SciTech Connect

    Kimura, Rino; Takahashi, Nobuyuki; Murota, Kaeko; Yamada, Yuko; Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko; Moriyama, Tatsuya; Goto, Tsuyoshi; Kawada, Teruo

    2011-06-24

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

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

    PubMed

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

    2016-05-01

    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

  7. 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

  8. 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. PMID:27161375

  9. Rosmarinic Acid suppressed high glucose-induced apoptosis in H9c2 cells by ameliorating the mitochondrial function and activating STAT3.

    PubMed

    Diao, Jiayu; Wei, Jin; Yan, Rui; Liu, Xin; Li, Qing; Lin, Lin; Zhu, Yanhe; Li, Hong

    2016-09-01

    Mitochondrial injury characterized by intracellular reactive oxygen species (ROS) accumulation plays a critical role in hyperglycemia-induced myocardium dysfunction. Previous studies have demonstrated that Rosmarinic Acid (RA) treatment and activating Signal transducer and activator of transcription 3 (STAT3) signaling pathway have protective effects on mitochondrial dysfunction in cardiomyocyte, but there is little data regarding cardiomyocyte under condition of high-glucose. The present study was undertaken to determine the relationship between RA and STAT3 activation, as well as their effects on high glucose-induced mitochondrial injury and apoptosis in H9c2 cardiomyocyte. Our results revealed that RA pretreatment suppressed high glucose-induced apoptosis in H9c2 cells. Moreover, the effect of RA on apoptosis was related with improved mitochondrial function, which was demonstrated by that RA attenuated high glucose-induced ROS generation, inhibited mitochondrial permeability transition pore (MPTP) activation, suppressed cytochrome c release and caspase-3 activation. In addition, the phosphorylation of STAT3 in H9c2 cells was inhibited under condition of high-glucose, but RA improved STAT3 phosphorylation. Importantly, inhibition of STAT3 expression by using STAT3-siRNA partly suppressed the effect of RA on high glucose-induced apoptosis. Taken together, pretreatment with RA suppressed high glucose-induced apoptosis in cardiomyocyte by ameliorating mitochondrial function and activating STAT3. PMID:27402269

  10. Smart functional nucleic acid chimeras: Enabling tissue specific RNA targeting therapy

    PubMed Central

    Aaldering, Lukas J; Tayeb, Hossam; Krishnan, Shilpa; Fletcher, Susan; Wilton, Stephen D; Veedu, Rakesh N

    2015-01-01

    A major obstacle for effective utilization of therapeutic oligonucleotides such as siRNA, antisense, antimiRs etc. is to deliver them specifically to the target tissues. Toward this goal, nucleic acid aptamers are re-emerging as a prominent class of biomolecules capable of delivering target specific therapy and therapeutic monitoring by various molecular imaging modalities. This class of short oligonucleotide ligands with high affinity and specificity are selected from a large nucleic acid pool against a molecular target of choice. Poor cellular uptake of therapeutic oligonucleotides impedes gene-targeting efficacy in vitro and in vivo. In contrast, aptamer-oligonucleotide chimeras have shown the capacity to deliver siRNA, antimiRs, small molecule drugs etc. toward various targets and showed very promising results in various studies on different diseases models. However, to further improve the bio-stability of such chimeric conjugates, it is important to introduce chemically-modified nucleic acid analogs. In this review, we highlight the applications of nucleic acid aptamers for target specific delivery of therapeutic oligonucleotides. PMID:25849197

  11. A novel biocompatible hyaluronic acid-chitosan hybrid hydrogel for osteoarthrosis therapy.

    PubMed

    Kaderli, S; Boulocher, C; Pillet, E; Watrelot-Virieux, D; Rougemont, A L; Roger, T; Viguier, E; Gurny, R; Scapozza, L; Jordan, O

    2015-04-10

    A conventional therapy for the treatment of osteoarthrosis is intra-articular injection of hyaluronic acid, which requires repeated, frequent injections. To extend the viscosupplementation effect of hyaluronic acid, we propose to associate it with another biopolymer in the form of a hybrid hydrogel. Chitosan was chosen because of its structural similarity to synovial glycosaminoglycans, its anti-inflammatory effects and its ability to promote cartilage growth. To avoid polyelectrolyte aggregation and obtain transparent, homogeneous gels, chitosan was reacetylated to a 50% degree, and different salts and formulation buffers were investigated. The biocompatibility of the hybrid gels was tested in vitro on human arthrosic synoviocytes, and in vivo assessments were made 1 week after subcutaneous injection in rats and 1 month after intra-articular injection in rabbits. Hyaluronic acid-chitosan polyelectrolyte complexes were prevented by cationic complexation of the negative charges of hyaluronic acid. The different salts tested were found to alter the viscosity and thermal degradation of the gels. Good biocompatibility was observed in rats, although the calcium-containing formulation induced calcium deposits after 1 week. The sodium chloride formulation was further tested in rabbits and did not show acute clinical signs of pain or inflammation. Hybrid HA-Cs hydrogels may be a valuable alternative viscosupplementation agent. PMID:25666331

  12. Co-delivery of doxorubicin and tumor-suppressing p53 gene using a POSS-based star-shaped polymer for cancer therapy.

    PubMed

    Li, Yongmao; Xu, Bing; Bai, Tao; Liu, Wenguang

    2015-07-01

    In this work, a star-shaped polymer consisting of a cationic poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) shell and a zwitterionic poly[N-(3-(methacryloylamino) propyl)-N,N-dimethyl-N-(3-sulfopropyl) ammonium hydroxide] (PMPD) corona was grafted from a polyhedral oligomeric silsesquioxanes (POSS)-based initiator via atomic transfer radical polymerization (ATRP). The reported star-shaped polymer could form stable micelles in aqueous solutions even in the presence of serum. In addition, anti-cancer drug doxorubicin and tumor-suppressing p53 gene were loaded in the process of micelle formation. The formed polyplex was biocompatible and highly efficient for both drug and gene delivery. Furthermore, the polyplex was able to cause a high apoptotic rate of tumor cells both in vitro and in vivo. This combination delivery strategy offers a promising method for cancer therapy and can be used for further clinical applications. PMID:25934448

  13. 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

  14. Inhibitory effects of ursolic acid on osteoclastogenesis and titanium particle-induced osteolysis are mediated primarily via suppression of NF-κB signaling.

    PubMed

    Jiang, Chuan; Xiao, Fei; Gu, Xinfeng; Zhai, Zanjing; Liu, Xuqiang; Wang, Wengang; Tang, Tingting; Wang, You; Zhu, Zhenan; Dai, Kerong; Qin, An; Wang, Jinwu

    2015-04-01

    Ursolic acid (UA), a pentacyclic triterpenoid found in a variety of plants, has attracted considerable attention because of its important biological and pharmacological activities. However, its effect on osteoclasts and mechanism of action require further investigation. In this study, we evaluated the effects of UA on osteoclastogenesis and osteoclast-mediated osteolysis in vitro and in vivo, and explored its possible mechanism of action. The results indicated that UA could inhibit receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and the bone resorptive function of osteoclasts in a concentration-dependent manner in vitro. Further, UA effectively inhibited the mRNA and protein expression of NFATc1, primarily via the suppression of nuclear factor-κB (NF-κB) signaling, and partly through the suppression of c-Jun N-terminal kinase (JNK) signaling. Additionally, UA treatment downregulated the expression of NFATc1-regulated osteoclast marker genes. Likewise, UA induced dose-dependent attenuation of titanium (Ti) particle-induced mouse calvarial bone loss, and decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. In conclusion, these results demonstrate that UA protects against wear particle-induced osteolysis by suppressing osteoclast formation and function. These effects are associated with the inhibition of the NF-κB- and JNK-related signaling pathways. PMID:25681755

  15. Downregulation of Nrf2 by the combination of TRAIL and Valproic acid induces apoptotic cell death of TRAIL-resistant papillary thyroid cancer cells via suppression of Bcl-xL.

    PubMed

    Cha, Hyun-Young; Lee, Bok-Soon; Chang, Jae Won; Park, Ju Kyeong; Han, Jae Ho; Kim, Yong-Sung; Shin, Yoo Seob; Byeon, Hyung Kwon; Kim, Chul-Ho

    2016-03-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents an effective agent for the treatment of many cancers, though the majority of thyroid cancers are found to be resistant. Therefore it would be necessary to identify agents capable of increasing the sensitivity of these cancers to TRAIL-mediated cell death. Here, we examined the therapeutic effect and its underlying mechanism of combination treatment of TRAIL and histone deacetylase inhibitor, Valproic acid (VPA) in vitro using human papillary thyroid cancer (PTC) cells and in vivo using an orthotopic mouse model of PTC. TRAIL-VPA combination therapy synergistically induced apoptotic cell death in TRAIL-resistant PTC through caspase activation. In addition, downregulation of antioxidant transcription factor, Nrf2 by co-treatment of TRAIL-VPA induces cell death via suppression of Bcl-xL in vitro and in vivo; these effects were further enhanced following siRNA inhibition of these proteins in combination with TRAIL or TRAIL-VPA. Taken together, VPA sensitized TRAIL-resistant PTC cells to apoptotic cell death through involvement of Nrf2 and Bcl-xL. Thus, the combination of VPA and TRAIL may be a promising therapy for TRAIL-resistant PTC. PMID:26721202

  16. Antiretroviral Therapy and Viral Suppression Among Foreign-Born HIV-Infected Persons Receiving Medical Care in the United States: A Complex Sample, Cross-Sectional Survey.

    PubMed

    Myers, Tanya R; Lin, Xia; Skarbinski, Jacek

    2016-03-01

    Immigrants to the United States are more likely to be diagnosed with human immunodeficiency virus (HIV) infection compared with native-born persons. Navigating access to healthcare in the United States can be challenging for foreign-born persons, and HIV treatment outcomes may be suboptimal for these persons. We compared characteristics of and assessed disparities in clinical outcomes of foreign-born persons in care for HIV in the United States. The Medical Monitoring Project is a complex sample, cross-sectional survey designed to be nationally representative of HIV-infected adults receiving medical care in the United States. Using data from 2009, 2010, and 2011, we conducted descriptive analyses and multivariable logistic regression to assess associations between foreign-born status and antiretroviral therapy (ART) prescription, and between foreign-born status and viral suppression. In all, 13.4% of HIV-infected persons were self-identified as foreign-born; the most common regions of birth were Central America and Mexico (45.4%) and the Caribbean (16.0%). Nearly 90% of foreign-born persons were diagnosed with HIV after entry into the United States. Compared with US-born persons, foreign-born persons were more likely to be younger, Hispanic, less educated, and uninsured. The prevalence of ART prescription (prevalence ratio 1.00; 95% confidence interval 0.98-1.02) was not significantly different between foreign-born and US-born persons. A higher percentage of foreign-born persons achieved viral suppression compared with US-born persons (prevalence ratio 1.05; 95% confidence interval 1.00-1.09). No major disparities in ART prescription and viral suppression were found between foreign-born and US-born HIV-infected persons receiving medical care, despite higher percentages being uninsured. PMID:26986128

  17. Suppression of human breast tumors in NOD/SCID mice by CD44 shRNA gene therapy combined with doxorubicin treatment

    PubMed Central

    Van Pham, Phuc; Vu, Ngoc Bich; Duong, Thuy Thanh; Nguyen, Tam Thanh; Truong, Nhung Hai; Phan, Nhan Lu Chinh; Vuong, Tue Gia; Pham, Viet Quoc; Nguyen, Hoang Minh; Nguyen, Kha The; Nguyen, Nhung Thi; Nguyen, Khue Gia; Khat, Lam Tan; Van Le, Dong; Truong, Kiet Dinh; Phan, Ngoc Kim

    2012-01-01

    Background Breast cancer stem cells with a CD44+CD24− phenotype are the origin of breast tumors. Strong CD44 expression in this population indicates its important role in maintaining the stem cell phenotype. Previous studies show that CD44 down-regulation causes CD44+CD24− breast cancer stem cells to differentiate into non-stem cells that are sensitive to antitumor drugs and lose many characteristics of the original cells. In this study, we determined tumor suppression in non-obese severe combined immunodeficiency mice using CD44 shRNA therapy combined with doxorubicin treatment. Methods Tumor-bearing non-obese severe combined immunodeficiency mice were established by injection of CD44+CD24− cells. To track CD44+CD24− cells, green fluorescence protein was stably transduced using a lentiviral vector prior to injection into mice. The amount of CD44 shRNA lentiviral vector used for transduction was based on CD44 down-regulation by in vitro CD44 shRNA transduction. Mice were treated with direct injection of CD44 shRNA lentiviral vector into tumors followed by doxorubicin administration after 48 hours. The effect was evaluated by changes in the size and weight of tumors compared with that of the control. Results The combination of CD44 down-regulation and doxorubicin strongly suppressed tumor growth with significant differences in tumor sizes and weights compared with that of CD44 down-regulation or doxorubicin treatment alone. In the combination of CD44 down-regulation and doxorubicin group, the tumor weight was significantly decreased by 4.38-fold compared with that of the control group. Conclusion These results support a new strategy for breast cancer treatment by combining gene therapy with chemotherapy. PMID:22649280

  18. Abscisic Acid Suppression of Phenylalanine Ammonia-Lyase Activity and mRNA, and Resistance of Soybeans to Phytophthora megasperma f.sp. glycinea1

    PubMed Central

    Ward, Edmund W. B.; Cahill, David M.; Bhattacharyya, Madan K.

    1989-01-01

    Etiolated hypocotyls of the resistant soybean (Glycine max [L.] Merr.) cultivar Harosoy 63 became susceptible to Phytophthora megasperma (Drechs.) f.sp. glycinea (Hildeb.) Kuan and Erwin race 1 after treatment with abscisic acid. Susceptibility was expressed by increases in lesion size and a major decrease in accumulation of the isoflavonoid phytoalexin, glyceollin. In untreated hypocotyls, activity of phenylalanine ammonia-lyase and accumulation of mRNA for this enzyme increased rapidly after infection, but these increases were suppressed in abscisic acid-treated hypocotyls. The results suggest the possibility that biosynthesis of glyceollin in the resistance response of soybeans may be controlled at the transcriptional level by changes in abscisic acid concentrations caused by infection. Images Figure 2 PMID:16667002

  19. Identification and removal of colanic acid from plasmid DNA preparations: implications for gene therapy

    PubMed Central

    Firozi, P; Zhang, W; Chen, L; Quiocho, FA; Worley, KC; Templeton, NS

    2012-01-01

    Polysaccharide contaminants in plasmid DNA, including current good manufacturing practices (cGMP) clinical preparations, must be removed to provide the greatest safety and efficacy for use in gene therapy and other clinical applications. We developed assays and methods for the detection and removal of these polysaccharides, our Super Clean DNA (SC-DNA) process, and have shown that these contaminants in plasmid DNA preparations are responsible for toxicity observed post-injection in animals. Furthermore, these contaminants limit the efficacy of low and high doses of plasmid DNA administered by numerous delivery routes. In particular, colanic acid (CA) that is mainly long-chained, branched and has high molecular weight (MW) is most refractory when complexed to cationic delivery vehicles and injected intravenously (IV). Because CA is often extremely large and tightly intertwined with DNA, it must be degraded, in order, to be effectively removed. We have produced a recombinant, truncated colanic acid degrading enzyme (CAE) that successfully accomplishes this task. Initially, we isolated a newly identified CAE from a bacteriophage that required truncation for proper folding while retaining its full enzymatic activity during production. Any plasmid DNA preparation can be digested with CAE and further purified, providing a critical advance to non-viral gene therapy. PMID:20664542

  20. Impact of HIV Infection and Zidovudine Therapy on RBC Parameters and Urine Methylmalonic Acid Levels

    PubMed Central

    Adediran, Adewumi; Osunkalu, Vincent; Wakama, Tamunomieibi; John-Olabode, Sarah; Akinbami, Akinsegun; Uche, Ebele; Akanmu, Sulaimon

    2016-01-01

    Background. Anaemia is a common complication of human immunodeficiency virus (HIV) infection. The aim of this study was to investigate the impact of HIV infection and zidovudine on red blood cells (RBC) parameters and urine methylmalonic acid (UMMA) levels in patients with HIV infection. Material and Methods. A cross-sectional study involving 114 subjects, 94 of which are HIV-infected nonanaemic and 20 HIV negative subjects (Cg) as control. Full blood count parameters and urine methylmalonic acid (UMMA) level of each subject were determined. Associations were determined by Chi-square test and logistic regression statistics where appropriate. Results. Subjects on zidovudine-based ART had mean MCV (93 fL) higher than that of control group (82.9 fL) and ART-naïve (85.9 fL) subjects and the highest mean RDW. Mean UMMA level, which reflects vitamin B12 level status, was high in all HIV-infected groups but was significantly higher in ART-naïve subjects than in ART-experienced subjects. Conclusion. Although non-zidovudine therapy may be associated with macrocytosis (MCV > 95 fL), zidovudine therapy and ART naivety may not. Suboptimal level of vitamin B12 as measured by high UMMA though highest in ART-naïve subjects was common in all HIV-infected subjects. PMID:26989408

  1. 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.

  2. Impact of HIV Infection and Zidovudine Therapy on RBC Parameters and Urine Methylmalonic Acid Levels.

    PubMed

    Adediran, Adewumi; Osunkalu, Vincent; Wakama, Tamunomieibi; John-Olabode, Sarah; Akinbami, Akinsegun; Uche, Ebele; Akanmu, Sulaimon

    2016-01-01

    Background. Anaemia is a common complication of human immunodeficiency virus (HIV) infection. The aim of this study was to investigate the impact of HIV infection and zidovudine on red blood cells (RBC) parameters and urine methylmalonic acid (UMMA) levels in patients with HIV infection. Material and Methods. A cross-sectional study involving 114 subjects, 94 of which are HIV-infected nonanaemic and 20 HIV negative subjects (Cg) as control. Full blood count parameters and urine methylmalonic acid (UMMA) level of each subject were determined. Associations were determined by Chi-square test and logistic regression statistics where appropriate. Results. Subjects on zidovudine-based ART had mean MCV (93 fL) higher than that of control group (82.9 fL) and ART-naïve (85.9 fL) subjects and the highest mean RDW. Mean UMMA level, which reflects vitamin B12 level status, was high in all HIV-infected groups but was significantly higher in ART-naïve subjects than in ART-experienced subjects. Conclusion. Although non-zidovudine therapy may be associated with macrocytosis (MCV > 95 fL), zidovudine therapy and ART naivety may not. Suboptimal level of vitamin B12 as measured by high UMMA though highest in ART-naïve subjects was common in all HIV-infected subjects. PMID:26989408

  3. Nucleic acid targeting: towards personalized therapy for head and neck cancer.

    PubMed

    Parsel, S M; Grandis, J R; Thomas, S M

    2016-06-23

    In light of a detailed characterization of genetic aberrations in cancer, nucleic acid targeting represents an attractive therapeutic approach with significant translational potential. Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer deaths worldwide with stagnant 5-year survival rates. Advances in conventional treatment have done little to improve survival and combined chemoradiation is associated with significant adverse effects. Recent reports have characterized the genetic alterations in HNSCC and demonstrated that mutations confer resistance to conventional and molecular targeted therapies. The ability to use specific nucleic acid sequences to inhibit cancer-associated genes including non-druggable targets facilitates personalized medicine approaches with less adverse effects. Additionally, advances in drug delivery mechanisms have increased the transfection efficiency aiding in greater therapeutic responses. Given these advances, the stage has been set to translate the information garnered from genomic studies into personalized treatment strategies. Genes involved in the tumor protein 53 and epidermal growth factor receptor pathways have been extensively investigated and many promising preclinical studies have shown tumor inhibition through genetic modulation. We, and others, have demonstrated that targeting oncogene expression with gene therapy approaches is feasible in patients. Other methods such as RNA interference have proven to be effective and are potential candidates for clinical studies. This review summarizes the major advances in sequence-specific gene modulation in the preclinical setting and in clinical trials in head and neck cancer patients. PMID:26592450

  4. Nucleic Acid Targeting: Towards Personalized Therapy for Head and Neck Cancer

    PubMed Central

    Parsel, Sean M; Grandis, Jennifer R; Thomas, Sufi M

    2015-01-01

    In light of a detailed characterization of genetic aberrations in cancer, nucleic acid targeting represents an attractive therapeutic approach with significant translational potential. Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer deaths worldwide with stagnant 5-year survival rates. Advances in conventional treatment have done little to improve survival and combined chemoradiation is associated with significant adverse effects. Recent reports have characterized the genetic alterations in HNSCC and demonstrated that mutations confer resistance to conventional and molecular targeted therapies. The ability to use specific nucleic acid sequences to inhibit cancer-associated genes including non-druggable targets facilitates personalized medicine approaches with less adverse effects. Additionally, advances in drug delivery mechanisms have increased the transfection efficiency aiding in greater therapeutic responses. Given these advances, the stage has been set to translate the information garnered from genomic studies into personalized treatment strategies. Genes involved in the tumor protein 53 (TP53) and epidermal growth factor receptor (EGFR) pathways have been extensively investigated and many promising preclinical studies have shown tumor inhibition through genetic modulation. We, and others, have demonstrated that targeting oncogene expression with gene therapy approaches is feasible in patients. Other methods such as RNA interference have proven to be effective and are potential candidates for clinical studies. This review summarizes the major advances in sequence-specific gene modulation in the preclinical setting and in clinical trials in head and neck cancer patients. PMID:26592450

  5. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis.

    PubMed

    Jacquemin, E; Hermans, D; Myara, A; Habes, D; Debray, D; Hadchouel, M; Sokal, E M; Bernard, O

    1997-03-01

    Progressive familial intrahepatic cholestasis (PFIC) is a lethal inherited childhood cholestasis of hepatocellular origin. Different subtypes of PFIC have been described according to serum gamma-glutamyl transpeptidase (GGT) activity. There is currently no effective medical therapy available for children with PFIC. We report on 39 patients with PFIC who received ursodeoxycholic acid (UDCA) orally (20-30 mg/kg b.w./day) for a period of 2 to 4 years. Group 1 (n = 26) consisted of children with normal GGT activity, and group 2 (n = 13) of children with high GGT activity. Within group 1, liver tests normalized in 11 children, improved in 5, and stabilized or worsened in 10. Within group 2, liver tests normalized in six children, improved in four, and stabilized or worsened in three. Improvement of parameters was associated with an enrichment of the circulating pool of bile acids with UDCA. Hepatosplenomegaly and pruritus disappeared or diminished in children in whom liver tests normalized. In nine of these children, liver tests worsened and normalized again after stopping and restarting UDCA. Liver histology assessed in four children after normalization of liver tests and 2 years of treatment showed a decrease in fibrosis. We conclude that UDCA should be considered in the initial therapeutic management of children with PFIC, because it appears effective in resolving or improving the liver function and the clinical status of a fair proportion of children. Chronic UDCA therapy might thus avoid the need for liver transplantation in some children with PFIC. PMID:9049190

  6. Hormone therapy for prostate cancer

    MedlinePlus

    Androgen deprivation therapy; ADT; Androgen suppression therapy; Combined androgen blockade ... Androgens cause prostate cancer cells to grow. Hormone therapy for prostate cancer lowers the effect level of ...

  7. Comparison of 5-aminolevulinic acid-encapsulated liposome versus ethosome for skin delivery for photodynamic therapy.

    PubMed

    Fang, Yi-Ping; Tsai, Yi-Hung; Wu, Pao-Chu; Huang, Yaw-Bin

    2008-05-22

    Topical photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an alternative therapy for many non-melanoma skin cancers. The major limitation of this therapy, however, is the low permeability of ALA through the stratum corneum (SC) of the skin. The objective of the present work was to characterize ethosomes containing ALA and to enhance the skin production of protoporphyrin IX (PpIX), compared to traditional liposomes. Results showed that the average particle sizes of the ethosomes were less than those of liposomes. Moreover, the entrapment efficiency of ALA in the ethosome formulations was 8-66% depending on the surfactant added. The particle size of the ethosomes was still approximately <200 nm after 32 days of storage. An in vivo animal study observed the presence of PpIX in the skin by confocal laser scanning microscopy (CLSM). The results indicated that the penetration ability of ethosomes was greater than that of liposomes. The enhancements of all the formulations were ranging from 11- to 15-fold in contrast to that of control (ALA in an aqueous solution) in terms of PpIX intensity. In addition, colorimetry detected no erythema in the irradiated skin. The results demonstrated that the enhancement ratio of ethosome formulations did not significantly differ between the non-irradiated and irradiated groups except for PE/CH/SS, which may have been due to a photobleaching effect of the PDT-irradiation process. PMID:18325699

  8. Adenovirus-mediated suppression of HMGI(Y) protein synthesis as potential therapy of human malignant neoplasias

    PubMed Central

    Scala, Stefania; Portella, Giuseppe; Fedele, Monica; Chiappetta, Gennaro; Fusco, Alfredo

    2000-01-01

    High mobility group I (HMGI) proteins are overexpressed in several human malignant tumors. We previously demonstrated that inhibition of HMGI synthesis prevents thyroid cell transformation. Here, we report that an adenovirus carrying the HMGI(Y) gene in an antisense orientation (Ad-Yas) induced programmed cell death of two human thyroid anaplastic carcinoma cell lines (ARO and FB-1), but not normal thyroid cells. The Ad-Yas virus led to death of lung, colon, and breast carcinoma cells. A control adenovirus carrying the lacZ gene did not inhibit the growth of either normal or neoplastic cells. Ad-Yas treatment of tumors induced in athymic mice by ARO cells caused a drastic reduction in tumor size. Therefore, suppression of HMGI(Y) protein synthesis by an HMGI(Y) antisense adenoviral vector may be a useful treatment strategy in a variety of human malignant neoplasias, in which HMGI(Y) gene overexpression is a general event. PMID:10759549

  9. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation.

    PubMed

    Robertson, Stacy; Martínez, Gonzalo J; Payet, Cloe A; Barraclough, Jennifer Y; Celermajer, David S; Bursill, Christina; Patel, Sanjay

    2016-07-01

    Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (P<0.01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P<0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (P<0.05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P<0.05 for both). Monocytes from ACS patients are 'primed' to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β. PMID:27129183

  10. Induction of suppression of delayed type hypersensitivity to herpes simplex virus by epidermal cells exposed to UV-irradiated urocanic acid in vivo

    SciTech Connect

    Ross, J.A.; Howie, S.E.; Norval, M.; Maingay, J.P. )

    1987-01-01

    Urocanic acid (UCA), the putative photoreceptor for ultraviolet radiation (UV)-induced suppression, undergoes a UV-dependent trans to cis isomerisation. Epidermal cells from mice painted with UCA, containing a known proportion of the cis-isomer, generate suppression of the delayed type hypersensitivity response to herpes simplex virus type 1 (HSV-1) when transferred to naive syngeneic recipients at the same time and site as infection with HSV-1. One T suppressor cell subset, of phenotype (Thy1+, L3T4+, Ly2-), is induced by the cis-UCA modified epidermal cell transfer. Flow cytometric analysis of the epidermal cells from skin treated with UV or cis-UCA indicates an overall reduction from normal in the number of cells expressing MHC Class II antigens, but no alteration in the number expressing I-J antigens.

  11. 3,4-Dihydroxy-Benzohydroxamic Acid (Didox) Suppresses Pro-inflammatory Profiles and Oxidative Stress in TLR4-Activated RAW264.7 Murine Macrophages

    PubMed Central

    Matsebatlela, Thabe M.; Anderson, Amy L.; Gallicchio, Vincent S.; Elford, Howard; Rice, Charles D.

    2015-01-01

    Didox (3,4-dihydroxy-benzohydroxamic acid), is a synthetic ribonucleotide reductase (RR) inhibitor derived from polyhydroxy-substituted benzohydroxamic acid, and originally developed as an anti-cancer agent. Some studies indicate that didox may have anti-oxidative stress-like properties, while other studies hint that didox may have anti-inflammatory properties. Using nitric oxide production in response to LPS treatment as a sensitive screening assay for anti-inflammatory compounds, we show that didox is very potent at levels as low as 6.25 μM, with maximal inhibition at 100 μM. A qRT-PCR array was then employed to screen didox for other potential anti-inflammatory and anti-oxidative stress-related properties. Didox was very potent in suppressing the expression of these arrayed mRNA in response to LPS, and in some cases didox alone suppressed expression. Using qRT-PCR as a follow up to the array, we demonstrated that didox suppresses LPS-induced mRNA levels of iNOS, IL-6, IL-1, TNF-α, NF-κβ (p65), and p38-α, after 24 h of treatment. Treatment with didox also suppresses the secretion of nitric oxide, IL-6, and IL-10. Furthermore, oxidative stress, as quantified by intracellular ROS levels in response to macrophage activators LPS and phorbol ester (PMA), and the glutathione depleting agent BSO, is reduced by treatment with didox. Moreover, we demonstrate that nuclear translocation of NF-κβ (p65) in response to LPS is inhibited by didox. These findings were supported by qRT-PCR for oxidative stress genes SOD1 and catalase. Overall, this study supports the conclusion that didox may have a future role in managing acute and chronic inflammatory diseases and oxidative stress due to high production of ROS. PMID:25843059

  12. Eicosapentaenoic acid suppression of systemic inflammatory responses and inverse up-regulation of 15-deoxyΔ12,14 Prostaglandin J2 production

    PubMed Central

    Davidson, Jillian; Higgs, Warren; Rotondo, Dino

    2013-01-01

    Background and Purpose Eicosapentaenoic acid (EPA) has been shown to suppress immune cell responses, such as cytokine production and downstream PG production in vitro. Studies in vivo, however, have used EPA as a minor constituent of fish oil with variable results. We investigated the effects of EPA on systemic inflammatory responses as pure EPA has not been evaluated on immune/inflammatory responses in vivo. Experimental Approach Rabbits were administered polyinosinic: polycytidylic acid (poly I:C) i.v. before and after oral treatment with EPA for 42 days (given daily). The responses to IL-1β and TNF-α were also studied. Immediately following administration of poly I:C, body temperature was continuously monitored and blood samples were taken. Plasma levels of IL-1β, PGE2 (PGE2), and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) were measured by enzyme immunoassay. Key Results Following EPA treatment, the fever response to poly I:C was markedly suppressed compared with pretreatment responses. This was accompanied by a parallel reduction in the poly I:C-stimulated elevation in plasma levels of IL-1β and PGE2. Paradoxically, the levels of 15d-PGJ2 were higher following EPA treatment. EPA treatment did not significantly alter the fever response or plasma levels of PGE2 in response to either IL-1β or TNF-α. Conclusion and Implications Oral treatment with EPA can suppress immune/inflammatory responses in vivo via a suppression of upstream cytokine production resulting in a decreased fever response and indirectly reducing circulating levels of PGE2. EPA also enhances the production of the cytoprotective prostanoid 15d-PGJ2 indicating the therapeutic benefit of EPA. PMID:23586396

  13. Preparation of Oxaliplatin-Deoxycholic Acid Derivative Nanocomplexes and In Vivo Evaluation of Their Oral Absorption and Tumor Growth Suppression.

    PubMed

    Jeon, Ok-Cheol; Byun, Youngro; Park, Jin Woo

    2016-02-01

    To prepare orally available oxaliplatin (OXA), nanocomplexes were formed by ionic conjugation of OXA with the deoxycholic acid derivative, Nalpha-deoxycholy-L-lysyl-methylester (DCK), as an oral absorption enhancer. We characterized the DCK-conjugated OXA nanocomplexes by differential scanning calorimetry, particle size determination, and morphological analysis. To evaluate the effects of DCK on the intestinal permeability of OXA, we assessed the solubilities and partition coefficients of OXA and the OXA/DCK nanocomplex, and then conducted in vitro artificial intestinal membrane and Caco-2 cell permeability studies. Finally, bioavailability in rats and tumor growth inhibition in the squamous cell carcinoma (SCC7) model after oral administration of the OXA/DCK nanocomplex were investigated compared to pure OXA. Analysis of the ionic complex formation of OXA with DCK revealed that OXA existed in an amorphous form within the complex, resulting in for- mation of nanocomp;exes (35.05 +/- 4.48 nm in diameter). The solubility of OXA in water was approximately 7.07 mg/mL, whereas the water solubility of OXA/DCK was approximately 2.04 mg/mL and its partition coefficient was approximately 1.2-fold higher than that of OXA. The in vitro intestinal membrane permeability of OXA was significantly enhanced by complex formation with DCK. An in vivo pharmacokinetic study revealed that the Cm value of the OXA/DCK nanocomplex was 3.18-fold higher than that of OXA (32.22 +/- 10.24 ng/mL), and the resulting oral bioavailability of the OXA/DCK nanocomplex was 39.3-fold more than that of OXA. Furthermore, the oral administration of OXA/DCK significantly inhibited tumor growth in SCC7-bearing mice, and maximally inhibited tumor volume by 54% compared to the control. These findings demonstrate the therapeutic potential of the OXA/DCK nanocomplex as an oral anti-cancer therapy because it improves the oral absorption of OXA, which may improve patient compliance and expand the therapeutic

  14. Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma

    PubMed Central

    Jensen, Samuel A.; Day, Emily S.; Ko, Caroline H.; Hurley, Lisa A.; Luciano, Janina P.; Kouri, Fotini M.; Merkel, Timothy J.; Luthi, Andrea J.; Patel, Pinal C.; Cutler, Joshua I.; Daniel, Weston L.; Scott, Alexander W.; Rotz, Matthew W.; Meade, Thomas J.; Giljohann, David A.; Mirkin, Chad A.; Stegh, Alexander H.

    2014-01-01

    Glioblastoma multiforme (GBM) is a neurologically debilitating disease that culminates in death 14 to 16 months after diagnosis. An incomplete understanding of how cataloged genetic aberrations promote therapy resistance, combined with ineffective drug delivery to the central nervous system, has rendered GBM incurable. Functional genomics efforts have implicated several oncogenes in GBM pathogenesis but have rarely led to the implementation of targeted therapies. This is partly because many “undruggable” oncogenes cannot be targeted by small molecules or antibodies. We preclinically evaluate an RNA interference (RNAi)–based nanomedicine platform, based on spherical nucleic acid (SNA) nanoparticle conjugates, to neutralize oncogene expression in GBM. SNAs consist of gold nanoparticles covalently functionalized with densely packed, highly oriented small interfering RNA duplexes. In the absence of auxiliary transfection strategies or chemical modifications, SNAs efficiently entered primary and transformed glial cells in vitro. In vivo, the SNAs penetrated the blood-brain barrier and blood-tumor barrier to disseminate throughout xenogeneic glioma explants. SNAs targeting the oncoprotein Bcl2Like12 (Bcl2L12)—an effector caspase and p53 inhibitor overexpressed in GBM relative to normal brain and low-grade astrocytomas—were effective in knocking down endogenous Bcl2L12 mRNA and protein levels, and sensitized glioma cells toward therapy-induced apoptosis by enhancing effector caspase and p53 activity. Further, systemically delivered SNAs reduced Bcl2L12 expression in intracerebral GBM, increased intratumoral apoptosis, and reduced tumor burden and progression in xenografted mice, without adverse side effects. Thus, silencing antiapoptotic signaling using SNAs represents a new approach for systemic RNAi therapy for GBM and possibly other lethal malignancies. PMID:24174328

  15. Suppression of casein kinase 2 sensitizes tumor cells to antitumor TRAIL therapy by regulating the phosphorylation and localization of p65 in prostate cancer.

    PubMed

    Gang, Xiaokun; Wang, Yao; Wang, Yingdi; Zhao, Yu; Ding, Liya; Zhao, Jingwen; Sun, Lin; Wang, Guixia

    2015-09-01

    In the United States, prostate cancer (PCa) is the most commonly diagnosed cancer in males. For PCa at the late hormone-refractory stage, substantial improvement in treatment strategies is critically needed. TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, but both intrinsic and acquired resistance to TRAIL poses a huge problem in establishing clinically effective TRAIL therapies. In the present study, we examined the role played by casein kinase 2 (CK2) in the TRAIL‑induced nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) pathway in a PCa cell line. Downregulation of CK2 combined with a sub-dose of TRAIL suppressed p65 phosphorylation at serine 536. The combination treatment of TRAIL and the CK2 inhibitor decreased p65 nuclear translocation. Under the treatment of a sub-dose of TRAIL, downregulation of CK2, using both genetic and pharmacological approaches, decreased the transcriptional activity of NF-κB and the expression of NF-κB downstream anti-apoptosis genes. Therefore, we provided novel molecular mechanistic insight reporting that CK2 regulates the sensitivity of PCa cells to the antitumor effect of TRAIL. This is important for understanding how the TRAIL pathway is disrupted in PCa and may help to develop an effective combinatorial therapy for PCa. PMID:26165401

  16. 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

  17. 5-aminovaleric acid suppresses the development of severe seizures in the methionine sulfoximine model of mesial temporal lobe epilepsy.

    PubMed

    Dhaher, Roni; Damisah, Eyiyemisi C; Wang, Helen; Gruenbaum, Shaun E; Ong, Caroline; Zaveri, Hitten P; Gruenbaum, Benjamin F; Eid, Tore

    2014-07-01

    Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant, localization-related epilepsies in humans. One potential therapeutic target is the brain glutamine-glutamate-GABA metabolic pathway, which is perturbed in patients with MTLE. Loss of glutamine synthetase (GS) in astrocytes may be critically involved in this perturbation, which can be modeled by infusing the GS inhibitor methionine sulfoximine (MSO) into the entorhinal-hippocampal area in rats. Because 5-aminovaleric acid (5-AV) has been implicated in modulation of the glutamine-glutamate-GABA metabolic pathway, we hypothesized that 5-AV would alter the expression of seizures in the MSO model of MTLE. Male Sprague Dawley rats (300-330g) were implanted with an Alzet pump placed subcutaneously in the abdominal region to release either 5-AV (0.05mg/mL, n=6) or phosphate buffered saline (PBS, n=6) at a rate of 2.5μl/h over 28days. Five to 7days after surgery, all rats were implanted with an intracranial pump infusing MSO (2.5mg/mL; 0.25μl/h) unilaterally into the hippocampal formation. Following the second surgery, intracranial EEG was measured from the left and right hemispheres above the dorsal hippocampal formations for a continuous period of 21days. The EEG was correlated with simultaneous video recordings to determine the stage of seizures according to a modified Racine scale. Five-AV-treated rats experienced a 3.5 fold reduction in the number of seizures (6.7±1.4seizures/day) than PBS-treated rats (23.2±6.3seizures/day) during the first 2days following MSO pump placement (p<0.005). Both groups showed similar seizure frequency over days 3-21 (~1seizure/day). However, the fraction of the most severe type of seizures (Racine stages 4 and 5) increased over time in the PBS treated group, but not in the 5-AV treated group. Notably, 5-AV treated rats experienced a 2.3 and 2.6 fold lower fraction of stage 4 and 5 seizures than PBS-treated rats during the 2nd and 3rd weeks of MSO

  18. 5-Aminovaleric Acid Suppresses the Development of Severe Seizures in the Methionine Sulfoximine Model of Mesial Temporal Lobe Epilepsy

    PubMed Central

    Dhaher, Roni; Damisah, Eyiyemisi C; Wang, Helen; Gruenbaum, Shaun; Ong, Caroline; Zaveri, Hitten P; Gruenbaum, Benjamin; Eid, Tore

    2014-01-01

    Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant, localization-related epilepsies in humans. One potential therapeutic target is the brain glutamine-glutamate-GABA metabolic pathway, which is perturbed in patients with MTLE. Loss of glutamine synthetase (GS) in astrocytes may be critically involved in this perturbation, which can be modeled by infusing the GS inhibitor methionine sulfoximine (MSO) into the entorhinal-hippocampal area in rats. Because 5-aminovaleric acid (5-AV) has been implicated in modulation of the glutamine-glutamate-GABA metabolic pathway, we hypothesized that 5-AV would alter the expression of seizures in the MSO model of MTLE. Male Sprague Dawley rats (300-330 g) were implanted with an Alzet pump placed subcutaneously in the abdominal region to release either 5-AV (0.05 mg/mL, n = 6) or phosphate buffered saline (PBS, n = 6) at a rate of 2.5 μl/hr over 28 days. Five to 7 days after surgery, all rats were implanted with an intracranial pump infusing MSO (2.5 mg/mL; 0.25 μl/hr) unilaterally into the hippocampal formation. Following the second surgery, intracranial EEG was measured from the left and right hemispheres above the dorsal hippocampal formations for a continuous period of 21 days. The EEG was correlated with simultaneous video recordings to determine the stage of seizures according to a modified Racine scale. Five-AV-treated rats experienced a 3.5 fold reduction in the number of seizures (6.7 ± 1.4 seizures/day) than PBS-treated rats (23.2 ± 6.3 seizures/day) during the first 2 days following MSO pump placement (p < 0.005). Both groups showed similar seizure frequency over days 3-21 (~ 1 seizure/day). However, the fraction of the most severe type of seizures (Racine stage 4 and 5) increased over time in the PBS treated group, but not in the 5-AV treated group. Notably, 5-AV treated rats experienced a 2.3 and 2.6 fold lower fraction of stage 4 and 5 seizures than PBS-treated rats during the 2nd

  19. Prevention of comorbidity and acute attack of gout by uric acid lowering therapy.

    PubMed

    Joo, Kowoon; Kwon, Seong-Ryul; Lim, Mie-Jin; Jung, Kyong-Hee; Joo, Hoyeon; Park, Won

    2014-05-01

    The object of this study was to evaluate the effect of uric acid lowering therapy in reducing the new development of comorbidities and the frequency of acute attacks in gout patients. We retrospectively reviewed patients who were diagnosed to have gout with at least 3 yr of follow up. They were divided into 2 groups; 53 patients with mean serum uric acid level (sUA)<6 mg/dL and 147 patients with mean sUA≥6 mg/dL. Comorbidities of gout such as hypertension (HTN), type II diabetes mellitus (DM), chronic kidney disease, cardiovascular disease (CVD) and urolithiasis were compared in each group at baseline and at last follow-up visit. Frequency of acute gout attacks were also compared between the groups. During the mean follow up period of 7.6 yr, the yearly rate of acute attack and the new development of HTN, DM, CVD and urolithiasis was lower in the adequately treated group compared to the inadequately treated group. Tight control of uric acid decreases the incidence of acute gout attacks and comorbidities of gout such as HTN, DM, CVD and urolithiasis. PMID:24851021

  20. Betulinic Acid Suppresses STAT3 Activation Pathway Through Induction of Protein Tyrosine Phosphatase SHP-1 in Human Multiple Myeloma Cells

    PubMed Central

    Pandey, Manoj K.; Sung, Bokyung; Aggarwal, Bharat B.

    2009-01-01

    STAT3 activation has been associated with survival, proliferation and invasion of various human cancers. Whether betulinic acid, a pentacyclic triterpene, can modulates the STAT3 pathway, was investigated in human multiple myeloma (MM) cells. We found that betulinic acid inhibited constitutive activation of STAT3, Src kinase, JAK1 and JAK2. Pervanadate reversed the betulinic acid -induced down regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, betulinic acid induced the expression of the PTP SHP-1 and silencing of the SHP-1 gene abolished the ability of betulinic acid to inhibit STAT3 activation and rescues betulinic acid-induced cell death. Betulinic acid also downregulated the expression of STAT3-regulated gene products such as bcl-xL, bcl-2, cyclin D1, and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3–induced PARP cleavage. Consistent with these results, over expression of constitutive active STAT3 significantly reduced the betulinic acid-induced apoptosis. Betulinic acid also enhanced the apoptosis induced by thalidomide (from 10% to 55%) and bortezomib (from 5% to 70%) in MM cells. Overall, our results suggest that betulinic acid down regulates STAT3 activation through upregulation of SHP-1 and this may have potential in sensitization of STAT3 over expressing tumors to chemotherapeutic agents. PMID:19937797

  1. Intermittent Androgen Suppression: Estimating Parameters for Individual Patients Based on Initial PSA Data in Response to Androgen Deprivation Therapy

    PubMed Central

    Hirata, Yoshito; Morino, Kai; Akakura, Koichiro; Higano, Celestia S.; Bruchovsky, Nicholas; Gambol, Teresa; Hall, Susan; Tanaka, Gouhei; Aihara, Kazuyuki

    2015-01-01

    When a physician decides on a treatment and its schedule for a specific patient, information gained from prior patients and experience in the past is taken into account. A more objective way to make such treatment decisions based on actual data would be useful to the clinician. Although there are many mathematical models proposed for various diseases, so far there is no mathematical method that accomplishes optimization of the treatment schedule using the information gained from past patients or “rapid learning” technology. In an attempt to use this approach, we integrate the information gained from patients previously treated with intermittent androgen suppression (IAS) with that from a current patient by first fitting the time courses of clinical data observed from the previously treated patients, then constructing the prior information of the parameter values of the mathematical model, and finally, maximizing the posterior probability for the parameters of the current patient using the prior information. Although we used data from prostate cancer patients, the proposed method is general, and thus can be applied to other diseases once an appropriate mathematical model is established for that disease. PMID:26107379

  2. Multiple disturbances of free fatty acid metabolism in noninsulin-dependent diabetes. Effect of oral hypoglycemic therapy.

    PubMed Central

    Taskinen, M R; Bogardus, C; Kennedy, A; Howard, B V

    1985-01-01

    To assess the mechanisms for the elevation of free fatty acids in noninsulin-dependent diabetes, free fatty acid metabolism and lipid and carbohydrate oxidation were compared in 14 obese diabetic Pima Indians and in 13 age-, sex-, and weight-matched nondiabetics. The studies were repeated in 10 of the diabetics after 1 mo of oral hypoglycemic therapy. Fasting plasma glucose concentrations were elevated in diabetics (242 +/- 14 vs. 97 +/- 3 mg/dl, P less than 0.01) and decreased to 142 +/- 12 (P less than 0.01) after therapy. Fasting free fatty acid concentrations were elevated in diabetics (477 +/- 26 vs. 390 +/- 39 mumol/liter, P less than 0.01) and declined to normal values after therapy (336 +/- 32, P less than 0.01). Although free fatty acid transport rate was correlated with obesity (r = 0.75, P less than 0.001), the transport of free fatty acid was not higher in diabetics than in nondiabetics and did not change after therapy. On the other hand, the fractional catabolic rate for free fatty acid was significantly lower in untreated diabetics (0.55 +/- 0.04 vs. 0.71 +/- 0.06 min-1, P less than 0.05); it increased after therapy to 0.80 +/- 0.09 min-1, P less than 0.05, and was inversely correlated with fasting glucose (r = -0.52, P less than 0.01). In diabetics after therapy, lipid oxidation rates fell significantly (from 1.35 +/- 0.06 to 1.05 +/- 0.01 mg/min per kg fat-free mass, P less than 0.01), whereas carbohydrate oxidation increased (from 1.21 +/- 0.10 to 1.73 +/- 0.13 mg/min per kg fat-free mass, P less than 0.01); changes in lipid and carbohydrate oxidation were correlated (r = 0.72, P less than 0.02), and in all subjects lipid oxidation accounted for only approximately 40% of free fatty acid transport. The data suggest that in noninsulin-dependent diabetics, although free fatty acid production may be elevated because of obesity, the elevations in plasma free fatty acid concentrations are also a result of reduced removal, and fractional clearance of free

  3. Bile Acid Malabsorption After Pelvic and Prostate Intensity Modulated Radiation Therapy: An Uncommon but Treatable Condition

    SciTech Connect

    Harris, Victoria; Benton, Barbara; Sohaib, Aslam; Dearnaley, David; Andreyev, H. Jervoise N.

    2012-12-01

    Purpose: 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. Methods and Materials: 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. Results: 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 {alpha}/{beta} 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. Conclusions: 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

  4. Suppression of asymmetric acid efflux and gravitropism in maize roots treated with auxin transport inhibitors of sodium orthovanadate

    NASA Technical Reports Server (NTRS)

    Mulkey, T. J.; Evans, M. L.

    1982-01-01

    In gravitropically stimulated roots of maize (Zea mays L., hybrid WF9 x 38MS), there is more acid efflux on the rapidly growing upper side than on the slowly growing lower side. In light of the Cholodny/Went hypothesis of gravitropism which states that gravitropic curvature results from lateral redistribution of auxin, the effects of auxin transport inhibitors on the development of acid efflux asymmetry and curvature in gravistimulated roots were examined. All the transport inhibitors tested prevented both gravitropism and the development of asymmetric acid efflux in gravistimulated roots. The results indicate that auxin redistribution may cause the asymmetry of acid efflux, a finding consistent with the Cholodny/Went hypothesis of gravitropism. As further evidence that auxin-induced acid efflux asymmetry may mediate gravitropic curvature, sodium orthovanadate, an inhibitor of auxin-induced H+ efflux was found to prevent both gravitropism and the development of asymmetric acid efflux in gravistimulated roots.

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

    SciTech Connect

    Luo, Guanghua; Shi, Yuanping; Zhang, Jun; Mu, Qinfeng; Qin, Li; Zheng, Lu; Feng, Yuehua; Berggren-Söderlund, Maria; Nilsson-Ehle, Peter; Zhang, Xiaoying; Xu, Ning

    2014-02-28

    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 for 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.

  6. Carnosic acid nanoparticles suppress liver ischemia/reperfusion injury by inhibition of ROS, Caspases and NF-κB signaling pathway in mice.

    PubMed

    Li, Hui; Sun, Jian-Jun; Chen, Guo-Yong; Wang, Wei-Wei; Xie, Zhan-Tao; Tang, Gao-Feng; Wei, Si-Dong

    2016-08-01

    Living donor liver transplantation (LDLT) requires ischemia/reperfusion (I/R), which can lead to early graft injury. However, the detailed molecular mechanism of I/R injury remains unclear. Carnosic acid, as a phenolic diterpene with function of anti-inflammation, anti-cancer, anti-bacterial, anti-diabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Nanoparticulate drug delivery systems have been known to better the bioavailability of drugs on intranasal administration compared with only drug solutions. Administration of carnosic acid nanoparticles was thought to be sufficient to lead to considerable inhibition of liver injury progression induced by ischemia/reperfusion. In our study, liver ischemia/reperfusion injury was established successfully with C57BL/6 animal model. 10 and 20mg/kg carnosic acid nanoparticles were injected to mice for five days prior to ischemia. After liver ischemia/reperfusion, the levels of serum AST, ALT and APL were increased, which was attenuated by pre-treatment with carnosic acid nanoparticles. In addition, carnosic acid nanoparticles inhibited ROS production via its related signals regulation. And carnosic acid nanoparticles also suppressed the ischemia/reperfusion-induced up-regulation in the pro-apoptotic protein and mRNA levels of Bax, Cyto-c, Apaf-1 and Caspase-9/3 while increased ischemia/reperfusion-induced decrease of anti-apoptotic factor of Bcl-2. Further, ischemia/reperfusion-induced inflammation was also inhibited for carnosic acid nanoparticles administration via inactivating NF-κB signaling pathway, leading to down-regulation of pro-inflammatory cytokines releasing. In conclusion, our study suggested that carnosic acid nanoparticles protected against liver ischemia/reperfusion injury via its role of anti-oxidative, anti-apoptotic and anti-inflammatory bioactivity. PMID:27470360

  7. Decreased Vitamin B12 and Folic Acid Concentrations in Acne Patients After Isotretinoin Therapy: A Controlled Study

    PubMed Central

    Gökalp, Hilal; Bulur, I; Gürer, MA

    2014-01-01

    Background: Oral isotretinoin treatment might influence the levels of vitamin B12 and folic acid. Aims and Objectives: The aim of this study is to compare vitamin B12 and folic acid levels in patients with moderate and severe acne vulgaris with those of the healthy control group and to investigate the effect of isotretinoin treatment on these vitamins. Materials and Methods: Patients who completed 6 months of isotretinoin therapy for moderate and severe forms of acne vulgaris and a control group consisting of healthy individuals between February 2011 and March 2012 were included in the study. Before isotretinoin therapy and at 6.- months of the therapy, serum vitamin B12 and folic acid levels were measured. In the healthy control group, vitamin B12 and folic acid levels were assessed only once. Results: In total, 120 patients with moderate and severe acne vulgaris who completed 6 months isotretinoin therapy and 100 healthy individuals who constituted the control group were included in the study. Pre-treatment vitamin B12 values of the patient group were found to be statistically significantly higher (P = 0.002), but any statistically significant difference was not detected in folic acid measurements (P = 0.566). A statistically significant decrease was detected in post-treatment vitamin B12 and folic acid levels (P < 0.05). Conclusion: Vitamin B12/folic acid treatment should be given under medical surveillance before and during isotretinoin therapy. Supplementation of these vitamins should be recommended in cases of their deficiency, so as to decrease the risks of neuropsychiatric and occlusive vascular diseases. PMID:25484410

  8. Methamphetamine Use in HIV-infected Individuals Affects T-cell Function and Viral Outcome during Suppressive Antiretroviral Therapy.

    PubMed

    Massanella, Marta; Gianella, Sara; Schrier, Rachel; Dan, Jennifer M; Pérez-Santiago, Josué; Oliveira, Michelli F; Richman, Douglas D; Little, Susan J; Benson, Constance A; Daar, Eric S; Dube, Michael P; Haubrich, Richard H; Smith, Davey M; Morris, Sheldon R

    2015-01-01

    We investigated the associations between methamphetamine (meth) use, immune function, and the dynamics of HIV and cytomegalovirus [CMV] in the blood and genital tract of HIV-infected ART-suppressed subjects. Self-reported meth use was associated with increased CD4(+) and CD8(+) T-cell proliferation (Ki67(+), p < 0.005), CD4(+) T-cell activation (CD45RA(-)CD38(+), p = 0.005) and exhaustion (PD-1(+), p = 0.0004) in blood, compared to non-meth users. Meth use was also associated with a trend towards higher blood HIV DNA levels (p = 0.09) and more frequent shedding of CMV in seminal plasma (p = 0.002). To explore possible mechanisms, we compared ex vivo spontaneous and antigen-specific proliferation in PBMC collected from subjects with and without positive meth detection in urine (Utox+ vs. Utox-). Despite higher levels of spontaneous proliferation, lymphocytes from Utox+ meth users had a significantly lower proliferative capacity after stimulation with a number of pathogens (CMV, candida, mycobacterium, toxoplasma, HIV, p < 0.04 in all cases), compared to Utox- participants. Our findings suggest that meth users have greater proliferation and exhaustion of the immune system. Meth use is also associated with a loss of control of CMV replication, which could be related to loss of immune response to pathogens. Future studies should consider meth use as a potential modulator of T-cell responses. PMID:26299251

  9. Methamphetamine Use in HIV-infected Individuals Affects T-cell Function and Viral Outcome during Suppressive Antiretroviral Therapy

    PubMed Central

    Massanella, Marta; Gianella, Sara; Schrier, Rachel; Dan, Jennifer M.; Pérez-Santiago, Josué; Oliveira, Michelli F.; Richman, Douglas D.; Little, Susan J.; Benson, Constance A.; Daar, Eric S.; Dube, Michael P.; Haubrich, Richard H.; Smith, Davey M.; Morris, Sheldon R.

    2015-01-01

    We investigated the associations between methamphetamine (meth) use, immune function, and the dynamics of HIV and cytomegalovirus [CMV] in the blood and genital tract of HIV-infected ART-suppressed subjects. Self-reported meth use was associated with increased CD4+ and CD8+ T-cell proliferation (Ki67+, p < 0.005), CD4+ T-cell activation (CD45RA–CD38+, p = 0.005) and exhaustion (PD-1+, p = 0.0004) in blood, compared to non-meth users. Meth use was also associated with a trend towards higher blood HIV DNA levels (p = 0.09) and more frequent shedding of CMV in seminal plasma (p = 0.002). To explore possible mechanisms, we compared ex vivo spontaneous and antigen-specific proliferation in PBMC collected from subjects with and without positive meth detection in urine (Utox+ vs. Utox-). Despite higher levels of spontaneous proliferation, lymphocytes from Utox+ meth users had a significantly lower proliferative capacity after stimulation with a number of pathogens (CMV, candida, mycobacterium, toxoplasma, HIV, p < 0.04 in all cases), compared to Utox- participants. Our findings suggest that meth users have greater proliferation and exhaustion of the immune system. Meth use is also associated with a loss of control of CMV replication, which could be related to loss of immune response to pathogens. Future studies should consider meth use as a potential modulator of T-cell responses. PMID:26299251

  10. Magnetic Resonance Imaging of Therapy-Induced Necrosis Using Gadolinium-Chelated Polyglutamic Acids

    SciTech Connect

    Jackson, Edward F.; Esparza-Coss, Emilio; Wen Xiaoxia; Ng, Chaan S.; Daniel, Sherita L.; Price, Roger E.; Rivera, Belinda; Charnsangavej, Chusilp; Gelovani, Juri G.; Li Chun . E-mail: cli@di.mdacc.tmc.edu

    2007-07-01

    Purpose: Necrosis is the most common morphologic alteration found in tumors and surrounding normal tissues after radiation therapy or chemotherapy. Accurate measurement of necrosis may provide an early indication of treatment efficacy or associated toxicity. The purpose of this report is to evaluate the selective accumulation of polymeric paramagnetic magnetic resonance (MR) contrast agents-gadolinium p-aminobenzyl-diethylenetriaminepentaacetic acid-poly(glutamic acid) (L-PG-DTPA-Gd and D-PG-DTPA-Gd)-in necrotic tissue. Methods and Materials: Two different solid tumor models, human Colo-205 xenograft and syngeneic murine OCA-1 ovarian tumors, were used in this study. Necrotic response was induced by treatment with poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL). T{sub 1}-weighted spin-echo images were obtained immediately and up to 4 days after contrast injection and compared with corresponding histologic specimens. Two low-molecular-weight contrast agents, DTPA-Gd and oligomeric(L-glutamic acid)-DTPA-Gd, were used as nonspecific controls. Results: Initially, there was minimal tumor enhancement after injection of either L-PG-DTPA-Gd or D-PG-DTPA-Gd, but rapid enhancement after injection of low-molecular-weight agents. However, polymeric contrast agents, but not low-molecular-weight contrast agents, caused sustained enhancement in regions of tumor necrosis in both tumors treated with PG-TXL and untreated tumors. These data indicate that high molecular weight, rather than in vivo biodegradation, is necessary for the specific localization of polymeric MR contrast agents to necrotic tissue. Moreover, biotinylated L-PG-DTPA-Gd colocalized with macrophages in the tumor necrotic areas, suggesting that selective accumulation of L- and D-PG-DTPA-Gd in necrotic tissue was mediated through residing macrophages. Conclusions: Our data suggest that MR imaging with PG-DTPA-Gd may be a useful technique for noninvasive characterization of treatment-induced necrosis.

  11. Suppression by γ-Hydroxybutyric Acid of “Alcohol Deprivation Effect” in Rats: Preclinical Evidence of its anti-Relapse Properties

    PubMed Central

    Colombo, Giancarlo; Carai, Mauro A. M.; Gessa, Gian Luigi

    2012-01-01

    γ-Hydroxybutyric acid (GHB) reduces (a) alcohol intake and alcohol motivational properties in alcohol-preferring rats and (b) alcohol drinking and craving for alcohol in human alcoholics. The present study was designed to extend to relapse-like drinking the capacity of GHB to suppress different alcohol-related behaviors in alcohol-preferring rats. The “alcohol deprivation effect,” defined as the temporary increase in alcohol intake occurring in laboratory animals after a period of alcohol deprivation, was used as model of alcohol relapse. Acute administration of non-sedative doses of GHB (0, 100, 200, and 300 mg/kg, i.p.) resulted in the complete suppression of the extra-amount of alcohol consumed by Sardinian alcohol-preferring rats during the first hour of re-access to alcohol after a 14-day period of deprivation. These data demonstrate that GHB suppressed relapse-like drinking in a rat model of excessive alcohol consumption. PMID:23133426

  12. Review of dermatology use of 5-aminolevulinic acid photodynamic therapy in China from 1997 to 2013

    NASA Astrophysics Data System (ADS)

    Wang, Peiru; Zhang, Guolong; Wang, Xiuli

    2015-07-01

    The prodrug 5-aminolevulinic acid (ALA) and its ester derivatives have been used in photodynamic therapy (PDT) in dermatology worldwide. In China, ALA-PDT was first used to treat urethral condylomata acuminata and non-melanoma skin cancers in 1997. A powder formulation of ALA hydrochloride was approved by the Chinese Food and Drug Administration for the treatment of condylomata acuminata in 2007. Large successful experience of treating condylomatas was accumulated compared with Western countries. Meanwhile, numerous clinical studies as well as off-label use of ALAPDT have been carried out in China. To reflect the progress of ALA-PDT in China, several major Chinese and English databases were searched and published data were reviewed in this article.

  13. Hyaluronic acid-functionalized mesoporous silica nanoparticles for efficient photodynamic therapy of cancer cells.

    PubMed

    Gary-Bobo, Magali; Brevet, David; Benkirane-Jessel, Nadia; Raehm, Laurence; Maillard, Philippe; Garcia, Marcel; Durand, Jean-Olivier

    2012-09-01

    Mesoporous silica nanoparticles (MSN) for photodynamic therapy (PDT) were coated with poly-(L-lysine) and hyaluronic acid (HA) by using the layer-by-layer method. HA is able to target cancer cells over-expressing the corresponding CD44 receptor. MSN functionalized with HA (MSN-HA) were more efficient than MSN without the targeting moiety when PDT was performed at low fluence (14 Jcm(-2)) and low dosage of MSN (20 μgmL(-1)) on HCT 116 colorectal cancer cells, known to over-express the CD44 receptor. Incubation of HCT-116 cancer cells with an excess of HA impaired the PDT effect with MSN-HA thus demonstrating that an active endocytosis mechanism was involved in the uptake of MSN-HA by these cells. PMID:22959805

  14. Fluorescence-guided resections and photodynamic therapy for malignant gliomas using 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Stepp, Herbert G.; Beck, Tobias; Beyer, Wolfgang; Pongratz, Thomas; Sroka, Ronald; Baumgartner, Reinhold; Stummer, Walter; Olzowy, Bernhard; Mehrkens, Jan H.; Tonn, Joerg C.; Reulen, Hans J.

    2005-04-01

    Oral application of 20 mg/kg bw of 5-aminolevulinic acid results in a highly specific accumulation of fluorescent and phototoxic Protoporphyrin IX in malignant glioma tissue. Surgical removal with fluorescence guidance is studied in a phase III clinical trial, adjuvant Photodynamic Therapy (PDT) to the surgical cavity is in phase II and for interstitial PDT of recurrent gliomas, a phase I/II study has started. Fluorescence guided resections have been shown to be safe and effective in augmenting neurosurgical removal of malignant gliomas in 52 consecutive patients. Intra-operative fluorescence spectroscopy showed statistically significant higher sensitizer accumulation in vital brain tumor versus the infiltration zone and in the infiltration zone versus adjacent normal brain, which contained very little PPIX. This is promisingly exploited for PDT - both to the surgical cavity by surface irradiation and for stereotactically guided interstitial irradiation.

  15. Acid ceramidase and the treatment of ceramide diseases: The expanding role of enzyme replacement therapy.

    PubMed

    Schuchman, Edward H

    2016-09-01

    Ceramides are a diverse group of sphingolipids that play important roles in many biological processes. Acid ceramidase (AC) is one key enzyme that regulates ceramide metabolism. Early research on AC focused on the fact that it is the enzyme deficient in the rare genetic disorder, Farber Lipogranulomatosis. Recent research has revealed that deficiency of the same enzyme is responsible for a rare form of spinal muscular atrophy associated with myoclonic epilepsy (SMA-PME). Due to their diverse role in biology, accumulation of ceramides also has been implicated in the pathobiology of many other common diseases, including infectious lung diseases, diabetes, cancers and others. This has revealed the potential of AC as a therapy for many of these diseases. This review will focus on the biology of AC and the potential role of this enzyme in the treatment of human disease. PMID:27155573

  16. 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.

  17. Acid ceramidase upregulation in prostate cancer: role in tumor development and implications for therapy.

    PubMed

    Liu, Xiang; Cheng, Joseph C; Turner, Lorianne S; Elojeimy, Saeed; Beckham, Thomas H; Bielawska, Alicja; Keane, Thomas E; Hannun, Yusuf A; Norris, James S

    2009-12-01

    Bioactive sphingolipids, such as ceramide, sphingosine and sphingosine-1-phosphate are known bio-effector molecules which play important roles in various aspects of cancer biology including cell proliferation, growth arrest, apoptosis, metastasis, senescence and inflammation. Therefore, enzymes involved in ceramide metabolism are gaining recognition as being critical regulators of cancer cell growth and/or survival. We previously observed that the ceramide metabolizing enzyme, acid ceramidase (AC) is upregulated in tumor tissues. Studies have now concluded that this creates a dysfunctional ceramide pathway, which is responsible for tumor progression and resistance to chemotherapy and radiation. This suggests that development of small-molecule drugs that inhibit AC enzyme activity is a promising approach for improving standard cancer therapy and patient's clinical outcomes. PMID:19874262

  18. 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 Central

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

    2016-01-01

    Objective 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. Methods 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. Results 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. Conclusions The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here

  19. Comparison of 5-Aminolevulinic Acid Photodynamic Therapy and Clobetasol Propionate in Treatment of Vulvar Lichen Sclerosus.

    PubMed

    Shi, Lei; Miao, Fei; Zhang, Ling-Lin; Zhang, Guo-Long; Wang, Pei-Ru; Ji, Jie; Wang, Xiao-Jie; Huang, Zheng; Wang, Hong-Wei; Wang, Xiu-Li

    2016-06-15

    The aim of this study was to evaluate the effectiveness of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for the treatment of vulvar lichen sclerosus (VLS) and compare its effectiveness with that of clobetasol propionate. Four sessions of topical photodynamic therapy (PDT) were administered at 2-week intervals (n = 20). Clobetasol propionate (0.05%) was used daily for 8 weeks (n = 20). The rate of complete response in the PDT group (14/20) was double that of the clobetasol propionate group (7/20) (p < 0.05, 2 = 4.912). Horizontal visual analogue scores indicated that PDT was more effective than clobetasol propionate. Pain intensity numeric rating scale values for PDT were between 3.05 and 4.45. One month after the final session of PDT, only one patient relapsed and all 7 patients in clobetasol propionate group relapsed. ALA-PDT is a well-tolerated and effective option for the treatment of VLS. PMID:26775671

  20. Off-label photodynamic therapy for recalcitrant facial flat warts using topical 5-aminolevulinic acid.

    PubMed

    Yang, Ya-Li; Sang, Junjun; Liao, Ning-Xin; Wei, Fang; Liao, Wanqin; Chen, Jiang-Han

    2016-07-01

    The facial flat wart (verruca plana) is one of the most common reasons for dermatology and primary care visits. Although there are many therapeutic modalities, no single therapy has been proven to be completely curative. Case reports and uncontrolled studies suggested that photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) can effectively treat recalcitrant facial flat warts. A total of 12 patients with recalcitrant facial flat warts were enrolled in the study. ALA gel (10 %) was applied topically to lesions and incubated for 3 h. The lesions were irradiated by an LED light of 630 ± 10 nm at dose levels of 60-100 mW/cm. Clinical assessment was conducted before and after every treatment for up to 24 weeks. Among the ten patients completing three sessions of ALA-PDT, five had complete lesions clearance, and the other five patients were significantly improved. At the 24-week follow-up, the average effective rate was 88.8 %, with no recurrences. No significant side effects were reported. A low-dose topical ALA-PDT regimen using 10 % ALA, 3 h incubation, and a red light source for three treatment sessions are suggested as the optimal scheme for the treatment of recalcitrant flat warts on the face in Chinese patients. Superior efficacy is found in elevated or active period lesions with mild side effects. PMID:27059226

  1. Proteomic profiling of the autoimmune response to breast cancer antigens uncovers a suppressive effect of hormone therapy

    PubMed Central

    Chao, Timothy; Ladd, Jon J; Qiu, Ji; Johnson, Melissa M; Israel, Rebecca; Chin, Alice; Wang, Hong; Prentice, Ross L; Feng, Ziding; Disis, Mary L.; Hanash, Samir

    2015-01-01

    Purpose Proteomics technologies are well suited for harnessing the immune response to tumor antigens for diagnostic applications as in the case of breast cancer. We previously reported a substantial impact of hormone therapy (HT) on the proteome. Here we investigated the effect of HT on the immune response toward breast tumor antigens. Experimental design Plasmas collected 0-10 months prior to diagnosis of ER+ breast cancer from 190 post-menopausal women and 190 controls that participated in the Women's Health Initiative (WHI) Observational Study were analyzed for the effect of HT on IgG reactivity against arrayed proteins from MCF-7 or SKBR3 breast cancer cell line lysates following extensive fractionation. Results HT user cases exhibited significantly reduced autoantibody reactivity against arrayed proteins compared to cases who were not current users. An associated reduced level of IL-6 and other immune-related cytokines was observed among HT users relative to non-users. Conclusion and clinical relevance Our findings suggest occurrence of a global altered immune response to breast cancer derived proteins associated with HT. Thus a full understanding of factors that modulate the immune response is necessary to translate autoantibody panels into clinical applications. PMID:23401414

  2. Suppression of Cancer Growth by Nonviral Gene Therapy Based on a Novel Reactive Oxygen Species-responsive Promoter

    PubMed Central

    Policastro, Lucía L; Ibañez, Irene L; Durán, Hebe A; Soria, Gastón; Gottifredi, Vanesa; Podhajcer, Osvaldo L

    2009-01-01

    Increased reactive oxygen species (ROS) production has been reported as a distinctive feature of different pathologies including cancer. Therefore, we assessed whether increased ROS production in the cancer microenvironment could be selectively exploited to develop a selective anticancer therapy. For this purpose, we constructed a novel chimeric promoter, based on a ROS-response motif located in the VEGF gene promoter placed, in turn, downstream of a second ROS-response motif obtained from the early growth response 1 (Egr-1) gene promoter. The activity of the chimeric promoter was largely dependent on variations in intracellular ROS levels and showed a high inducible response to exogenous H2O2. Transient expression of the thymidine kinase (TK) gene driven by the chimeric promoter, followed by gancyclovir (GCV) administration, inhibited human colorectal cancer and melanoma cell growth in vitro and in vivo. Moreover, electrotransfer of the TK gene followed by GCV administration exerted a potent therapeutic effect on established tumors. This response was improved when combined with chemotherapeutic drugs. Thus, we show for the first time that a distinctive pro-oxidant state can be used to develop new selective gene therapeutics for cancer. PMID:19436270

  3. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts.

    PubMed

    Ngo, Michael; Han, Arum; Lakatos, Anita; Sahoo, Debashis; Hachey, Stephanie J; Weiskopf, Kipp; Beck, Andrew H; Weissman, Irving L; Boiko, Alexander D

    2016-08-01

    The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma. PMID:27477289

  4. Duration of Androgen Suppression Before Radiotherapy for Localized Prostate Cancer: Radiation Therapy Oncology Group Randomized Clinical Trial 9910

    PubMed Central

    Pisansky, Thomas M.; Hunt, Daniel; Gomella, Leonard G.; Amin, Mahul B.; Balogh, Alexander G.; Chinn, Daniel M.; Seider, Michael J.; Duclos, Marie; Rosenthal, Seth A.; Bauman, Glenn S.; Gore, Elizabeth M.; Rotman, Marvin Z.; Lukka, Himanshu R.; Shipley, William U.; Dignam, James J.; Sandler, Howard M.

    2015-01-01

    Purpose To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer. Patients and Methods One thousand five hundred seventy-nine men with intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up. Results There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio [HR], 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen–based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively. Conclusion Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate

  5. Combined dermal exposure to permethrin and cis-urocanic acid suppresses the contact hypersensitivity response in C57BL/6N mice in an additive manner.

    PubMed

    Prater, M R; Blaylock, B L; Holladay, S D

    2005-01-14

    Cutaneous exposure to the pyrethroid insecticide permethrin significantly suppresses contact hypersensitivity (CH) response to oxazolone in C57BL/6N mice. Additionally, cis-urocanic acid (cUCA), an endogenous cutaneous chromophore isomerized to its active form following exposure to ultraviolet radiation, modulates cell-mediated cutaneous immune responses. This study describes cutaneous immune alterations following combined topical permethrin and intradermal cUCA exposure. Female C57BL/6N mice were administered 5, 50 or 100 microg cUCA daily for 5 consecutive days. CH was then evaluated by the mouse ear swelling test (MEST) response to oxazolone. Decreased responses of 52.3%, 76.3% and 76.3%, respectively, as compared to controls were observed. Then, mice were co-exposed to 5 microg cUCA daily for 5 days and 1.5, 5, 15, or 25 microL permethrin, on either day 1, 3 or 5 of the cUCA treatment to evaluate combined immunomodulatory effects of the two chemicals, or cUCA daily for 5 days followed by permethrin on day 3, 5, or 7 after the last cUCA injection to demonstrate prolonged immunosuppressive effects. Two days after final treatment, mice were sensitized with oxazolone and MEST was performed. Mice receiving five cUCA injections and permethrin topically on cUCA injection day 1 showed up to 93.3% suppression of MEST compared to vehicle control. CH was suppressed by 87.5%, 86.6% and 74.2% in mice treated with 25 muL permethrin on days 3, 5 and 7 after cUCA, respectively, compared to vehicle control. Taken together, these data indicate co-exposure to cUCA and permethrin profoundly suppresses cell-mediated cutaneous immunity. PMID:15629246

  6. 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. PMID:21775083

  7. Conjugated linoleic acids suppress inflammatory response and ICAM-1 expression through inhibition of NF-κB and MAPK signaling in human bronchial epithelial cells.

    PubMed

    Huang, Wen-Chung; Tu, Rong-Syuan; Chen, Ya-Ling; Tsai, Yun-Yun; Lin, Chwan-Fwu; Liou, Chian-Jiun

    2016-04-20

    Conjugated linoleic acids (CLAs) comprise a group of natural unsaturated fatty acids. CLA was reported to have anti-asthma, anti-adiposity, and anti-tumor effects. The present study aimed to evaluate the suppressive effects of cis-9, trans-11-CLA (c9,t11-CLA) on the expression of proinflammatory cytokines and intercellular adhesion molecule 1 (ICAM-1) in TNF-α-stimulated human bronchial epithelial (BEAS-2B) cells. After treating with various doses of c9,t11-CLA (12.5-100 μg ml(-1)), BEAS-2B cells were induced into an inflamed state by adding TNF-α or TNF-α/IL-4. The presence of c9,t11-CLA significantly suppressed the secretion of cytokines IL-6, IL-8, CCL5, and MCP-1. We also found that c9,t11-CLA inhibited ICAM-1 expression, and decreased monocyte adhesion to inflamed bronchial epithelial cells. Interestingly, c9,t11-CLA attenuated the phosphorylation of mitogen-activated protein kinase (MAPK) and down-regulated the activation of nuclear factor-κB (NF-κB). These results suggested that the anti-inflammatory effects of c9,t11-CLA were mediated by inhibiting proinflammatory cytokines, chemokines, and ICAM-1 expression by blocking NF-κB transcription regulation and by attenuating MAPK signaling pathways. PMID:27007063

  8. Ganoderic acid C1 isolated from the anti-asthma formula, ASHMI™ suppresses TNF-α production by mouse macrophages and peripheral blood mononuclear cells from asthma patients.

    PubMed

    Liu, Changda; Yang, Nan; Song, Ying; Wang, Lixin; Zi, Jiachen; Zhang, Shuwei; Dunkin, David; Busse, Paula; Weir, David; Tversky, Jody; Miller, Rachel L; Goldfarb, Joseph; Zhan, Jixun; Li, Xiu-Min

    2015-08-01

    Asthma is a heterogeneous airway inflammatory disease, which is associated with Th2 cytokine-driven inflammation and non-Th2, TNF-α mediated inflammation. Unlike Th2 mediated inflammation, TNF-α mediated asthma inflammation is generally insensitive to inhaled corticosteroids (ICS). ASHMITM, aqueous extract of three medicinal herbs-Ganoderma lucidum (G. lucidum), Sophora flavescens Ait (S. flavescens) and Glycyrrhiza uralensis Fischer (G. uralensis), showed a high safety profile and was clinically beneficial in asthma patients. It also suppresses both Th2 and TNF-α associated inflammation in murine asthma models. We previously determined that G. uralensis flavonoids are the key active compounds responsible for ASHMITM suppression of Th2 mediated inflammation. Until now, there are limited studies on anti-TNF-α compounds presented in ASHMITM. The objective of this study was to isolate and identify TNF-α inhibitory compounds in ASHMITM. Here we report that G. lucidum, but not the other two herbal extracts, S. flavescens or G. uralensis inhibited TNF-α production by murine macrophages; and that the methylene chloride (MC)-triterpenoid-enriched fraction, but not the polysaccharide-enriched fraction, contained the inhibitory compounds. Of the 15 triterpenoids isolated from the MC fraction, only ganoderic acid C1 (GAC1) significantly reduced TNF-α production by murine macrophages (RAW 264.7 cells) and peripheral blood mononuclear cells (PBMCs) from asthma patients. Inhibition was associated with down-regulation of NF-κB expression, and partial suppression of MAPK and AP-1 signaling pathways. Ganoderic acid C1 may have potential for treating TNF-α mediated inflammation in asthma and other inflammatory diseases. PMID:26004313

  9. Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD)

    PubMed Central

    Oyomopito, R; Lee, MP; Phanuphak, P; Lim, PL; Ditangco, R; Zhou, J; Sirisanthana, T; Chen, YMA; Pujari, S; Kumarasamy, N; Sungkanuparph, S; Lee, CKC; Kamarulzaman, A; Oka, S; Zhang, FJ; Mean, CV; Merati, T; Tau, G; Smith, J; Li, PCK

    2010-01-01

    Objectives Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. Methods Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (≥ 3, 1–2 or <1) or CD4 (≥ 3 or <3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (<400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively. Results Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) and `Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P<0.001] and reporting `Other' HIV exposures experienced reduced suppression (OR=0.28; P<0.001). Conclusion Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites

  10. Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates.

    PubMed

    Battah, Sinan; Balaratnam, Sherina; Casas, Adriana; O'Neill, Sophie; Edwards, Christine; Batlle, Alcira; Dobbin, Paul; MacRobert, Alexander J

    2007-03-01

    Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (5-ALA) has been widely used in photodynamic therapy. However, cellular uptake of 5-ALA is limited by its hydrophilicity, and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers present a promising new approach to drug delivery because they have a well-defined structure capable of incorporating a high drug payload. In this work, a dendrimer conjugate was investigated, which incorporated 18 aminolaevulinic acid residues attached via ester linkages to a multipodent aromatic core. The ability of the dendrimer to deliver and release 5-ALA intracellularly for metabolism to the photosensitizer, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Up to an optimum concentration of 0.1 mmol/L, the dendrimer was significantly more efficient compared with 5-ALA for porphyrin synthesis. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, together with minimal dark toxicity. Cellular uptake of the dendrimer occurs through endocytic routes predominantly via a macropinocytosis pathway. In conclusion, macromolecular dendritic derivatives are capable of delivering 5-ALA efficiently to cells for sustained porphyrin synthesis. PMID:17363482

  11. Phenylbutyric acid protects against spatial memory deficits in a model of repeated electroconvulsive therapy.

    PubMed

    Yao, Zhao-Hui; Kang, Xiang; Yang, Liu; Niu, Yi; Lu, Ye; Gong, Cheng-Xin; Tian, Qing; Wang, Jian-Zhi

    2014-05-01

    Repeated electroconvulsive therapy (rECT) is widely applied in the treatment of refractory depression. Among the side effects of rECT, memory impairment is noticeable and needs effective protection. In this study, by employing a recognized repeated electroconvulsive shock (rECS) rat model, we found that rECS induced the significant spatial memory retention deficits with the simultaneous decreases in long-term potential (LTP), enhanced excitable postsynaptic potentials (EPSP), population spike (PS) and input/output curve in perforant pathway-dentate gyrus (PP-DG), but had no obvious neuron loss or dentritic spine loss in the brain by Nissle or Golgi stainings. Furthermore, the increased synaptic proteins of NR2A/B, PSD93, PSD95, the immediate early gene c-Fos and CREB protein were detected in hippocampus of rECS rats. rECS was also found to cause enhanced axon reorganization in DG region of hippocampus by Timm staining. Intraperitoneal injection of phenylbutyric acid (PBA), an aromatic short chain fatty acid acting as a molecule chaperon, could prevent rats from the rECS-induced memory deficits and synaptic potential enhancement by decreasing the levels of the abnormally increased memory-associated proteins and enhanced axon reorganization in hippocampus. Our data suggested that PBA might be potentially used to attenuate the rECS-induced memory impairment. PMID:24712645

  12. Aminolevulinic acid derivatives-based photodynamic therapy in human intra- and extrahepatic cholangiocarcinoma cells.

    PubMed

    Chung, Chung-Wook; Kim, Cy Hyun; Lee, Hye Myeong; Kim, Do Hyung; Kwak, Tae-Won; Chung, Kyu-Don; Jeong, Young-Il; Kang, Dae Hwan

    2013-11-01

    Hexyl-aminolevulinic acid (HALA) was compared with aminolevulinic acid (ALA) in terms of improving ALA-based photodynamic therapy (PDT) for human intra- and extrahepatic cholangiocarcinoma (CCA) HuCC-T1 and SNU1196 cells. Because of the different uptake mechanisms of HALA, a relatively higher amount of protoporphyrin IX (PpIX) was induced in the both CCA cell types at low concentrations of HALA. Furthermore, higher expression of porphobilinogen deaminase, coproporphyrinogen III oxidase, and protoporphyrinogen oxidase, the key enzymes for synthesizing PpIX in the heme biosynthetic pathway, facilitated the exuberant generation of PpIX in HuCC-T1 cells. PpIX accumulation with ALA was markedly different between the two CCA cell types. Even at lower concentrations of ALA, SNU1196 cell successfully synthesized PpIX, due to the higher expression of the ALA transporter, mammalian H (+)/peptide co-transporter PEPT1. Considering the difference of PEPT1 or key enzyme expression, HALA could be a very effective substitute for ALA in doing PDT for cure of CCA. PMID:23429232

  13. Preliminary characterization of dexamethasone-loaded cross-linked hyaluronic acid films for topical ocular therapy.

    PubMed

    Calles, J A; López-García, A; Vallés, E M; Palma, S D; Diebold, Y

    2016-07-25

    The aim of this work was to design and characterize cross-linked hyaluronic acid (HA)-itaconic acid (IT) films loaded with dexamethasone sodium phosphate salt (DEX) for topical therapy of inflammatory ocular surface diseases. Films were chemically cross-linked with polyethylene glycol diglycidyl ether (PEGDE), then physical and mechanical characterization by stress-strain, X-ray diffraction, X-ray fluorescence spectrometry and swelling assays was conducted. A sequential in vitro therapeutic efficacy model was designed to assess changes in interleukin (IL)-6 production in an inflamed human corneal epithelial (HCE) cell line after film exposure. Changes in cell proliferation after film exposure were assessed using the alamarBlue(®) proliferation assay. Experimental findings showed desirable mechanical properties and in vitro efficacy to reduce cell inflammation. A moderately decreased proliferation rate was induced in HCE cells by DEX-loaded films, compared to commercial DEX eye drops. These results suggest that DEX and HA have opposite effects. The sequential in vitro therapeutic efficacy model arises as an efficient tool to study drug release from delivery systems by indirect measurement of a biological response. PMID:27242313

  14. ANTIFUNGAL AND SPROUT REGULATORY BIOACTIVITIES OF PHENYLACETIC ACID, INDOLE-3-ACETIC ACID, AND TYROSOL ISOLATED FROM THE POTATO DRY ROT SUPPRESSIVE BACTERIUM ENTEROBACTER CLOACAE S11:T:07

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Enterobacter cloacae S11:T:07 (NRRL B-21050) is a promising biological control agent which has significantly reduced both fungal dry rot disease and sprouting in lab and pilot potato storages. The metabolites phenylacetic acid (PAA), indole-3-acetic acid (IAA), and tyrosol (TSL) were isolated from ...

  15. Suppression of Growth Rate of Colony-Associated Fungi by High Fructose Corn Syrup Feeding Supplement, Formic Acid, and Oxalic Acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Select colony-associated fungi (bee isolates). Absidia sp., Ascosphaera apis, Aspergillus flavus, Fusarium sp., Penicillium glabrum, Mucor sp., showed a 40% reduction in radial growth rate with formic acid, a 28% reduction with oxalic acid, and a 15% reduction with fructose and high fructose corn sy...

  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. Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapy.

    PubMed

    Martens, Thomas F; Remaut, Katrien; Deschout, Hendrik; Engbersen, Johan F J; Hennink, Wim E; van Steenbergen, Mies J; Demeester, Jo; De Smedt, Stefaan C; Braeckmans, Kevin

    2015-03-28

    Retinal gene therapy could potentially affect the lives of millions of people suffering from blinding disorders. Yet, one of the major hurdles remains the delivery of therapeutic nucleic acids to the retinal target cells. Due to the different barriers that need to be overcome in case of topical or systemic administration, intravitreal injection is an attractive alternative administration route for large macromolecular therapeutics. Here it is essential that the therapeutics do not aggregate and remain mobile in the vitreous humor in order to reach the retina. In this study, we have evaluated the use of hyaluronic acid (HA) as an electrostatic coating for nonviral polymeric gene nanomedicines, p(CBA-ABOL)/pDNA complexes, to provide them with an anionic hydrophilic surface for improved intravitreal mobility. Uncoated polyplexes had a Z-averaged diameter of 108nm and a zeta potential of +29mV. We evaluated polyplexes coated with HA of different molecular weights (22kDa, 137kDa and 2700kDa) in terms of size, surface charge and complexation efficiency and noticed their zeta potentials became anionic at 4-fold molar excess of HA-monomers compared to cationic monomers, resulting in submicron ternary polyplexes. Next, we used a previously optimized ex vivo model based on excised bovine eyes and fluorescence single particle tracking (fSPT) microscopy to evaluate mobility in intact vitreous humor. It was confirmed that HA-coated polyplexes had good mobility in bovine vitreous humor, similar to polyplexes functionalized with polyethylene glycol (PEG), except for those coated with high molecular weight HA (2700kDa). However, contrary to PEGylated polyplexes, HA-coated polyplexes were efficiently taken up in vitro in ARPE-19 cells, despite their negative charge, indicating uptake via CD44-receptor mediated endocytosis. Furthermore, the HA-polyplexes were able to induce GFP expression in this in vitro cell line without apparent cytotoxicity, where coating with low molecular

  18. A Phase 1/2 Trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for High-Risk Prostate Cancer

    SciTech Connect

    Bauman, Glenn; Ferguson, Michelle; Lock, Michael; Chen, Jeff; Ahmad, Belal; Venkatesan, V.M.; Sexton, Tracy; D'Souza, David; Loblaw, Andrew; Warner, Andrew; Rodrigues, George

    2015-07-15

    Purpose: To initiate a phase 1/2 trial to examine the tolerability of a condensed combined-modality protocol for high-risk prostate cancer. Methods and Materials: Men scoring ≥3 on the Vulnerable Elderly Scale (VES) or refusing conventionally fractionated treatment for high-risk prostate cancer were eligible to participate. Androgen suppression was delivered for 12 months, and radiation therapy was delivered using 25 Gy to pelvic nodes delivered synchronously with 40 Gy to the prostate given as 1 fraction per week over 5 weeks. The phase 1 component included predetermined stopping rules based on 6-month treatment-related toxicity, with trial suspension specified if there were ≥6 of 15 patients (40%) or ≥3 of 15 (20%) who experienced grade ≥2 or ≥3 gastrointestinal (GI) or genitourinary (GU) toxicity, respectively. Results: Sixteen men were enrolled, with 7 men meeting the criteria of VES ≥3 and 9 men having a VES <3 but choosing the condensed treatment. One man was not treated owing to discovery of a synchronous primary rectal cancer. Four patients (26%) experienced grade ≥2 toxicity at 6 weeks after treatment. There were 9 of 15 (60%) who experienced grade ≥2 GI or GU toxicity and 4 of 15 (26%) grade ≥3 GI or GU toxicity at 6 months, and 5 of 15 (30%) grade ≥2 GI and GU toxicity at 6 months. A review of the 15 cases did not identify any remedial changes, thus the phase 1 criteria were not met. Conclusion: This novel condensed treatment had higher than anticipated late toxicities and was terminated before phase 2 accrual. Treatment factors, such as inclusion of pelvic lymph node radiation therapy, planning constraints, and treatment margins, or patient factors related to the specific frail elderly population may be contributing.

  19. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity.

    PubMed

    Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul; Chaudhary, Kapil; Xiao, Wei; Bradley, Jillian; Koritzinsky, Marianne; Madaio, Michael P; McGaha, Tracy L

    2015-08-25

    Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity. PMID:26261340

  20. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

    PubMed Central

    Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul; Chaudhary, Kapil; Xiao, Wei; Bradley, Jillian; Koritzinsky, Marianne; Madaio, Michael P.; McGaha, Tracy L.

    2015-01-01

    Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity. PMID:26261340

  1. Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-α

    PubMed Central

    Weylandt, Karsten H.; Krause, Lena F.; Gomolka, Beate; Chiu, Cheng-Ying; Bilal, Süleyman; Nadolny, Anja; Waechter, Simon F.; Fischer, Andreas; Rothe, Michael

    2011-01-01

    Liver tumors, particularly hepatocellular carcinoma (HCC), are a major cause of morbidity and mortality worldwide. The development of HCC is mostly associated with chronic inflammatory liver disease of various etiologies. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) dampen inflammation in the liver and decrease formation of tumor necrosis factor (TNF)-α. In this study, we used the fat-1 transgenic mouse model, which endogenously forms n-3 PUFA from n-6 PUFA to determine the effect of an increased n-3 PUFA tissue status on tumor formation in the diethylnitrosamine (DEN)-induced liver tumor model. Our results showed a decrease in tumor formation, in terms of size and number, in fat-1 mice compared with wild-type littermates. Plasma TNF-α levels and liver cyclooxygenase-2 expression were markedly lower in fat-1 mice. Furthermore, there was a decreased fibrotic activity in the livers of fat-1 mice. Lipidomics analyses of lipid mediators revealed significantly increased levels of the n-3 PUFA-derived 18-hydroxyeicosapentaenoic acid (18-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHA) in the livers of fat-1 animals treated with DEN. In vitro experiments showed that 18-HEPE and 17-HDHA could effectively suppress lipopolysacharide-triggered TNF-α formation in a murine macrophage cell line. The results of this study provide evidence that an increased tissue status of n-3 PUFA suppresses liver tumorigenesis, probably through inhibiting liver inflammation. The findings also point to a potential anticancer role for the n-3 PUFA-derived lipid mediators 18-HEPE and 17-HDHA, which can downregulate the important proinflammatory and proproliferative factor TNF-α. PMID:21421544

  2. Hemoglobin levels do not predict biochemical outcome for localized prostate cancer treated with neoadjuvant androgen-suppression therapy and external-beam radiotherapy

    SciTech Connect

    Pai, Howard Huaihan . E-mail: hpai@bccancer.bc.ca; Ludgate, Charles; Pickles, Tom; Paltiel, Chuck M.Sc.; Agranovich, Alex; Berthelet, Eric; Duncan, Graeme; Kim-Sing, Charmaine; Kwan, Winkle; Lim, Jan; Liu, Mitchell; Tyldesley, Scott

    2006-07-15

    Purpose: To investigate whether hemoglobin (Hb) levels affect outcome in men with localized prostate adenocarcinoma (LPA) treated with neoadjuvant androgen-suppression therapy (NAST) and external-beam radiotherapy (EBRT). Methods and Materials: A total of 563 men with LPA treated with NAST (median: 5.3 months) and EBRT who had Hb levels during treatment were retrospectively reviewed. Patient, tumor, and treatment variables, including the following Hb variables, were subjected to univariate and multivariable analyses to identify factors that predict biochemical control (bNED) and overall survival (OS): pre-EBRT Hb, Hb nadir during EBRT, and change in Hb from pre-EBRT to nadir during EBRT. Results: Median PSA follow-up was 4.25 years. Forty-nine percent of men were anemic during EBRT, with a median Hb of 13.4 g/dL, and 68% experienced a decline in Hb from pre-EBRT to during EBRT of median 0.6 g/dL. Five-year Nadir + 2 bNED and OS rates were similar for anemic and nonanemic patients during EBRT. High percent-positive biopsies, PSA and Gleason score, and use of AA monotherapy predicted worse bNED. High stage and age predicted worse OS. Hb variables were not predictive of bNED or OS. Conclusions: Anemia is a common side effect of NAST and is usually mild. Hb levels, however, do not predict biochemical control or survival.

  3. n-3 polyunsaturated fatty acids suppress CD4(+) T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization.

    PubMed

    Hou, Tim Y; Barhoumi, Rola; Fan, Yang-Yi; Rivera, Gonzalo M; Hannoush, Rami N; McMurray, David N; Chapkin, Robert S

    2016-01-01

    The mechanisms by which n-3 polyunsaturated fatty acids (n-3 PUFA), abundant in fish oil, exert their anti-inflammatory effects have not been rigorously defined. We have previously demonstrated that n-3 PUFA decrease the amount of phosphatidylinositol-(4,5)-bisphosphate, [PI(4,5)P2], in CD4(+) T cells, leading to suppressed actin remodeling upon activation. Since discrete pools of PI(4,5)P2 exist in the plasma membrane, we determined whether n-3 PUFA modulate spatial organization of PI(4,5)P2 relative to raft and non-raft domains. We used Förster resonance energy transfer (FRET) to demonstrate that lipid raft mesodomains in the plasma membrane of CD4(+) T cells enriched in n-3 PUFA display increased co-clustering of Lck(N10) and LAT(ΔCP), markers of lipid rafts. CD4(+) T cells enriched in n-3 PUFA also exhibited a depleted plasma membrane non-raft PI(4,5)P2 pool as detected by decreased co-clustering of Src(N15), a non-raft marker, and PH(PLC-δ), a PI(4,5)P2 reporter. Incubation with exogenous PI(4,5)P2 rescued the effects on the non-raft PI(4,5)P2 pool, and reversed the suppression of T cell proliferation in CD4(+) T cells enriched with n-3 PUFA. Furthermore, CD4(+) T cells isolated from mice fed a 4% docosahexaenoic acid (DHA)-enriched diet exhibited a decrease in the non-raft pool of PI(4,5)P2, and exogenous PI(4,5)P2 reversed the suppression of T cell proliferation. Finally, these effects were not due to changes to post-translational lipidation, since n-3 PUFA did not alter the palmitoylation status of signaling proteins. These data demonstrate that n-3 PUFA suppress T cell proliferation by altering plasma membrane topography and the spatial organization of PI(4,5)P2. PMID:26476105

  4. Availability of Amino Acids Extends Chronological Lifespan by Suppressing Hyper-Acidification of the Environment in Saccharomyces cerevisiae

    PubMed Central

    Maruyama, Yo; Ito, Toshiyuki; Kodama, Hiroaki; Matsuura, Akira

    2016-01-01

    The chronological lifespan of Saccharomyces cerevisiae represents the duration of cell survival in the postdiauxic and stationary phases. Using a prototrophic strain derived from the standard auxotrophic laboratory strain BY4742, we showed that supplementation of non-essential amino acids to a synthetic defined (SD) medium increases maximal cell growth and extends the chronological lifespan. The positive effects of amino acids can be reproduced by modulating the medium pH, indicating that amino acids contribute to chronological longevity in a cell-extrinsic manner by alleviating medium acidification. In addition, we showed that the amino acid-mediated effects on extension of chronological longevity are independent of those achieved through a reduction in the TORC1 pathway, which is mediated in a cell-intrinsic manner. Since previous studies showed that extracellular acidification causes mitochondrial dysfunction and leads to cell death, our results provide a path to premature chronological aging caused by differences in available nitrogen sources. Moreover, acidification of culture medium is generally associated with culture duration and cell density; thus, further studies are required on cell physiology of auxotrophic yeast strains during the stationary phase because an insufficient supply of essential amino acids may cause alterations in environmental conditions. PMID:26991662

  5. Mono- and Combined Therapy of Metastasizing Breast Carcinoma 4T1 with Zoledronic Acid and Doxorubicin.

    PubMed

    Baklaushev, V P; Grinenko, N F; Yusubalieva, G M; Gubskii, I L; Burenkov, M S; Rabinovich, E Z; Ivanova, N V; Chekhonin, V P

    2016-08-01

    The efficiency of monotherapy with zoledronic acid (Resorba), doxorubicin, and their combination was studied on the model of metastasizing breast carcinoma in BALB/c mice. Doxorubicin monotherapy was accompanied by a significant increase in median survival up to 57 days (vs. 34 and 35 days in control groups); 27% animals survived for 90 days (duration of the study). Bioluminescence area of the primary tumor significantly decreased on days 21 and 28; the total number of visceral metastases also decreased according to magnetic-resonance imaging data. Resorba monotherapy produced no general toxic effect, the median survival increased to 64 days, and 90-day survival was 33%. Imaging techniques (magnetic-resonance imaging, microtomography, bioluminescent analysis) showed that Resorba delayed the development of the primary tumor (regression of luminescence area on days 21 and 28, regression of standardized bioluminescence intensity on day 28) and significantly reduced the number of visceral metastases in comparison with the control. Combination therapy was less effective than monotherapy with the same medications. Median survival was 55 days, 90-day survival was 13%, but magnetic-resonance imaging and bioluminescence analysis after combination therapy also showed delayed growth of the primary tumor and reduced number of visceral metastases. Microtomography revealed bone metastases in ~30% animals of the control group; in experimental groups, no bone metastases were found. The experiment with periosteal (distal epiphysis of the femur) injection of 4T1-Luc2 tumor cells demonstrated pronounced selective effectiveness of Resorba in relation to bone metastases. Monotherapy with Resorba can prevent the development of not only bone, but also visceral metastases of breast cancer. PMID:27590765

  6. Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy.

    PubMed

    Li, Zhitao; Sun, Xin; Guo, Shuyuan; Wang, Liping; Wang, Tengyu; Peng, Chenghai; Wang, Wei; Tian, Zhen; Zhao, Ruibo; Cao, Wenwu; Tian, Ye

    2015-10-01

    5-Aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) effectively induces the apoptosis of atherogenic macrophages, but whether it can stabilise atherosclerotic plaque in vivo is unclear. Here, we used an animal model to evaluate the effects of ALA-SDT on plaque stabilisation. Sixty rabbits were induced atherosclerotic plaques in the femoral artery with a combination of silastic tube placement with atherogenic diet, and randomly assigned into control (n = 12) and SDT (n = 48) groups. In the SDT group, after intravenous injected with ALA (60 mg/kg) animals underwent the treatment of ultrasound with intensities of 0.75, 1.00, 1.50 and 2.00 W/cm(²) (n = 12 for each intensity). Seven days after the treatment, the plaque disruption assay was performed to test plaque stability. We found that ALA-SDT with ultrasound intensity of 1.5 W/cm(²) showed the strongest efficacy to stabilise plaques. Under this condition, the frequency of plaque disruption decreased by 88% (p<0.01), positive area of macrophages reduced by 94% (p<0.001) and percentage content of lipids dropped by 60% (p < 0.001), while percentage content of collagens increased by 127% (p<0.001). We also found that the plaque stabilisation by ALA-SDT was associated with increased macrophage apoptosis and apoptotic cell clearance. Moreover, ALA-SDT decreased the contents and activities of matrix metalloproteinase-2,9 and increased the levels of tissue inhibitors of matrix metalloproteinase-1,2 in plaques. Our studies demonstrate that ALA-SDT promotes plaque stabilisation by inducing macrophage elimination and inhibiting matrix degradation. This method might be a promising regimen for atherosclerosis therapy. PMID:26179778

  7. Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

    SciTech Connect

    Barker, Christopher A.; Bishop, Andrew J.; Chang, Maria; Beal, Kathryn; Chan, Timothy A.

    2013-07-01

    Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.

  8. Photodynamic therapy of normal rat arteries after photosensitisation using disulphonated aluminium phthalocyanine and 5-aminolaevulinic acid.

    PubMed Central

    Grant, W. E.; Speight, P. M.; MacRobert, A. J.; Hopper, C.; Bown, S. G.

    1994-01-01

    Photodynamic therapy of cancer exposes adjacent arteries to the risk of injury and the possibility of haemorrhage and thrombosis. The nature of photodynamic injury to normal arteries has not been satisfactorily defined, and the ability of arteries to recover with time is unclear. To clarify these issues, we have investigated the effects of PDT on rat femoral arteries, using a second-generation photosensitiser, disulphonated aluminium phthalocyanine, and a new method of photosensitisation, using endogenous synthesis of protoporphyrin IX following systemic administration of 5-aminolaevulinic acid (ALA). Pharmacokinetic studies of sensitiser fluorescence were carried out to determine peak levels of sensitiser. Subsequently photodynamic therapy at times corresponding to maximal fluorescence was performed using two light doses, 100 and 250 J cm-2. The nature of injury sustained and recovery over a 6 month period was investigated. Three days following PDT, all vessels treated showed complete loss of endothelium, with death of all medial smooth muscle cells, leaving an acellular flaccid artery wall. No vascular occlusion, haemorrhage or thrombosis was found. A striking feature was the lack of inflammatory response in the vessel wall at any time studied. Re-endothelialisation occurred in all vessels by 2 weeks. The phthalocyanine group showed repopulation of the media with smooth muscle cells to be almost complete by 3 months. However, the ALA group failed to redevelop a muscular wall and remained dilated at 6 months. Luminal cross-sectional area of the ALA-treated group was significantly greater than both control and phthalocyanine groups at 6 months. All vessels remained patent. This study indicates that arteries exposed to PDT are not at risk of catastrophic haemorrhage or occlusion, a finding that is of significance for both the local treatment of tumours and the use of PDT as an intraoperative adjunct to surgery for the ablation of microscopic residual malignant

  9. Antisense Oligonucleotide-mediated Suppression of Muscle Glycogen Synthase 1 Synthesis as an Approach for Substrate Reduction Therapy of Pompe Disease.

    PubMed

    Clayton, Nicholas P; Nelson, Carol A; Weeden, Timothy; Taylor, Kristin M; Moreland, Rodney J; Scheule, Ronald K; Phillips, Lucy; Leger, Andrew J; Cheng, Seng H; Wentworth, Bruce M

    2014-01-01

    Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA; EC 3.2.1.20) and the resultant progressive lysosomal accumulation of glycogen in skeletal and cardiac muscles. Enzyme replacement therapy using recombinant human GAA (rhGAA) has proven beneficial in addressing several aspects of the disease such as cardiomyopathy and aberrant motor function. However, residual muscle weakness, hearing loss, and the risks of arrhythmias and osteopenia persist despite enzyme therapy. Here, we evaluated the relative merits of substrate reduction therapy (by inhibiting glycogen synthesis) as a potential adjuvant strategy. A phosphorodiamidate morpholino oligonucleotide (PMO) designed to invoke exon skipping and premature stop codon usage in the transcript for muscle specific glycogen synthase (Gys1) was identified and conjugated to a cell penetrating peptide (GS-PPMO) to facilitate PMO delivery to muscle. GS-PPMO systemic administration to Pompe mice led to a dose-dependent decrease in glycogen synthase transcripts in the quadriceps, and the diaphragm but not the liver. An mRNA response in the heart was seen only at the higher dose tested. Associated with these decreases in transcript levels were correspondingly lower tissue levels of muscle specific glycogen synthase and activity. Importantly, these reductions resulted in significant decreases in the aberrant accumulation of lysosomal glycogen in the quadriceps, diaphragm, and heart of Pompe mice. Treatment was without any overt toxicity, supporting the notion that substrate reduction by GS-PPMO-mediated inhibition of muscle specific glycogen synthase represents a viable therapeutic strategy for Pompe disease after further development. PMID:25350581

  10. Trans-Fatty Acids Aggravate Obesity, Insulin Resistance and Hepatic Steatosis in C57BL/6 Mice, Possibly by Suppressing the IRS1 Dependent Pathway.

    PubMed

    Zhao, Xiaona; Shen, Cheng; Zhu, Hong; Wang, Cong; Liu, Xiangwei; Sun, Xiaolei; Han, Shasha; Wang, Peng; Dong, Zhen; Ma, Xin; Hu, Kai; Sun, Aijun; Ge, Junbo

    2016-01-01

    Trans-fatty acid consumption has been reported as a risk factor for metabolic disorders and targeted organ damages. Nonetheless, little is known about the roles and mechanisms of trans-fatty acids in obesity, insulin resistance (IR) and hepatic steatosis. Adult C57BL/6 male mice were fed with four different diets for 20 weeks: normal diet (ND), high fat diet (HFD), low trans-fatty acids diet (LTD) and high trans-fatty acid diet (HTD). The diet-induced metabolic disorders were assessed by evaluating body weight, glucose tolerance test, hepatic steatosis and plasma lipid profiles post 20-week diet. Histological (H&E, Oil-Red-O) staining and western blot analysis were employed to assess liver steatosis and potential signaling pathways. After 20-weeks of diet, the body weights of the four groups were 29.61 ± 1.89 g (ND), 39.04 ± 4.27 g (HFD), 34.09 ± 2.62 g (LTD) and 43.78 ± 4.27 g (HTD) (p < 0.05), respectively. HFD intake significantly impaired glucose tolerance, which was impaired further in the mice consuming the HTD diet. The effect was further exacerbated by HTD diet. Moreover, the HTD group exhibited significantly more severe liver steatosis compared with HFD group possibly through regulating adipose triglyceride lipase. The group consuming the HTD also exhibited significantly reduced levels of IRS1, phosphor-PKC and phosphor-AKT. These results support our hypothesis that consumption of a diet high in trans-fatty acids induces higher rates of obesity, IR and hepatic steatosis in male C57BL/6 mice, possibly by suppressing the IRS1dependent pathway. PMID:27248994

  11. Allicin alleviates inflammation of trinitrobenzenesulfonic acid-induced rats and suppresses P38 and JNK pathways in Caco-2 cells.

    PubMed

    Li, Chen; Lun, Weijian; Zhao, Xinmei; Lei, Shan; Guo, Yandong; Ma, Jiayi; Zhi, Fachao

    2015-01-01

    Background. Allicin has anti-inflammatory, antioxidative and proapoptotic properties. Aims. To evaluate the effects and investigate the mechanism of allicin on trinitrobenzenesulfonic acid-induced colitis, specifically with mesalazine or sulfasalazine. Methods. 80 rats were divided equally into 8 groups: control; trinitrobenzenesulfonic acid; allicin prevention; allicin; mesalazine; sulfasalazine; allicin + sulfasalazine, and mesalazine + allicin. Systemic and colonic inflammation parameters were analysed. In addition, protein and culture medium of Caco-2 cells treated with various concentrations of IL-1β or allicin were collected for investigation of IL-8, NF-κB p65 P38, ERK, and JNK. One-way ANOVA and Kruskal-Wallis H test were used for parametric and nonparametric tests, respectively. Results. Allicin reduced the body weight loss of trinitrobenzenesulfonic acid-induced rats, histological score, serum TNF-α and IL-1β levels, and colon IL-1β mRNA level and induced serum IL-4 level, particularly in combination with mesalazine. In addition, 1 ng/mL IL-1β stimulated the P38, ERK, and JNK pathways, whereas pretreatment with allicin depressed this phenomenon, except for the ERK pathway. Conclusions. The inflammation induced by trinitrobenzenesulfonic acid is mitigated significantly by allicin treatment, particularly combined with mesalazine. Allicin inhibits the P38 and JNK pathways and the expression of NF-κB which explained the potential anti-inflammatory mechanisms of allicin. PMID:25729217

  12. Vaccenic acid suppresses intestinal inflammation by increasing anandamide and related N-acylethanolamines in the JCR:LA-cp rat.

    PubMed

    Jacome-Sosa, Miriam; Vacca, Claudia; Mangat, Rabban; Diane, Abdoulaye; Nelson, Randy C; Reaney, Martin J; Shen, Jianheng; Curtis, Jonathan M; Vine, Donna F; Field, Catherine J; Igarashi, Miki; Piomelli, Daniele; Banni, Sebastiano; Proctor, Spencer D

    2016-04-01

    Vaccenic acid (VA), the predominant ruminant-derivedtransfat in the food chain, ameliorates hyperlipidemia, yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (ECs) by altering the availability of their biosynthetic precursor, arachidonic acid (AA), in membrane phospholipids (PLs). JCR:LA-cprats were assigned to a control diet with or without VA (1% w/w),cis-9,trans-11 conjugated linoleic acid (CLA) (1% w/w) or VA+CLA (1% + 0.5% w/w) for 8 weeks. VA reduced the EC, 2-arachidonoylglycerol (2-AG), in the liver and visceral adipose tissue (VAT) relative to control diet (P< 0.001), but did not change AA in tissue PLs. There was no additive effect of combining VA+CLA on 2-AG relative to VA alone (P> 0.05). Interestingly, VA increased jejunal concentrations of anandamide and those of the noncannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to control diet (P< 0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase, as well as the mRNA expression of TNFα and interleukin 1β (P< 0.05). The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of ECs and other noncannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine. PMID:26891736

  13. Blueberry diet derived 3-(3-hydroxyphenyl) propionic acid (PPA) suppresses osteoblastic cell senescence to promote bone accretion in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A blueberry (BB) supplemented diet has been previously shown to significantly stimulate bone formation in rapidly growing male and female rodents. Phenolic acids (PAs) are metabolites derived from polyphenols found in fruits and vegetables as a result of the actions of gut bacteria, and the levels o...

  14. Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity

    PubMed Central

    Sodhi, Komal; Hilgefort, Jordan; Banks, George; Gilliam, Chelsea; Stevens, Sarah; Ansinelli, Hayden A.; Getty, Morghan; Abraham, Nader G.; Shapiro, Joseph I.

    2016-01-01

    Increased uric acid levels have been implicated in the pathogenesis of metabolic syndrome. To examine the mechanisms by which this occurs, we hypothesized that an increase in heme oxygenase 1, a potent antioxidant gene, will decrease uric acid levels and adipocyte dysfunction via suppression of ROS and xanthine oxidase (XO) levels. We examined the effect of uric acid on adipogenesis in human mesenchymal stem cells (MSCs) in the presence and absence of cobalt protoporphyrin (CoPP), an HO-1 inducer, and tin mesoporphyrin (SnMP), an HO activity inhibitor. Uric acid increased adipogenesis by increasing NADPH oxidase expression and elevation in the adipogenesis markers C/EBPα, PPARγ, and Mest, while decreasing small lipid droplets and Wnt10b levels. We treated MSCs with fructose, a fuel source that increases uric acid levels. Our results showed that fructose increased XO expression as compared to the control and concomitant treatment with CoPP significantly decreased XO expression and uric acid levels. These beneficial effects of CoPP were reversed by SnMP, supporting a role for HO activity in mediating these effects. These findings demonstrate that increased levels of HO-1 appear crucial in modulating the phenotype of adipocytes exposed to uric acid and in downregulating XO and NADPH oxidase levels. PMID:26681956

  15. Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity.

    PubMed

    Sodhi, Komal; Hilgefort, Jordan; Banks, George; Gilliam, Chelsea; Stevens, Sarah; Ansinelli, Hayden A; Getty, Morghan; Abraham, Nader G; Shapiro, Joseph I; Khitan, Zeid

    2016-01-01

    Increased uric acid levels have been implicated in the pathogenesis of metabolic syndrome. To examine the mechanisms by which this occurs, we hypothesized that an increase in heme oxygenase 1, a potent antioxidant gene, will decrease uric acid levels and adipocyte dysfunction via suppression of ROS and xanthine oxidase (XO) levels. We examined the effect of uric acid on adipogenesis in human mesenchymal stem cells (MSCs) in the presence and absence of cobalt protoporphyrin (CoPP), an HO-1 inducer, and tin mesoporphyrin (SnMP), an HO activity inhibitor. Uric acid increased adipogenesis by increasing NADPH oxidase expression and elevation in the adipogenesis markers C/EBPα, PPARγ, and Mest, while decreasing small lipid droplets and Wnt10b levels. We treated MSCs with fructose, a fuel source that increases uric acid levels. Our results showed that fructose increased XO expression as compared to the control and concomitant treatment with CoPP significantly decreased XO expression and uric acid levels. These beneficial effects of CoPP were reversed by SnMP, supporting a role for HO activity in mediating these effects. These findings demonstrate that increased levels of HO-1 appear crucial in modulating the phenotype of adipocytes exposed to uric acid and in downregulating XO and NADPH oxidase levels. PMID:26681956

  16. Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo

    PubMed Central

    Dračínská, Helena; Bárta, František; Levová, Kateřina; Hudecová, Alena; Moserová, Michaela; Schmeiser, Heinz H.; Kopka, Klaus; Frei, Eva; Arlt, Volker M.; Stiborová, Marie

    2016-01-01

    Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic NAD(P)H:quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the 32P-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts. PMID:26845733

  17. Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-κB- and MAPK-ERK1/2-mediated COX-2 expression

    PubMed Central

    Lin, Chun-Kuang; Tseng, Chin-Kai; Chen, Kai-Hsun; Wu, Shih-Hsiung; Liaw, Chih-Chuang; Lee, Jin-Ching

    2015-01-01

    Background and Purpose This study was designed to evaluate the effect of betulinic acid (BA), extracted from Avicennia marina, on the replication of hepatitis C virus (HCV) and to investigate the mechanism of this BA-mediated anti-HCV activity. Experimental Approach HCV replicon and infectious systems were used to evaluate the anti-HCV activity of BA. Exogenous COX-2 or knock-down of COX-2 expression was used to investigate the role of COX-2 in the anti-HCV activity of BA. The effects of BA on the phosphorylation of NF-κB and on kinases in the MAPK signalling pathway were determined. The anti-HCV activity of BA in combination with other HCV inhibitors was also determined to assess its use as an anti-HCV supplement. Key Results BA inhibited HCV replication in both Ava5 replicon cells and in a cell culture-derived infectious HCV particle system. Treatment with a combination of BA and IFN-α, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX-2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX-2. In particular, BA down-regulated HCV-induced COX-2 expression by reducing the phosphorylation of NF-κB and ERK1/2 of the MAPK signalling pathway. Conclusions and Implications BA inhibits HCV replication by suppressing the NF-κB- and ERK1/2-mediated COX-2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV-infected patients. PMID:26102077

  18. Fasciola hepatica fatty acid binding protein inhibits TLR4 activation and suppresses the inflammatory cytokines induced by LPS in vitro and in vivo

    PubMed Central

    Martin, Ivelisse; Cabán-Hernández, Kimberly; Figueroa-Santiago, Olgary; Espino, Ana M.

    2015-01-01

    Toll-like receptor 4 (TLR4), the innate immunity receptor for bacterial endotoxins, plays a pivotal role in the induction of inflammatory responses. There is a need to develop molecules that block either activation through TLR4 or the downstream signaling pathways to inhibit the storm of inflammation typically elicited by bacterial lipopolysaccharide (LPS), which is a major cause of the high mortality associated with bacterial sepsis. We report here that a single intraperitoneal injection of 15μg Fasciola hepatica fatty acid binding protein (Fh12) 1 hour before exposure to LPS suppressed significantly the expression of serum inflammatory cytokines in a model of septic shock using C57BL/6 mice. Because macrophages are good source of IL12p70 and TNFα, and critical in driving adaptive immunity, we investigated the effect of Fh12 on the function of mouse bone marrow derived macrophages (bmMΦs). Whereas Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL12, TNFα, IL6 and IL1β cytokines as well as iNOS2 in bmMΦs, and also impaired the phagocytic capacity of bmMΦs. Fh12 had a limited effect on the expression of inflammatory cytokines induced in response to other TLR-ligands. One mechanism used by Fh12 to exert its anti-inflammatory effect is binding to the CD14 co-receptor. Moreover, it suppresses phosphorylation of ERK, p38 and JNK. The potent anti-inflammatory properties of Fh12 demonstrated here open doors to further studies directed at exploring the potential of this molecule as a new class of drug against septic shock or other inflammatory diseases. PMID:25780044

  19. 4-Hydroxyphenylacetic Acid Attenuated Inflammation and Edema via Suppressing HIF-1α in Seawater Aspiration-Induced Lung Injury in Rats

    PubMed Central

    Liu, Zhongyang; Xi, Ronggang; Zhang, Zhiran; Li, Wangping; Liu, Yan; Jin, Faguang; Wang, Xiaobo

    2014-01-01

    4-Hydroxyphenylacetic acid (4-HPA) is an active component of Chinese herb Aster tataricus which had been widely used in China for the treatment of pulmonary diseases. The aim of this study is to investigate the effect of 4-HPA on seawater aspiration-induced lung injury. Pulmonary inflammation and edema were assessed by enzyme-linked immunosorbent assay (ELISA), bronchoalveolar lavage fluid (BALF) white cell count, Evans blue dye analysis, wet to dry weight ratios, and histology study. Hypoxia-inducible factor-1α (HIF-1α) siRNA and permeability assay were used to study the effect of 4-HPA on the production of inflammatory cytokines and monolayer permeability in vitro. The results showed that 4-HPA reduced seawater instillation-induced mortality in rats. In lung tissues, 4-HPA attenuated hypoxia, inflammation, vascular leak, and edema, and decreased HIF-1α protein level. In primary rat alveolar epithelial cells (AEC), 4-HPA decreased hypertonicity- and hypoxia-induced HIF-1α protein levels through inhibiting the activations of protein translational regulators and via promoting HIF-1α protein degradation. In addition, 4-HPA lowered inflammatory cytokines levels through suppressing hypertonicity- and hypoxia-induced HIF-1α in NR8383 macrophages. Moreover, 4-HPA decreased monolayer permeability through suppressing hypertonicity and hypoxia-induced HIF-1α, which was mediated by inhibiting vascular endothelial growth factor (VEGF) in rat lung microvascular endothelial cell line (RLMVEC). In conclusion, 4-HPA attenuated inflammation and edema through suppressing hypertonic and hypoxic induction of HIF-1α in seawater aspiration-induced lung injury in rats. PMID:25050781

  20. Antiretroviral Therapy (ART) Use, Human Immunodeficiency Virus (HIV)-1 RNA Suppression, and Medical Causes of Hospitalization Among HIV-Infected Intravenous Drug Users in the Late ART Era

    PubMed Central

    Vallecillo, Gabriel; Mojal, Sergio; Torrens, Marta; Muga, Roberto

    2014-01-01

    Background.  Antiretroviral therapy (ART) has reduced the rates and changed the causes of hospital admission. However, human immunodeficiency virus-positive intravenous drug users (HIV-IDU) continue to have increased hospitalizations and discharge diagnosis are less defined in the late ART era. Our aim was to examine ART use, HIV-1 RNA suppression, and hospital discharge diagnoses among HIV-IDU admitted to an urban hospital. Methods.  A retrospective analysis was made of HIV-IDU admitted for medical causes for the first time (2006–2010). Surgical, obstetric, or mental (except HIV-associated neurocognitive disorder) diagnoses were excluded. Clinical characteristics, number of admissions, and primary discharge diagnoses were determined for each patient. Results.  Three hundred and seventy-five admissions were recorded among 197 hospitalized HIV-IDU. Lifetime prevalence of ART use was 83.2% (164 of 197) and the rate of HIV-1 RNA <50 copies/mL was 38.1% (75 of 197). Primary discharge diagnosis groups were as follows: bacterial infections (59.2%), chronic end-organ damage (16.8%), complications derived from injected drug use (16.8%), malignancies (9.1%), and opportunistic infections (6.6%). Chronic end-organ damage was diagnosed more frequently in patients with HIV-1 RNA <50 copies/mL (36% vs 4.9%; P < .000), and complications derived from injected drug use (23.8% vs 5.3%; P < .0008) and acquired immune deficiency syndrome (AIDS) opportunistic infections (19.8% vs 1.3% P < .019) were usually diagnosed in patients with HIV-1 RNA detectable viral load. Conclusions.  Human immunodeficiency virus-positive intravenous drug users are admitted to hospitals mainly for non-AIDS-related illnesses; however, sustained HIV-1 RNA viral load suppression is poor and determines hospital discharge diagnoses. Providers need to be aware of the management of HIV-related comorbidities and reinforce strategies to improve ART retention in this population. PMID:25734084

  1. Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

    PubMed Central

    Wei, Datsen George; Chiang, Vicki; Fyne, Elizabeth; Balakrishnan, Mini; Barnes, Tiffany; Graupe, Michael; Hesselgesser, Joseph; Irrinki, Alivelu; Murry, Jeffrey P.; Stepan, George; Stray, Kirsten M.; Tsai, Angela; Yu, Helen; Spindler, Jonathan; Kearney, Mary; Spina, Celsa A.; McMahon, Deborah; Lalezari, Jacob; Sloan, Derek; Mellors, John; Geleziunas, Romas; Cihlar, Tomas

    2014-01-01

    Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART. PMID:24722454

  2. The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling

    PubMed Central

    Pan, Hao; Lin, Qiu-Ru; Huang, Mei-Yun; Cai, Ji-Ye; Ouyang, Dong-Yun; He, Xian-Hui

    2015-01-01

    Previously we reported that valproic acid (VPA) acts in synergy with GOS to enhance cell death in human DU145 cells. However, the underlying mechanism remains elusive. In this study, we observed that such synergistic cytotoxicity of GOS and VPA could be extended to human A375, HeLa, and PC-3 cancer cells. GOS and VPA co-treatment induced robust apoptosis as evidenced by caspase-8/-9/-3 activation, PARP cleavage, and nuclear fragmentation. GOS and VPA also markedly decreased cyclin A2 protein expression. Owing to the reduction of cyclin A2, Akt signaling was suppressed, leading to dephosphorylation of FOXO3a. Consequently, FOXO3a was activated and the expression of its target genes, including pro-apoptotic FasL and Bim, was upregulated. Supporting this, FOXO3a knockdown attenuated FasL and Bim upregulation and apoptosis induction in GOS+VPA-treated cells. Furthermore, blocking proteasome activity by MG132 prevented the downregulation of cyclin A2, dephosphorylation of Akt and FOXO3a, and induction of apoptosis in cells co-treated with GOS and VPA. In mouse model, GOS and VPA combination significantly inhibited the growth of A375 melanoma xenografts. Our findings indicate that GOS and VPA co-treatment induces apoptosis in human cancer cells by suppressing the cyclin-A2/Akt/FOXO3a pathway. PMID:26517515

  3. Ternatin, a cyclic peptide isolated from mushroom, and its derivative suppress hyperglycemia and hepatic fatty acid synthesis in spontaneously diabetic KK-A(y) mice.

    PubMed

    Kobayashi, Misato; Kawashima, Haruna; Takemori, Kumiko; Ito, Hiroyuki; Murai, Atsushi; Masuda, Shun; Yamada, Kaoru; Uemura, Daisuke; Horio, Fumihiko

    2012-10-19

    (-)-Ternatin is a highly methylated cyclic heptapeptide isolated from mushroom Coriolus versicolor. Ternatin has an inhibitory effect on fat accumulation in 3T3-L1 adipocytes. [D-Leu(7)]ternatin, a ternatin derivative, also inhibited fat accumulation in 3T3-L1 cells, although the effectiveness of [D-Leu(7)]ternatin was lower than that of ternatin. In this study, we investigated the effects of ternatin and [D-Leu(7)]ternatin on obesity and type 2 diabetes in KK-A(y) mice, an animal model for spontaneously developed type 2 diabetes. We continuously administered ternatin (8.5 or 17 nmol/day) or [D-Leu(7)]ternatin (68 nmol/day) to mice via a subcutaneous osmotic pump. Unexpectedly, neither ternatin nor [D-Leu(7)]ternatin affected body weight or adipose tissue weight in KK-A(y) mice. In contrast, it was demonstrated that both ternatin and [D-Leu(7)]ternatin suppress the development of hyperglycemia. In liver, the SREBP-1c mRNA level tended to be lower or significantly decreased in mice treated with ternatin or [D-Leu(7)]ternatin, respectively. Moreover, we found that ternatin directly lowered the SREBP-1c mRNA level in Hepa1-6 hepatocyte cells. This study showed that ternatin and [D-Leu(7)]ternatin each had a preventive effect on hyperglycemia and a suppressive effect on fatty acid synthesis in KK-A(y) mice. PMID:23000156

  4. Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages.

    PubMed

    Jonsson, Charlotte A; Carlsten, Hans

    2002-01-01

    Mycophenolic acid (MPA) inhibits reversibly inosine 5(')-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. Previously, mycophenolate mofetil (MMF), the pro-drug of MPA, was shown to exert beneficial effects on the systemic lupus erythematosus (SLE)-like disease in MRLlpr/lpr mice. In this study MPA's immunomodulating effects in vitro on the murine macrophage cell line IC-21 were investigated. The cells were exposed to MPA together with lipopolysaccharide and IFN-gamma. Cytokine, NO(2)(-), and lactate dehydrogenase levels in supernatants and cell lysates were analysed as well as the proliferation of IC-21 cells. MPA exposure reduced the total levels of all molecules investigated and suppressed the proliferation. All MPA-induced effects were reversed by the addition of guanosine to the cultures. Since macrophages play a role in lupus nephritis, our results indicate that modulation of macrophages may be involved in the ameliorating effects of MMF in SLE. PMID:12381354

  5. The G-protein-coupled bile acid receptor Gpbar1 (TGR5) suppresses gastric cancer cell proliferation and migration through antagonizing STAT3 signaling pathway

    PubMed Central

    Guo, Cong; Su, Jia; Li, Zhijun; Xiao, Rui; Wen, Jianxun; Li, Yanyan; Zhang, Meng; Zhang, Xueting; Yu, Donna; Huang, Wendong

    2015-01-01

    Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. Here we show that TGR5 is a suppressor of gastric cancer cell proliferation and migration through antagonizing STAT3 signaling pathway. We firstly show that TGR5 activation greatly inhibited proliferation and migration of human gastric cancer cells and strongly induced gastric cancer cell apoptosis. We then found that TGR5 activation antagonized STAT3 signaling pathway through suppressing the phosphorylation of STAT3 and its transcription activity induced by lipopolysaccharide (LPS) or interleukin-6. TGR5 overexpression with ligand treatment inhibited gene expression mediated by STAT3. It suggests that TGR5 antagonizes gastric cancer proliferation and migration at least in part by inhibiting STAT3 signaling. These findings identify TGR5 as a suppressor of gastric cancer cell proliferation and migration that may serve as an attractive therapeutic tool for human gastric cancer. PMID:26417930

  6. A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation.

    PubMed

    Ribeiro, Alison; Pontis, Silvia; Mengatto, Luisa; Armirotti, Andrea; Chiurchiù, Valerio; Capurro, Valeria; Fiasella, Annalisa; Nuzzi, Andrea; Romeo, Elisa; Moreno-Sanz, Guillermo; Maccarrone, Mauro; Reggiani, Angelo; Tarzia, Giorgio; Mor, Marco; Bertozzi, Fabio; Bandiera, Tiziano; Piomelli, Daniele

    2015-08-21

    Fatty acid ethanolamides such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are lipid-derived mediators that potently inhibit pain and inflammation by ligating type-α peroxisome proliferator-activated receptors (PPAR-α). These bioactive substances are preferentially degraded by the cysteine hydrolase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages. Here, we describe a new class of β-lactam derivatives that are potent, selective, and systemically active inhibitors of intracellular NAAA activity. The prototype of this class deactivates NAAA by covalently binding the enzyme's catalytic cysteine and exerts profound anti-inflammatory effects in both mouse models and human macrophages. This agent may be used to probe the functions of NAAA in health and disease and as a starting point to discover better anti-inflammatory drugs. PMID:25874594

  7. Retigeric Acid B Exhibits Antitumor Activity through Suppression of Nuclear Factor-κB Signaling in Prostate Cancer Cells in Vitro and in Vivo

    PubMed Central

    Liu, Yong-Qing; Hu, Xiao-Yan; Lu, Tao; Cheng, Yan-Na; Young, Charles Y. F.; Yuan, Hui-Qing; Lou, Hong-Xiang

    2012-01-01

    Previously, we reported that retigeric acid B (RB), a natural pentacyclic triterpenic acid isolated from lichen, inhibited cell growth and induced apoptosis in androgen-independent prostate cancer (PCa) cells. However, the mechanism of action of RB remains unclear. In this study, we found that using PC3 and DU145 cells as models, RB inhibited phosphorylation levels of IκBα and p65 subunit of NF-κB in a time- and dosage-dependent manner. Detailed study revealed that RB blocked the nuclear translocation of p65 and its DNA binding activity, which correlated with suppression of NF-κB-regulated proteins including Bcl-2, Bcl-xL, cyclin D1 and survivin. NF-κB reporter assay suggested that RB was able to inhibit both constitutive activated-NF-κB and LPS (lipopolysaccharide)-induced activation of NF-κB. Overexpression of RelA/p65 rescued RB-induced cell death, while knockdown of RelA/p65 significantly promoted RB-mediated inhibitory effect on cell proliferation, suggesting the crucial involvement of NF-κB pathway in this event. We further analyzed antitumor activity of RB in in vivo study. In C57BL/6 mice carrying RM-1 homografts, RB inhibited tumor growth and triggered apoptosis mainly through suppressing NF-κB activity in tumor tissues. Additionally, DNA microarray data revealed global changes in the gene expression associated with cell proliferation, apoptosis, invasion and metastasis in response to RB treatment. Therefore, our findings suggested that RB exerted its anti-tumor effect by targeting the NF-κB pathway in PCa cells, and this could be a general mechanism for the anti-tumor effect of RB in other types of cancers as well. PMID:22666431

  8. Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility.

    PubMed

    Murase, Remi; Sato, Hiroyasu; Yamamoto, Kei; Ushida, Ayako; Nishito, Yasumasa; Ikeda, Kazutaka; Kobayashi, Tetsuyuki; Yamamoto, Toshinori; Taketomi, Yoshitaka; Murakami, Makoto

    2016-03-25

    Within the secreted phospholipase A2(sPLA2) family, group X sPLA2(sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies usingPla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ω3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2(cPLA2α) protects from colitis by mobilizing ω6 arachidonic acid metabolites, including prostaglandin E2 Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizerin vivo, segregated mobilization of ω3 and ω6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization. PMID:26828067

  9. Development of a stable solution of 5-aminolaevulinic acid for intracutaneous injection in photodynamic therapy.

    PubMed

    de Blois, A W; Grouls, R J E; Ackerman, E W; Wijdeven, W J A

    2002-01-01

    Photodynamic therapy using 5-aminolaevulinic acid (ALA) as a photosensitiser is a new treatment modality for basal cell carcinomas. Until now ALA has been used topically as a cream. As this administration route leads sometimes to insufficient penetration in the skin, an intracutaneously injectable solution of ALA was developed. The influence of pH, concentration and temperature on the degradation of ALA in aqueous solution was investigated in order to optimise the formulation of the injection. In 0.1% ALA solutions with pH values between 4 and 8 a pH dependency of ALA degradation was shown, comprising fast decomposition at pH values higher than 7, whereas at a pH value of 6 or lower the solutions remained within the range of 90-110% of the initial concentration for at least 128 days. An increase of degradation rate with increasing concentrations became evident which is consistent with the supposed second-order degradation kinetics. After accelerated stability research at 63 degrees C and 85 degrees C a shelf life of 281 days for a 0.1% ALA solution pH 5 was calculated from an Arrhenius plot. A 2% ALA solution was proven to be isotonic. From our results a 0.1-2% ALA solution with pH 5 and an appropriate amount of sodium chloride to obtain isotonicity is recommended as an injectable solution. PMID:12181635

  10. Role of 5-aminolevulinic acid-conjugated gold nanoparticles for photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Zhang, Zhenxi; Wang, Sijia; Xu, Hao; Wang, Bo; Yao, Cuiping

    2015-05-01

    There are three possible mechanisms for 5-aminolevulinic acid (5-ALA) conjugated gold nanoparticles (GNPs) through electrostatic bonding for photodynamic therapy (PDT) of cancer: GNPs delivery function, singlet oxygen generation (SOG) by GNPs irradiated by light, and surface resonance enhancement (SRE) of SOG. Figuring out the exact mechanism is important for further clinical treatment. 5-ALA-GNPs and human chronic myeloid leukemia K562 cells were used to study delivery function and SOG by GNPs. The SRE of SOG enabled by GNPs was explored by protoporphyrin IX (PpIX)-GNPs conjugate through electrostatic bonding. Cell experiments show that the GNPs can improve the efficiency of PDT, which is due to the vehicle effect of GNPs. PpIX-GNPs conjugate experiments demonstrated that SOG can be improved about 2.5 times over PpIX alone. The experiments and theoretical results show that the local field enhancement (LFE) via localized surface plasmon resonance (LSPR) of GNPs is the major role; the LFE was dependent on the irradiation wavelength and the GNP's size. The LFE increased with an increase of the GNP size (2R ≤50 nm). However, the LSPR function of the GNPs was not found in cell experiments. Our study shows that in 5-ALA-conjugated GNPs PDT, the delivery function of GNPs is the major role.

  11. Enhanced cellular uptake of protoporphyrine IX/linolenic acid-conjugated spherical nanohybrids for photodynamic therapy.

    PubMed

    Lee, Hye-In; Kim, Young-Jin

    2016-06-01

    Protoporphyrin IX (PpIX) has wide applications in photodynamic diagnosis and photodynamic therapy (PDT) in many human diseases. However, poor water solubility and cancer cell localization limit its direct application for PDT. We improved the water-solubility and cellular internalization of PpIX to enhance PDT efficacy by developing biocompatible PpIX/linolenic acid-conjugated polyhedral oligomeric silsesquioxane (PPLA) nanohybrids. The resulting PPLA nanohybrids exhibited a quasi-spherical shape with a size of <200nm. (1)H NMR analysis confirmed the synthesis of PPLA. The singlet oxygen formation of PPLA nanohybrids on laser irradiation was detected by photoluminescence emission. Fluorescence-activated cell sorting (FACS) analysis displayed higher cellular internalization of PPLA compared with free PpIX. In addition, PPLA nanohybrids exhibited significantly reduced dark-toxicity and a high phototoxicity mostly because of apoptotic cell death against human gastric cancer cells. These results imply that the PPLA nanohybrid system may be applicable in PDT. PMID:26954084

  12. Prostate Hypofractionated Radiation Therapy: Injection of Hyaluronic Acid to Better Preserve The Rectal Wall

    SciTech Connect

    Chapet, Olivier; Udrescu, Corina; Devonec, Marian; Tanguy, Ronan; Sotton, Marie-Pierre; Enachescu, Ciprian; Colombel, Marc; Azria, David; Jalade, Patrice; Ruffion, Alain

    2013-05-01

    Purpose: The aim of this study was to evaluate the contribution of an injection of hyaluronic acid (HA) between the rectum and the prostate for reducing the dose to the rectal wall in a hypofractionated irradiation for prostate cancer. Methods and Materials: In a phase 2 study, 10 cc of HA was injected between the rectum and prostate. For 16 patients, the same intensity modulated radiation therapy plan (62 Gy in 20 fractions) was optimized on 2 computed tomography scans: CT1 (before injection) and CT2 (after injection). Rectal parameters were compared: dose to 2.5 cc (D2.5), 5 cc (D5), 10 cc (D10), 15 cc (D15), and 20 cc (D20) of rectal wall and volume of rectum covered by the 90% isodose line (V90), 80% (V80), 70% (V70), 60% (V60), and 50% (V50). Results: The mean V90, V80, V70, V60, and V50 values were reduced by 73.8% (P<.0001), 55.7% (P=.0003), 43.0% (P=.007), 34% (P=.002), and 25% (P=.036), respectively. The average values of D2.5, D5, D10, D15, and D20 were reduced by 8.5 Gy (P<.0001), 12.3 Gy (P<.0001), 8.4 Gy (P=.005), 3.7 Gy (P=.026), and 1.2 Gy (P=.25), respectively. Conclusions: The injection of HA significantly limited radiation doses to the rectal wall.

  13. Sonodynamic therapy using 5-aminolevulinic acid enhances the efficacy of bleomycin.

    PubMed

    Osaki, Tomohiro; Ono, Misato; Uto, Yoshihiro; Ishizuka, Masahiro; Tanaka, Tohru; Yamanaka, Nobuyasu; Kurahashi, Tsukasa; Azuma, Kazuo; Murahata, Yusuke; Tsuka, Takeshi; Ito, Norihiko; Imagawa, Tomohiro; Okamoto, Yoshiharu

    2016-04-01

    Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound and a sonosensitizer agent. We examined whether 5-aminolevulinic acid (5-ALA)-based SDT at 1 or 3 MHz could enhance the cytotoxicity of bleomycin (BLM) toward mouse mammary tumor cells both in vitro and in vivo. At 1 MHz, cell viability in the 5-ALA-based SDT group at 1, 2, and 3 W/cm(2) was 34.30%, 50.90%, and 60.16%, respectively. Cell viability in the 5-ALA-based SDT+BLM group at 1, 2, and 3 W/cm(2) was 0.09%, 0.32%, and 0.17%, respectively. In contrast, at 3 MHz, 5-ALA-based SDT+BLM did not show pronounced cytotoxicity. In the in vivo study, 5-ALA-based SDT+BLM was significantly more cytotoxic than 5-ALA-based SDT at 1 MHz and 3 MHz. These findings suggest that the mechanism of tumor shrinkage induced by 5-ALA-based SDT+BLM might involve not only direct cell killing, but also vascular shutdown. Thus, we show here that 5-ALA-based SDT enhances the efficacy of BLM both in vitro and in vivo. PMID:26799128

  14. Injectable hyaluronic-acid-doxycycline hydrogel therapy in experimental rabbit osteoarthritis

    PubMed Central

    2013-01-01

    Background Osteoarthritis (OA) is a common joint disease that causes disabilities in elderly adults. However, few long-lasting pharmacotherapeutic agents with low side effects have been developed to treat OA. We evaluated the therapeutic effects of intra-articular injections of hydrogels containing hyaluronic acid (HA) and doxycycline (DOX) in a rabbit OA model. Results Thirteen week old New Zealand White rabbits undergone a partial meniscectomy and unilateral fibular ligament transection were administered with either normal saline (NT), HA, DOX or HA-DOX hydrogels on day 0, 3, 6, 9 and 12; animals were also examined the pain assessment in every three days. The joint samples were taken at day 14 post-surgery for further histopathological evaluation. The degree of pain was significantly attenuated after day 7 post-treatment with both HA and HA-DOX hydrogels. In macroscopic appearance, HA-DOX hydrogel group showed a smoother cartilage surface, no or minimal signs of ulceration, smaller osteophytes, and less fissure formation in compare to HA or DOX treatment alone. In the areas with slight OA changes, HA-DOX hydrogel group exhibited normal distribution of chondrocytes, indicating the existence of cartilage regeneration. In addition, HA-DOX hydrogels also ameliorated the progression of OA by protecting the injury of articular cartilage layer and restoring the elastoviscosity. Conclusion Overall, from both macroscopic and microscopic data of this study indicate the injectable HA-DOX hydrogels presented as a long-lasting pharmacotherapeutic agent to apply for OA therapy. PMID:23574696

  15. Efficacy of intravenous delta-aminolaevulinic acid photodynamic therapy on rabbit papillomas.

    PubMed Central

    Lofgren, L. A.; Ronn, A. M.; Nouri, M.; Lee, C. J.; Yoo, D.; Steinberg, B. M.

    1995-01-01

    Endogenously induced protoporphyrin IX (PPIX), a metabolite of delta-aminolaevulinic acid (ALA), has been evaluated as a photosensitising agent for destruction of papillomas in cottontail rabbit papillomavirus-infected Dutch belted and New Zealand rabbits. Three factors were evaluated: (1) relative retention ratio of drug in normal tissue, papilloma and plasma over time; (2) tissue tolerance to treatment factors; and (3) efficacy of treatment protocol. Three drug doses of ALA were examined: 50, 100 and 200 mg kg-1. Actual PPIX concentrations in tissue and plasma were determined spectrophotofluorometrically. The optimal treatment time occurred 3-6 h post ALA injection. The highest PPIX concentration ratio between papilloma and normal skin was 6:1. Different light doses were investigated, using an injection to exposure interval of 3 h and an irradiance of 100 mW cm-2 at a wavelength of 630 nm. Efficacy without risk of significant damage to normal skin was obtained using 100-200 mg kg-1 ALA and 40-60 J cm-2. A long-term (3 months) cure rate of 82% was obtained with a single treatment, provided that papilloma depth did not exceed 8 mm, volume was not more than 1000 mm3 and the plasma concentration of PPIX immediately before exposure was above 500 micrograms ml-1. The short time between injection and treatment and high efficacy, together with PPIX disappearance from plasma and tissue within 24 h, make injected ALA a highly attractive drug for photodynamic therapy. PMID:7547231

  16. Chlorin p6-Based Water-Soluble Amino Acid Derivatives as Potent Photosensitizers for Photodynamic Therapy.

    PubMed

    Meng, Zhi; Yu, Bin; Han, Guiyan; Liu, Minghui; Shan, Bin; Dong, Guoqiang; Miao, Zhenyuan; Jia, Ningyang; Tan, Zou; Li, Buhong; Zhang, Wannian; Zhu, Haiying; Sheng, Chunquan; Yao, Jianzhong

    2016-05-26

    The development of novel photosensitizer with high phototoxicity, low dark toxicity, and good water solubility is a challenging task for photodynamic therapy (PDT). A series of chlorin p6-based water-soluble amino acid conjugates were synthesized and investigated for antitumor activity. Among them, aspartylchlorin p6 dimethylester (7b) showed highest phototoxicity against melanoma cells with weakest dark toxicity, which was more phototoxic than verteporfin while with less dark toxicity. It also exhibited better in vivo PDT antitumor efficacy on mice bearing B16-F10 tumor than verteporfin. The biological assays revealed that 7b was localized in multiple subcellular organelles and could cause both cell necrosis and apoptosis after PDT in a dose-dependent manner, resulting in more effective cell destruction. As a result, 7b represents a promising photosensitizer for PDT applications because of its strong absorption in the phototherapeutic window, relatively high singlet oxygen quantum yield, highest dark toxicity/phototoxicity ratio, good water solubility, and excellent in vivo PDT antitumor efficacy. PMID:27136389

  17. 5-aminolaevulinic acid for fluorescence diagnosis and photodynamic therapy of bronchial cancer: a case report

    NASA Astrophysics Data System (ADS)

    Gamarra, Fernando; Baumgartner, Reinhold; Stepp, Herbert G.; Rick, Kai; Leberig, A.; Huber, Rudolf M.

    1995-03-01

    Five-aminolaevulinic acid (ALA) was applied orally and by aerosol inhalation to one patient in order to check the feasibility of photodynamic therapy (PDT) and photodynamic fluorescence diagnosis (PDD) of lung cancer. For PDD, ALA was given by inhalation using a conventional jet nebulizer. Protoporphyrin IX (PP IX)-fluorescence in the bronchial mucosa and the tumor was assessed visually and by spectroscopy using an optical multichannel analyzer. At a second session ALA was given orally and PDD as well as PDT were performed. The therapeutic effect on the tumor was controlled by bronchoscopy 5 and 12 weeks after PDT. Inhalative and oral application of ALA were both well tolerated. No adverse effects were observed. PP IX- fluorescence could be easily detected 3 h after ALA administered by inhalation or 5 h after ALA orally. Fluorescence ratio between tumor and normal tissues was better after the oral administration of ALA. Five and twelve weeks after PDT, marked reduction of tumor volume and recanalization of the left upper lobe were found.

  18. 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. PMID:17045253

  19. Photobleaching-based method to individualize irradiation time during interstitial 5-aminolevulinic acid photodynamic therapy.

    PubMed

    Hennig, Georg; Stepp, Herbert; Johansson, Ann

    2011-09-01

    Interstitial photodynamic therapy (iPDT) is being investigated for the treatment of high-grade human brain malignancies. In recent clinical studies, fluorescence monitoring during iPDT of glioblastoma multiforme has revealed patient-specific accumulation of photosensitizer (aminolevulinic acid (ALA) induced protoporphyrin IX, PpIX) and its photobleaching kinetics. As photosensitizer degradation, also referred to as photobleaching, and tissue damage are caused by the same underlying processes, the photobleaching kinetics might provide a tool for real-time treatment supervision. Here, we show with computer simulations that varying optical properties have a strong influence on the irradiation time required to fully bleach the photosensitizer. We propose a method to potentially determine the time point during iPDT, when the photosensitizer within the target volume has been largely photobleached. Simulations show that it is possible to determine this time point by continuously monitoring the ratio of the fluorescence intensities at two time points during irradiation. We show that this method works for a large range of optical properties, different photobleaching rates and varying inter-fibre distances. In conclusion, the relative fluorescence method offers the potential to individualize irradiation times to consume the photosensitizer within the target tissue during iPDT. PMID:21864802

  20. Effect of combined therapy of diabinese and nicotinic acid on liver enzymes in rabbits with dithizone-induced diabetes

    PubMed Central

    Monago, Comfort C; Onwuka, Frank; Osaro, Erhabor

    2010-01-01

    The effects of diabinese, a known antidiabetic drug, and the combined effects of diabinese and nicotinic acid, a vitamin and antilipidemic drug, were studied in rabbits with dithizone-induced diabetes. Side effects of diabinese include hypoglycemia and liver toxicity. Dithizone was used to induce partial experimental diabetes and to increase blood glucose significantly (P < 0.05) by 31.3%, 23.5%, 19.5, 24.7%, and 23.9% in groups A (single therapy of diabinese 10 mg/kg body weight), B (10 mg of diabinese and nicotinic acid 150 mg/kg), C (10 mg diabinese and nicotinic acid 200 mg/kg), D (10 mg diabinese and nicotinic acid 250 mg/kg) and E control (distilled water 5 mL), respectively. Dithizone administration also increased bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels by 28.9%–35.6%, 41.2%–54.8%, 40.1%–46.1%, and 60.9%–68.4%, respectively. Diabinese monotherapy reduced bilirubin levels, while combined therapy reduced glucose, ALP, AST, and ALT levels more than single therapy. Reduction from the hyperglycemic level 48 hours after drug administration was 20.0%, 24.6%, 41.0%, and 42.0% for groups A, B, C, and D, respectively, and was concentration-dependent. Also, combined therapy produced a significant (P < 0.05) decrease in AST and ALT levels, especially at 72 hours after drug administration, but did not affect ALP levels. No significant changes in glucose, bilirubin, ALP, AST, and ALT levels were observed in Group E (control). This study shows that liver toxicity and the hypoglycemic side effects of diabinese could be managed by the concomitant administration of nicotinic acid.

  1. Methane Suppression: The Impacts of Fe(III) and Humic Acids on Net Methane Flux from Arctic Tundra Wetlands in Alaska and Finland (Invited)

    NASA Astrophysics Data System (ADS)

    Lipson, D.; Miller, K.; Lai, C.

    2013-12-01

    Arctic soils contain large reservoirs of carbon (C) that are vulnerable to loss from climatic warming. However the potential global impacts of this C depend on whether it is lost primarily in the form of methane (CH4) or carbon dioxide (CO2), two gases with very different greenhouse warming potentials. In anaerobic environments, the relative production of CH4 vs. CO2 may be controlled by the presence of alternative terminal electron acceptors, which allow more thermodynamically favorable anaerobic respiratory pathways to dominate over methanogenesis. This work investigated how the addition of terminal electron acceptors, ferric iron (Fe(III)) and humic acids, affected net CH4 fluxes from high-latitude wetland ecosystems. We conducted two manipulative field experiments in Barrow, Alaska (71° N) and Finnish Lapland (69° N). The ecosystem in Barrow was known from previous studies to be rich in Fe(III) and to harbor a microbial community that is dominated by Fe(III)- and humic acid-reducing microorganisms. The role of these alternative electron acceptors had not previously been studied at the Finnish site. CH4 and CO2 fluxes were measured using a portable trace gas analyzer from experimental plots, before and after amendments with Fe(III) (in the chelated form, ferric nitrilotriacetic acid), humic acids, or water as a control. Both in the ecosystem with permafrost and naturally high levels of soil Fe (Barrow, AK) and in the ecosystem with no permafrost and naturally low levels of soil Fe (Petsikko, Finland), the addition of the alternative electron acceptors Fe(III) and humic acids significantly reduced net CH4 flux. CO2 fluxes were not significantly altered by the treatments. The reduction in CH4 flux persisted for at least several weeks post-treatment. There was no significant difference between the reduction caused by humic acids versus that from Fe(III). These results show that the suppression of CH4 flux by Fe(III) and humic acids is a widespread phenomenon that

  2. Interleukin-4 and CpG oligonucleotide therapy suppresses the outgrowth of tumors by activating tumor-specific Th1-type immune responses.

    PubMed

    Kajiwara, Atsushi; Doi, Hiroyoshi; Eguchi, Junichi; Ishii, Shigeaki; Hiraide-Sasagawa, Ayako; Sakaki, Masashi; Omori, Risa; Hiroishi, Kazumasa; Imawari, Michio

    2012-06-01

    Because IL-4 and CpG oligodeoxynucleotides (CpG-ODNs) are immune stimulants, we evaluated the antitumor effects of IL-4 gene therapy and CpG-ODN treatment in a poorly immunogenic murine cancer model. We used a murine colorectal cancer MC38 cell line overexpressing the IL-4 gene (MC38-IL4). Incubation with MC38-IL4 and CpG-ODN enhanced bone marrow-derived dendritic cell (DC) maturation in vitro. In addition, interferon (IFN)-γ production was significantly increased in naïve splenocytes after they were coincubated with MC38-IL4 and CpG-ODN. When mice bearing MC38 wild-type tumors were inoculated subcutaneously with MC38-IL4 cells and CpG-ODN, the outgrowth of established parental tumors was significantly suppressed compared to those in the MC38-IL4-treated group (IL-4 vs. IL-4 + CpG-ODN, p=0.015). A marked infiltration of CD8+ cells in the established parental tumors of mice treated with MC38-IL4 and CpG-ODN was confirmed by immunohistochemical analyses (MC38-IL4, 2.8 ± 1.9 cells/field vs. MC38-IL4 + CpG-ODN, 20.7 ± 15.3 cells/field, p=0.027). Significant tumor-specific cytolysis was detected when splenocytes of MC38-IL4 + CpG-ODN-treated mice were stimulated by γ-irradiated MC38-IL4 cells and CpG-ODN twice weekly in vitro and used as effector cells in a chromium-release assay (32.2 ± 3.5% for MC38 cells vs. 3.2 ± 1.1% for YAC-1 cells; at an effector to target ratio of 40). These results suggest that IL-4 and CpG-ODN treatment promotes potent Th1-type antitumor immune responses. Therefore, the combination of IL-4 gene therapy and CpG-ODN treatment for cancer should be evaluated in clinical trials. PMID:22426807

  3. Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats

    SciTech Connect

    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 (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 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.

  4. Radioiodine Treatment and Thyroid Hormone Suppression Therapy for Differentiated Thyroid Carcinoma: Adverse Effects Support the Trend toward Less Aggressive Treatment for Low-Risk Patients

    PubMed Central

    Klein Hesselink, E.N.; Links, T.P.

    2015-01-01

    Over the past decades, the incidence of differentiated thyroid carcinoma (DTC) has steadily increased, with especially a growing number of low-risk patients. Whereas DTC used to be treated rather aggressively, it is now acknowledged that aggressive treatment does not affect outcome for low-risk patients and that it can induce adverse effects. In this review an overview of the most clinically relevant adverse effects of radioiodine treatment and thyroid hormone suppression therapy (THST) is presented, and the trend toward less aggressive treatment for low-risk patients is outlined. Salivary gland dysfunction occurs in roughly 30% of patients, and is probably due to the concentration of radioiodine in the salivary glands by the sodium/iodide symporter. Beta radiation from radioiodine can result in sialoadenitis and eventually fibrosis and loss of salivary function. Furthermore, patients can experience bone marrow dysfunction following radioiodine treatment. Although this is in general subclinical and transient, patients that receive very high cumulative radioiodine doses may be at risk for more severe bone marrow dysfunction. THST can induce adverse cardiovascular effects in patients with DTC, such as diastolic and systolic dysfunction, and also adverse vascular and prothrombotic effects have been described. Finally, the effects of THST on bone formation and resorption are outlined; especially postmenopausal women with DTC on THST seem to be at risk of bone loss. In the past years, advances have been made in preventing low-risk patients from being overtreated. Improved biomarkers are still needed to further optimize risk stratification and personalize medicine. PMID:26279993

  5. Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells

    PubMed Central

    Kim, Seong-Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe-Youn; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eunji; Baek, Nam-In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong-Tai

    2015-01-01

    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. PMID:26412148

  6. Sea Cucumber Saponin Echinoside A (EA) Stimulates Hepatic Fatty Acid β-Oxidation and Suppresses Fatty Acid Biosynthesis Coupling in a Diurnal Pattern.

    PubMed

    Wen, Min; Fu, Xueyuan; Han, Xiuqing; Hu, Xiaoqian; Dong, Ping; Xu, Jie; Xue, Yong; Wang, Jingfeng; Xue, Changhu; Wang, Yuming

    2016-01-01

    Circadian rhythms control aspects of physiological events, including lipid metabolism, showing rhythmic fluctuation over 24 h. Therefore, it is not sufficient to evaluate thoroughly how dietary components regulate lipid metabolism with a single time-point assay. In the present study, a time-course study was performed to analyze the effect of sea cucumber saponin echinoside A (EA) on lipid metabolism over 24 h. Results showed that EA lowered the levels of TC and TG in both serum and liver at most time-points during the 24 h. Activities of hepatic lipogenic enzymes and lipolytic enzymes were inhibited and elevated respectively by EA to varied degrees at different time-points. Meanwhile, parallel variation trends of gene expression involved in fatty acid synthesis and β-oxidation were observed accordingly. The interaction between EA and lipid metabolism showed a time-dependent effect. Overall, EA impaired fatty acid synthesis and enhanced mitochondrial fatty acid β-oxidation in ad libitum feeding over 24 h. PMID:27465723

  7. Continuous Renal Replacement Therapy for the Management of Acid-Base and Electrolyte Imbalances in Acute Kidney Injury.

    PubMed

    Yessayan, Lenar; Yee, Jerry; Frinak, Stan; Szamosfalvi, Balazs

    2016-05-01

    Continuous renal replacement therapy (CRRT) is used to manage electrolyte and acid-base imbalances in critically ill patients with acute kidney injury. Although a standard solution and prescription is acceptable in most clinical circumstances, specific disorders may require a tailored approach such as adjusting fluid composition, regulating CRRT dose, and using separate intravenous infusions to mitigate and correct these disturbances. Errors in fluid prescription, compounding, or delivery can be rapidly fatal. This article provides an overview of the principles of acid-base and electrolyte management using CRRT. PMID:27113697

  8. Cichoric Acid Reverses Insulin Resistance and Suppresses Inflammatory Responses in the Glucosamine-Induced HepG2 Cells.

    PubMed

    Zhu, Di; Wang, Yutang; Du, Qingwei; Liu, Zhigang; Liu, Xuebo

    2015-12-30

    Cichoric acid, a caffeic acid derivative found in Echinacea purpurea, basil, and chicory, has been reported to have bioactive effects, such as anti-inflammatory, antioxidant, and preventing insulin resistance. In this study, to explore the effects of CA on regulating insulin resistance and chronic inflammatory responses, the insulin resistance model was constructed by glucosamine in HepG2 cells. CA stimulated glucosamine-mediated glucose uptake by stimulating translocation of the glucose transporter 2. Moreover, the production of reactive oxygen, the expression of COX-2 and iNOS, and the mRNA levels of TNF-α and IL-6 were attenuated. Furthermore, CA was verified to promote glucosamine-mediated glucose uptake and inhibited inflammation through PI3K/Akt, NF-κB, and MAPK signaling pathways in HepG2 cells. These results implied that CA could increase glucose uptake, improve insulin resistance, and attenuate glucosamine-induced inflammation, suggesting that CA is a potential natural nutraceutical with antidiabetic properties and anti-inflammatory effects. PMID:26592089

  9. On-line cation exchange for suppression of adduct formation in negative-ion electrospray mass spectrometry of nucleic acids.

    PubMed

    Huber, C G; Buchmeiser, M R

    1998-12-15

    One major difficulty in the analysis of nucleic acids by electrospray mass spectrometry is represented by the affinity of the polyanionic sugar-phosphate backbone for nonvolatile cations, especially ubiquitous sodium and potassium ions. A simple on-line sample preparation system comprising a microflow pumping system and 45 x 0.8-mm-i.d. microcolumns packed with weak or strong cation-exchange resins is described for the efficient removal of cations from nucleic acid samples. Samples were analyzed by flow injection analysis at a 3-5 microL/min flow of 10 mM triethylamine in 50% water-50% acetonitrile. After on-line desalting, mass spectra of oligonucleotides revealed no significant sodium adduct peaks. Moreover, signal-to-noise ratios were greatly enhanced compared to direct injection of the samples. Electrospray mass spectrometry with on-line sample preparation allowed accurate molecular mass determinations of picomole amounts of crude oligonucleotide preparations ranging in size from 8 to 80 nucleotides within a few minutes. The good linearity of the calibration plot (R2 = 0.9988) over at least 2 orders of magnitude and a relative standard deviation in peak areas of less than 9% permitted the sensitive quantitative measurement of oligonucleotides in a concentration range of 0.2-20 microM with selected-ion monitoring. Finally, the on-line sample preparation system was evaluated for the mass spectrometric analysis of complex oligonucleotide mixtures. PMID:9868919

  10. Rupestonic acid derivative YZH-106 suppresses influenza virus replication by activation of heme oxygenase-1-mediated interferon response.

    PubMed

    Ma, Lin-Lin; Wang, Hui-Qiang; Wu, Ping; Hu, Jin; Yin, Jin-Qiu; Wu, Shuo; Ge, Miao; Sun, Wen-Fang; Zhao, Jiang-Yu; Aisa, Haji Akber; Li, Yu-Huan; Jiang, Jian-Dong

    2016-07-01

    Given the limitation of available antiviral drugs and vaccines, there remains to be a pressing need for novel anti-influenza drugs. Rupestonic acid derivatives were reported to have an anti-influenza virus activity, but their mechanism remains to be elucidated. Herein, we aim to evaluate the antiviral activity of YZH-106, a rupestonic acid derivative, against a broad-spectrum of influenza viruses and to dissect its antiviral mechanisms. Our results demonstrated that YZH-106 exhibited a broad-spectrum antiviral activity against influenza viruses, including drug-resistant strains in vitro. Furthermore, YZH-106 provided partial protection of the mice to Influenza A virus (IAV) infection, as judged by decreased viral load in lungs, improved lung pathology, reduced body weight loss and partial survival benefits. Mechanistically, YZH-106 induced p38 MAPK and ERK1/2 phosphorylation, which led to the activation of erythroid 2-related factor 2 (Nrf2) that up-regulated heme oxygenase-1 (HO-1) expression in addition to other genes. HO-1 inhibited IAV replication by activation of type I IFN expression and subsequent induction of IFN-stimulated genes (ISGs), possibly in a HO-1 enzymatic activity-independent manner. These results suggest that YZH-106 inhibits IAV by up-regulating HO-1-mediated IFN response. HO-1 is thus a promising host target for antiviral therapeutics against influenza and other viral infectious diseases. PMID:27107768

  11. Oxidized eicosapentaenoic acids more potently reduce LXRα-induced cellular triacylglycerol via suppression of SREBP-1c, PGC-1β and GPA than its intact form

    PubMed Central

    2013-01-01

    Dietary polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), improve lipid metabolism and contribute to the prevention of vascular diseases such as atherosclerosis. However, EPA in the diet is easily oxidized at room temperature and several types of oxidized EPA (OEPA) derivatives are generated. To compare the efficiencies of OEPAs on lipid metabolism with EPA, human hepatocellular liver carcinoma cell line (HepG2) was treated with EPA or OEPAs and their effects on lipid metabolism related genes were studied. OEPAs more potently suppressed the expression of sterol-responsive element-binding protein (SREBP)-1c, a major transcription factor that activates the expression of lipogenic genes, and its downstream target genes than did EPA under conditions of lipid synthesis enhanced by T0901317, a synthetic liver X receptor (LXR) agonist. Furthermore, PGC-1β, a coactivator of both LXRα and SREBP-1, was markedly down-regulated by OEPAs compared with EPA. The treatment of OEPAs also significantly down-regulated the expression of glycerol-3-phosphate acyltransferase (GPA), the initiating enzyme in triacylglycerol (TG) synthesis, more than EPA. Therefore, the advantageous effects of OEPAs on cardiovascular diseases might be due to their SREBP-1c, PGC-1β and GPA mediated ameliorating effects. PMID:23680128

  12. Enhanced porphyrin accumulation using dendritic derivatives of 5-aminolaevulinic acid for photodynamic therapy: an in vitro study.

    PubMed

    Battah, Sinan; O'Neill, Sophie; Edwards, Christine; Balaratnam, Sherina; Dobbin, Paul; MacRobert, Alexander J

    2006-01-01

    Intracellular porphyrin generation following administration of 5-aminolaevulinic acid has been widely used in photodynamic therapy for a range of malignant and certain non-malignant lesions. However, cellular uptake of 5-aminolaevulinic acid is limited by its hydrophilic nature and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers are a promising new approach to drug delivery. The aim of this study was to investigate the efficacy of dendrimers conjugated with 5-aminolaevulinic acid for porphyrin production in the transformed PAM 212 keratinocyte cell line and skin explants. Each dendritic derivative incorporated three 5-aminolaevulinic acid residues which were conjugated as esters via methyl or propyl linkers to a central tertiary carbon whose remaining terminal bore an amino, aminobenzyloxycarbonyl or nitro group. In the cell line, all compounds were more efficient at low concentrations compared to equimolar 5-aminolaevulinic acid for porphyrin production, with the most efficient incorporating the longer propyl linker. This compound was also the most lipophilic according to partition coefficient measurements. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure for all the compounds, together with minimal dark toxicity. Our findings indicate that the key factors influencing the efficacy of the dendritic derivatives are lipophilicity and steric hindrance within the dendritic structure which could restrict access to intracellular esterases for liberation of 5-aminolaevulinic acid. These findings should be taken into account in the design of larger dendrimers of 5-aminolaevulinic acid. PMID:16546435

  13. Photodynamic therapy with topical delta-aminolevulinic acid delays UV photocarcinogenesis in hairless mice.

    PubMed

    Stender, I M; Bech-Thomsen, N; Poulsen, T; Wulf, H C

    1997-10-01

    Photodynamic therapy (PDT) with topical application of delta-aminolevulinic acid (ALA) followed by irradiation with visible light (ALA-PDT) is a relatively new and promising experimental treatment of superficial premalignant and malignant skin neoplasms. The purpose of this study was to determine whether ALA-PDT can prevent photocarcinogenesis in hairless mice exposed to solar UV. A total of 140 mice was divided into seven groups of 20 mice each. Group 1: solar-UV exposure. Group 2: solar UV and a cream base+visible light once a week. Group 3: solar UV and ALA-PDT once a week. Group 4: solar UV and ALA-PDT once every second week. Group 5: solar UV and ALA-PDT every fourth week. Group 6: ALA-PDT once a week. Group 7: no treatment. The time to first and to second tumor > or = 1 mm was registered. Predefined endpoints, such as one tumor > or = 4 mm or an area of small confluent tumors on the back of the mice were criteria for withdrawal from the experiment. The time to first and to second tumor was significantly longer in the ALA-PDT-treated mice than in mice only exposed to solar UV and solar-UV/cream base-visible light (P < 0.005). However, we observed an increased death and accident rate in the ALA-PDT-treated groups compared to the groups not treated with ALA-PDT (chi-square test, P = 0.0250). Significantly more ALA-PDT-treated mice were withdrawn because of a tumor > or = 4 mm (P = 0.0005). The UV unexposed mice developed no tumors. Repetitive treatments with ALA-PDT delay photoinduced carcinogenesis in mice. PMID:9337620

  14. Prostate Hypofractionated Radiation Therapy With Injection of Hyaluronic Acid: Acute Toxicities in a Phase 2 Study

    SciTech Connect

    Chapet, Olivier; Decullier, Evelyne; Bin, Sylvie; Faix, Antoine; Ruffion, Alain; Jalade, Patrice; Fenoglietto, Pascal; Udrescu, Corina; Enachescu, Ciprian; Azria, David

    2015-03-15

    Purpose: Hypofractionated radiation therapy (RT) in prostate cancer can be developed only if the risk of rectal toxicity is controlled. In a multicenter phase 2 trial, hypofractionated irradiation was combined with an injection of hyaluronic acid (HA) to preserve the rectal wall. Tolerance of the injection and acute toxicity rates are reported. Methods and Materials: The study was designed to assess late grade 2 toxicity rates. The results described here correspond to the secondary objectives. Acute toxicity was defined as occurring during RT or within 3 months after RT and graded according to the Common Terminology Criteria for Adverse Events version 4.0. HA tolerance was evaluated with a visual analog scale during the injection and 30 minutes after injection and then by use of the Common Terminology Criteria at each visit. Results: From 2010 to 2012, 36 patients with low-risk to intermediate-risk prostate cancer were included. The HA injection induced a mean pain score of 4.6/10 ± 2.3. Thirty minutes after the injection, 2 patients still reported pain (2/10 and 3/10), which persisted after the intervention. Thirty-three patients experienced at least 1 acute genitourinary toxicity and 20 patients at least 1 acute gastrointestinal toxicity. Grade 2 toxicities were reported for 19 patients with urinary obstruction, frequency, or both and for 1 patient with proctitis. No grade 3 or 4 toxicities were reported. At the 3-month visit, 4 patients described grade 2 obstruction or frequency, and no patients had any grade 2 gastrointestinal toxicities. Conclusions: The injection of HA makes it possible to deliver hypofractionated irradiation over 4 weeks with a dose per fraction of > 3 Gy, with limited acute rectal toxicity.

  15. Photodynamic therapy of urethral condylomata acuminata using topically 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Wang, Xiuli; Wang, Hongwei; Wang, Haishan; Xu, Shizheng; Liao, Kanghuang; Hillemanns, Peter

    2005-07-01

    Background Electrocoagulation and laser evaporation for urethral condylomata acuminata have high recurrence rates and can be associated with urethral malformations. Objective To investigate the effect of photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) on urethral condylomata acuminata and to examine the histological changes in lesions of condylomata acuminata after ALA-PDT. Methods One hundred and sixty-four urethral condylomata patients were given topical ALA followed by intraurethral PDT through a cylindrical fiber. Among the cases, 16 penile and vulval condylomatous lesions in 11 patients were treated with topical ALA-PDT at same time. After the treatment, biopsy specimens were collected from the 16 penile and vulval lesions. The histological changes were then evaluated by light microscope and electron microscope. Results The complete response rate for urethral condylomata by topical ALA-PDT was 95.12% and the recurrence rate was 5.13% after 6 to 24 months follow-up. Keratinocytes in middle and upper layers of the epidermis with marked vacuolation and some necrocytosis were detected one and three hours after PDT. Necrosis in all layers of the epidermis was noted five hours after PDT by microscopy. In electron microscopy of kerationcytes, distinct ultrastructural abnormalities of mitochondrion, endoplasmic reticulum and membrane damage were observed. Apoptotic bodies were detected three hours after PDT and a large number of the keratinocytes exhibited necrosis five hours after PDT by electron microscope. Conclusions Results suggests that topical ALA-PDT is a simple, effective, relatively safe, less recurrent and comparatively well tolerated treatment for urethral condylomata acuminata. The mechanisms might be that ALA-PDT could trigger apoptotic process and necrosis in the HPV infected keratinocytes. Key words:

  16. Efficacy of microencapsulated lactic acid bacteria in Helicobater pylori eradication therapy

    PubMed Central

    Khalil, Maha A.; El-Sheekh, Mostafa M.; El-Adawi, Hala I.; El-Deeb, Nehal M.; Hussein, Mohamed Z.

    2015-01-01

    Background: Probiotic delivery systems are widely used nutraceutical products for the supplementation of natural intestinal flora. These delivery systems vary greatly in the effectiveness to exert health benefits for a patient. This study focuses on providing probiotic living cells with a physical barrier against adverse environmental conditions. Materials and Methods: Microencapsulation of the selected lactic acid bacteria (LAB) using chitosan and alginate was performed. Physical examination of the formulated LAB microcapsules was observed using phase contrast inverted microscope and scanning electron microscope (SEM). Finally, the survival of microencapsulated and noncapsulated bacteria was cheeked in the simulated human gastric tract (GT). The potential antimicrobial activity of the most potent microencapsulated LAB strain was in vivo evaluated in rabbit models. Results: Microencapsulated L. plantarum, L. acidophilus, and L. bulgaricus DSMZ 20080 were loaded with 1.03 × 1010 CFU viable bacteria/g, 1.9 × 1010 CFU viable bacteria/g, and 5.5 × 109 CFU viable bacteria/g, respectively. The survival of microencapsulated cells was significantly higher than that of the free cells after exposure to simulated gastric juice (SGJ) at pH 2. Additionally, in simulated small intestine juice (SSJ), larger amounts of the selected LAB cells were found, whereas in simulated colon juice (SCJ), the released LAB reached the maximum counts. In vivo results pointed out that an 8-week supplementation with a triple therapy of a microencapsulated L. plantarum, L. acidophilus, and L. bulgaricus DSMZ 20080 might be able to reduce H. pylori. Conclusion: Microencapsulated probiotics could possibly compete with and downregulate H. pylori infection in humans. PMID:26929759

  17. Hyaluronic acid conjugated superparamagnetic iron oxide nanoparticle for cancer diagnosis and hyperthermia therapy.

    PubMed

    Thomas, Reju George; Moon, Myeong Ju; Lee, Hyegyeong; Sasikala, Arathyram Ramachandra Kurup; Kim, Cheol Sang; Park, In-Kyu; Jeong, Yong Yeon

    2015-10-20

    Recently, superparamagnetic iron oxide nanoparticles (SPIONs) have been prepared for magnetic resonance (MR) imaging and hyperthermia therapy. Here, we have developed hyaluronic acid (HA) coated SPIONs primarily for use in a hyperthermia application with an MR diagnostic feature with hydrodynamic size measurement of 176nm for HA-PEG10-SPIONs and 149nm for HA-SPIONs. HA-coated SPIONs (HA-SPIONs) were prepared to target CD44-expressed cancer where the carrier was conjugated to PEG for analyzing longer circulation in blood as well as for biocompatibility (HA-PEG10 SPIONs). Characterization was conducted with TEM (shape), DLS (size), ELS (surface charge), TGA (content of polymer) and MRI (T2-relaxation time). The heating ability of both the HA-SPIONs and HA-PEG10-SPIONs was studied by AMF and SAR calculation. Cellular level tests were conducted using SCC7 and NIH3T3 cell lines to confirm cell viability and cell specific uptake. HA-SPIONs and HA-PEG10-SPIONs were injected to xenograft mice bearing the SCC7 cell line for MRI cancer diagnosis. We found that HA-SPION-injected mice tumors showed nearly 40% MR T2 contrast compared to the 20% MR T2 contrast of the HA-PEG10-SPION group over a 3h time period. Finally, in vitro hyperthermia studies were conducted in the SCC7 cell line that showed less than 40% cell viability for both HA-SPIONs and HA-PEG10-SPIONs in AMF treated cells. In conclusion, HA-SPIONs were targeted specifically to the CD44, and the hyperthermia effect of HA-SPIONs and HA-PEG10-SPIONs was found to be significant for future studies. PMID:26256205

  18. Cisplatin Loaded Poly(L-glutamic acid)-g-Methoxy Poly(ethylene glycol) Complex Nanoparticles for Potential Cancer Therapy: Preparation, In Vitro and In Vivo Evaluation.

    PubMed

    Yu, Haiyang; Tang, Zhaohui; Li, Mingqiang; Song, Wantong; Zhang, Dawei; Zhang, Ying; Yang, Yan; Sun, Hai; Deng, Mingxiao; Chen, Xuesi

    2016-01-01

    A series of novel polypeptide-based graft copolymer poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol) (PLG-g-mPEG) was synthesized through a Steglich esterification reaction of PLG with mPEG. The structure of the copolymers was confirmed by nuclear magnetic resonance spectra (NMR) and gel permeation chromatography (GPC). MTT assay demonstrated that the PLG-g-mPEGs had good cell compatibility. The unreacted carboxyl groups of the PLG-g-mPEGs were used to complex cisplatin to form polymer-metal complex nanoparticles (CDDP/PLG-g-mPEG) for cancer therapy. The average hydrodynamic radius of the CDDP/PLG-g-mPEG nanoparticles was inr the range of 14-25 nm, which was beneficial for solid tumor targeting delivery. A sustained release without initial burst was achieved for the CDDP/PLG-g-mPEG nanoparticles, indicating that the CDDP-loaded nanoparticles had great potential to suppress the drug release in blood circulation before the nanoparticles had arrived at targeting tumors. The CDDP/PLG-g-mPEG nanoparticles showed a much longer blood retention profile as compared with the free CDDP. This indicated that the CDDP-loaded nanoparticles had much more opportunity to accumulate in tumor tissue by exerting the EPR effect. In vitro tests demonstrated that the CDDP/PLG-g-mPEG nanoparticles could inhibit the proliferation of HeLa, MCF-7 and A549 cancer cells. At equal dose (4 mg kg(-1)), the CDDP/PLG-g-mPEG nanoparticles showed comparable in vivo antitumor efficacy and significantly lower systemic toxicity as compared with free cis-Diaminedichloroplatinum (cisplatin, CDDP) in MCF-7 tumor bearing mice. These suggested that the CDDP/PLG-g-mPEG nanoparticle drug delivery system had a great potential to be used for cancer therapy. PMID:27301173

  19. Diferulic acids in the cell wall may contribute to the suppression of shoot growth in the first phase of salt stress in maize.

    PubMed

    Uddin, Md Nesar; Hanstein, Stefan; Faust, Franziska; Eitenmüller, Philipp T; Pitann, Britta; Schubert, Sven

    2014-06-01

    In the first phase of salt stress the elongation growth of maize shoots is severely affected. The fixation of shape at the end of the elongation phase in Poaceae leaves has frequently been attributed to the formation of phenolic cross-links in the cell wall. In the present work it was investigated whether this process is accelerated under salt stress in different maize hybrids. Plants were grown in nutrient solution in a growth chamber. Reduction of shoot fresh mass was 50% for two hybrids which have recently been developed for improved salt resistance (SR 03, SR 12) and 60% for their parental genotype (Pioneer 3906). For SR 12 and Pioneer 3906, the upper three leaves were divided into elongated and elongating tissue and cell walls were isolated from which phenolic substances and neutral sugars were determined. Furthermore, for the newly developed hybrids the activity of phenolic peroxidase in the cell wall was analysed in apoplastic washing fluids and after sequential extraction of cell-wall material with CaCl2 and LiCl. The concentration of ferulic acid, the predominant phenolic cross-linker in the grass cell wall, was about 5mgg(-1) dry cell wall in elongating and in elongated tissue. The concentration of diferulic acids (DFA) was 2-3mgg(-1) dry cell wall in both tissues. Salt stress increased the concentration of ferulic acid (FA) and DFA in the parental genotype Pioneer 3906, but not in SR 12. Both genotypes showed an increase in arabinose, which is the molecule at which FA and DFA are coupled to interlocking arabinoxylan polymers. In SR 12, the activity of phenolic peroxidase was not influenced by salt stress. However, in SR 03 salt stress clearly increased the phenolic peroxidase activity. Results are consistent with the hypothesis that accelerated oxidative fixation of shape contributes to growth suppression in the first phase of salt stress in a genotype-specific manner. PMID:24661612

  20. A conjugated linoleic acid-enriched beef diet attenuates lipopolysaccharide-induced inflammation in mice in part through PPARgamma-mediated suppression of toll-like receptor 4.

    PubMed

    Reynolds, Clare M; Draper, Eve; Keogh, Brian; Rahman, Arman; Moloney, Aidan P; Mills, Kingston H G; Loscher, Christine E; Roche, Helen M

    2009-12-01

    Conjugated linoleic acid (CLA) is a PUFA found in beef and dairy products that has immunoregulatory properties. The level of CLA in beef can be enhanced by feeding cattle fresh grass rather than concentrates. This study determined the effect of feeding a high-CLA beef diet on inflammation in an in vivo model of septic shock. Mice were fed a high-CLA beef (4.3% total fatty acid composition) or low-CLA beef diet (0.84% total fatty acid composition) for 6 wk. Lipopolysaccharide (LPS; 3 microg) or sterile PBS was injected i.v. and serum was harvested 6 h after injection. Serum interleukin (IL)-1beta, IL-12p70, IL-12p40, and interferon-gamma concentrations were significantly reduced in response to the LPS challenge in the high-CLA beef diet group. Bone marrow-derived dendritic cells (BMDC) from the high-CLA beef diet group had significantly less IL-12 and more IL-10 in response to ex vivo LPS stimulation. Furthermore, toll-like receptor 4 (TLR4) and CD14 protein and mRNA expression on BMDC was significantly attenuated in the high-CLA compared with the low-CLA beef diet group. Complimentary in vitro experiments to determine the specificity of the effect showed that synthetic cis9, trans11-CLA suppressed surface expression of CD14 and TLR4 on BMDC. Treatment with the PPARgamma inhibitor GW9662 partially reversed TLR4 expression in immature BMDC. The results of this study demonstrate that feeding a diet enriched in high-beef CLA exerts profound antiinflammatory effects in vivo within the context of LPS-induced sepsis. In addition, downregulation of BMDC TLR4 is mediated through induction of PPARgamma. PMID:19846417

  1. Suppression of Aflatoxin Biosynthesis in Aspergillus flavus by 2-Phenylethanol Is Associated with Stimulated Growth and Decreased Degradation of Branched-Chain Amino Acids.

    PubMed

    Chang, Perng-Kuang; Hua, Sui Sheng T; Sarreal, Siov Bouy L; Li, Robert W

    2015-10-01

    branched-chain amino acid degradation. Since secondary metabolism occurs after active growth has ceased, this growth stimulation resulted in suppression of expression of aflatoxin biosynthesis genes. On the other hand, increased activities in degradation pathways for branched-chain amino acids probably are required for the activation of the aflatoxin pathway by providing building blocks and energy regeneration. Metabolic flux in primary metabolism apparently has an important role in the expression of genes of secondary metabolism. PMID:26404375

  2. Suppression of Aflatoxin Biosynthesis in Aspergillus flavus by 2-Phenylethanol Is Associated with Stimulated Growth and Decreased Degradation of Branched-Chain Amino Acids

    PubMed Central

    Chang, Perng-Kuang; Hua, Sui Sheng T.; Sarreal, Siov Bouy L.; Li, Robert W.

    2015-01-01

    . Since secondary metabolism occurs after active growth has ceased, this growth stimulation resulted in suppression of expression of aflatoxin biosynthesis genes. On the other hand, increased activities in degradation pathways for branched-chain amino acids probably are required for the activation of the aflatoxin pathway by providing building blocks and energy regeneration. Metabolic flux in primary metabolism apparently has an important role in the expression of genes of secondary metabolism. PMID:26404375

  3. Suppression of 9-cis-Epoxycarotenoid Dioxygenase, Which Encodes a Key Enzyme in Abscisic Acid Biosynthesis, Alters Fruit Texture in Transgenic Tomato1[W][OA

    PubMed Central

    Sun, Liang; Sun, Yufei; Zhang, Mei; Wang, Ling; Ren, Jie; Cui, Mengmeng; Wang, Yanping; Ji, Kai; Li, Ping; Li, Qian; Chen, Pei; Dai, Shengjie; Duan, Chaorui; Wu, Yan; Leng, Ping

    2012-01-01

    Cell wall catabolism during fruit ripening is under complex control and is key for fruit quality and shelf life. To examine the role of abscisic acid (ABA) in tomato (Solanum lycopersicum) fruit ripening, we suppressed SlNCED1, which encodes 9-cis-epoxycarotenoid dioxygenase (NCED), a key enzyme in the biosynthesis of ABA. To suppress SlNCED1 specifically in tomato fruits, and thus avoid the pleiotropic phenotypes associated with ABA deficiency, we used an RNA interference construct driven by the fruit-specific E8 promoter. ABA accumulation and SlNCED1 transcript levels in the transgenic fruit were down-regulated to between 20% and 50% of the levels measured in the control fruit. This significant reduction in NCED activity led to a down-regulation in the transcription of genes encoding major cell wall catabolic enzymes, specifically polygalacturonase (SlPG), pectin methyl esterase (SlPME), β-galactosidase precursor mRNA (SlTBG), xyloglucan endotransglycosylase (SlXET), endo-1,4-β-cellulose (SlCels), and expansin (SlExp). This resulted in an increased accumulation of pectin during ripening. In turn, this led to a significant extension of the shelf life to 15 to 29 d compared with a shelf life of only 7 d for the control fruit and an enhancement of fruit firmness at the mature stage by 30% to 45%. In conclusion, ABA affects cell wall catabolism during tomato fruit ripening via down-regulation of the expression of major catabolic genes (SlPG, SlPME, SlTBG, SlXET, SlCels, and SlExp). PMID:22108525

  4. Regulatory CD8{sup +} T cells induced by exposure to all-trans retinoic acid and TGF-{beta} suppress autoimmune diabetes

    SciTech Connect

    Kishi, Minoru; Yasuda, Hisafumi; Abe, Yasuhisa; Sasaki, Hirotomo; Shimizu, Mami; Arai, Takashi; Okumachi, Yasuyo; Moriyama, Hiroaki; Hara, Kenta; Yokono, Koichi; Nagata, Masao

    2010-03-26

    Antigen-specific regulatory CD4{sup +} T cells have been described but there are few reports on regulatory CD8{sup +} T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8{sup +} T cells from 8.3-NOD transgenic mice. CD8{sup +} T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-{beta}, and all-trans retinoic acid (ATRA) for 5 days. CD8{sup +} T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-{beta} and ATRA had low Foxp3{sup +} expression (1.7 {+-} 0.9% and 3.2 {+-} 4.5%, respectively). In contrast, CD8{sup +} T cells induced by exposure to IGRP, SpDCs, TGF-{beta}, and ATRA showed the highest expression of Foxp3{sup +} in IGRP-reactive CD8{sup +} T cells (36.1 {+-} 10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8{sup +} T cells cultured with IGRP, SpDCs, TGF-{beta}, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8{sup +} T cells suppressed the proliferation of diabetogenic CD8{sup +} T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-{beta} induces CD8{sup +}Foxp3{sup +} T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.

  5. Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway

    PubMed Central

    Yin, Guojian; Fan, Yuting; Wu, Deqing; Qiu, Lei; Yu, Ge; Xing, Miao; Hu, Guoyong; Wang, Xingpeng; Wan, Rong

    2015-01-01

    Pancreatic fibrosis, a prominent feature of chronic pancreatitis (CP), induces persistent and permanent damage in the pancreas. Pancreatic stellate cells (PSCs) provide a major source of extracellular matrix (ECM) deposition during pancreatic injury, and persistent activation of PSCs plays a vital role in the progression of pancreatic fibrosis. Retinoic acid (RA), a retinoid, has a broad range of biological functions, including regulation of cell differentiation and proliferation, attenuating progressive fibrosis of multiple organs. In the present study, we investigated the effects of RA on fibrosis in experimental CP and cultured PSCs. CP was induced in mice by repetitive cerulein injection in vivo, and mouse PSCs were isolated and activated in vitro. Suppression of pancreatic fibrosis upon administration of RA was confirmed based on reduction of histological damage, α-smooth muscle actin (α-SMA) expression and mRNA levels of β-catenin, platelet-derived growth factor (PDGF)-Rβ transforming growth factor (TGF)-βRII and collagen 1α1 in vivo. Wnt 2 and β-catenin protein levels were markedly down-regulated, while Axin 2 expression level was up-regulated in the presence of RA, both in vivo and in vitro. Nuclear translation of β-catenin was significantly decreased following RA treatment, compared with cerulein-induced CP in mice and activated PSCs. Furthermore, RA induced significant PSC apoptosis, inhibited proliferation, suppressed TCF/LEF-dependent transcriptional activity and ECM production of PSC via down-regulation of TGFβRII, PDGFRβ and collagen 1α1 in vitro. These results indicate a critical role of the Wnt/β-catenin signaling pathway in RA-induced effects on CP and PSC regulation and support the potential of RA as a suppressor of pancreatic fibrosis in mice. PMID:26556479

  6. Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice[S

    PubMed Central

    Fu, Zidong Donna; Cui, Julia Yue; Klaassen, Curtis D.

    2014-01-01

    Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na+/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine. PMID:25278499

  7. Apo-10’-lycopenoic acid induces Nrf2-mediated expression of phase II antioxidant genes and suppresses H2O2 induced oxidative damage in human bronchial epithelial cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our previous study has demonstrated that apo-10’-lycopenoic acid (ALA), an enzymatic metabolite of lycopene, can suppress lung carcinogenesis in an animal model. However, the potential mechanism(s) underlying this protection is not well defined. It has been suggested that lycopene or its hydrophilic...

  8. The parasitic plant Cuscuta australis is highly insensitive to abscisic acid-induced suppression of hypocotyl elongation and seed germination.

    PubMed

    Li, Juan; Hettenhausen, Christian; Sun, Guiling; Zhuang, Huifu; Li, Jian-Hong; Wu, Jianqiang

    2015-01-01

    Around 1% of angiosperms are parasitic plants. Their growth and development solely or partly depend on host plants from which they extract water, nutrients, and other molecules using a parasitic plant-specific organ, the haustorium. Strong depletion of nutrients can result in serious growth retardation and in some cases, death of the hosts. The genus Cuscuta (dodder) comprises about 200 holoparasitic species occurring on all continents. Their seedlings have no roots and cotyledons but are only string-like hypocotyls. When they contact suitable host plants, haustoria are formed and thereafter seedlings rapidly develop into vigorously growing branches without roots and leaves. This highly specialized lifestyle suggests that Cuscuta plants likely have unique physiology in development and stress responses. Using germination and seedling growth assays, we show that C. australis seeds and seedlings are highly insensitive to abscisic acid (ABA). Transcriptome analysis and protein sequence alignment with Arabidopsis, tomato, and rice homologs revealed that C. australis most likely consists of only four functional ABA receptors. Given that Cuscuta plants are no longer severely challenged by drought stress, we hypothesize that the ABA-mediated drought resistance pathway in Cuscuta spp. might have had degenerated over time during evolution. PMID:26258814

  9. The Parasitic Plant Cuscuta australis Is Highly Insensitive to Abscisic Acid-Induced Suppression of Hypocotyl Elongation and Seed Germination

    PubMed Central

    Li, Juan; Hettenhausen, Christian; Sun, Guiling; Zhuang, Huifu; Li, Jian-Hong; Wu, Jianqiang

    2015-01-01

    Around 1% of angiosperms are parasitic plants. Their growth and development solely or partly depend on host plants from which they extract water, nutrients, and other molecules using a parasitic plant-specific organ, the haustorium. Strong depletion of nutrients can result in serious growth retardation and in some cases, death of the hosts. The genus Cuscuta (dodder) comprises about 200 holoparasitic species occurring on all continents. Their seedlings have no roots and cotyledons but are only string-like hypocotyls. When they contact suitable host plants, haustoria are formed and thereafter seedlings rapidly develop into vigorously growing branches without roots and leaves. This highly specialized lifestyle suggests that Cuscuta plants likely have unique physiology in development and stress responses. Using germination and seedling growth assays, we show that C. australis seeds and seedlings are highly insensitive to abscisic acid (ABA). Transcriptome analysis and protein sequence alignment with Arabidopsis, tomato, and rice homologs revealed that C. australis most likely consists of only four functional ABA receptors. Given that Cuscuta plants are no longer severely challenged by drought stress, we hypothesize that the ABA-mediated drought resistance pathway in Cuscuta spp. might have had degenerated over time during evolution. PMID:26258814

  10. Menstrual suppression: current perspectives

    PubMed Central

    Hillard, Paula Adams

    2014-01-01

    Menstrual suppression to provide relief of menstrual-related symptoms or to manage medical conditions associated with menstrual morbidity or menstrual exacerbation has been used clinically since the development of steroid hormonal therapies. Options range from the extended or continuous use of combined hormonal oral contraceptives, to the use of combined hormonal patches and rings, progestins given in a variety of formulations from intramuscular injection to oral therapies to intrauterine devices, and other agents such as gonadotropin-releasing hormone (GnRH) antagonists. The agents used for menstrual suppression have variable rates of success in inducing amenorrhea, but typically have increasing rates of amenorrhea over time. Therapy may be limited by side effects, most commonly irregular, unscheduled bleeding. These therapies can benefit women’s quality of life, and by stabilizing the hormonal milieu, potentially improve the course of underlying medical conditions such as diabetes or a seizure disorder. This review addresses situations in which menstrual suppression may be of benefit, and lists options which have been successful in inducing medical amenorrhea. PMID:25018654

  11. Amino Acid Metabolism in Acute Renal Failure: Influence of Intravenous Essential L-Amino Acid Hyperalimentation Therapy

    PubMed Central

    Abel, Ronald M.; Shih, Vivian E.; Abbott, William M.; Beck, Clyde H.; Fischer, Josef E.

    1974-01-01

    A solution of 8 essential I-amino acids and hypertonic dextrose was administered to 5 patients in acute postoperative renal failure in a program of hyperalimentation designed to decrease the patient's catabolic state and to accrue certain metabolic benefits. A sixth patient receiving intravenous glucose alone served as a control. The pretreatment plasma concentrations of amino acids in all 6 patients did not differ significantly from normal; following intravenous essential amino acids at a dose of approximately 12.6 gm/24 hours, no significant elevations out of the normal range of these substances occurred. Since urinary excretion rates did not dramatically increase, urinary loss was excluded as a possible cause for the failure of increase of plasma concentrations. The results suggest that the administration of an intravenous solution of 1-amino acids and hypertonic dextrose is associated with rapid clearance from the blood of these substances and, with a failure of increased urinary excretion, indirect evidence of amino acid utilization for protein synthesis has been obtained. Histidine supplementation in patients with acute renal failure is probably unnecessary based on the lack of significant decreases in histidine concentrations in these patients. PMID:4850497

  12. Radiation With or Without 6 Months of Androgen Suppression Therapy in Intermediate- and High-Risk Clinically Localized Prostate Cancer: A Postrandomization Analysis by Risk Group

    SciTech Connect

    Nguyen, Paul L.; Chen, Ming-Hui; Beard, Clair J.; Suh, W. Warren

    2010-07-15

    Purpose: Six months of androgen suppression therapy (AST) plus radiation (RT) prolongs survival vs. RT alone in men with unfavorable risk localized prostate cancer (PCa), but it is unknown if this benefit applies to all risk subgroups and, in particular, the intermediate-risk group. Methods and Materials: Among 206 men with stages T1b to T2b PCa and either a prostate-specific antigen level of >10 or a Gleason score of {>=}7 or MRI evidence of T3 disease randomized to receive 70 Gy of RT with or without 6 months of AST, Cox multivariable analysis was used to assess the impact of AST on overall survival in intermediate- and high-risk localized PCa, adjusting for age, Adult Comorbidity Evaluation 27 comorbidity score, interaction between comorbidity and treatment, and known prognostic factors. Survival estimates were compared using a two-sided log-rank test. Results: After an 8.2-year median follow-up, 74 men died. Compared to treatment with AST plus RT, treatment with RT alone was associated with an increased risk of death in intermediate-risk (adjusted hazard ratio, 3.0 [95% confidence interval, 1.3-7.2]; p = 0.01) and high-risk PCa (adjusted hazard ratio, 3.3 [95% confidence interval, 0.94-11.3]; p = 0.06). The survival benefit of adding AST was restricted to men with no or mild comorbidity in both the intermediate-risk (90.9% vs. 85.8% survival, respectively, at 7 years for AST plus RT vs. RT alone; p = 0.009) and high-risk (88.9% vs. 51.2% survival, respectively, at 7 years for AST plus RT vs. RT alone; p = 0.007) subgroups. Conclusions: In men with localized PCa who have no or mild comorbidity, adding 6 months of AST to RT was associated with improved survival for those with both intermediate-risk and high-risk disease, but in men with moderate to severe comorbidity, no benefit was observed in either risk group.

  13. Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

    SciTech Connect

    Vuky, Jacqueline; Badiozamani, Kasra; Song Guobin

    2012-03-15

    Purpose: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. Methods and Materials: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. Results: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Conclusions: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be

  14. Twelve-Month Antiretroviral Therapy Suppresses Plasma and Genital Viral Loads but Fails to Alter Genital Levels of Cytokines, in a Cohort of HIV-Infected Rwandan Women

    PubMed Central

    Ondoa, Pascale; Gautam, Raju; Rusine, John; Lutter, Rene; Jurriaans, Suzanne; Kootstra, Neeltje; Karita, Etienne; van de Wijgert, Janneke

    2015-01-01

    Background Genital viral load (GVL) is the main determinant of sexual transmission of human immune-deficiency virus (HIV). The effect of antiretroviral therapy (ART) on local cervico-vaginal immunological factors associated with GVL is poorly described. We aimed to identify the risk factors of detectable GVL, and the impact of ART on HIV genital shedding and its correlates in a cohort of HIV-infected women, attending HIV care in Kigali, Rwanda. Materials and Methods All participants were evaluated for GVL, plasma viral load (PVL), CD4 count, various sexually-transmitted infections (STIs) at baseline and at month 12. Genital concentration of 19 cytokines and mRNA expression of APOBEC3G and BST2, two host HIV restriction factors, were evaluated at baseline in all participants. Cytokine levels were re-assessed at month 12 only in participants eligible for ART at baseline. Risk factors of GVL ≥40copies/mL at baseline and month 12 were assessed using logistic regression. Effect of 12-month ART on various local and systemic immunological parameters was examined using a paired t-test and McNemar as appropriate. Results 96 of the 247 women enrolled in the study were eligible for ART. After 12 months of ART, PVL and GVL decreased to undetectable level in respectively 74 and 88% of treated participants. ART did not affect cytokine levels. HIV genital shedding occurred only when PVL was detectable. At baseline, GVL was independently associated with IL-1β after controlling for PVL, age and N. gonorrhea infection (95% CI 1.32-2.15) and at month 12 with MIP-1β (95% CI 0.96-21.32) after controlling for baseline GVL, PVL and month 12 IL-8. Conclusion Suppressive ART does not necessarily reduce genital level of immune activation. Minimizing all conditions favoring genital inflammation, including active detection and treatment of STIs, might reduce the risk of HIV transmission as supplement to the provision of potent ART. PMID:26010956

  15. Dolutegravir-based monotherapy or dual therapy maintains a high proportion of viral suppression even in highly experienced HIV-1-infected patients

    PubMed Central

    Gubavu, Camelia; Prazuck, Thierry; Niang, Mohamadou; Buret, Jennifer; Mille, Catherine; Guinard, Jérôme; Avettand-Fènoël, Véronique; Hocqueloux, Laurent

    2016-01-01

    Background Dolutegravir is a powerful, well-tolerated integrase inhibitor with a high genetic barrier to resistance and may thus constitute the backbone of lightened regimens. Methods This was a monocentric, retrospective study. HIV-1-infected patients receiving dolutegravir as monotherapy (mDGV) or dual therapy (dDGV) were systematically identified. The primary outcome was the proportion of patients who maintained undetectable (<50 copies/mL) plasma HIV RNA [plasma viral load (PVL)]. Results We identified 21 patients on mDGV (50 mg/day) and 31 on dDGV (50 or 100 mg/day, with atazanavir ± ritonavir, n = 12; rilpivirine, n = 11; maraviroc, n = 3; lamivudine, n = 3; darunavir/ritonavir, n = 1; or abacavir, n = 1). All of the patients were treatment experienced and 48% had experienced at least one virological failure. The baseline characteristics were as follows (for the mDGV/dDGV patients, respectively): 5%/29% had a history of AIDS; the median (IQR) highest PVL was 4.5 (4.3–5.5)/5.3 (4.7–5.6) log copies/mL; the median (IQR) nadir CD4+ count was 310 (280–468)/199 (134–281) cells/mm3; 100% had undetectable PVL before the mDGV for a median (IQR) duration of 5.9 (3.5–9.9) years/81% had undetectable PVL before the dDGV for a median (IQR) duration of 3.7 (1.4–8.3) years; and the median (IQR) HIV DNA level was 2.7 (2.1–3.1)/2.9 (2.7–3) log copies/106 PBMCs. At the last follow-up visit, 100% and 97% of patients showed undetectable PVL following mDGV and dDGV, respectively [median (IQR) follow-up of 32 (29–45) and 50 (30–74) weeks, respectively]. Conclusions In our experience, dolutegravir-based lightened regimens provided a high proportion of viral suppression, even in highly treatment-experienced patients. PMID:26712907

  16. 5, 8, 11, 14-eicosatetraynoic acid suppresses CCL2/MCP-1 expression in IFN-γ-stimulated astrocytes by increasing MAPK phosphatase-1 mRNA stability

    PubMed Central

    2012-01-01

    Background The peroxisome proliferator-activated receptor (PPAR)-α activator, 5,8,11,14-eicosatetraynoic acid (ETYA), is an arachidonic acid analog. It is reported to inhibit up-regulation of pro-inflammatory genes; however, its underlying mechanism of action is largely unknown. In the present study, we focused on the inhibitory action of ETYA on the expression of the chemokine, CCL2/MCP-1, which plays a key role in the initiation and progression of inflammation. Methods To determine the effect of ETYA, primary cultured rat astrocytes and microglia were stimulated with IFN-γ in the presence of ETYA and then, expression of CCL2/MCP-1 and MAPK phosphatase (MKP-1) were determined using RT-PCR and ELISA. MKP-1 mRNA stability was evaluated by treating actinomycin D. The effect of MKP-1 and human antigen R (HuR) was analyzed by using specific siRNA transfection system. The localization of HuR was analyzed by immunocytochemistry and subcellular fractionation experiment. Results We found that ETYA suppressed CCL2/MCP-1 transcription and secretion of CCL2/MCP-1 protein through up-regulation of MKP-1mRNA levels, resulting in suppression of c-Jun N-terminal kinase (JNK) phosphorylation and activator protein 1 (AP1) activity in IFN-γ-stimulated brain glial cells. Moreover, these effects of ETYA were independent of PPAR-α. Experiments using actinomycin D revealed that the ETYA-induced increase in MKP-1 mRNA levels reflected an increase in transcript stability. Knockdown experiments using small interfering RNA demonstrated that this increase in MKP-1 mRNA stability depended on HuR, an RNA-binding protein known to promote enhanced mRNA stability. Furthermore, ETYA-induced, HuR-mediated mRNA stabilization resulted from HuR-MKP-1 nucleocytoplasmic translocation, which served to protect MKP-1 mRNA from the mRNA degradation machinery. Conclusion ETYA induces MKP-1 through HuR at the post-transcriptional level in a receptor-independent manner. The mechanism revealed here suggests

  17. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

    SciTech Connect

    Abhilash, P.A.; Harikrishnan, R.; Indira, M.

    2014-01-15

    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 30 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 of

  18. Treating cutaneous squamous cell carcinoma using 5-aminolevulinic acid polylactic-co-glycolic acid nanoparticle-mediated photodynamic therapy in a mouse model

    PubMed Central

    Wang, Xiaojie; Shi, Lei; Tu, Qingfeng; Wang, Hongwei; Zhang, Haiyan; Wang, Peiru; Zhang, Linglin; Huang, Zheng; Zhao, Feng; Luan, Hansen; Wang, Xiuli

    2015-01-01

    Background Squamous cell carcinoma (SCC) is a common skin cancer, and its treatment is still difficult. The aim of this study was to evaluate the effectiveness of nanoparticle (NP)-assisted 5-aminolevulinic acid (ALA) delivery for topical photodynamic therapy (PDT) of cutaneous SCC. Materials and methods Ultraviolet-induced cutaneous SCCs were established in hairless mice. ALA-loaded polylactic-co-glycolic acid (PLGA) NPs were prepared and characterized. The kinetics of ALA PLGA NP-induced protoporphyrin IX fluorescence in SCCs, therapeutic efficacy of ALA NP-mediated PDT, and immune responses were examined. Results PLGA NPs enhanced protoporphyrin IX production in SCC. ALA PLGA NP-mediated topical PDT was more effective than free ALA of the same concentration in treating cutaneous SCC. Conclusion PLGA NPs provide a promising strategy for delivering ALA in topical PDT of cutaneous SCC. PMID:25609949

  19. Combination of Anti-Diabetic Drug Metformin and Boswellic Acid Nanoparticles: A Novel Strategy for Pancreatic Cancer Therapy.

    PubMed

    Snima, K S; Nair, Reshmi S; Nair, Shantikumar V; Kamath, C Ravindranath; Lakshmanan, Vinoth-Kumar

    2015-01-01

    Pancreatic cancer has an infaust prognosis and is the fourth common cause of cancer related death in India. It is highly resistant to conventional treatment modalities such as chemotherapy, radiation therapy and surgery. The association of pancreatic cancer and diabetes mellitus is explored in our study. Pancreatic cancer is more likely to occur in people who have diabetes than people devoid of it, which is supported by the observation that hyperglycaemia occurs at an early stage of pancreatic cancer and is indeed a risk factor. In the present study, we have demonstrated a synergistic relationship between metformin and boswellic acid nanoparticles with varying doses of boswellic acid nanoparticles and constant metformin (20 mM). The effect revealed increased synergism between metformin and boswellic acid nanoparticles through the inhibition of cell proliferation with an effect of 80% for the combination with 0.3 mg/mL and 0.4 mg/mL and a constant concentration of metformin. We examined the effect of combination on cell migration which revealed time dependent inhibitory effect on pancreatic cell line (MiaPaCa-2). Also, we found that the combinatorial approach significantly decreased colony formation and exhibited high rate of induction of apoptosis through DNA fragmentation in pancreatic cancer cells. In-vitro hemolysis confirmed the hemocompatibility of the combination therapy with metformin and boswellic acid nanoparticles. Flow cytometry based apoptosis assay and Caspase mediated apoptosis proved apoptosis mediated cell death. Further, the cells were analysed with mitochondrial membrane potential kit which revealed depolarization of mitochondrial membrane potential due to apoptosis after treatment with drug combination. Hence, the combination approach proved to be a promising therapy towards pancreatic cancer. PMID:26301303

  20. 5-Aminolevulinic Acid-Based Sonodynamic Therapy Induces the Apoptosis of Osteosarcoma in Mice

    PubMed Central

    Li, Yongning; Zhou, Qi; Hu, Zheng; Yang, Bin; Li, Qingsong; Wang, Jianhua; Zheng, Jinhua; Cao, Wenwu

    2015-01-01

    Objective Sonodynamic therapy (SDT) is promising for treatment of cancer, but its effect on osteosarcoma is unclear. This study examined the effect of 5-Aminolevulinic Acid (5-ALA)-based SDT on the growth of implanted osteosarcoma and their potential mechanisms in vivo and in vitro. Methods The dose and metabolism of 5-ALA and ultrasound periods were optimized in a mouse model of induced osteosarcoma and in UMR-106 cells. The effects of ALA-SDT on the proliferation and apoptosis of UMR-106 cells and the growth of implanted osteosarcoma were examined. The levels of mitochondrial membrane potential (ΔψM), ROS production, BcL-2, Bax, p53 and caspase 3 expression in UMR-106 cells were determined. Results Treatment with 5-ALA for eight hours was optimal for ALA-SDT in the mouse tumor model and treatment with 2 mM 5-ALA for 6 hours and ultrasound (1.0 MHz 2.0 W/cm2) for 7 min were optimal for UMR-106 cells. SDT, but not 5-ALA, alone inhibited the growth of implanted osteosarcoma in mice (P<0.01) and reduced the viability of UMR-106 cells (p<0.05). ALA-SDT further reduced the tumor volumes and viability of UMR-106 cells (p<0.01 for both). Pre-treatment with 5-ALA significantly enhanced the SDT-mediated apoptosis (p<0.01) and morphological changes. Furthermore, ALA-SDT significantly reduced the levels of ΔψM, but increased levels of ROS in UMR-106 cells (p<0.05 or p<0.01 vs. the Control or the Ultrasound). Moreover, ALA-SDT inhibited the proliferation of osteosarcoma cells and BcL-2 expression, but increased levels of Bax, p53 and caspase 3 expression in the implanted osteosarcoma tissues (p<0.05 or p<0.01 vs. the Control or the Ultrasound). Conclusions The ALA-SDT significantly inhibited osteosarcoma growth in vivo and reduced UMR-106 cell survival by inducing osteosarcoma cell apoptosis through the ROS-related mitochondrial pathway. PMID:26161801

  1. Cilostazol suppresses β-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-β.

    PubMed

    Lee, Hye Rin; Shin, Hwa Kyoung; Park, So Youn; Kim, Hye Young; Lee, Won Suk; Rhim, Byung Yong; Hong, Ki Whan; Kim, Chi Dae

    2014-11-01

    The accumulation of plaques of β-amyloid (Aβ) peptides, a hallmark of Alzheimer's disease, results from the sequential cleavage of amyloid precursor protein (APP) by activation of β- and γ-secretases. However, the production of Aβ can be avoided by alternate cleavage of APP by α-and γ-secretases. We hypothesized that cilostazol attenuates Aβ production by increasing a disintegrin and metalloproteinase 10 (ADAM10)/α-secretase activity via SIRT1-coupled retinoic acid receptor-β (RARβ) activation in N2a cells expressing human APP Swedish mutation (N2aSwe). To evoke endogenous Aβ overproduction, the culture medium was switched from medium containing 10% fetal bovine serum (FBS) to medium containing 1% FBS, and cells were cultured for 3∼24 hr. After depletion of FBS in media, N2aSwe cells showed increased accumulations of full-length APP (FL-APP) and Aβ in a time-dependent manner (3-24 hr) in association with decreased ADAM10 protein expression. When pretreated with cilostazol (10-30 μM), FL-APP and Aβ levels were significantly reduced, and ADAM10 and α-secretase activities were restored. Furthermore, the effect of cilostazol on ADAM10 expression was antagonized by pretreating Rp-cAMPS and sirtinol and by SIRT1-gene silencing. In the N2aSwe cells overexpressing the SIRT1 gene, ADAM10, and sAPPα levels were significantly elevated. In addition, like all-trans retinoic acid, cilostazol enhanced the protein expressions of RARβ and ADAM10, and the cilostazol-stimulated ADAM10 elevation was significantly attenuated by LE135 (a RARβ inhibitor), sirtinol, and RARβ-gene silencing. In conclusion, cilostazol suppresses the accumulations of FL-APP and Aβ by activating ADAM10 via the upregulation of SIRT1-coupled RARβ. PMID:24903973

  2. Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice.

    PubMed

    Subramanian, Umadevi; Kumar, Prerna; Mani, Indra; Chen, David; Kessler, Isaac; Periyasamy, Ramu; Raghavaraju, Giri; Pandey, Kailash N

    2016-07-01

    The objective of the present study was to examine the genetically determined differences in the natriuretic peptide receptor-A (NPRA) gene (Npr1) copies affecting the expression of cardiac hypertrophic markers, proinflammatory mediators, and matrix metalloproteinases (MMPs) in a gene-dose-dependent manner. We determined whether stimulation of Npr1 by all-trans retinoic acid (RA) and histone deacetylase (HDAC) inhibitor sodium butyric acid (SB) suppress the expression of cardiac disease markers. In the present study, we utilized Npr1 gene-disrupted heterozygous (Npr1(+/-), 1-copy), wild-type (Npr1(+/+), 2-copy), gene-duplicated (Npr1(++/+), 3-copy) mice, which were treated intraperitoneally with RA, SB, and a combination of RA/SB, a hybrid drug (HB) for 2 wk. Untreated 1-copy mice showed significantly increased heart weight-body weight (HW/BW) ratio, blood pressure, hypertrophic markers, including beta-myosin heavy chain (β-MHC) and proto-oncogenes (c-fos and c-jun), proinflammatory mediator nuclear factor kappa B (NF-κB), and MMPs (MMP-2, MMP-9) compared with 2-copy and 3-copy mice. The heterozygous (haplotype) 1-copy mice treated with RA, SB, or HB, exhibited significant reduction in the expression of β-MHC, c-fos, c-jun, NF-κB, MMP-2, and MMP-9. In drug-treated animals, the activity and expression levels of HDAC were significantly reduced and histone acetyltransferase activity and expression levels were increased. The drug treatments significantly increased the fractional shortening and reduced the systolic and diastolic parameters of the Npr1(+/-) mice hearts. Together, the present results demonstrate that a decreased Npr1 copy number enhanced the expression of hypertrophic markers, proinflammatory mediators, and MMPs, whereas an increased Npr1 repressed the cardiac disease markers in a gene-dose-dependent manner. PMID:27199456

  3. 12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid suppresses UV-induced IL-6 synthesis in keratinocytes, exerting an anti-inflammatory activity

    PubMed Central

    Lee, Jin-Wook; Ryu, Ho-Cheol; Ng, Yee Ching; Kim, Cheolmin; Wei, Jun-Dong; Sabaratnam, Vikineswary

    2012-01-01

    12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) is an enzymatic product of prostaglandin H2 (PGH2) derived from cyclooxygenase (COX)-mediated arachidonic acid metabolism. Despite the high level of 12-HHT present in tissues and bodily fluids, its precise function remains largely unknown. In this study, we found that 12-HHT treatment in HaCaT cells remarkably down-regulated the ultraviolet B (UVB) irradiation-induced synthesis of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation. In an approach to identify the down-stream signaling mechanism by which 12-HHT down-regulates UVB-induced IL-6 synthesis in keratinocytes, we observed that 12-HHT inhibits the UVB-stimulated activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB). In addition, we found that 12-HHT markedly up-regulates MAPK phosphatase-1 (MKP-1), a critical negative regulator of p38 MAPK. When MKP-1 was suppressed by siRNA knock-down, the 12-HHT-mediated inhibitory effects on the UVB-stimulated activation of p38 MAPK and NF-κB, as well as the production of IL-6, were attenuated in HaCaT cells. Taken together, our results suggest that 12-HHT exerts anti-inflammatory effect via up-regulation of MKP-1, which negatively regulates p38 MAPK and NF-κB, thus attenuating IL-6 production in UVB-irradiated HaCaT cells. Considering the critical role of IL-6 in cutaneous inflammation, our findings provide the basis for the application of 12-HHT as a potential anti-inflammatory therapeutic agent in UV-induced skin diseases. PMID:22391335

  4. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage

    PubMed Central

    Sasso, Oscar; Migliore, Marco; Habrant, Damien; Armirotti, Andrea; Albani, Clara; Summa, Maria; Moreno-Sanz, Guillermo; Scarpelli, Rita; Piomelli, Daniele

    2015-01-01

    The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointes