Altered lipid metabolism in the aging kidney identified by three layered omic analysis.

PubMed

Braun, Fabian; Rinschen, Markus M; Bartels, Valerie; Frommolt, Peter; Habermann, Bianca; Hoeijmakers, Jan H J; Schumacher, Björn; Dollé, Martijn E T; Müller, Roman-Ulrich; Benzing, Thomas; Schermer, Bernhard; Kurschat, Christine E

2016-03-01

Aging-associated diseases and their comorbidities affect the life of a constantly growing proportion of the population in developed countries. At the center of these comorbidities are changes of kidney structure and function as age-related chronic kidney disease predisposes to the development of cardiovascular diseases such as stroke, myocardial infarction or heart failure. To detect molecular mechanisms involved in kidney aging, we analyzed gene expression profiles of kidneys from adult and aged wild-type mice by transcriptomic, proteomic and targeted lipidomic methodologies. Interestingly, transcriptome and proteome analyses revealed differential expression of genes primarily involved in lipid metabolism and immune response. Additional lipidomic analyses uncovered significant age-related differences in the total amount of phosphatidylethanolamines, phosphatidylcholines and sphingomyelins as well as in subspecies of phosphatidylserines and ceramides with age. By integration of these datasets we identified Aldh1a1, a key enzyme in vitamin A metabolism specifically expressed in the medullary ascending limb, as one of the most prominent upregulated proteins in old kidneys. Moreover, ceramidase Asah1 was highly expressed in aged kidneys, consistent with a decrease in ceramide C16. In summary, our data suggest that changes in lipid metabolism are involved in the process of kidney aging and in the development of chronic kidney disease.

Synthesis of sphingosine is essential for oxidative stress-induced apoptosis of photoreceptors.

PubMed

Abrahan, Carolina E; Miranda, Gisela E; Agnolazza, Daniela L; Politi, Luis E; Rotstein, Nora P

2010-02-01

Oxidative stress is involved in inducing apoptosis of photoreceptors in many retinal neurodegenerative diseases. It has been shown that oxidative stress increases in photoreceptors the synthesis of ceramide, a sphingolipid precursor that then activates apoptosis. In several cell types, ceramide is converted by ceramidases to sphingosine (Sph), another apoptosis mediator; hence, this study was undertaken to determine whether Sph participates in triggering photoreceptor apoptosis. Rat retina neurons were incubated with [(3)H]palmitic acid and treated with the oxidant paraquat (PQ) to evaluate Sph synthesis. Sph was added to cultures with or without docosahexaenoic acid (DHA), the major retina polyunsaturated fatty acid and a photoreceptor survival factor, to evaluate apoptosis. Synthesis of Sph and sphingosine-1-phosphate (S1P), a prosurvival signal, were inhibited with alkaline ceramidase or sphingosine kinase inhibitors, respectively, before adding PQ, C(2)-ceramide, or Sph. Apoptosis, mitochondrial membrane polarization, cytochrome c localization, and reactive oxygen species (ROS) production were determined. PQ increased [(3)H]Sph synthesis in photoreceptors and blocking this synthesis by inhibiting alkaline ceramidase decreased PQ-induced apoptosis. Addition of Sph induced photoreceptor apoptosis, increased ROS production, and promoted cytochrome c release from mitochondria. Although DHA prevented this apoptosis, inhibiting Sph conversion to S1P blocked DHA protection. These results suggest that oxidative stress enhances formation of ceramide and its subsequent breakdown to Sph; ceramide and/or Sph would then trigger photoreceptor apoptosis. Preventing Sph synthesis or promoting its phosphorylation to S1P rescued photoreceptors, suggesting that Sph is a mediator of their apoptosis and modulation of Sph metabolism may be crucial for promoting photoreceptor survival.

Anti-ceramidase LCL385 acutely reduces BCL-2 expression in the hippocampus but is not associated with an increase of learned helplessness in rats.

PubMed

Nahas, Ziad; Jiang, Yan; Zeidan, Youssef H; Bielawska, Alicja; Szulc, Zdzislaw; Devane, Lindsay; Kalivas, Peter; Hannun, Yusuf A

2009-01-30

Evidence from in situ studies supports the role of anti-apoptotic factors in the antidepressant responses of certain psychotropics. The availability of anti-ceramidase pro-apoptocic compound (LCL385) provides an opportunity to test in vivo the relation between hippocampal apopotosis and learned helplessness. 40 Sprague-Dawley male rodents underwent an FST after a treatment with LCL385, desipramine (DMI), or placebo (SAL) over 3 days. Behavioral responses, including immobility, swimming and climbing were counted during the 6min test. Western blot labeling was used to detect anti-apoptosis in hippocampus. DMI alone was associated with reduced immobility and increased climbing whereas LCL385 alone showed a decrease in Bcl-2/beta-actin ratio. Direct modulation of Bcl-2 expression in the hippocampus is not associated with learned helplessness in stressed rats. Three-day administration of DMI and LCL385 show divergent effects on behavioral and anti-apoptotic measures.

Association of Recreational Marijuana Use with Aneurysmal Subarachnoid Hemorrhage.

PubMed

Rumalla, Kavelin; Reddy, Adithi Y; Mittal, Manoj K

2016-02-01

Our objective was to evaluate the effect of cannabis use on hospitalizations for aneurysmal subarachnoid hemorrhage (aSAH). The Nationwide Inpatient Sample (2004-2011) was used to identify all patients (age 15-54) with a primary diagnosis of aSAH (International Classification of Diseases, Ninth Edition, Clinical Modification 430). We identified patients testing positive for cannabis use using all available diagnosis fields. The incidence and characteristics of aSAH hospitalizations among cannabis users were examined. Bivariate and multivariate analyses were performed to determine the effect of cannabis use on aSAH and in-hospital outcomes. Prior to adjustment, the incidence of aSAH in the cannabis cohort was slightly increased relative to the noncannabis cohort (relative risk: 1.07, 95% confidence interval [CI]: 1.02-1.11). Cannabis use in aSAH was more frequent among younger patients (40.44 ± 10.17 versus 43.74 ± 8.68, P < .0001), males (53.3% versus 40.76%, P < .0001), black patients (35.92% versus 19.10%, P < .0001), and Medicaid enrollees (31.13% versus 18.31%, P < .0001). The cannabis use cohort had greater overall illicit drug use but fewer medical risk factors for aSAH. Cannabis use (odds ratio: 1.18, 95% CI: 1.12-1.24) was found to be an independent predictor of aSAH when adjusting for demographics, substance use, and risk factors. Cannabis use was not associated with symptomatic cerebral vasospasm, inpatient mortality, or adverse discharge disposition. Our analysis suggests that recreational marijuana use is independently associated with an 18% increased likelihood of aSAH. Further case-control studies may analyze inpatient outcomes and other understudied mechanisms behind cannabis-associated stroke. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Effects of Meteorological Variables on the Incidence of Rupture of Intracranial Aneurysms in Central New Jersey.

PubMed

Kellogg, Marissa; Petrov, Dimitriy; Agarwal, Nitin; Patel, Nitesh V; Hansberry, David Richard; Agarwal, Prateek; Brimacombe, Michael; Gandhi, Chirag D; Prestigiacomo, Charles

2017-05-01

Introduction  Previous studies have suggested relationships between the rupture of intracranial aneurysms and meteorological variables such as season, barometric pressure, and temperature. Our objective was to examine the relationship between the incidence of hospital admissions secondary to aneurysmal subarachnoid hemorrhage (aSAH) and meteorological variables in central New Jersey. Methods  The study population consisted of 312 patients who presented to University Hospital in Newark, New Jersey, between January 1, 2003, and December 31, 2008, with aSAH. Days in the 6-year period were classified as nonbleed days (no aSAH), bleed days (one or more aSAHs within 1 calendar day), cluster days (two or more aSAHs within 2 calendar days), and multiple-bleed days (two or more aSAHs within 1 calendar day). Results  The only significant meteorological risk factor for the occurrence of multiple-bleed days was high barometric pressure (1018.5 versus 1016.5 millibars [mbars]; p <  0.04), but an increase in barometric pressure (+ 2.8 mbars) over the 2 days prior to the multiple-bleed day, although not statistically significant, may be a risk factor ( p <  0.09). Barometric pressure was also noted to be increased on bleed days (1017.2 versus 1016.5 mbars) and cluster days (1017.7 versus 1016.5 mbars), but this relationship was not significant ( p <  0.1 and p <  0.1, respectively). Although aSAH days demonstrated consistently lower temperatures than non-aSAH days and dropping temperatures were consistently found in the days preceding the aSAH, these relationships were not significant. Conclusion  Among meteorological factors, high barometric pressure and low temperature may be risk factors for the onset of aSAH. Georg Thieme Verlag KG Stuttgart · New York.

Socioeconomic Disadvantage Is Associated with a Higher Incidence of Aneurysmal Subarachnoid Hemorrhage.

PubMed

Nichols, Linda; Stirling, Christine; Otahal, Petr; Stankovich, Jim; Gall, Seana

2018-03-01

Aneurysmal subarachnoid hemorrhage (aSAH) incidence is not well studied. Varied definitions of "subarachnoid hemorrhage" have led to a lack of clarity regarding aSAH incidence. The impact of area-level socioeconomic disadvantage and geographical location on the incidence of aSAH also remains unclear. Using a population-based statewide study, we examined the incidence of aSAH in relation to socioeconomic disadvantage and geographical location. A retrospective cohort study of nontraumatic subarachnoid hemorrhages from 2010 to 2014 was undertaken. Researchers manually collected data from multiple overlapping sources including statewide administrative databases, individual digital medical records, and death registers. Age-standardized rates (ASRs) per 100,000 person years were calculated using the 2001 Australian population. Differences in incidence rate ratios were calculated by age, sex, area-level socioeconomic status, and geographical location using Poisson regression. The cohort of 237 cases (mean age, 61.0 years) with a female predominance of 166 (70.04%) included 159 confirmed aSAH, 52 community-based deaths, and 26 probable cases. The ASR for aSAH was 9.99 (95% confidence interval [CI], 8.69-11.29). A significant association between area-level socioeconomic disadvantage and incidence was observed, with the rate of aSAH in disadvantaged geographical areas being 1.40 times higher than that in advantaged areas (95% CI, 1.11-1.82; P = .012). This study uses a comprehensive search of multiple data sources to define a new baseline of aSAH within an Australian population. This study presents a higher incidence rate of aSAH with socioeconomic variations. As a key risk factor that may explain this paradox, addressing socioeconomic inequalities is important for effective prevention and management interventions. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Lifetime risks for aneurysmal subarachnoid haemorrhage: multivariable risk stratification.

PubMed

Vlak, Monique H M; Rinkel, Gabriel J E; Greebe, Paut; Greving, Jacoba P; Algra, Ale

2013-06-01

The overall incidence of aneurysmal subarachnoid haemorrhage (aSAH) in western populations is around 9 per 100 000 person-years, which confers to a lifetime risk of around half per cent. Risk factors for aSAH are usually expressed as relative risks and suggest that absolute risks vary considerably according to risk factor profiles, but such estimates are lacking. We aimed to estimate incidence and lifetime risks of aSAH according to risk factor profiles. We used data from 250 patients admitted with aSAH and 574 sex-matched and age-matched controls, who were randomly retrieved from general practitioners files. We determined independent prognostic factors with multivariable logistic regression analyses and assessed discriminatory performance using the area under the receiver operating characteristic curve. Based on the prognostic model we predicted incidences and lifetime risks of aSAH for different risk factor profiles. The four strongest independent predictors for aSAH, namely current smoking (OR 6.0; 95% CI 4.1 to 8.6), a positive family history for aSAH (4.0; 95% CI 2.3 to 7.0), hypertension (2.4; 95% CI 1.5 to 3.8) and hypercholesterolaemia (0.2; 95% CI 0.1 to 0.4), were used in the final prediction model. This model had an area under the receiver operating characteristic curve of 0.73 (95% CI 0.69 to 0.76). Depending on sex, age and the four predictors, the incidence of aSAH ranged from 0.4/100 000 to 298/100 000 person-years and lifetime risk between 0.02% and 7.2%. The incidence and lifetime risk of aSAH in the general population varies widely according to risk factor profiles. Whether persons with high risks benefit from screening should be assessed in cost-effectiveness studies.

Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response

PubMed Central

Xu, Ruijuan; Wang, Kai; Mileva, Izolda; Hannun, Yusuf A.; Obeid, Lina M.; Mao, Cungui

2016-01-01

Human cells respond to DNA damage by elevating sphingosine, a bioactive sphingolipid that induces programmed cell death (PCD) in response to various forms of stress, but its regulation and role in the DNA damage response remain obscure. Herein we demonstrate that DNA damage increases sphingosine levels in tumor cells by upregulating alkaline ceramidase 2 (ACER2) and that the upregulation of the ACER2/sphingosine pathway induces PCD in response to DNA damage by increasing the production of reactive oxygen species (ROS). Treatment with the DNA damaging agent doxorubicin increased both ACER2 expression and sphingosine levels in HCT116 cells in a dose-dependent manner. ACER2 overexpression increased sphingosine in HeLa cells whereas knocking down ACER2 inhibited the doxorubicin-induced increase in sphingosine in HCT116 cells, suggesting that DNA damage elevates sphingosine by upregulating ACER2. Knocking down ACER2 inhibited an increase in the apoptotic and necrotic cell population and the cleavage of poly ADP ribose polymerase (PARP) in HCT116 cells in response to doxorubicin as well as doxorubicin-induced release of lactate dehydrogenase (LDH) from these cells. Similar to treatment with doxorubicin, ACER2 overexpression induced an increase in the apoptotic and necrotic cell population and PARP cleavage in HeLa cells and LDH release from cells, suggesting that ACER2 upregulation mediates PCD in response to DNA damage through sphingosine. Mechanistic studies demonstrated that the upregulation of the ACER2/sphingosine pathway induces PCD by increasing ROS levels. Taken together, these results suggest that the ACER2/sphingosine pathway mediates PCD in response to DNA damage through ROS production. PMID:26943039

Aspirin and Risk of Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis.

PubMed

Phan, Kevin; Moore, Justin M; Griessenauer, Christoph J; Ogilvy, Christopher S; Thomas, Ajith J

2017-05-01

Recent studies have suggested that the use of low-dose aspirin may reduce the risk of aneurysmal subarachnoid hemorrhage (aSAH). We aimed to evaluate any association between aspirin use and risk of aSAH based on the literature, and whether this is influenced by duration or frequency of aspirin use. A search of electronic databases was done from inception to September 2016. For each study, data on risk of aSAH in aspirin versus nonaspirin users were used to generate odds ratios and 95% confidence intervals, and combined using inverse variance-weighted averages of logarithmic odds ratios in a random-effects models. From 7 included studies, no significant difference was noted between aspirin use of any duration or frequency and nonaspirin users (odds ratio, 1.00; 95% confidence interval, 0.81-1.24; P =0.99). We found a significant association between short-term use of aspirin (<3 months) and the risk of aSAH (odds ratio, 1.61; 95% confidence interval, 1.20-2.18; P =0.002). No significant difference was found in terms of risk of aSAH for 3 to 12 months, 1 to 3 years, and >3 years of durations of use. No significant association was found between infrequent aspirin use (≤2× per week) or frequent use (≥3× per week) with risk of aSAH. Current evidence suggests that short-term (<3 months) use of aspirin is associated with increased risk of aSAH. Limitations include substantial heterogenity of the included studies. The role of long-term aspirin in reducing risk of aSAH remains unclear and ideally should be addressed by an appropriately designed randomized controlled trial. © 2017 American Heart Association, Inc.

The investigation of ceranib-2 on apoptosis and drug interaction with carboplatin in human non small cell lung cancer cells in vitro.

PubMed

Yildiz-Ozer, Merve; Oztopcu-Vatan, Pinar; Kus, Gokhan

2018-02-01

Ceramide is found to be involved in inhibition of cell division and induction of apoptosis in certain tumour cells. Ceranib-2 is an agent that increases ceramide levels by inhibiting ceramidase in cancer cells. Therefore, we aimed to investigate the effects of ceranib-2 on cell survival, apoptosis and interaction with carboplatin in human non-small cell lung cancer cells. The cytotoxic effect of ceranib-2 (1-100 µM) was determined by MTT assay in human lung adenocarcinoma (A549) and large cell lung carcinoma (H460) cells. Carboplatin (1-100 µM) and lung bronchial epithelial cells (BEAS-2B) were used as positive controls. Morphological and ultrastructural changes were analysed by light microscope and TEM. Apoptotic/necrotic cell death and acid ceramidase activity were analysed by ELISA. Combination effects of ceranib-2 and carboplatin were investigated by MTT. The expression levels of CASP3, CASP9, BAX and BCL-2 were examined by qRT-PCR. The IC 50 of ceranib-2 was determined as 22 μM in A549 cells and 8 μM in H460 cells for 24 h. Morphological changes and induction of DNA fragmentation have revealed apoptotic effects of ceranib-2 in both cell lines. Ceranib-2 and carboplatin has shown synergism in combined treatment at 10 and 25 μM doses in H460 cells for 24 h. Ceranib-2 inhibited acid ceramidase activity by 44% at 25 µM in H460 cells. Finally, CASP3, CASP9 and BAX expressions were increased while BCL-2 expression was reduced in both cells. Our results obtained some preliminary results about the cytotoxic and apoptotic effects of ceranib-2 for the first time in NSCLC cell lines.

Quality of Life after Brain Injury (QOLIBRI) Overall Scale for patients after aneurysmal subarachnoid hemorrhage.

PubMed

Wong, George Kwok Chu; Lam, Sandy Wai; Ngai, Karine; Wong, Adrian; Mok, Vincent; Poon, Wai Sang

2014-06-01

The Quality of Life after Brain Injury Overall Scale (QOLIBRI-OS) is a recently developed instrument that provides a brief summary measure of health-related quality of life (HRQoL) in domains typically affected by brain injury. This study examined the application of the six item QOLIBRI-OS in patients after aneurysmal subarachnoid hemorrhage (aSAH). Hong Kong Chinese aSAH patients were evaluated prospectively within the chronic phase of 1 year after aSAH in this multi-center observational study. Cronbach's α was 0.88, and correlations were satisfactory for all six items. QOLIBRI-OS demonstrated good criterion validity with other 1 year outcome assessments. In conclusion, QOLIBRI-OS can be used as a brief index for disease-specific HRQoL assessment after aSAH. Further validation in another population of aSAH patients is recommended. Copyright © 2013 Elsevier Ltd. All rights reserved.

My journey into the world of sphingolipids and sphingolipidoses

PubMed Central

SANDHOFF, Konrad

2012-01-01

Analysis of lipid storage in postmortem brains of patients with amaurotic idiocy led to the recognition of five lysosomal ganglioside storage diseases and identification of their inherited metabolic blocks. Purification of lysosomal acid sphingomyelinase and ceramidase and analysis of their gene structures were the prerequisites for the clarification of Niemann-Pick and Farber disease. For lipid catabolism, intraendosomal vesicles are formed during the endocytotic pathway. They are subjected to lipid sorting processes and were identified as luminal platforms for cellular lipid and membrane degradation. Lipid binding glycoproteins solubilize lipids from these cholesterol poor membranes and present them to water-soluble hydrolases for digestion. Biosynthesis and intracellular trafficking of lysosomal hydrolases (hexosaminidases, acid sphingomyelinase and ceramidase) and lipid binding and transfer proteins (GM2 activator, saposins) were analyzed to identify the molecular and metabolic basis of several sphingolipidoses. Studies on the biosynthesis of glycosphingolipids yielded the scheme of Combinatorial Ganglioside Biosynthesis involving promiscuous glycosyltransferases. Their defects in mutagenized mice impair brain development and function. PMID:23229750

[Angiopoietins predict long-term outcomes after aneurysmal subarachnoid hemorrhage during an early period].

PubMed

Wang, Yi; Wang, Dong; Wei, Huijie; Tian, Ye; Jiang, Rongcai; Yue, Shuyuan; Zhang, Jianning

2015-05-19

To evaluate the association between serum levels of angiopoietins (Ang) during an early period (within 72 h) and clinical outcomes after aneurysmal subarachnoid haemorrhage (aSAH). This prospective study was conducted at Department of Neurosurgery, Tianjin Medical University General Hospital. Blood samples from 37 aSAH patients were collected at 8 h (or < 8 h), 24 h, 72 h after an onset of SAH. The serum levels of Ang-1, Ang-2 and Tie-2 were measured by enzyme-linked immunosorbent assay (ELISA). They were followed up for 3 months by Glasgow outcome score extended (GOSE). Those with GOSE > 5 were counted as a good outcome while those with GOSE ≤ 5 had a poor outcome. A total of 37 patients with aSAH and 39 healthy controls (HC) were enrolled. The aSAH patients showed a significant rise of Ang-1 within 8 h as compared with HC. The outcomes were good (n = 15) and poor (n = 22). Serum Ang-1 at 8 h (or < 8 h), 24 h and 72 h in good outcomers showed significantly higher than that in poor outcomers [(52 ± 24) vs (37 ± 17) mg/L, (62 ± 26) vs (45 ± 17) mg/L, (107 ± 27) vs (72 ± 18) mg/L]. The serum level of Ang-1 at 8 h and 24 h was one of independent risk factors for aSAH patients by multiariable Logistic regression analysis [adjected OR (95% CI) 1.095 (1.015-1.181) and 1.109 (1.016-1.211)] (P < 0.05). High serum level of Ang-1 during an early period (within 72 h) was associated with good outcomers (r = 0.627, P < 0.001). The serum levels of angiopoietins are significantly altered in aSAH patients, especially higher in good outcomers. And abnormal levels of angiopoietins may affect early brain injury (EBI) after SAH, structural integrity and recovery of blood-brain barrier (BBB) and long-term outcomes in aSAH patients.

Acid Sphingomyelinase Mediates Oxidized-LDL Induced Apoptosis in Macrophage via Endoplasmic Reticulum Stress

PubMed Central

Zhao, Min; Pan, Wei; Shi, Rui-zheng; Bai, Yong-ping; You, Bo-yang; Zhang, Kai; Fu, Qiong-mei; Schuchman, Edward H.

2016-01-01

Aim: Macrophage apoptosis is a vital event in advanced atherosclerosis, and oxidized low-density lipoprotein (ox-LDL) is a major contributor to this process. Acid sphingomyelinase (ASM) and ceramide are also involved in the induction of apoptosis, particularly in macrophages. Our current study focuses on ASM and investigates its role in ox-LDL-induced macrophage apoptosis. Methods: Human THP-1 and mouse peritoneal macrophages were cultured in vitro and treated with ox-LDL. ASM activity and ceramide levels were quantified using ultra performance liquid chromatography. Protein and mRNA levels were analyzed using Western blot analysis and quantitative realtime PCR, respectively. Cell apoptosis was determined using Hoechst staining and flow cytometry. Results: Ox-LDL-induced macrophage apoptosis was triggered by profound endoplasmic reticulum (ER) stress, leading to an upregulation of ASM activity and ceramide levels at an early stage. ASM was inhibited by siRNA or desipramine (DES), and/or ceramide was degraded by recombinant acid ceramidase (AC). These events attenuated the effect of ox-LDL on ER stress. In contrast, recombinant ASM upregulated ceramide and ER stress. ASM siRNA, DES, recombinant AC, and ER stress inhibitor 4-phenylbutyric acid were blocked by elevated levels of C/EBP homologous protein (CHOP); ox-LDL induced elevated levels of CHOP. These events attenuated macrophage apoptosis. Conclusion: These results indicate that ASM/ceramide signaling pathway is involved in ox-LDL-induced macrophage apoptosis via ER stress pathway. PMID:26923251

Aneurysmal subarachnoid hemorrhage lead to systemic upregulation of IL-23/IL-17 inflammatory axis.

PubMed

Chaudhry, Shafqat Rasul; Güresir, Erdem; Vatter, Hartmut; Kinfe, Thomas M; Dietrich, Dirk; Lamprecht, Alf; Muhammad, Sajjad

2017-09-01

IL-23 and IL-17 are pro-inflammatory cytokines. IL-23 is secreted by activated macrophages and dendritic cells, while IL-17 by Th17 cells. Serum IL-23 and IL-17 are known to be elevated in numerous inflammatory diseases including neurodegenerative diseases. The role of serum IL-23 and IL-17 in aneurysmal subarachnoid hemorrhage (aSAH) has still not been investigated. The present work investigates the serum IL-23 and IL-17 levels and their association with post hemorrhagic complications and clinical outcome in patients with aSAH. In this study, 80 patients with aSAH (Hunt and Hess grade I-V) were prospectively recruited. We enrolled 24 control patients with lumbar spinal stenosis. Peripheral venous blood was withdrawn from controls and from aSAH patients at day 1 and day 7, allowed to clot and centrifuged to obtain serum. Enzyme linked immunoassay kits were employed to quantify the serum levels of IL-23 and IL-17 by applying 50µL of serum samples. Post hemorrhagic complications and clinical outcome were documented prospectively from patient's hospital record. Serum IL-23 and IL-17 levels were significantly elevated in aSAH patients at day 1 and day 7 (n=80) as compared to control patients (n=24). Further analysis after dichotomy of patients who suffered from post hemorrhagic complications including cerebral vasospasm, chronic hydrocephalus, seizures, cerebral ischemia, delayed neurological deficits showed differential correlations with different post hemorrhagic complications (Table 1). Serum IL-23 and IL-17 levels did not correlate with clinical outcome. Serum IL-23 and IL-17 levels were elevated in patients with aSAH showing upregulation of IL-23/IL-17 inflammatory axis after aSAH. Serum IL-23 and IL-17 showed differential correlations with post hemorrhagic complications and no correlation with clinical outcome. Copyright © 2017 Elsevier Ltd. All rights reserved.

Predictors of Shunt-dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage? A Systematic Review and Meta-Analysis.

PubMed

Xie, Zhiyi; Hu, Xin; Zan, Xin; Lin, Sen; Li, Hao; You, Chao

2017-10-01

Hydrocephalus is a well-recognized complication after aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to identify predictors for shunt-dependent hydrocephalus (SDHC) after aSAH via a systematic review and meta-analysis. A systematic search was conducted using the Embase, MEDLINE, and Web of Science databases for studies pertaining to aSAH and SDHC. Risk factors were assessed by meta-analysis when they were reported by at least 2 studies. The results were presented as odd ratios or risk ratios according to the study design with the corresponding 95% confidence intervals (CI). Twenty-five studies were included. In primary analysis of 14 potential risk factors, 12 were identified as predictors of SDHC after aSAH including age ≥50 years, female gender, high Hunt-Hess grade, Glasgow Coma Scale ≤8, Fisher grade ≥3, acute hydrocephalus, external ventricular drainage insertion, intraventricular hemorrhage, postcirculation aneurysm, anterior communicating artery aneurysm, meningitis, and rebleeding. The meta-analysis based on cohort studies found a significantly increased risk for SDHC in patients with aSAH treated by coiling (risk ratio, 1.16; 95% CI, 1.05-1.29), while the meta-analysis based on case-controlled studies failed to replicate this finding (odds ratio, 1.27; 95% CI, 0.95-1.71). Several new predictors of SDHC after aSAH were identified that may assist with the early recognition and prevention of SDHC. The controversial evidence found in this study was insufficient to support the potential of neurosurgical clipping for reducing the risk of shunt dependency. Further well-designed studies are warranted to explore the effect of treatment modality on SDHC risk. Copyright © 2017 Elsevier Inc. All rights reserved.

Measuring the Impact of Delayed Cerebral Ischemia on Neuropsychological Outcome After Aneurysmal Subarachnoid Hemorrhage-Protocol of a Swiss Nationwide Observational Study (MoCA-DCI Study).

PubMed

Stienen, Martin N; Fung, Christian; Bijlenga, Philippe; Zumofen, Daniel W; Maduri, Rodolfo; Robert, Thomas; Seule, Martin A; Marbacher, Serge; Geisseler, Olivia; Brugger, Peter; Gutbrod, Klemens; Chicherio, Christian; Monsch, Andreas U; Beaud, Valérie; Rossi, Stefania; Früh, Severin; Schmid, Nicole; Smoll, Nicolas R; Keller, Emanuela; Regli, Luca

2018-05-11

The exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results. To evaluate the relationship between DCI and neuropsychological outcome after aSAH by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 mo with a baseline examination before the DCI-period (part 1). To determine the reliability of the MoCA, when applied in an ICU setting (part 2). Prospective, multicenter, and observational study performed at all Swiss neurovascular centers. For part 1, n = 240 consecutive aSAH patients and for part 2, n = 50 patients with acute brain injury are recruited. Part 1: Effect size of the relationship between DCI and neuropsychological outcome (MoCA). Part 2: Reliability measures for the MoCA. The institutional review boards approved this study on July 4, 2017 under case number BASEC 2017-00103. After completion, the results will be offered to an international scientific journal for peer-reviewed publication. This study determines the exact impact of DCI on the neuropsychological outcome after aSAH, unbiased by confounding factors such as early brain injury or patient-specific characteristics. The study provides unique insights in the neuropsychological state of patients in the early period after aSAH.

Defining a Role for Acid Sphingomyelinase in the p38/Interleukin-6 Pathway*

PubMed Central

Perry, David M.; Newcomb, Benjamin; Adada, Mohamad; Wu, Bill X.; Roddy, Patrick; Kitatani, Kazuyuki; Siskind, Leah; Obeid, Lina M.; Hannun, Yusuf A.

2014-01-01

Acid sphingomyelinase (ASM) is one of the key enzymes involved in regulating the metabolism of the bioactive sphingolipid ceramide in the sphingolipid salvage pathway, yet defining signaling pathways by which ASM exerts its effects has proven difficult. Previous literature has implicated sphingolipids in the regulation of cytokines such as interleukin-6 (IL-6), but the specific sphingolipid pathways and mechanisms involved in inflammatory signaling need to be further elucidated. In this work, we sought to define the role of ASM in IL-6 production because our previous work showed that a parallel pathway of ceramide metabolism, acid β-glucosidase 1, negatively regulates IL-6. First, silencing ASM with siRNA abrogated IL-6 production in response to the tumor promoter, 4β-phorbol 12-myristate 13-acetate (PMA), in MCF-7 cells, in distinction to acid β-glucosidase 1 and acid ceramidase, suggesting specialization of the pathways. Moreover, treating cells with siRNA to ASM or with the indirect pharmacologic inhibitor desipramine resulted in significant inhibition of TNFα- and PMA-induced IL-6 production in MDA-MB-231 and HeLa cells. Knockdown of ASM was found to significantly inhibit PMA-dependent IL-6 induction at the mRNA level, probably ruling out mechanisms of translation or secretion of IL-6. Further, ASM knockdown or desipramine blunted p38 MAPK activation in response to TNFα, revealing a key role for ASM in activating p38, a signaling pathway known to regulate IL-6 induction. Last, knockdown of ASM dramatically blunted invasion of HeLa and MDA-MB-231 cells through Matrigel. Taken together, these results demonstrate that ASM plays a critical role in p38 signaling and IL-6 synthesis with implications for tumor pathobiology. PMID:24951586

Clinical prevalence and outcome impact of pituitary dysfunction after aneurysmal subarachnoid hemorrhage: a systematic review with meta-analysis.

PubMed

Robba, Chiara; Bacigaluppi, Susanna; Bragazzi, Nicola; Lavinio, Andrea; Gurnell, Mark; Bilotta, Federico; Menon, David K

2016-10-01

Pituitary dysfunction is reported to be a common complication following aneurysmal subarachnoid hemorrhage (aSAH). The aim of this meta-analysis is to analyze the literature on clinical prevalence, risk factors and outcome impact of pituitary dysfunction after aSAH, and to assess the possible need for pituitary screening in aSAH patients. We performed a systematic review with meta-analysis based on a comprehensive search of four databases (PubMed/MEDLINE, ISI/Web of Science, Scopus and Google Scholar). A total of 20 papers met criteria for inclusion. The prevalence of pituitary dysfunction in the acute phase (within the first 6 months after aSAH) was 49.30 % (95 % CI 41.6-56.9), decreasing in the chronic phase (after 6 months from aSAH) to 25.6 % (95 % CI 18.0-35.1). Abnormalities in basal hormonal levels were more frequent when compared to induction tests, and the prevalence of a single pituitary hormone dysregulation was more frequent than multiple pituitary hormone dysregulation. Increasing age was associated with a lower prevalence of endocrine dysfunction in the acute phase, and surgical treatment of the aneurysm (clipping) was related to a higher prevalence of single hormone dysfunction. The prevalence of pituitary dysfunction did not correlate with the outcome of the patient. Neuroendocrine dysfunction is common after aSAH, but these abnormalities have not been shown to consistently impact outcome in the data available. There is a need for well-designed prospective studies to more precisely assess the incidence, clinical course, and outcome impact of pituitary dysfunction after aSAH.

Psyllium and fat in diets differentially affect the activities and expressions of colonic sphingomyelinases and caspase in mice.

PubMed

Cheng, Yajun; Ohlsson, Lena; Duan, Rui-Dong

2004-05-01

Dietary fibre and fat affect colonic tumourigenesis and inflammation. Sphingomyelin metabolism may have implications for the pathogenesis of colonic tumours and ulcerative colitis. The present study examined the effects of psyllium and fat on the enzymes responsible for sphingomyelin metabolism and apoptosis in the colon. Mice were fed control, psyllium-containing (100 g/kg), high-fat (313 g/kg, 53 % energy as fat) or high-fat plus psyllium diets for 4 weeks. The activities of acid, neutral and alkaline sphingomyelinase (SMase), neutral ceramidase, and caspase 3, 8 and 9 in colonic mucosa were determined. The expressions of alkaline SMase and caspase 3 were examined. The psyllium-containing diet was found to increase significantly the activities of alkaline SMase and caspase 3 and decreased those of acid SMase and neutral ceramidase. The high-fat diet had opposite effects on these enzymes and attenuated the effects of psyllium. Western blotting showed that psyllium increased and high-fat decreased the levels of alkaline SMase and caspase 3 in colonic mucosa. The change in caspase 3 activity was positively correlated with that of alkaline SMase and negatively with acid SMase. No similar changes of acid and alkaline phosphatase activities in the colon or acid and neutral SMase activity in the liver were identified. In conclusion, colonic sphingomyelin metabolism and apoptosis were affected by psyllium and fat in an opposite manner. The results may have implications for colorectal tumourigenesis and inflammation.

Time Courses of Inflammatory Markers after Aneurysmal Subarachnoid Hemorrhage and Their Possible Relevance for Future Studies.

PubMed

Höllig, Anke; Stoffel-Wagner, Birgit; Clusmann, Hans; Veldeman, Michael; Schubert, Gerrit A; Coburn, Mark

2017-01-01

Aneurysmal subarachnoid hemorrhage triggers an intense inflammatory response, which is suspected to increase the risk for secondary complications such as delayed cerebral ischemia (DCI). However, to date, the monitoring of the inflammatory response to detect secondary complications such as DCI has not become part of the clinical routine diagnostic. Here, we aim to illustrate the time courses of inflammatory parameters after aneurysmal subarachnoid hemorrhage (aSAH) and discuss the problems of inflammatory parameters as biomarkers but also their possible relevance for deeper understanding of the pathophysiology after aSAH and sophisticated planning of future studies. In this prospective cohort study, 109 patients with aSAH were initially included, n  = 28 patients had to be excluded. Serum and-if possible-cerebral spinal fluid samples ( n  = 48) were retrieved at days 1, 4, 7, 10, and 14 after aSAH. Samples were analyzed for leukocyte count and C-reactive protein (CRP) (serum samples only) as well as matrix metallopeptidase 9 (MMP9), intercellular adhesion molecule 1 (ICAM1), and leukemia inhibitory factor (LIF) [both serum and cerebrospinal fluid (CSF) samples]. Time courses of the inflammatory parameters were displayed and related to the occurrence of DCI. We illustrate the time courses of leukocyte count, CRP, MMP9, ICAM1, and LIF in patients' serum samples from the first until the 14th day after aSAH. Time courses of MMP9, ICAM1, and LIF in CSF samples are demonstrated. Furthermore, no significant difference was shown relating the time courses to the occurrence of DCI. We estimate that the wide range of the measured values hampers their interpretation and usage as a biomarker. However, understanding the inflammatory response after aSAH and generating a multicenter database may facilitate further studies: realistic sample size calculations on the basis of a multicenter database will increase the quality and clinical relevance of the acquired results.

Estimating the Global Incidence of Aneurysmal Subarachnoid Hemorrhage: A Systematic Review for Central Nervous System Vascular Lesions and Meta-Analysis of Ruptured Aneurysms.

PubMed

Hughes, Joshua D; Bond, Kamila M; Mekary, Rania A; Dewan, Michael C; Rattani, Abbas; Baticulon, Ronnie; Kato, Yoko; Azevedo-Filho, Hildo; Morcos, Jacques J; Park, Kee B

2018-04-09

There is increasing acknowledgement that surgical care is important in global health initiatives. In particular, neurosurgical care is as limited as 1 per 10 million people in parts of the world. We performed a systematic literature review to examine the worldwide incidence of central nervous system vascular lesions and a meta-analysis of aneurysmal subarachnoid hemorrhage (aSAH) to define the disease burden and inform neurosurgical global health efforts. A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to estimate the global epidemiology of central nervous system vascular lesions, including unruptured and ruptured aneurysms, arteriovenous malformations, cavernous malformations, dural arteriovenous fistulas, developmental venous anomalies, and vein of Galen malformations. Results were organized by World Health Organization regions. After literature review, because of a lack of data from particular World Health Organization regions, we determined we could only provide an estimate of aSAH. Using data from studies with aSAH and 12 high-quality stroke studies from regions lacking data, we meta-analyzed the yearly crude incidence of aSAH per 100,000 persons. Estimates were generated via random-effects models. From an initial yield of 1492 studies, 46 manuscripts on aSAH incidence were included. The final meta-analysis included 58 studies from 31 different countries. We estimated the global crude incidence for aSAH to be 6.67 per 100,000 persons with a wide variation across WHO regions from 0.71 to 12.38 per 100,000 persons. Worldwide, almost 500,000 individuals will suffer from aSAH each year, with almost two-thirds in low- and middle-income countries. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of high fat diet enriched with unsaturated and diet rich in saturated fatty acids on sphingolipid metabolism in rat skeletal muscle.

PubMed

Blachnio-Zabielska, Agnieszka; Baranowski, Marcin; Zabielski, Piotr; Gorski, Jan

2010-11-01

Consumption of high fat diet leads to muscle lipid accumulation which is an important factor involved in induction of insulin resistance. Ceramide is likely to partially inhibit insulin signaling cascade. The aim of this study was to examine the effect of different high fat diets on ceramide metabolism in rat skeletal muscles. The experiments were carried out on rats fed for 5 weeks: (1) a standard chow and (2) high fat diet rich in polyunsaturated fatty acids (PUFA) and (3) diet enriched with saturated fatty acids (SAT). Assays were performed on three types of muscles: slow-twitch oxidative (soleus), fast-twitch oxidative-glycolytic, and fast-twitch glycolytic (red and white section of the gastrocnemius, respectively). The activity of serine palmitoyltransferase (SPT), neutral and acid sphingomyelinase (n- and aSMase), and neutral and alkaline ceramidase (n- and alCDase) was examined. The content of ceramide, sphinganine, sphingosine, and sphingosine-1-phosphate was also measured. The ceramide content did not change in any muscle from PUFA diet group but increased in the SAT diet group by 46% and 52% in the soleus and red section of the gastrocnemius, respectively. Elevated ceramide content in the SAT diet group could be a result of increased SPT activity and simultaneously decreased activity of nCDase. Unchanged ceramide content in the PUFA diet group might be a result of increased activity of SPT and alCDase and simultaneously decreased activity of SMases. We conclude that regulation of muscle ceramide level depends on the diet and type of skeletal muscle. © 2010 Wiley-Liss, Inc.

Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke, traumatic brain injury, and bacterial meningitis - a systematic review and meta-analysis.

PubMed

Beez, Thomas; Steiger, Hans-Jakob; Etminan, Nima

2017-12-07

The effectiveness of pharmacological strategies exclusively targeting secondary brain damage (SBD) following ischemic stroke, aneurysmal subarachnoid hemorrhage, aSAH, intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and bacterial meningitis is unclear. This meta-analysis studied the effect of SBD targeted treatment on clinical outcome across the pathological entities. Randomized, controlled, double-blinded trials on aforementioned entities with 'death' as endpoint were identified. Effect sizes were analyzed and expressed as pooled risk ratio (RR) estimates with 95% confidence intervals (CI). 123 studies fulfilled the criteria, with data on 66,561 patients. In the pooled analysis, there was a minor reduction of mortality for aSAH [RR 0.93 (95% CI:0.85-1.02)], ICH [RR 0.92 (95% CI:0.82-1.03)] and bacterial meningitis [RR 0.86 (95% CI:0.68-1.09)]. No reduction of mortality was found for ischemic stroke [RR 1.05 (95% CI:1.00-1.11)] and TBI [RR 1.03 (95% CI:0.93-1.15)]. Additional analysis of "poor outcome" as endpoint gave similar results. Subgroup analysis with respect to effector mechanisms showed a tendency towards a reduced mortality for the effector mechanism category "oxidative metabolism/stress" for aSAH with a risk ratio of 0.86 [95% CI: 0.73-1.00]. Regarding specific medications, a statistically significant reduction of mortality and poor outcome was confirmed only for nimodipine for aSAH and dexamethasone for bacterial meningitis. Our results show that only a few selected SBD directed medications are likely to reduce the rate of death and poor outcome following aSAH, and bacterial meningitis, while no convincing evidence could be found for the usefulness of SBD directed medications in ischemic stroke, ICH and TBI. However, a subtle effect on good or excellent outcome might remain undetected. These results should lead to a new perspective of secondary reactions following cerebral injury. These processes should not be seen as suicide mechanisms

Predicting symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage with an artificial neural network in a pediatric population.

PubMed

Skoch, Jesse; Tahir, Rizwan; Abruzzo, Todd; Taylor, John M; Zuccarello, Mario; Vadivelu, Sudhakar

2017-12-01

Artificial neural networks (ANN) are increasingly applied to complex medical problem solving algorithms because their outcome prediction performance is superior to existing multiple regression models. ANN can successfully identify symptomatic cerebral vasospasm (SCV) in adults presenting after aneurysmal subarachnoid hemorrhage (aSAH). Although SCV is unusual in children with aSAH, the clinical consequences are severe. Consequently, reliable tools to predict patients at greatest risk for SCV may have significant value. We applied ANN modeling to a consecutive cohort of pediatric aSAH cases to assess its ability to predict SCV. A retrospective chart review was conducted to identify patients < 21 years of age who presented with spontaneously ruptured, non-traumatic, non-mycotic, non-flow-related intracranial arterial aneurysms to our institution between January 2002 and January 2015. Demographics, clinical, radiographic, and outcome data were analyzed using an adapted ANN model using learned value nodes from the adult aneurysmal SAH dataset previously reported. The strength of the ANN prediction was measured between - 1 and 1 with - 1 representing no likelihood of SCV and 1 representing high likelihood of SCV. Sixteen patients met study inclusion criteria. The median age for aSAH patients was 15 years. Ten underwent surgical clipping and 6 underwent endovascular coiling for definitive treatment. One patient experienced SCV and 15 did not. The ANN applied here was able to accurately predict all 16 outcomes. The mean strength of prediction for those who did not exhibit SCV was - 0.86. The strength for the one patient who did exhibit SCV was 0.93. Adult-derived aneurysmal SAH value nodes can be applied to a simple AAN model to accurately predict SCV in children presenting with aSAH. Further work is needed to determine if ANN models can prospectively predict SCV in the pediatric aSAH population in toto; adapted to include mycotic, traumatic, and flow

Cannabis Use and Outcomes in Patients With Aneurysmal Subarachnoid Hemorrhage.

PubMed

Behrouz, Réza; Birnbaum, Lee; Grandhi, Ramesh; Johnson, Jeremiah; Misra, Vivek; Palacio, Santiago; Seifi, Ali; Topel, Christopher; Garvin, Rachel; Caron, Jean-Louis

2016-05-01

The incidence of cannabis use in patients with aneurysmal subarachnoid hemorrhage (aSAH) and its impact on morbidity, mortality, and outcomes are unknown. Our objective was to evaluate the relationship between cannabis use and outcomes in patients with aSAH. Records of consecutive patients admitted with aSAH between 2010 and 2015 were reviewed. Clinical features and outcomes of aSAH patients with negative urine drug screen and cannabinoids-positive (CB+) were compared. Regression analyses were used to assess for associations. The study group consisted of 108 patients; 25.9% with CB+. Delayed cerebral ischemia was diagnosed in 50% of CB+ and 23.8% of urine drug screen negative patients (P=0.01). CB+ was independently associated with development of delayed cerebral ischemia (odds ratio, 2.68; 95% confidence interval, 1.03-6.99; P=0.01). A significantly higher number of CB+ than urine drug screen negative patients had poor outcome (35.7% versus 13.8%; P=0.01). In univariate analysis, CB+ was associated with the composite end point of hospital mortality/severe disability (odds ratio, 2.93; 95% confidence interval, 1.07-8.01; P=0.04). However, after adjusting for other predictors, this effect was no longer significant. We offer preliminary data that CB+ is independently associated with delayed cerebral ischemia and possibly poor outcome in patients with aSAH. Our findings add to the growing evidence on the association of cannabis with cerebrovascular risk. © 2016 American Heart Association, Inc.

Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3

PubMed Central

Suga, Takahiro; Sato, Toshihiro; Maekawa, Masamitsu; Goto, Junichi; Mano, Nariyasu

2017-01-01

Bile acids, the metabolites of cholesterol, are signaling molecules that play critical role in many physiological functions. They undergo enterohepatic circulation through various transporters expressed in intestine and liver. Human organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of bile acids such as taurocholic acid. However, the transport properties of individual bile acids are not well understood. Therefore, we selected HEK293 cells overexpressing OATP1B1 and OATP1B3 to evaluate the transport of five major human bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, lithocholic acid) together withtheir glycine and taurine conjugates via OATP1B1 and OATP1B3. The bile acids were quantified by liquid chromatography-tandem mass spectrometry. The present study revealed that cholic acid, chenodeoxyxcholic acid, and deoxycholic acid were transported by OATP1B1 and OATP1B3, while ursodeoxycholic acid and lithocholic acid were not significantly transported by OATPs. However, all the conjugated bile acids were taken up rapidly by OATP1B1 and OATP1B3. Kinetic analyses revealed the involvement of saturable OATP1B1- and OATP1B3-mediated transport of bile acids. The apparent Km values for OATP1B1 and OATP1B3 of the conjugated bile acids were similar (0.74–14.7 μM for OATP1B1 and 0.47–15.3 μM for OATP1B3). They exhibited higher affinity than cholic acid (47.1 μM for OATP1B1 and 42.2 μM for OATP1B3). Our results suggest that conjugated bile acids (glycine and taurine) are preferred to unconjugated bile acids as substrates for OATP1B1 and OATP1B3. PMID:28060902

Cerebral Taurine Levels are Associated with Brain Edema and Delayed Cerebral Infarction in Patients with Aneurysmal Subarachnoid Hemorrhage.

PubMed

Kofler, Mario; Schiefecker, Alois; Ferger, Boris; Beer, Ronny; Sohm, Florian; Broessner, Gregor; Hackl, Werner; Rhomberg, Paul; Lackner, Peter; Pfausler, Bettina; Thomé, Claudius; Schmutzhard, Erich; Helbok, Raimund

2015-12-01

Cerebral edema and delayed cerebral infarction (DCI) are common complications after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome. Experimental data suggest that the amino acid taurine is released into the brain extracellular space secondary to cytotoxic edema and brain tissue hypoxia, and therefore may serve as a biomarker for secondary brain injury after aSAH. On the other hand, neuroprotective mechanisms of taurine treatment have been described in the experimental setting. We analyzed cerebral taurine levels using high-performance liquid chromatography in the brain extracellular fluid of 25 consecutive aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD). Patient characteristics and clinical course were prospectively recorded. Associations with CMD-taurine levels were analyzed using generalized estimating equations with an autoregressive process to handle repeated observations within subjects. CMD-taurine levels were highest in the first days after aSAH (11.2 ± 3.2 µM/l) and significantly decreased over time (p < 0.001). Patients with brain edema on admission or during hospitalization (N = 20; 80 %) and patients developing DCI (N = 5; 20 %) had higher brain extracellular taurine levels compared to those without (Wald = 7.3, df = 1, p < 0.01; Wald = 10.1, df = 1, p = 0.001, respectively) even after adjusting for disease severity and CMD-probe location. There was no correlation between parenteral taurine supplementation and brain extracellular taurine (p = 0.6). Moreover, a significant correlation with brain extracellular glutamate (r = 0.82, p < 0.001), lactate (r = 0.56, p < 0.02), pyruvate (r = 0.39, p < 0.01), potassium (r = 0.37, p = 0.01), and lactate-to-pyruvate ratio (r = 0.24, p = 0.02) was found. Significantly higher CMD-taurine levels were found in patients with brain edema or DCI after aneurysmal subarachnoid hemorrhage. Its value as a

A Preliminary Observational Study of Anovulatory Uterine Bleeding After Aneurysmal Subarachnoid Hemorrhage.

PubMed

Brown, Suzanne M; Fifield, Susan W; Pizzi, Michael A; Alejos, David; Richie, Alexa N; Dinh, Tri A; Cheshire, William P; Meek, Shon E; Freeman, William D

2017-12-01

It was observed that women with aneurysmal subarachnoid hemorrhage (aSAH) tended to have earlier menses than a typical 21- to 28-day cycle. The goal was to determine whether there is an association between aSAH and early onset of menses. All cases of aSAH in women aged 18 to 55 years who were admitted to our facility's neuroscience intensive care unit from June 1, 2011, to June 30, 2012, were reviewed. The electronic healthcare record for each of these patients was examined for documentation of menses onset, computed tomography of the head, brain aneurysm characteristics, modified Fisher score and Glasgow Coma Scale on admission, presence/absence of vasospasm, medical/surgical history, and use of medications that affect the menstrual cycle. The mean onset of menses in this study population was compared with the mean of 21 to 28 days with the 1-sample t test. During the study period, 103 patients with subarachnoid hemorrhage were admitted. Sixty-one were women, and 15 were aged 18 to 55 years. Nine of the 15 (60%) had documentation of menses occurring during their initial week of hospitalization; 1 patient had documentation of menses on hospital day 12. There is a significant difference when the mean onset of menses in our patient population is compared with the approximate normal menstrual cycle of 21 to 28 days (P < .01). Early onset of menses or abnormal uterine bleeding after SAH may occur in women with aSAH and typically within the first 7 to 10 days after intracranial aneurysm rupture. The physiologic cause of early onset of menses after aSAH, whether primary or secondary, remains unknown.

Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin.

PubMed

Keitsch, Simone; Riethmüller, Joachim; Soddemann, Matthias; Sehl, Carolin; Wilker, Barbara; Edwards, Michael J; Caldwell, Charles C; Fraunholz, Martin; Gulbins, Erich; Becker, Katrin Anne

2018-05-01

Pulmonary infections of cystic fibrosis (CF) patients with Staphylococcus aureus (S. aureus) occur very early in the disease. The molecular details that cause infection-susceptibility of CF patients to and mediate infection with S. aureus are poorly characterized. Therefore, we aimed to identify the role of α-toxin, a major S. aureus toxin, for pulmonary infection of CF mice. Infection with S. aureus JE2 resulted in severe pneumonia in CF mice, while wildtype mice were almost unaffected. Deficiency of α-toxin in JE2-Δhla reduced the pathogenicity of S. aureus in CF mice. However, CF mice were still more susceptible to the mutant S. aureus strain than wildtype mice. The S. aureus JE2 induced a marked increase of ceramide and a downregulation of sphingosine and acid ceramidase expression in bronchi of CF mice. Deletion of α-toxin reduced these changes after infection of CF mice. Similar changes were observed in wildtype mice, but at much lower levels. Our data indicate that expression of α-toxin is a major factor causing S. aureus infections in CF mice. Wildtype S. aureus induces a marked increase of ceramide and a reduction of sphingosine and acid ceramidase expression in bronchial epithelial cells of wildtype and CF mice, changes that determine infection susceptibility.

Synthesis and characterization of 3-ketohexadecanoic acid-1-14-C, DL-3-hydroxyhexadecanoic acid-1-14-C, and trans-2-hexadecenoic acid-1-14-C.

PubMed

Jones, J A; Blecher, M

1966-05-01

The chemical synthesis and characterization of three intermediates in the Beta oxidation of palmitic acid-1-(14)C by rat liver mitochondria, namely, 3-ketohexadecanoic acid-1-(14)C, DL-3-hydroxyhexadecanoic acid-1-(14)C, and trans-2-hexadecenoic acid-1-(14)C, are described.

Effect of short-term ε-aminocaproic acid treatment on patients undergoing endovascular coil embolization following aneurysmal subarachnoid hemorrhage.

PubMed

Malekpour, Mahdi; Kulwin, Charles; Bohnstedt, Bradley N; Radmand, Golnar; Sethia, Rishabh; Mendenhall, Stephen K; Weyhenmeyer, Jonathan; Hendricks, Benjamin K; Leipzig, Thomas; Payner, Troy D; Shah, Mitesh V; Scott, John; DeNardo, Andrew; Sahlein, Daniel; Cohen-Gadol, Aaron A

2017-05-01

OBJECTIVE Aneurysmal rebleeding before definitive obliteration of the aneurysm is a cause of mortality and morbidity. There are limited data on the role of short-term antifibrinolytic therapy among patients undergoing endovascular intervention. METHODS All consecutive patients receiving endovascular therapy for their ruptured saccular aneurysm at the authors' institution between 2000 and 2011 were included in this study. These patients underwent endovascular coiling of their aneurysm within 72 hours of admission. In patients receiving ε-aminocaproic acid (EACA), the EACA administration was continued until the time of the endovascular procedure. Complications and clinical outcomes of endovascular treatment after aneurysmal subarachnoid hemorrhage (aSAH) were compared between EACA-treated and untreated patients. RESULTS During the 12-year study period, 341 patients underwent endovascular coiling. Short-term EACA treatment was administered in 146 patients and was withheld in the other 195 patients. EACA treatment did not change the risk of preinterventional rebleeding in this study (OR 0.782, 95% CI 0.176-3.480; p = 0.747). Moreover, EACA treatment did not increase the rate of thromboembolic events. On the other hand, patients who received EACA treatment had a significantly longer duration of hospital stay compared with their counterparts who were not treated with EACA (median 19 days, interquartile range [IQR] 12.5-30 days vs median 14 days, IQR 10-23 days; p < 0.001). EACA treatment was associated with increased odds of shunt requirement (OR 2.047, 95% CI 1.043-4.018; p = 0.037) and decreased odds of developing cardiac complications (OR 0.138, 95% CI 0.031-0.604; p = 0.009) and respiratory insufficiency (OR 0.471, 95% CI 0.239-0.926; p = 0.029). Short-term EACA treatment did not affect the Glasgow Outcome Scale score at discharge, 6 months, or 1 year following discharge. CONCLUSIONS In this study, short-term EACA treatment in patients who suffered from aSAH and

Continuous infusion of low-dose unfractionated heparin after aneurysmal subarachnoid hemorrhage: a preliminary study of cognitive outcomes.

PubMed

James, Robert F; Khattar, Nicolas K; Aljuboori, Zaid S; Page, Paul S; Shao, Elaine Y; Carter, Lacey M; Meyer, Kimberly S; Daniels, Michael W; Craycroft, John; Gaughen, John R; Chaudry, M Imran; Rai, Shesh N; Everhart, D Erik; Simard, J Marc

2018-05-11

OBJECTIVE Cognitive dysfunction occurs in up to 70% of aneurysmal subarachnoid hemorrhage (aSAH) survivors. Low-dose intravenous heparin (LDIVH) infusion using the Maryland protocol was recently shown to reduce clinical vasospasm and vasospasm-related infarction. In this study, the Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive changes in aSAH patients treated with the Maryland LDIVH protocol compared with controls. METHODS A retrospective analysis of all patients treated for aSAH between July 2009 and April 2014 was conducted. Beginning in 2012, aSAH patients were treated with LDIVH in the postprocedural period. The MoCA was administered to all aSAH survivors prospectively during routine follow-up visits, at least 3 months after aSAH, by trained staff blinded to treatment status. Mean MoCA scores were compared between groups, and regression analyses were performed for relevant factors. RESULTS No significant differences in baseline characteristics were observed between groups. The mean MoCA score for the LDIVH group (n = 25) was 26.4 compared with 22.7 in controls (n = 22) (p = 0.013). Serious cognitive impairment (MoCA ≤ 20) was observed in 32% of controls compared with 0% in the LDIVH group (p = 0.008). Linear regression analysis demonstrated that only LDIVH was associated with a positive influence on MoCA scores (β = 3.68, p =0.019), whereas anterior communicating artery aneurysms and fevers were negatively associated with MoCA scores. Multivariable linear regression analysis resulted in all 3 factors maintaining significance. There were no treatment complications. CONCLUSIONS This preliminary study suggests that the Maryland LDIVH protocol may improve cognitive outcomes in aSAH patients. A randomized controlled trial is needed to determine the safety and potential benefit of unfractionated heparin in aSAH patients.

A Twelve-Week Moderate Exercise Programme Improved Symptoms of Depression, Insomnia, and Verbal Learning in Post-Aneurysmal Subarachnoid Haemorrhage Patients: A Comparison with Meningioma Patients and Healthy Controls.

PubMed

Colledge, Flora; Brand, Serge; Pühse, Uwe; Holsboer-Trachsler, Edith; Zimmerer, Stefan; Schleith, Ramona; Gerber, Markus

2018-04-25

Deficits in psychological functioning, cognitive functioning, and sleep are frequently experienced by individuals who have survived aneurysmal subarachnoid haemorrhage (aSAH). Exercise has been shown to improve these domains; to date, it has never been explored in patients following aSAH. The aim of this exploratory study is to compare the effects of an exercise programme in this population with another patient group, and a group of healthy controls. The present study explored the effects of 12 weeks of moderate aerobic exercise training on 15 aSAH patients, 16 meningioma patients, and 17 healthy controls. Data on symptoms of depression, hypochondria, perceived stress, satisfaction with life, verbal learning and memory, and subjective and objective sleep, were gathered at baseline, following intervention, and at 6-month follow-up. aSAH patients and meningioma patients had decreased symptoms of depression and insomnia at follow-up. While perceived stress decreased in the meningioma group, in aSAH patients it increased. Total learning performance increased in all three groups. An exercise programme had a positive effect on symptoms of depression, insomnia, and verbal learning in patients following aSAH. No positive changes in other domains were observed. This may be due to the cautious approach taken with regard to exercise intensity. © 2018 S. Karger AG, Basel.

Inactive lifestyles and sedentary behavior in persons with chronic aneurysmal subarachnoid hemorrhage: evidence from accelerometer-based activity monitoring.

PubMed

Harmsen, Wouter J; Ribbers, Gerard M; Heijenbrok-Kal, Majanka H; Bussmann, Johannes B J; Sneekes, Emiel M; Khajeh, Ladbon; van Kooten, Fop; Neggers, Sebastian J C M M; van den Berg-Emons, Rita J

2017-11-23

Aneurysmal subarachnoid hemorrhage (a-SAH) is a potential life-threatening stroke. Because survivors may be at increased risk for inactive and sedentary lifestyles, this study evaluates physical activity (PA) and sedentary behavior (SB) in the chronic phase after a-SAH. PA and SB were objectively measured at six months post a-SAH with an accelerometer-based activity monitor, with the aim to cover three consecutive weekdays. Total time spent in PA (comprising walking, cycling, running and non-cyclic movement) and SB (comprising sitting and lying) was determined. Also, in-depth analyses were performed to determine the accumulation and distribution of PA and SB throughout the day. Binary time series were created to determine the mean bout length and the fragmentation index. Measures of PA and SB in persons with a-SAH were compared to those in sex- and age-matched healthy controls. The 51 participants comprised 33 persons with a-SAH and 18 controls. None of the participants had signs of paresis or spasticity. Persons with a-SAH spent 105 min/24 h being physically active, which was 35 min/24 h less than healthy controls (p = 0.005). For PA, compared with healthy controls, the mean bout length was shorter in those with a-SAH (12.0 vs. 13.5 s, p = 0.006) and the fragmentation index was higher (0.053 vs. 0.041, p < 0.001). Total sedentary time during waking hours showed no significant difference between groups (514 min vs. 474 min, p = 0.291). For SB, the mean bout length was longer in persons with a-SAH (122.3 vs. 80.5 s, p = 0.024), whereas there was no difference in fragmentation index between groups (0.0032 vs 0.0036, p = 0.396). Persons with a-SAH are less physically active, they break PA time into shorter periods, and SB periods last longer compared to healthy controls. Since inactive lifestyles and prolonged uninterrupted periods of SB are independent risk factors for poor cardiovascular health, interventions seem necessary and should target both

Ethane-1,1,2-trisphosphonic acid hemihydrate.

PubMed

Delain-Bioton, Lise; Lohier, Jean François; Villemin, Didier; Sopková-de Oliveira Santos, Jana; Hix, Gary; Jaffrès, Paul Alain

2008-02-01

Ethane-1,1,2-trisphosphonic acid crystallizes as a hemihydrate, C(2)H(9)O(9)P(3).0.5H(2)O, in which the water O atom lies on an inversion centre in the space group P2(1)/c. The acid component, which contains a short but noncentred O-H...O hydrogen bond, adopts a gauche conformation. The acid components are linked by an extensive series of O-H...O hydrogen bonds to form layers, which are linked into pairs by the water molecules.

Role of levosimendan in the management of subarachnoid hemorrhage.

PubMed

Varvarousi, Giolanda; Xanthos, Theodoros; Sarafidou, Pavlina; Katsioula, Ellisavet; Georgiadou, Marianthi; Eforakopoulou, Maria; Pavlou, Hlias

2016-02-01

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the leading causes of neurologic disability accounting for dismal long term survival rates. aSAH leads to a sudden increase in intracranial pressure and a massive sympathetic discharge. Excessive sympathetic stimulation leads to catecholamine mediated myocardial dysfunction and hemodynamic instability which may critically hamper brain perfusion and oxygenation. In the setting of acute aSAH, administration of vasoactive drugs aims at stabilizing impaired hemodynamics. However, studies have shown that conventional treatment with vasoactive drugs that lead to Ca(+2) overload and increase myocardial oxygen consumption, fail to restore hemodynamics and decrease cerebral blood flow. Levosimendan is a non-adrenergic inotropic Ca(+2) sensitizer with not only beneficial hemodynamic properties but also pleiotropic effects, contributing to its cardioprotective and neuroprotective role. Although there have been limited data available regarding the use of levosimendan in patients with aSAH, current evidence suggests that levosimendan may have a role in the setting of post-aSAH cardiomyopathy and decreased cerebral blood flow both in the emergency departments and in intensive care units. The purpose of this review is to provide an overview of studies of levosimendan therapy for aSAH, and describe current knowledge about the effects of levosimendan in the management of aSAH. Copyright © 2015 Elsevier Inc. All rights reserved.

Magnetic Resonance Imaging in Aneurysmal Subarachnoid Hemorrhage: Current Evidence and Future Directions.

PubMed

Nelson, Sarah E; Sair, Haris I; Stevens, Robert D

2018-04-09

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with an unacceptably high mortality and chronic disability in survivors, underscoring a need to validate new approaches for treatment and prognosis. The use of advanced imaging, magnetic resonance imaging (MRI) in particular, could help address this gap given its versatile capacity to quantitatively evaluate and map changes in brain anatomy, physiology and functional activation. Yet there is uncertainty about the real value of brain MRI in the clinical setting of aSAH. In this review, we discuss current and emerging MRI research in aSAH. PubMed was searched from inception to June 2017, and additional studies were then chosen on the basis of relevance to the topics covered in this review. Available studies suggest that brain MRI is a feasible, safe, and valuable testing modality. MRI detects brain abnormalities associated with neurologic examination, outcomes, and aneurysm treatment and thus has the potential to increase knowledge of aSAH pathophysiology as well as to guide management and outcome prediction. Newer pulse sequences have the potential to reveal structural and physiological changes that could also improve management of aSAH. Research is needed to confirm the value of MRI-based biomarkers in clinical practice and as endpoints in clinical trials, with the goal of improving outcome for patients with aSAH.

Exploratory study of the course of posttraumatic stress disorder after aneurysmal subarachnoid hemorrhage.

PubMed

Huenges Wajer, Irene M C; Smits, Anouk R; Rinkel, Gabriel J E; van Zandvoort, Martine J E; Wijngaards-de Meij, Leoniek; Visser-Meily, Johanna M A

2018-05-09

Posttraumatic stress disorder (PTSD) occurs often in aneurysmal subarachnoid hemorrhage (aSAH) survivors, but how PTSD develops over time post-aSAH is still unclear. We examined the course of PTSD symptoms during the first year after aSAH. In this prospective cohort study, the Impact of Event Scale (IES) was applied in 128 patients 3, 6 and 12 months after aSAH. Multilevel modelling was used to assess changes in levels of PTSD symptoms over time and to explore if demographic characteristics, aSAH characteristics, level of education, cognitive functioning and neuroticism are associated to the course of PTSD symptoms. Multilevel analyses showed at group level no differences in the average level of PTSD symptoms between 3, 6 of 12 months post-aSAH (p = 0.22). At individual level, changes in PTSD symptoms over time were present (X 2 (121) = 149.73 p = 0.04). None of the factors could explain the variance in change of PTSD symptoms over time. The course of PTSD appears to differ between individuals after aSAH. We found no factors that explain these differences. There is not one optimal moment in time to assess PTSD. Therefore, it is important to assess PTSD at several time points after aSAH. Copyright © 2018. Published by Elsevier Inc.

Efficacy of Early Rehabilitation After Surgical Repair of Acute Aneurysmal Subarachnoid Hemorrhage: Outcomes After Verticalization on Days 2-5 Versus Day 12 Post-Bleeding.

PubMed

Milovanovic, Andjela; Grujicic, Danica; Bogosavljevic, Vojislav; Jokovic, Milos; Mujovic, Natasa; Markovic, Ivana Petronic

2017-01-01

To develop a specific rehabilitation protocol for patients who have undergone surgical repair of acute aneurysmal subarachnoid hemorrhage (aSAH), and to determine the time at which verticalization should be initiated after aSAH. Sixty-five patients who underwent acute-term surgery for aSAH and early rehabilitation were evaluated in groups: Group 1 (n=34) started verticalization on days 2-5 post-bleeding whereas Group 2 (n=31) started verticalization approximately day 12 post-bleeding. All patients were monitored for early complications, vasospasm and ischemia. Assessments of motor status, depression and anxiety (using Zung scales), and cognitive status (using the Mini-Mental State Examination (MMSE)) were conducted at discharge and at 1 and 3 months post-surgery. At discharge, Group 1 had a significantly higher proportion of patients with ischemia than Group 2 (p=0.004). Group 1 had a higher proportion of patients with hemiparesis than Group 2 three months post-surgery (p=0.015). Group 1 patients scored significantly higher on the Zung depression scale than Group 2 patients at 1 month (p=0.005) and 3 months post-surgery (p=0.001; the same applies to the Zung anxiety scale (p=0.006 and p=0.000, respectively). Group 2 patients scored significantly higher on the MMSE than those in Group 1 at discharge (p=0.040) and 1 month post-surgery (p=0.025). Early verticalization had no effect with respect to preventing early postoperative complications in this patient group. Once a patient has undergone acute surgical repair of aSAH, it is safe and preferred that rehabilitation be initiated immediately postsurgery. However, verticalization should not start prior to day 12 post-bleeding.

A Propensity Score Analysis of the Impact of Dexamethasone Use on Delayed Cerebral Ischemia and Poor Functional Outcomes After Subarachnoid Hemorrhage.

PubMed

Mohney, Nathaniel; Williamson, Craig A; Rothman, Edward; Ball, Ron; Sheehan, Kyle M; Pandey, Aditya S; Fletcher, Jeffrey J; Jacobs, Teresa L; Thompson, B Gregory; Rajajee, Venkatakrishna

2018-01-01

An inflammatory response occurs after aneurysmal subarachnoid hemorrhage (aSAH) and predicts poor outcomes. Glucocorticoids suppress inflammation and promote fluid retention. Dexamethasone is often administered after aSAH for postoperative cerebral edema and refractory headache. Our objective was to examine the impact of dexamethasone use on functional outcomes and delayed cerebral ischemia (DCI) after aSAH. Patients with aSAH admitted between 2010 and 2015 were included; the data source was a single-center subarachnoid hemorrhage registry. The intervention of interest was a dexamethasone taper used <7 days from ictus. The primary outcome was poor discharge functional outcome, with a modified Rankin Scale score >3. Other outcomes included DCI and infection. A propensity score for use of dexamethasone was calculated using a logistic regression model that included potential predictors of dexamethasone use and outcome. The impact of dexamethasone on outcomes of interest was calculated and the propensity score was controlled for. A total of 440 patients with subarachnoid hemorrhage were admitted during the study period and 309 met eligibility criteria. Dexamethasone was administered in 101 patients (33%). A total of 127 patients (41%) had a discharge modified Rankin Scale score >3, 105 (34%) developed DCI, and 94 (30%) developed an infection. After propensity score analysis, dexamethasone use was associated with a significant reduction in poor functional outcomes (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.19-0.66) but showed no significant association with DCI (OR, 0.93; 95% CI, 0.53-1.64) or infection (OR, 0.60; 95% CI, 0.34-1.06). Dexamethasone use after aSAH was associated with a reduction in poor functional outcomes at discharge but not DCI, controlling for predictors of dexamethasone use. Copyright © 2017 Elsevier Inc. All rights reserved.

Restrictions and satisfaction with participation in patients who are ADL-independent after an aneurysmal subarachnoid hemorrhage.

PubMed

Huenges Wajer, Irene M C; Visser-Meily, Johanna M A; Greebe, Paut; Post, Marcel W M; Rinkel, Gabriel J E; van Zandvoort, Martine J E

2017-03-01

Most survivors of an aneurysmal subarachnoid hemorrhage (aSAH) are ADL-independent, but they often experience restrictions in (social) activities and, therefore, cannot regain their pre-morbid level of participation. In this study, participation restrictions and participation satisfaction experienced after aSAH were assessed. Moreover, possible predictors of participation after aSAH were examined to identify goals for rehabilitation. Participation restrictions experienced by a series of 67 patients visiting our SAH outpatient clinic were assessed as part of standard clinical care using the Participation Restrictions and Satisfaction sections of the Utrecht Scale for Evaluation of Rehabilitation Participation (USER-Participation) 6 months after aSAH. Cognitive impairments, cognitive and emotional complaints, and symptoms of depression and anxiety, assessed 10 weeks after aSAH, were examined as possible predictors of participation by means of linear regression analysis. Although patients were ADL-independent, 64% reported one or more participation restrictions and 60% were dissatisfied in one or more participation domains. Most commonly experienced restrictions concerned housekeeping, chores in and around the house, and physical exercise. Dissatisfaction was most often reported about outdoor activities, mobility, and work/housekeeping. The main predictors of participation restrictions as well as satisfaction with participation were cognitive complaints (subjective) (β = -.30, p = .03 and β = -.40, p = .002, respectively) and anxiety (β = .32, p = .02 and β = -.34, p = .007, respectively). Almost two-thirds of the ADL-independent patients experienced problems of participation 6 months after aSAH. Cognitive complaints (subjective) and anxiety symptoms showed the strongest association with participation restrictions and satisfaction. Cognitive rehabilitation and anxiety-reducing interventions may help to optimize rehabilitation and increase

Determining rural risk for aneurysmal subarachnoid hemorrhages: A structural equation modeling approach.

PubMed

Nichols, Linda Jayne; Gall, Seana; Stirling, Christine

2016-01-01

An aneurysmal subarachnoid hemorrhage (aSAH) carries a high disability burden. The true impact of rurality as a predictor of outcome severity is unknown. Our aim is to clarify the relationship between the proposed explanations of regional and rural health disparities linked to severity of outcome following an aSAH. An initial literature search identified limited data directly linking geographical location, rurality, rural vulnerability, and aSAH. A further search noting parallels with ischemic stroke and acute myocardial infarct literature presented a number of diverse and interrelated predictors. This a priori knowledge informed the development of a conceptual framework that proposes the relationship between rurality and severity of outcome following an aSAH utilizing structural equation modeling. The presented conceptual framework explores a number of system, environmental, and modifiable risk factors. Socioeconomic characteristics, modifiable risk factors, and timely treatment that were identified as predictors of severity of outcome following an aSAH and within each of these defined predictors a number of contributing specific individual predictors are proposed. There are considerable gaps in the current knowledge pertaining to the impact of rurality on the severity of outcome following an aSAH. Absent from the literature is any investigation of the cumulative impact and multiplicity of risk factors associated with rurality. The proposed conceptual framework hypothesizes a number of relationships between both individual level and system level predictors, acknowledging that intervening predictors may mediate the effect of one variable on another.

40 CFR 721.10382 - Diphosphoric acid, calcium salt (1:1).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Diphosphoric acid, calcium salt (1:1... Specific Chemical Substances § 721.10382 Diphosphoric acid, calcium salt (1:1). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as diphosphoric acid, calcium...

40 CFR 721.10382 - Diphosphoric acid, calcium salt (1:1).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Diphosphoric acid, calcium salt (1:1... Specific Chemical Substances § 721.10382 Diphosphoric acid, calcium salt (1:1). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as diphosphoric acid, calcium...

40 CFR 721.10382 - Diphosphoric acid, calcium salt (1:1).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Diphosphoric acid, calcium salt (1:1... Specific Chemical Substances § 721.10382 Diphosphoric acid, calcium salt (1:1). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as diphosphoric acid, calcium...

Evaluation of risk factors and development of acute kidney injury in aneurysmal subarachnoid hemorrhage, head injury, and severe sepsis/septic shock patients during ICU treatment.

PubMed

Kamar, Ceren; Ali, Achmet; Altun, Demet; Orhun, Günseli; Sabancı, Akın; Sencer, Altay; Akıncı, İbrahim Özkan

2017-01-01

There are few studies examining development of acute kidney injury (AKI) in the various types of patients in intensive care units (ICUs). Presently described is evaluation of risk factors and development of AKI in different groups of ICU patients. Present study was performed in 3 different ICUs. Development of AKI was measured using Acute Kidney Injury Network (AKIN) classification system. Total of 300 patients who were treated in trauma, neurosurgery, or general ICU departments (due to head injury, aneurysmal subarachnoid hemorrhage [aSAH], or severe sepsis/septic shock, respectively) were assessed for incidence, risk factors, and development of AKI. AKI did not develop in aSAH patients when evaluated based on serum creatinine level; however, it was observed in 5% of aSAH patients according to volume adjusted creatinine (VACr) level. AKI developed in 76% of sepsis group, and in 20% of head injury group, based on AKIN classification, according to both serum and VACr levels. Incidence of AKI was significantly higher in sepsis group (p<0.001). Only use of vasopressor was significantly related to AKI development in sepsis and head injury groups. Mortality rate was 8%, 22%, and 42% in aSAH, head injury, and sepsis groups, respectively. AKI development and vasopressor use were significantly related to mortality in sepsis group. Despite similar characteristics and risk factors, there were fewer instances of AKI in aSAH group. Hypertension or hydration therapy used to treat vasospasm and polyuria due to cerebral salt-wasting syndrome may prevent aSAH patients from developing AKI.

Sleep Quality, Sleep EEG Pattern, Mental Well-Being and Cortisol Secretion in Patients with Ruptured Aneurysm Post-Treatment: A Comparison with Post-Surgery Meningioma Patients and Controls.

PubMed

Gerber, Markus; Colledge, Flora; Pühse, Uwe; Holsboer-Trachsler, Edith; Zimmerer, Stefan; Brand, Serge

2016-01-01

Although the chance of surviving an aneurysmal subarachnoid haemorrhage (aSAH) has increased steadily, disturbed sleep and persistent psychological complaints are frequently experienced post-ictus. To date, however, few studies have sought to determine whether physiological parameters, such as objectively measured sleep and cortisol secretion, interrelate significantly with low sleep quality and psychological complaints such as depression. Furthermore, there is little evidence as to whether post-ictal complaints differ between aSAH patients and other groups who have experienced stressful medical intervention. Data on objective and subjective sleep, sleep-related dysfunctional cognitions, psychological functioning and cortisol secretion were collected from 15 patients who had undergone medical intervention for aSAH. Data were also collected from a group of 16 individuals who had undergone surgery for a meningioma and a third group made up of 17 healthy participants. aSAH patients and meningioma patients had significantly poorer subjective sleep than healthy controls and reported more sleep-related dysfunctional cognitions and hypochondriacal beliefs. They also had a significantly higher morning cortisol response. Finally, a non-significant trend was found showing that aSAH patients and meningioma patients reported poorer psychological functioning than healthy controls. Following treatment, aSAH patients and meningioma patients experience poorer subjective sleep and some differences in objectively measured sleep, which might be attributable to increased sleep-related dysfunctional cognitions and poorer overall psychological functioning. Differences in cortisol production were also observed, suggesting that some physiological imbalances are still present post-ictus. © 2016 S. Karger AG, Basel.

Global miRNA expression profile reveals novel molecular players in aneurysmal subarachnoid haemorrhage.

PubMed

Lopes, Katia de Paiva; Vinasco-Sandoval, Tatiana; Vialle, Ricardo Assunção; Paschoal, Fernando Mendes; Bastos, Vanessa Albuquerque P Aviz; Bor-Seng-Shu, Edson; Teixeira, Manoel Jacobsen; Yamada, Elizabeth Sumi; Pinto, Pablo; Vidal, Amanda Ferreira; Ribeiro-Dos-Santos, Arthur; Moreira, Fabiano; Santos, Sidney; Paschoal, Eric Homero Albuquerque; Ribeiro-Dos-Santos, Ândrea

2018-06-08

The molecular mechanisms behind aneurysmal subarachnoid haemorrhage (aSAH) are still poorly understood. Expression patterns of miRNAs may help elucidate the post-transcriptional gene expression in aSAH. Here, we evaluate the global miRNAs expression profile (miRnome) of patients with aSAH to identify potential biomarkers. We collected 33 peripheral blood samples (27 patients with cerebral aneurysm, collected 7 to 10 days after the haemorrhage, when usually is the cerebral vasospasm risk peak, and six controls). Then, were performed small RNA sequencing using an Illumina Next Generation Sequencing (NGS) platform. Differential expression analysis identified eight differentially expressed miRNAs. Among them, three were identified being up-regulated, and five down-regulated. miR-486-5p was the most abundant expressed and is associated with poor neurological admission status. In silico miRNA gene target prediction showed 148 genes associated with at least two differentially expressed miRNAs. Among these, THBS1 and VEGFA, known to be related to thrombospondin and vascular endothelial growth factor. Moreover, MYC gene was found to be regulated by four miRNAs, suggesting an important role in aneurysmal subarachnoid haemorrhage. Additionally, 15 novel miRNAs were predicted being expressed only in aSAH, suggesting possible involvement in aneurysm pathogenesis. These findings may help the identification of novel biomarkers of clinical interest.

Milrinone via lumbar subarachnoid catheter for vasospasm after aneurysmal subarachnoid hemorrhage.

PubMed

Sadamasa, Nobutake; Yoshida, Kazumichi; Narumi, Osamu; Chin, Masaki; Yamagata, Sen

2014-12-01

Delayed ischemic neurological deficit (DIND) due to symptomatic vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to elucidate the safety and feasibility of intrathecal milrinone infusion via lumber subarachnoid catheter for prevention of DIND after aSAH. We diagnosed 425 consecutive patients with aSAH who received clipping or coil embolization within 48 h after arrival. Patients with the evidence of vasospasm on CT angiography (CTA) received the milrinone therapy via lumbar subarachnoid catheter. DIND, delayed cerebral infarction (DCI), and modified Rankin scale at 3 months after SAH were used for the assessment of outcome. Of 425 patients, 170 patients (40.0 %) with CTA-proven vasospasm received the milrinone therapy. DIND was observed in 68 patients (16.0 %), DCI in 30 patients (7.1 %), and the overall mortality was 7.2 %. In patients with WFNS grade IV and V aSAH, 26 out of 145 patients (17.9 %) were presented with DIND, 12 (8.3 %) with DCI, and the mortality was 16.0 %. No major complication related to the milrinone injection was observed. Intrathecal milrinone injection via lumbar catheter was safe and feasible, and further randomized prospective studies are needed to confirm the effectiveness of this regimen in the patients with SAH.

Plasma 8-iso-Prostaglandin F2α, a possible prognostic marker in aneurysmal subarachnoid hemorrhage.

PubMed

Pan, De-Sheng; Yan, Min; Hassan, Muhammad; Fang, Ze-Bin; Chen, Man-Tao

2017-06-01

8-iso-Prostaglandin F2α (8-iso-PGF2α) is a potential biomarker of oxidative stress. This study clarified whether plasma 8-iso-PGF2α concentrations were affected and its underlying relevance to prognosis in aneurysmal subarachnoid hemorrhage (aSAH). In this prospective, observational study, a total of 170 controls and 170 aSAH patients were enrolled. Plasma 8-iso-PGF2α concentrations were detected using an ELISA. Severity was assessed by World Federation of Neurological Surgeons (WFNS) scale and modified Fisher grading scale. Clinical outcomes included 6-month mortality and poor outcome referred to as Glasgow outcome scale score of 1-3. As compared to controls, admission plasma 8-iso-PGF2α concentrations were significantly enhanced. Increased concentrations of plasma 8-iso-PGF2α correlated with WFNS scores and modified Fisher scores. 8-iso-PGF2α in plasma was an independent predictor for clinical outcomes. Under ROC curve, the predictive values of 8-iso-PGF2α concentrations resembled those of WFNS scores and modified Fisher scores for clinical outcomes. An elevation in plasma 8-iso-PGF2α concentrations is associated with the severity and poor outcome after aSAH, substantializing 8-iso-PGF2α as a potential prognostic biomarker of aSAH. Copyright © 2017. Published by Elsevier B.V.

Compared to controls, patients with ruptured aneurysm and surgical intervention show increase in symptoms of depression and lower cognitive performance, but their objective sleep is not affected.

PubMed

Brand, Serge; Zimmerer, Stefan; Kalak, Nadeem; Planta, Sandra Von; Schwenzer-Zimmerer, Katja; Müller, Andreas Albert; Zeilhofer, Hans-Florian; Holsboer-Trachsler, Edith

2015-02-01

Patients with aneurysmal subarachnoid haemorrhage (aSAH) have impaired sleep and cognitive performance together with more difficulties in social and everyday life. Hypocortisolism has also been reported. However, a study assessing all dimensions between aSAH severity, objective and subjective sleep, cortisol secretion, cognitive performance and social and everyday life has not so far been performed. The aim of the present study was therefore two-fold: (1) to assess, in a sample of patients with aSAH, objective and subjective sleep, cognitive functioning, social skills and cortisol secretion concurrently, and (2) to compare patients on these variables with a control group. Twenty-one patients (17 females; mean age: 58.80 years) with ruptured aneurysm and surgical intervention and 21 (14 females; mean age: 58.90 years) age- and gender-matched controls took part in the study. Assessments covered objective sleep-EGG recordings, subjective sleep, salivary cortisol analysis, and psychological functioning including memory performance, mood, and emotion recognition. Compared to healthy controls, patients had lower scores for verbal memory performance and emotion recognition; they also reported more marked depressive symptoms and complained of poor sleep. However, no differences were found for objective sleep or cortisol secretion. Subjective and objective sleep, cortisol secretion and psychological functioning were unrelated. Findings indicate that patients with aSAH face psychological rather than physiological issues.

Precision medicine of aneurysmal subarachnoid hemorrhage, vasospasm and delayed cerebral ischemia.

PubMed

Burrell, Christian; Avalon, Nicole E; Siegel, Jason; Pizzi, Michael; Dutta, Tumpa; Charlesworth, M Cristine; Freeman, William D

2016-11-01

Precision medicine provides individualized treatment of diseases through leveraging patient-to-patient variation. Aneurysmal subarachnoid hemorrhage carries tremendous morbidity and mortality with cerebral vasospasm and delayed cerebral ischemia proving devastating and unpredictable. Lack of treatment measures for these conditions could be improved through precision medicine. Areas covered: Discussed are the pathophysiology of CV and DCI, treatment guidelines, and evidence for precision medicine used for prediction and prevention of poor outcomes following aSAH. A PubMed search was performed using keywords cerebral vasospasm or delayed cerebral ischemia and either biomarkers, precision medicine, metabolomics, proteomics, or genomics. Over 200 peer-reviewed articles were evaluated. The studies presented cover biomarkers identified as predictive markers or therapeutic targets following aSAH. Expert commentary: The biomarkers reviewed here correlate with CV, DCI, and neurologic outcomes after aSAH. Though practical use in clinical management of aSAH is not well established, using these biomarkers as predictive tools or therapeutic targets demonstrates the potential of precision medicine.

The Hijdra scale has significant prognostic value for the functional outcome of Fisher grade 3 patients with subarachnoid hemorrhage.

PubMed

Bretz, Julia S; Von Dincklage, Falk; Woitzik, Johannes; Winkler, Maren K L; Major, Sebastian; Dreier, Jens P; Bohner, Georg; Scheel, Michael

2017-09-01

Despite its high prevalence among patients with aneurysmal subarachnoid hemorrhage (aSAH) and high risk of delayed cerebral ischemia (DCI), the Fisher grade 3 category remains a poorly studied subgroup. The aim of this cohort study has been to investigate the prognostic value of the Hijdra sum scoring system for the functional outcome in patients with Fisher grade 3 aSAH, in order to improve the risk stratification within this Fisher category. Initial CT scans of 72 prospectively enrolled patients with Fisher grade 3 aSAH were analyzed, and cisternal, ventricular, and total amount of blood were graded according to the Hijdra scale. Additionally, space-occupying subarachnoid blood clots were assessed. Outcome was evaluated after 6 months. Within the subgroup of Fisher grade 3, aSAH patients with an unfavorable outcome showed a significantly larger cisternal Hijdra sum score (HSS: 21.1 ± 5.2) than patients with a favorable outcome (HSS: 17.6 ± 5.9; p = 0.009). However, both the amount of ventricular blood (p = 0.165) and space-occupying blood clots (p = 0.206) appeared to have no prognostic relevance. After adjusting for the patient's age, gender, tobacco use, clinical status at admission, and presence of intracerebral hemorrhage, the cisternal and total HSS remained the only independent parameters included in multivariate logistic regression models to predict functional outcome (p < 0.01). The cisternal Hijdra score is fairly easy to perform and the present study indicates that it has an additional predictive value for the functional outcome within the Fisher 3 category. We suggest that the Hijdra scale is a practically useful prognostic instrument for the risk evaluation after aSAH and should be applied more often in the clinical setting.

Cognitive deficits after aneurysmal and angiographically negative subarachnoid hemorrhage: Memory, attention, executive functioning, and emotion recognition.

PubMed

Buunk, Anne M; Groen, Rob J M; Veenstra, Wencke S; Metzemaekers, Jan D M; van der Hoeven, Johannes H; van Dijk, J Marc C; Spikman, Jacoba M

2016-11-01

The authors' aim was to investigate cognitive outcome in patients with aneurysmal and angiographically negative subarachnoid hemorrhage (aSAH and anSAH), by comparing them to healthy controls and to each other. Besides investigating cognitive functions as memory and attention, they focused on higher-order prefrontal functions, namely executive functioning (EF) and emotion recognition. Patients and healthy controls were assessed with tests measuring memory (15 Words Test, Digit Span), attention and processing speed (Trail Making Test A and B), EF (Zoo Map, Letter Fluency, Dysexecutive Questionnaire), and emotion recognition (Facial Expressions of Emotion Stimuli and Tests). Between-groups comparisons of test performances were made. Patients with aSAH scored significantly lower than healthy controls on measures of memory, processing speed, and attention, but anSAH patients did not. In the higher-order prefrontal functions (EF and emotion recognition), aSAH patients were clearly impaired when compared to healthy controls. However, anSAH patients did not perform significantly better than aSAH patients on the majority of the tests. In the subacute phase after SAH, cognitive functions, including the higher-order prefrontal functions EF and emotion recognition, were clearly impaired in aSAH patients. Patients with anSAH did not perform better than aSAH patients, which indicates that these functions may also be affected to some extent in anSAH patients. Considering the importance of these higher-order prefrontal functions for daily life functioning, and following the results of the present study, tests that measure emotion recognition and EF should be part of the standard neuropsychological assessment after SAH. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Fatty Acids Change the Conformation of Uncoupling Protein 1 (UCP1)*

PubMed Central

Divakaruni, Ajit S.; Humphrey, Dickon M.; Brand, Martin D.

2012-01-01

UCP1 catalyzes proton leak across the mitochondrial inner membrane to disengage substrate oxidation from ATP production. It is well established that UCP1 is activated by fatty acids and inhibited by purine nucleotides, but precisely how this regulation occurs remains unsettled. Although fatty acids can competitively overcome nucleotide inhibition in functional assays, fatty acids have little effect on purine nucleotide binding. Here, we present the first demonstration that fatty acids induce a conformational change in UCP1. Palmitate dramatically changed the binding kinetics of 2′/3′-O-(N-methylanthraniloyl)-GDP, a fluorescently labeled nucleotide analog, for UCP1. Furthermore, palmitate accelerated the rate of enzymatic proteolysis of UCP1. The altered kinetics of both processes indicate that fatty acids change the conformation of UCP1, reconciling the apparent discrepancy between existing functional and ligand binding data. Our results provide a framework for how fatty acids and nucleotides compete to regulate the activity of UCP1. PMID:22952235

Incorporation of Oxygen into Abscisic Acid and Phaseic Acid from Molecular Oxygen 1

PubMed Central

Creelman, Robert A.; Zeevaart, Jan A. D.

1984-01-01

Abscisic acid accumulates in detached, wilted leaves of Xanthium strumarium. When these leaves are subsequently rehydrated, phaseic acid, a catabolite of abscisic acid, accumulates. Analysis by gas chromatography-mass spectrometry of phaseic acid isolated from stressed and subsequently rehydrated leaves placed in an atmosphere containing 20% 18O2 and 80% N2 indicates that one atom of 18O is incorporated in the 6′-hydroxymethyl group of phaseic acid. This suggests that the enzyme that converts abscisic acid to phaseic acid is an oxygenase. Analysis by gas chromatography-mass spectrometry of abscisic acid isolated from stressed leaves kept in an atmosphere containing 18O2 indicates that one atom of 18O is present in the carboxyl group of abscisic acid. Thus, when abscisic acid accumulates in water-stressed leaves, only one of the four oxygens present in the abscisic acid molecule is derived from molecular oxygen. This suggests that either (a) the oxygen present in the 1′-, 4′-, and one of the two oxygens at the 1-position of abscisic acid arise from water, or (b) there exists a stored precursor with oxygen atoms already present in the 1′- and 4′-positions of abscisic acid which is converted to abscisic acid under conditions of water stress. PMID:16663564

Involvement of Sp1 in butyric acid-induced HIV-1 gene expression.

PubMed

Imai, Kenichi; Okamoto, Takashi; Ochiai, Kuniyasu

2015-01-01

The ability of human immunodeficiency virus-1(HIV-1) to establish latent infection and its re-activation is considered critical for progression of HIV-1 infection. We previously reported that a bacterial metabolite butyric acid, acting as a potent inhibitor of histone deacetylases (HDACs), could lead to induction of HIV-1 transcription; however, the molecular mechanism remains unclear. The aim of this study was to investigate the effect of butyric acid on HIV-1 gene expression. Butyric acid-mediated HIV-1 gene expression was determined by luciferase assay and Chromatin immunoprecipitation assay. Western blot analysis and ELISA were used for the detection of HIV-1. We found that Sp1 binding sites within the HIV-1 promoter are primarily involved in butyric acid-mediated HIV-1 activation. In fact, Sp1 knockdown by small interfering RNA and the Sp1 inhibitor mithramycin A abolished the effect of butyric acid. We also observed that cAMP response element-binding-binding protein (CBP) was required for butyric acid-induced HIV-1 activation. These results suggest that butyric acid stimulates HIV-1 promoter through inhibition of the Sp1-associated HDAC activity and recruitment of CBP to the HIV-1 LTR. Our findings suggest that Sp1 should be considered as one of therapeutic targets in anti-viral therapy against HIV-1 infection aggravated by butyric acid-producing bacteria. © 2015 S. Karger AG, Basel.

Long-term reintegration and quality of life in patients with subarachnoid hemorrhage and a good neurological outcome: findings after more than 20 years.

PubMed

Sonesson, Bengt; Kronvall, Erik; Säveland, Hans; Brandt, Lennart; Nilsson, Ola G

2018-03-01

OBJECTIVE The goal of this study was to examine long-term quality of life (QOL) and reintegration in patients with good neurological recovery after aneurysmal subarachnoid hemorrhage (aSAH) and SAH of unknown cause (SAH NUD). METHODS A long-term follow-up was performed in an original cohort of 113 individuals who had suffered SAH (93 with aSAH and 20 with SAH NUD) between 1977 and 1984. Self-reporting assessments, performed > 20 years after the bleeding episode, included the Quality of Life Scale (QOLS), Psychological General Well-Being (PGWB) index, and Reintegration to Normal Living (RNL) index, along with information on sleep disturbances and work status. RESULTS Seventy-one survivors were identified. Questionnaires were returned by 67 individuals who had suffered SAH 20-28 years previously. The QOL was rated in the normal range for both the QOLS score (aSAH 90.3 vs SAH NUD 88.6) and the PGWB index (aSAH 105.9 vs SAH NUD 102.8). Ninety percent of patients had returned to their previous employment. Complete RNL was reported by 40% of patients with aSAH and by 46% of patients with SAH NUD; mild to moderate readjustment difficulties by 55% and 38%, respectively; and severe difficulties by 5% of patients with aSAH and 15% of patients with SAH NUD. Self-rated aspects of cognition, mood, and energy resources in addition resulted in a substantial drop in overall reintegration. Sleep disturbances were reported by 26%. CONCLUSIONS More than half of patients with SAH who had early good neurological recovery experienced reintegration difficulties after > 20 years. However, the general QOL was not adversely affected by this impairment. Inability to return to work after SAH was associated with lower QOLS scores. Sleep disturbances were associated with lower PGWB scores.

Implication of Ceramide, Ceramide 1-Phosphate and Sphingosine 1-Phosphate in Tumorigenesis

PubMed Central

Gangoiti, Patricia; Granado, Maria H.; Alonso, Alicia; Goñi, Félix M.; Gómez-Muñoz, Antonio

2008-01-01

In the last two decades there has been considerable progress in our understanding of the role of sphingolipids in controlling signal transduction processes, particularly in the mechanisms leading to regulation of cell growth and death. Ceramide is a well-characterized sphingolipid metabolite and second messenger that can be produced by cancer cells in response to a variety of stimuli, including therapeutic drugs, leading to cell cycle arrest and apoptosis. Although this is a promising aspect when thinking of treating cancer, it should be borne in mind that ceramide production may not always be a growth inhibitory or pro-apoptotic signal. In fact, ceramide can be readily converted to sphingosine 1-phosphate (S1P) by the concerted actions of ceramidases and sphingosine kinases, or to ceramide 1-phosphate (C1P) by the action of ceramide kinase. In general, S1P and C1P have opposing effects to ceramide, acting as pro-survival or mitogenic signals in most cell types. This review will address our current understanding of the many roles of ceramide, S1P and C1P in the regulation of cell growth and survival with special emphasis to the emerging role of these molecules and their metabolizing enzymes in controlling tumor progression and metastasis. PMID:21566746

Early Brain Injury Associated with Systemic Inflammation After Subarachnoid Hemorrhage.

PubMed

Savarraj, Jude; Parsha, Kaushik; Hergenroeder, Georgene; Ahn, Sungho; Chang, Tiffany R; Kim, Dong H; Choi, H Alex

2018-04-01

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) is defined as brain injury occurring within 72 h of aneurysmal rupture. Although EBI is the most significant predictor of outcomes after aSAH, its underlying pathophysiology is not well understood. We hypothesize that EBI after aSAH is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes in associations between cytokines. aSAH patients were enrolled into a prospective observational study and were assessed for markers of EBI: global cerebral edema (GCE), subarachnoid hemorrhage early brain edema score (SEBES), and Hunt-Hess grade. Serum samples collected at ≤ 48 h of admission were analyzed using multiplex bead-based assays to determine levels of 13 pro- and anti-inflammatory cytokines. Pairwise correlation coefficients between cytokines were represented as networks. Cytokine levels and differences in correlation networks were compared between EBI groups. Of the 71 patients enrolled in the study, 17 (24%) subjects had GCE, 31 (44%) subjects had SEBES ≥ 3, and 21 (29%) had HH ≥ 4. IL-6 was elevated in groups with GCE, SEBES ≥ 3, and HH ≥ 4. MIP1β was independently associated with high-grade SEBES. Correlation network analysis suggests higher systematic inflammation in subjects with SEBES ≥ 3. EBI after SAH is associated with increased levels of specific cytokines. Peripheral levels of IL-10, IL-6, and MIP1β may be important markers of EBI. Investigating systematic correlations in addition to expression levels of individual cytokines may offer deeper insight into the underlying mechanisms related to EBI.

Relation of RhoA in Peripheral Blood Mononuclear Cells With Severity of Aneurysmal Subarachnoid Hemorrhage and Vasospasm.

PubMed

González-Montelongo, María Del Carmen; Egea-Guerrero, Juan José; Murillo-Cabezas, Francisco; González-Montelongo, Rafaela; Ruiz de Azúa-López, Zaida; Rodríguez-Rodríguez, Ana; Vilches-Arenas, Angel; Castellano, Antonio; Ureña, Juan

2018-06-01

Rho-kinase, an effector of RhoA, is associated with various cardiovascular diseases in circulating blood cells. However, the role of RhoA/Rho-kinase in peripheral blood mononuclear cells from patients with spontaneous aneurysmal subarachnoid hemorrhage (aSAH) has not yet been studied in relation to the severity of this disease. Therefore, we analyzed the expression and activity of RhoA as a possible biomarker in aSAH. Twenty-four patients with aSAH and 15 healthy subjects were examined. Peripheral blood mononuclear cells were collected, and RhoA activity and expression were determined by RhoA activation assay kit (G-LISA) and enzyme-linked immunosorbent assay tests, respectively. The severity of aSAH was determined from the World Federation of Neurological Surgeon scale, and vasospasm was evaluated using clinical symptoms, arteriography, and sonography. RhoA expression was significantly increased in peripheral blood mononuclear cells from patients on days 0, 2, and 4 after aSAH versus healthy subjects ( P =0.036, 0.010, and 0.018, respectively, by U Mann-Whitney analysis). There was a significant correlation between RhoA expression and injury severity on days 2 and 4 (Spearman test, day 2: r =0.682, n=14, P =0.007; day 4: r =0.721, n=14, P =0.004). No significant correlation was observed on day 0 (day 0: r =0.131, n=6, P =0.805). Active RhoA was not significantly different in patients and healthy subjects on days 0, 2, and 4 ( P =0.243, 0.222, and 0.600, respectively) nor did it increase significantly on days 0 and 2 in patients with vasospasm versus patients without vasospasm ( P =0.064 and 0.519, respectively). In contrast, active RhoA was significantly higher on day 4 in patients who developed vasospasm versus patients without vasospasm ( P =0.028). Our preliminary results indicate that RhoA expression and activity in peripheral blood mononuclear cells might be related with aSAH severity and cerebral vasospasm. RhoA is a potential biomarker of the risks

Incidence, epidemiology, and treatment of aneurysmal subarachnoid hemorrhage in 12 midwest communities.

PubMed

Ziemba-Davis, Mary; Bohnstedt, Bradley N; Payner, Troy D; Leipzig, Thomas J; Palmer, Erin; Cohen-Gadol, Aaron A

2014-01-01

Only 8 studies have investigated the incidence and epidemiology of aneurysmal subarachnoid hemorrhage (aSAH) in the United States. This is the first investigation in Indiana, which has some of the highest rates of tobacco smoking and obesity in the nation. The authors prospectively identified 441 consecutive patients with aSAH from 2005 to 2010 at 2 hospitals where the majority of cases are treated. Incidence calculations were based on US Census populations. Epidemiologic variables included demography; risk factors; Hunt and Hess scale; Fisher grade; number, location, and size of aneurysms; treatment type; and complications. Overall incidence was 21.8 per 100,000 population. Incidence was higher in women, increased with age, and did not vary by race. One third to half of patients were hypertensive and/or smoked cigarettes at the time of ictus. Variations by count were partially explained by Health Factor and Morbidity Rankings. Complications varied by treatment. These findings deviate from estimates that 6-16 per 100,000 people in the United States will develop aSAH and are double the incidence in a Minnesota population between 1945 and 1974. The results also deviate from the worldwide estimate of 9.0 aSAHs per 100,000 person-years. The predictive value of variations in Health Factor and Morbidity Rankings implicates the importance of future research on multivariate biopsychosocial causation of aSAH. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Aneurysmal SubArachnoid Hemorrhage—Red Blood Cell Transfusion And Outcome (SAHaRA): a pilot randomised controlled trial protocol

PubMed Central

English, Shane W; Fergusson, D; Chassé, M; Lauzier, F; Griesdale, D; Algird, A; Kramer, A; Tinmouth, A; Lum, C; Sinclair, J; Marshall, S; Dowlatshahi, D; Boutin, A; Pagliarello, G; McIntyre, L A

2016-01-01

Introduction Anaemia is common in aneurysmal subarachnoid haemorrhage (aSAH) and is a potential critical modifiable factor affecting secondary injury. Despite physiological evidence and management guidelines that support maintaining a higher haemoglobin level in patients with aSAH, current practice is one of a more restrictive approach to transfusion. The goal of this multicentre pilot trial is to determine the feasibility of successfully conducting a red blood cell (RBC) transfusion trial in adult patients with acute aSAH and anaemia (Hb ≤100 g/L), comparing a liberal transfusion strategy (Hb ≤100 g/L) with a restrictive strategy (Hb ≤80 g/L) on the combined rate of death and severe disability at 12 months. Methods Design This is a multicentre open-label randomised controlled pilot trial at 5 academic tertiary care centres. Population We are targeting adult aSAH patients within 14 days of their initial bleed and with anaemia (Hb ≤110 g/L). Randomisation Central computer-generated randomisation, stratified by centre, will be undertaken from the host centre. Randomisation into 1 of the 2 treatment arms will occur when the haemoglobin levels of eligible patients fall to ≤100 g/L. Intervention Patients will be randomly assigned to either a liberal (threshold: Hb ≤100 g/L) or a restrictive transfusion strategy (threshold: Hb ≤80 g/L). Outcome Primary: Centre randomisation rate over the study period. Secondary: (1) transfusion threshold adherence; (2) study RBC transfusion protocol adherence; and (3) outcome assessment including vital status at hospital discharge, modified Rankin Score at 6 and 12 months and Functional Independence Measure and EuroQOL Quality of Life Scale scores at 12 months. Outcome measures will be reported in aggregate. Ethics and dissemination The study protocol has been approved by the host centre (OHSN-REB 20150433-01H). This study will determine the feasibility of conducting the large pragmatic RCT comparing 2

Effects of decompressive craniectomy on functional outcomes and death in poor-grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

PubMed

Alotaibi, Naif M; Elkarim, Ghassan Awad; Samuel, Nardin; Ayling, Oliver G S; Guha, Daipayan; Fallah, Aria; Aldakkan, Abdulrahman; Jaja, Blessing N R; de Oliveira Manoel, Airton Leonardo; Ibrahim, George M; Macdonald, R Loch

2017-12-01

OBJECTIVE Patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) (World Federation of Neurosurgical Societies Grade IV or V) are often considered for decompressive craniectomy (DC) as a rescue therapy for refractory intracranial hypertension. The authors performed a systematic review and meta-analysis to assess the impact of DC on functional outcome and death in patients after poor-grade aSAH. METHODS A systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles were identified through the Ovid Medline, Embase, Web of Science, and Cochrane Library databases from inception to October 2015. Only studies dedicated to patients with poor-grade aSAH were included. Primary outcomes were death and functional outcome assessed at any time period. Patients were grouped as having a favorable outcome (modified Rankin Scale [mRS] Scores 1-3, Glasgow Outcome Scale [GOS] Scores 4 and 5, extended Glasgow Outcome Scale [GOSE] Scores 5-8) or unfavorable outcome (mRS Scores 4-6, GOS Scores 1-3, GOSE Scores 1-4). Pooled estimates of event rates and odds ratios with 95% confidence intervals were calculated using the random-effects model. RESULTS Fifteen studies encompassing 407 patients were included in the meta-analysis (all observational cohorts). The pooled event rate for poor outcome across all studies was 61.2% (95% CI 52%-69%) and for death was 27.8% (95% CI 21%-35%) at a median of 12 months after aSAH. Primary (or early) DC resulted in a lower overall event rate for unfavorable outcome than secondary (or delayed) DC (47.5% [95% CI 31%-64%] vs 74.4% [95% CI 43%-91%], respectively). Among studies with comparison groups, there was a trend toward a reduced mortality rate 1-3 months after discharge among patients who did not undergo DC (OR 0.58 [95% CI 0.27-1.25]; p = 0.168). However, this trend was not sustained at the 1-year follow-up (OR 1.09 [95% CI 0

40 CFR 721.10690 - Benzenedicarboxylic acid, polymer with substituted alkanediol, dodecanedioic acid, 1,2-ethanediol...

Code of Federal Regulations, 2014 CFR

2014-07-01

..., alkanediol,.alpha.-hydro-.omega.-hydroxypoly[oxyalkanediyl], 1,3-isobenzofurandione, methylene diphenyl...-ethanediol, alkanedioic acid, alkanediol,.alpha.-hydro-.omega.-hydroxypoly[oxyalkanediyl], 1,3... substituted alkanediol, dodecanedioic acid, 1,2-ethanediol, alkanedioic acid, alkanediol,.alpha.-hydro-.omega...

Interactive Effects of Jasmonic Acid, Salicylic Acid, and Gibberellin on Induction of Trichomes in Arabidopsis1

PubMed Central

Traw, M. Brian; Bergelson, Joy

2003-01-01

Leaf trichomes protect plants from attack by insect herbivores and are often induced following damage. Hormonal regulation of this plant induction response has not been previously studied. In a series of experiments, we addressed the effects of artificial damage, jasmonic acid, salicylic acid, and gibberellin on induction of trichomes in Arabidopsis. Artificial damage and jasmonic acid caused significant increases in trichome production of leaves. The jar1-1 mutant exhibited normal trichome induction following treatment with jasmonic acid, suggesting that adenylation of jasmonic acid is not necessary. Salicylic acid had a negative effect on trichome production and consistently reduced the effect of jasmonic acid, suggesting negative cross-talk between the jasmonate and salicylate-dependent defense pathways. Interestingly, the effect of salicylic acid persisted in the nim1-1 mutant, suggesting that the Npr1/Nim1 gene is not downstream of salicylic acid in the negative regulation of trichome production. Last, we found that gibberellin and jasmonic acid had a synergistic effect on the induction of trichomes, suggesting important interactions between these two compounds. PMID:14551332

Modification on ursodeoxycholic acid (UDCA) scaffold. discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1).

PubMed

Sepe, Valentina; Renga, Barbara; Festa, Carmen; D'Amore, Claudio; Masullo, Dario; Cipriani, Sabrina; Di Leva, Francesco Saverio; Monti, Maria Chiara; Novellino, Ettore; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano

2014-09-25

Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3α,7β-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.

Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage

PubMed Central

2010-01-01

Background Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. Methods We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients. Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. Results The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). Conclusion We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. Although generalizability of the model is limited due to the selected population in which it was developed, this model could eventually be used to support clinical decision making after external validation. Trial Registration International Standard Randomised Controlled Trial, Number ISRCTN49866681 PMID:20920243

77 FR 15357 - 1-Hydroxyethylidene-1, 1-Diphosphonic Acid From India: Final Results of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-15

...-Diphosphonic Acid From India: Final Results of Antidumping Duty Administrative Review AGENCY: Import... the antidumping duty order on 1-Hydroxyethylidene-1, 1-Diphosphonic Acid from India. The review covers...-Diphosphonic Acid from India (76 FR 78237). We invited parties to comment on the preliminary results of the...

Impaired muscle strength may contribute to fatigue in patients with aneurysmal subarachnoid hemorrhage.

PubMed

Harmsen, Wouter J; Ribbers, Gerard M; Zegers, Bart; Sneekes, Emiel M; Praet, Stephan F E; Heijenbrok-Kal, Majanka H; Khajeh, Ladbon; van Kooten, Fop; Neggers, Sebastiaan J C M M; van den Berg-Emons, Rita J

2017-03-01

Patients with aneurysmal subarachnoid hemorrhage (a-SAH) show long-term fatigue and face difficulties in resuming daily physical activities. Impaired muscle strength, especially of the lower extremity, impacts the performance of daily activities and may trigger the onset of fatigue complaints. The present study evaluated knee muscle strength and fatigue in patients with a-SAH. This study included 33 patients, 6 months after a-SAH, and 33 sex-matched and age-matched healthy controls. Isokinetic muscle strength of the knee extensors and flexors was measured at 60 and 180°/s. Maximal voluntary muscle strength was defined as peak torque and measured in Newton-meter. Fatigue was examined using the Fatigue Severity Scale. In patients with a-SAH, the maximal knee extension was 22% (60°/s) and 25% (180°/s) lower and maximal knee flexion was 33% (60°/s) and 36% (180°/s) lower compared with that of matched controls (P≤0.001). The Fatigue Severity Scale score was related to maximal knee extension (60°/s: r=-0.426, P=0.015; 180°/s: r=-0.376, P=0.034) and flexion (60°/s: r=-0.482, P=0.005; 180°/s: r=-0.344, P=0.083). The knee muscle strength was 28-47% lower in fatigued (n=13) and 11-32% lower in nonfatigued (n=20) patients; deficits were larger in fatigued patients (P<0.05), particularly when the muscle strength (peak torque) was measured at 60°/s. The present results indicate that patients with a-SAH have considerably impaired knee muscle strength, which is related to more severe fatigue. The present findings are exploratory, but showed that knee muscle strength may play a role in the severity of fatigue complaints, or vice versa. Interventions targeting fatigue after a-SAH seem necessary and may consider strengthening exercise training in order to treat a debilitating condition.

Supramolecular architectures in two 1:1 cocrystals of 5-fluorouracil with 5-bromothiophene-2-carboxylic acid and thiophene-2-carboxylic acid.

PubMed

Mohana, Marimuthu; Thomas Muthiah, Packianathan; McMillen, Colin D

2017-06-01

In solid-state engineering, cocrystallization is a strategy actively pursued for pharmaceuticals. Two 1:1 cocrystals of 5-fluorouracil (5FU; systematic name: 5-fluoro-1,3-dihydropyrimidine-2,4-dione), namely 5-fluorouracil-5-bromothiophene-2-carboxylic acid (1/1), C 5 H 3 BrO 2 S·C 4 H 3 FN 2 O 2 , (I), and 5-fluorouracil-thiophene-2-carboxylic acid (1/1), C 4 H 3 FN 2 O 2 ·C 5 H 4 O 2 S, (II), have been synthesized and characterized by single-crystal X-ray diffraction studies. In both cocrystals, carboxylic acid molecules are linked through an acid-acid R 2 2 (8) homosynthon (O-H...O) to form a carboxylic acid dimer and 5FU molecules are connected through two types of base pairs [homosynthon, R 2 2 (8) motif] via a pair of N-H...O hydrogen bonds. The crystal structures are further stabilized by C-H...O interactions in (II) and C-Br...O interactions in (I). In both crystal structures, π-π stacking and C-F...π interactions are also observed.

78 FR 38941 - 1-Hydroxyethylidene-1, 1-Diphosphonic Acid From India: Rescission of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-28

... DEPARTMENT OF COMMERCE International Trade Administration [A-533-847] 1-Hydroxyethylidene-1, 1-Diphosphonic Acid From India: Rescission of Antidumping Duty Administrative Review; 2012-2013 AGENCY: Import...- hydroxyethylidene-1, 1-diphosphonic acid (HEDP) from India for the period of review (POR) of April 1, 2012, through...

Novel Three-Component Phenazine-1-Carboxylic Acid 1,2-Dioxygenase in Sphingomonas wittichii DP58

PubMed Central

Zhao, Qiang; Wang, Wei; Huang, Xian-Qing; Zhang, Xue-Hong

2017-01-01

ABSTRACT Phenazine-1-carboxylic acid, the main component of shenqinmycin, is widely used in southern China for the prevention of rice sheath blight. However, the fate of phenazine-1-carboxylic acid in soil remains uncertain. Sphingomonas wittichii DP58 can use phenazine-1-carboxylic acid as its sole carbon and nitrogen sources for growth. In this study, dioxygenase-encoding genes, pcaA1A2, were found using transcriptome analysis to be highly upregulated upon phenazine-1-carboxylic acid biodegradation. PcaA1 shares 68% amino acid sequence identity with the large oxygenase subunit of anthranilate 1,2-dioxygenase from Rhodococcus maanshanensis DSM 44675. The dioxygenase was coexpressed in Escherichia coli with its adjacent reductase-encoding gene, pcaA3, and ferredoxin-encoding gene, pcaA4, and showed phenazine-1-carboxylic acid consumption. The dioxygenase-, ferredoxin-, and reductase-encoding genes were expressed in Pseudomonas putida KT2440 or E. coli BL21, and the three recombinant proteins were purified. A phenazine-1-carboxylic acid conversion capability occurred in vitro only when all three components were present. However, P. putida KT2440 transformed with pcaA1A2 obtained phenazine-1-carboxylic acid degradation ability, suggesting that phenazine-1-carboxylic acid 1,2-dioxygenase has low specificities for its ferredoxin and reductase. This was verified by replacing PcaA3 with RedA2 in the in vitro enzyme assay. High-performance liquid chromatography–mass spectrometry (HPLC-MS) and nuclear magnetic resonance (NMR) analysis showed that phenazine-1-carboxylic acid was converted to 1,2-dihydroxyphenazine through decarboxylation and hydroxylation, indicating that PcaA1A2A3A4 constitutes the initial phenazine-1-carboxylic acid 1,2-dioxygenase. This study fills a gap in our understanding of the biodegradation of phenazine-1-carboxylic acid and illustrates a new dioxygenase for decarboxylation. IMPORTANCE Phenazine-1-carboxylic acid is widely used in southern China

Inactivation of H1N1 viruses exposed to acidic ozone water

NASA Astrophysics Data System (ADS)

Uhm, Han S.; Lee, Kwang H.; Seong, Baik L.

2009-10-01

The inactivation of H1N1 viruses upon exposure to acidic ozone water was investigated using chicken allantoic fluids of different dilutions, pH values, and initial ozone concentrations. The inactivation effect of the acidic ozone water was found to be stronger than the inactivation effect of the ozone water combined with the degree of acidity, indicating a synergic effect of acidity on ozone decay in water. It is also shown that acidic ozone water with a pH value of 4 or less is very effective means of virus inactivation if provided in conjunction with an ozone concentration of 20 mg/l or higher.

Chemoselective synthesis of sialic acid 1,7-lactones.

PubMed

Allevi, Pietro; Rota, Paola; Scaringi, Raffaella; Colombo, Raffaele; Anastasia, Mario

2010-08-20

The chemoselective synthesis of the 1,7-lactones of N-acetylneuraminic acid, N-glycolylneuraminic acid, and 3-deoxy-d-glycero-d-galacto-nononic acid is accomplished in two steps: a simple treatment of the corresponding free sialic acid with benzyloxycarbonyl chloride and a successive hydrogenolysis of the formed 2-benzyloxycarbonyl 1,7-lactone. The instability of the 1,7-lactones to protic solvents has been also evidenced together with the rationalization of the mechanism of their formation under acylation conditions. The results permit to dispose of authentic 1,7-sialolactones to be used as reference standards and of a procedure useful for the preparation of their isotopologues to be used as inner standards in improved analytical procedures for the gas liquid chromatography-mass spectrometry (GLC-MS) analysis of 1,7-sialolactones in biological media.

Benzamide-picric acid (1/1).

PubMed

Sivaramkumar, M S; Velmurugan, R; Sekar, M; Ramesh, P; Ponnuswamy, M N

2010-06-26

In the title compound, C(7)H(7)NO·C(6)H(3)N(3)O(7), one of the nitro groups of the picric acid mol-ecule lies in the plane of the attached benzene ring [dihedral angle = 1.4 (1)°] while the other two are twisted away by 9.9 (1) and 30.3 (1)°. In the benzamide mol-ecule, the amide group is almost coplanar with the benzene ring [dihedral angle = 4.4 (1)°]. An intra-molecular O-H⋯O hydrogen bond generates an S6 ring motif. In the crystal, mol-ecules are linked into a ribbon-like structure along the b axis by O-H⋯O and N-H⋯O inter-molecular hydrogen bonds. In addition, C-H⋯O hydrogen bonds and short O⋯O contacts [2.828 (2) Å] are observed.

External Ventricular Drain and Hemorrhage in Aneurysmal Subarachnoid Hemorrhage Patients on Dual Antiplatelet Therapy: A Retrospective Cohort Study.

PubMed

Hudson, Joseph S; Prout, Benjamin S; Nagahama, Yasunori; Nakagawa, Daichi; Guerrero, Waldo R; Zanaty, Mario; Chalouhi, Nohra; Jabbour, Pascal; Dandapat, Sudeepta; Allan, Lauren; Ortega-Gutierrez, Santiago; Samaniego, Edgar A; Hasan, David

2018-04-11

Stenting and flow diversion for aneurysmal sub arachnoid hemorrhage (aSAH) require the use of dual antiplatelet therapy (DAPT). To investigate whether DAPT is associated with hemorrhagic complication following placement of external ventricular drains (EVD) in patients with aSAH. Rates of radiographically identified hemorrhage associated with EVD placement were compared between patients who received DAPT for stenting or flow diversion, and patients who underwent microsurgical clipping or coiling and did not receive DAPT by way of a backward stepwise multivariate analysis. Four hundred forty-three patients were admitted for aSAH management. Two hundred ninety-eight patients required placement of an EVD. One hundred twenty patients (40%) were treated with stent-assisted coiling or flow diversion and required DAPT, while 178 patients (60%) were treated with coiling without stents or microsurgical clipping and did not receive DAPT. Forty-two (14%) cases of new hemorrhage along the EVD catheter were identified radiographically. Thirty-two of these hemorrhages occurred in patients on DAPT, while 10 occurred in patients without DAPT. After multivariate analysis, DAPT was significantly associated with radiographic hemorrhage [odds ratio: 4.92, 95% confidence interval: 2.45-9.91, P = .0001]. We did not observe an increased proportion of symptomatic hemorrhage in patients receiving DAPT (10 of 32 [31%]) vs those without (5 of 10 [50%]; P = .4508). Patients with aSAH who receive stent-assisted coiling or flow diversion are at higher risk for radiographic hemorrhage associated with EVD placement. The timing between EVD placement and DAPT initiation does not appear to be of clinical significance. Stenting and flow diversion remain viable options for aSAH patients.

Gallic Acid Inhibited Matrix Invasion and AP-1/ETS-1-Mediated MMP-1 Transcription in Human Nasopharyngeal Carcinoma Cells

PubMed Central

S. Pang, Jong-Hwei; Yen, Jia-Hau; Wu, Hsiao-Ting; Huang, Sheng-Teng

2017-01-01

Gallic acid is a trihydroxybenzoic acid found in natural herbal plants. Gallic acid has been reported to inhibit the migration and invasive capability of various cancers. Little is known about the underlying mechanisms of invasion responsible for cancer metastasis via gallic acid. The present study was intended to investigate the anti-invasive effect of gallic acid on human nasopharyngeal carcinoma cells (NPC-BM1) and its related mechanism. Gallic acid inhibited the invasion of NPC-BM1 cells dose- and time-dependently without significant cytotoxic effect. Affymetrix oligonucleotide microarray analysis revealed matrix metalloproteinase-1 (MMP-1) as the most down-regulated gene in NPC-BM1 cells by gallic acid. The cytosolic and secreted MMP-1 levels were both found to be inhibited by gallic acid as demonstrated by western blot analysis and ELISA respectively. The mRNA expression and transcription of MMP-1 gene was also down-regulated as determined by RT/real-time PCR and promoter activity assay. The expression of two major transcription binding factors in the MMP-1 promoter, AP-1 and ETS-1, were demonstrated to be reduced by gallic acid in NPC-BM1 cells. The effect of gallic acid was associated with the inhibition of p38 MAPK signaling pathway. In addition, gallic acid enhanced the gene expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) which further suppressed the MMP-1 activity. These findings may be useful to develop a novel chemotherapeutic agent to inhibit the metastasis of nasopharyngeal cancer. PMID:28672814

Gallic Acid Inhibited Matrix Invasion and AP-1/ETS-1-Mediated MMP-1 Transcription in Human Nasopharyngeal Carcinoma Cells.

PubMed

Pang, Jong-Hwei S; Yen, Jia-Hau; Wu, Hsiao-Ting; Huang, Sheng-Teng

2017-06-24

Gallic acid is a trihydroxybenzoic acid found in natural herbal plants. Gallic acid has been reported to inhibit the migration and invasive capability of various cancers. Little is known about the underlying mechanisms of invasion responsible for cancer metastasis via gallic acid. The present study was intended to investigate the anti-invasive effect of gallic acid on human nasopharyngeal carcinoma cells (NPC-BM1) and its related mechanism. Gallic acid inhibited the invasion of NPC-BM1 cells dose- and time-dependently without significant cytotoxic effect. Affymetrix oligonucleotide microarray analysis revealed matrix metalloproteinase-1 (MMP-1) as the most down-regulated gene in NPC-BM1 cells by gallic acid. The cytosolic and secreted MMP-1 levels were both found to be inhibited by gallic acid as demonstrated by western blot analysis and ELISA respectively. The mRNA expression and transcription of MMP-1 gene was also down-regulated as determined by RT/real-time PCR and promoter activity assay. The expression of two major transcription binding factors in the MMP-1 promoter, AP-1 and ETS-1, were demonstrated to be reduced by gallic acid in NPC-BM1 cells. The effect of gallic acid was associated with the inhibition of p38 MAPK signaling pathway. In addition, gallic acid enhanced the gene expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) which further suppressed the MMP-1 activity. These findings may be useful to develop a novel chemotherapeutic agent to inhibit the metastasis of nasopharyngeal cancer.

Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells.

PubMed

Lajczak, Natalia K; Saint-Criq, Vinciane; O'Dwyer, Aoife M; Perino, Alessia; Adorini, Luciano; Schoonjans, Kristina; Keely, Stephen J

2017-09-01

Bile acids and epithelial-derived human β-defensins (HβDs) are known to be important factors in the regulation of colonic mucosal barrier function and inflammation. We hypothesized that bile acids regulate colonic HβD expression and aimed to test this by investigating the effects of deoxycholic acid (DCA) and ursodeoxycholic acid on the expression and release of HβD1 and HβD2 from colonic epithelial cells and mucosal tissues. DCA (10-150 µM) stimulated the release of both HβD1 and HβD2 from epithelial cell monolayers and human colonic mucosal tissue in vitro In contrast, ursodeoxycholic acid (50-200 µM) inhibited both basal and DCA-induced defensin release. Effects of DCA were mimicked by the Takeda GPCR 5 agonist, INT-777 (50 μM), but not by the farnesoid X receptor agonist, GW4064 (10 μM). INT-777 also stimulated colonic HβD1 and HβD2 release from wild-type, but not Takeda GPCR 5 -/- , mice. DCA stimulated phosphorylation of the p65 subunit of NF-κB, an effect that was attenuated by ursodeoxycholic acid, whereas an NF-κB inhibitor, BMS-345541 (25 μM), inhibited DCA-induced HβD2, but not HβD1, release. We conclude that bile acids can differentially regulate colonic epithelial HβD expression and secretion and discuss the implications of our findings for intestinal health and disease.-Lajczak, N. K., Saint-Criq, V., O'Dwyer, A. M., Perino, A., Adorini, L., Schoonjans, K., Keely, S. J. Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells. © FASEB.

Benzamide–picric acid (1/1)

PubMed Central

Sivaramkumar, M. S.; Velmurugan, R.; Sekar, M.; Ramesh, P.; Ponnuswamy, M. N.

2010-01-01

In the title compound, C7H7NO·C6H3N3O7, one of the nitro groups of the picric acid mol­ecule lies in the plane of the attached benzene ring [dihedral angle = 1.4 (1)°] while the other two are twisted away by 9.9 (1) and 30.3 (1)°. In the benzamide mol­ecule, the amide group is almost coplanar with the benzene ring [dihedral angle = 4.4 (1)°]. An intra­molecular O—H⋯O hydrogen bond generates an S6 ring motif. In the crystal, mol­ecules are linked into a ribbon-like structure along the b axis by O—H⋯O and N—H⋯O inter­molecular hydrogen bonds. In addition, C—H⋯O hydrogen bonds and short O⋯O contacts [2.828 (2) Å] are observed. PMID:21588027

Single-stranded nucleic acids promote SAMHD1 complex formation.

PubMed

Tüngler, Victoria; Staroske, Wolfgang; Kind, Barbara; Dobrick, Manuela; Kretschmer, Stefanie; Schmidt, Franziska; Krug, Claudia; Lorenz, Mike; Chara, Osvaldo; Schwille, Petra; Lee-Kirsch, Min Ae

2013-06-01

SAM domain and HD domain-containing protein 1 (SAMHD1) is a dGTP-dependent triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs) thereby limiting the intracellular dNTP pool. Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy that mimics congenital viral infection and that phenotypically overlaps with the autoimmune disease systemic lupus erythematosus. Both disorders are characterized by activation of the antiviral cytokine interferon-α initiated by immune recognition of self nucleic acids. Here we provide first direct evidence that SAMHD1 associates with endogenous nucleic acids in situ. Using fluorescence cross-correlation spectroscopy, we demonstrate that SAMHD1 specifically interacts with ssRNA and ssDNA and establish that nucleic acid-binding and formation of SAMHD1 complexes are mutually dependent. Interaction with nucleic acids and complex formation do not require the SAM domain, but are dependent on the HD domain and the C-terminal region of SAMHD1. We finally demonstrate that mutations associated with AGS exhibit both impaired nucleic acid-binding and complex formation implicating that interaction with nucleic acids is an integral aspect of SAMHD1 function.

ALD5, PAD1, ATF1 and ATF2 facilitate the catabolism of coniferyl aldehyde, ferulic acid and p-coumaric acid in Saccharomyces cerevisiae

PubMed Central

Adeboye, Peter Temitope; Bettiga, Maurizio; Olsson, Lisbeth

2017-01-01

The ability of Saccharomyces cerevisiae to catabolize phenolic compounds remains to be fully elucidated. Conversion of coniferyl aldehyde, ferulic acid and p-coumaric acid by S. cerevisiae under aerobic conditions was previously reported. A conversion pathway was also proposed. In the present study, possible enzymes involved in the reported conversion were investigated. Aldehyde dehydrogenase Ald5, phenylacrylic acid decarboxylase Pad1, and alcohol acetyltransferases Atf1 and Atf2, were hypothesised to be involved. Corresponding genes for the four enzymes were overexpressed in a S. cerevisiae strain named APT_1. The ability of APT_1 to tolerate and convert the three phenolic compounds was tested. APT_1 was also compared to strains B_CALD heterologously expressing coniferyl aldehyde dehydrogenase from Pseudomonas, and an ald5Δ strain, all previously reported. APT_1 exhibited the fastest conversion of coniferyl aldehyde, ferulic acid and p-coumaric acid. Using the intermediates and conversion products of each compound, the catabolic route of coniferyl aldehyde, ferulic acid and p-coumaric acid in S. cerevisiae was studied in greater detail. PMID:28205618

Mitochondrial biotransformation of ω-(phenoxy)alkanoic acids, 3-(phenoxy)acrylic acids, and ω-(1-methyl-1H-imidazol-2-ylthio)alkanoic acids: A prodrug strategy for targeting cytoprotective antioxidants to mitochondria

PubMed Central

Roser, Kurt S.; Brookes, Paul S.; Wojtovich, Andrew P.; Olson, Leif P.; Shojaie, Jalil; Parton, Richard L.; Anders, M. W.

2010-01-01

Mitochondrial reactive oxygen species (ROS) generation and the attendant mitochondrial dysfunction are implicated in a range of disease states. The objective of the present studies was to test the hypothesis that the mitochondrial β-oxidation pathway could be exploited to deliver and biotransform the prodrugs ω-(phenoxy)alkanoic acids, 3-(phenoxy)acrylic acids, and ω-(1-methyl-1H-imidazol-2-ylthio)alkanoic acids to the corresponding phenolic antioxidants or methimazole. 3 -and 5-(Phenoxy)alkanoic acids and methyl-substituted analogs were biotransformed to phenols; rates of biotransformation decreased markedly with methyl-group substitution on the phenoxy moiety. 2,6-Dimethylphenol formation from the analogs 3-([2,6-dimethylphenoxy]methylthio)propanoic acid and 3-(2,6-dimethylphenoxy)acrylic acid was greater than that observed with ω-(2,6-dimethylphenoxy)alkanoic acids. 3- and 5-(1-Methyl-1H-imidazol-2-ylthio)alkanoic acids were rapidly biotransformed to the antioxidant methimazole and conferred significant cytoprotection against hypoxia-reoxygenation injury in isolated cardiomyocytes. Both 3-(2,6-dimethylphenoxy)propanoic acid and 3-(2,6-dimethylphenoxy)acrylic acid also afforded cytoprotection against hypoxia-reoxygenation injury in isolated cardiomyocytes. These results demonstrate that mitochondrial β-oxidation is a potentially useful delivery system for targeting antioxidants to mitochondria. PMID:20129794

76 FR 19325 - 1-Hydroxyethylidene-1, 1-Diphosphonic Acid From the People's Republic of China: Preliminary...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-07

...-Diphosphonic Acid From the People's Republic of China: Preliminary Results of Antidumping Duty Administrative... People's Republic of China (``PRC''). The period of review (``POR'') is April 23, 2009, through March 31....\\4\\ \\1\\ See 1-Hydroxyethylidene-1, 1-Diphosphonic Acid from India and the People's Republic of China...

Clinical Outcome Prediction in Aneurysmal Subarachnoid Hemorrhage Using Bayesian Neural Networks with Fuzzy Logic Inferences

PubMed Central

Lo, Benjamin W. Y.; Macdonald, R. Loch; Baker, Andrew; Levine, Mitchell A. H.

2013-01-01

Objective. The novel clinical prediction approach of Bayesian neural networks with fuzzy logic inferences is created and applied to derive prognostic decision rules in cerebral aneurysmal subarachnoid hemorrhage (aSAH). Methods. The approach of Bayesian neural networks with fuzzy logic inferences was applied to data from five trials of Tirilazad for aneurysmal subarachnoid hemorrhage (3551 patients). Results. Bayesian meta-analyses of observational studies on aSAH prognostic factors gave generalizable posterior distributions of population mean log odd ratios (ORs). Similar trends were noted in Bayesian and linear regression ORs. Significant outcome predictors include normal motor response, cerebral infarction, history of myocardial infarction, cerebral edema, history of diabetes mellitus, fever on day 8, prior subarachnoid hemorrhage, admission angiographic vasospasm, neurological grade, intraventricular hemorrhage, ruptured aneurysm size, history of hypertension, vasospasm day, age and mean arterial pressure. Heteroscedasticity was present in the nontransformed dataset. Artificial neural networks found nonlinear relationships with 11 hidden variables in 1 layer, using the multilayer perceptron model. Fuzzy logic decision rules (centroid defuzzification technique) denoted cut-off points for poor prognosis at greater than 2.5 clusters. Discussion. This aSAH prognostic system makes use of existing knowledge, recognizes unknown areas, incorporates one's clinical reasoning, and compensates for uncertainty in prognostication. PMID:23690884

1-Aminocyclopentane-1,2,4-tricarboxylic acids screening on glutamatergic and serotonergic systems.

PubMed

Gelmi, Maria Luisa; Caputo, Francesco; Clerici, Francesca; Pellegrino, Sara; Giannaccini, Gino; Betti, Laura; Fabbrini, Laura; Schmid, Lara; Palego, Lionella; Lucacchini, Antonio

2007-12-15

Enantiopure constrained 1-aminocyclopentane-1,2,4-tricarboxylic acids containing the glutamic acid skeleton were prepared as two diastereomers characterized by having the carboxylic groups in position two and four cis-oriented to each other and trans with respect to 1-carboxylic group and all cis-oriented carboxylic groups, respectively. A biochemical screening of activity of the above amino acids was investigated on glutamate and 5-HT receptors to find a possible metabotropic agonist, acting on the serotoninergic system.

Interaction of humic acids and humic-acid-like polymers with herpes simplex virus type 1

NASA Astrophysics Data System (ADS)

Klöcking, Renate; Helbig, Björn

The study was performed in order to compare the antiviral activity against herpes simplex virus type 1 (HSV-1) of synthetic humic-acid-like polymers to that of their low-molecular-weight basic compounds and naturally occurring humic acids (HA) in vitro. HA from peat water showed a moderate antiviral activity at a minimum effective concentration (MEC) of 20 µg/ml. HA-like polymers, i.e. the oxidation products of caffeic acid (KOP), hydrocaffeic acid (HYKOP), chlorogenic acid (CHOP), 3,4-dihydroxyphenylacetic acid (3,4-DHPOP), nordihydroguaretic acid (NOROP), gentisinic acid (GENOP), pyrogallol (PYROP) and gallic acid (GALOP), generally inhibit virus multiplication, although with different potency and selectivity. Of the substances tested, GENOP, KOP, 3,4-DHPOP and HYKOP with MEC values in the range of 2 to 10 µg/ml, proved to be the most potent HSV-1 inhibitors. Despite its lower antiviral potency (MEC 40 µg/ml), CHOP has a remarkable selectivity due to the high concentration of this polymer that is tolerated by the host cells (>640 µg/ml). As a rule, the antiviral activity of the synthetic compounds was restricted to the polymers and was not preformed in the low-molecular-weight basic compounds. This finding speaks in favour of the formation of antivirally active structures during the oxidative polymerization of phenolic compounds and, indirectly, of corresponding structural parts in different HA-type substances.

Metabolic Conversion of l-Ascorbic Acid to Oxalic Acid in Oxalate-accumulating Plants 1

PubMed Central

Yang, Joan C.; Loewus, Frank A.

1975-01-01

l-Ascorbic acid-1-14C and its oxidation product, dehydro-l-ascorbic acid, produced labeled oxalic acid in oxalate-accumulating plants such as spinach seedlings (Spinacia oleracea) and the detached leaves of woodsorrel (Oxalis stricta and O. oregana), shamrock (Oxalis adenopylla), and begonia (Begonia evansiana). In O. oregana, conversion occurred equally well in the presence or absence of light. This relationship between l-ascorbic acid metabolism and oxalic acid formation must be given careful consideration in attempts to explain oxalic accumulation in plants. PMID:16659288

Agdc1p - a Gallic Acid Decarboxylase Involved in the Degradation of Tannic Acid in the Yeast Blastobotrys (Arxula) adeninivorans.

PubMed

Meier, Anna K; Worch, Sebastian; Böer, Erik; Hartmann, Anja; Mascher, Martin; Marzec, Marek; Scholz, Uwe; Riechen, Jan; Baronian, Kim; Schauer, Frieder; Bode, Rüdiger; Kunze, Gotthard

2017-01-01

Tannins and hydroxylated aromatic acids, such as gallic acid (3,4,5-trihydroxybenzoic acid), are plant secondary metabolites which protect plants against herbivores and plant-associated microorganisms. Some microbes, such as the yeast Arxula adeninivorans are resistant to these antimicrobial substances and are able to use tannins and gallic acid as carbon sources. In this study, the Arxula gallic acid decarboxylase (Agdc1p) which degrades gallic acid to pyrogallol was characterized and its function in tannin catabolism analyzed. The enzyme has a higher affinity for gallic acid (K m -0.7 ± 0.2 mM, k cat -42.0 ± 8.2 s -1 ) than to protocatechuic acid (3,4-dihydroxybenzoic acid) (K m -3.2 ± 0.2 mM, k cat -44.0 ± 3.2 s -1 ). Other hydroxylated aromatic acids, such as 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid are not gallic acid decarboxylase substrates. A. adeninivorans G1212/YRC102-AYNI1-AGDC1, which expresses the AGDC1 gene under the control of the strong nitrate inducible AYNI1 promoter achieved a maximum gallic acid decarboxylase activity of 1064.4 U/l and 97.5 U/g of dry cell weight in yeast grown in minimal medium with nitrate as nitrogen source and glucose as carbon source. In the same medium, gallic acid decarboxylase activity was not detected for the control strain G1212/YRC102 with AGDC1 expression under the control of the endogenous promoter. Gene expression analysis showed that AGDC1 is induced by gallic acid and protocatechuic acid. In contrast to G1212/YRC102-AYNI1-AGDC1 and G1212/YRC102, A. adeninivorans G1234 [Δ agdc1 ] is not able to grow on medium with gallic acid as carbon source but can grow in presence of protocatechuic acid. This confirms that Agdc1p plays an essential role in the tannic acid catabolism and could be useful in the production of catechol and cis,cis -muconic acid. However, the protocatechuic acid catabolism via Agdc1p to catechol seems to be

Overexpression of PAD1 and FDC1 results in significant cinnamic acid decarboxylase activity in Saccharomyces cerevisiae.

PubMed

Richard, Peter; Viljanen, Kaarina; Penttilä, Merja

2015-01-01

The S. cerevisiae PAD1 gene had been suggested to code for a cinnamic acid decarboxylase, converting trans-cinnamic acid to styrene. This was suggested for the reason that the over-expression of PAD1 resulted in increased tolerance toward cinnamic acid, up to 0.6 mM. We show that by over-expression of the PAD1 together with the FDC1 the cinnamic acid decarboxylase activity can be increased significantly. The strain over-expressing PAD1 and FDC1 tolerated cinnamic acid concentrations up to 10 mM. The cooperation of Pad1p and Fdc1p is surprising since the PAD1 has a mitochondrial targeting sequence and the FDC1 codes for a cytosolic protein. The cinnamic acid decarboxylase activity was also seen in the cell free extract. The activity was 0.019 μmol per minute and mg of extracted protein. The overexpression of PAD1 and FDC1 resulted also in increased activity with the hydroxycinnamic acids ferulic acid, p-coumaric acid and caffeinic acid. This activity was not seen when FDC1 was overexpressed alone. An efficient cinnamic acid decarboxylase is valuable for the genetic engineering of yeast strains producing styrene. Styrene can be produced from endogenously produced L-phenylalanine which is converted by a phenylalanine ammonia lyase to cinnamic acid and then by a decarboxylase to styrene.

9-cis Retinoic Acid is the ALDH1A1 Product that Stimulates Melanogenesis

PubMed Central

Paterson, Elyse K.; Ho, Hsiang; Kapadia, Rubina; Ganesan, Anand K.

2013-01-01

Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyzes the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis, and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1A1 product all-trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9-cis retinal and its corresponding product 9-cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA, and melanin. ALDH1A1 depletion inhibited the ability of 9-cis retinal but not 9-cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalyzing the conversion of 9-cis retinal to 9-cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli’s salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9-cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9-cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo. PMID:23489423

Timing of deep vein thrombosis formation after aneurysmal subarachnoid hemorrhage

PubMed Central

Liang, Conrad W.; Su, Kimmy; Liu, Jesse J.; Dogan, Aclan; Hinson, Holly E.

2015-01-01

OBJECT Deep vein thrombosis (DVT) is a common complication of aneurysmal subarachnoid hemorrhage (aSAH). The time period of greatest risk for developing DVT after aSAH is not currently known. aSAH induces a prothrombotic state, which may contribute to DVT formation. Using repeated ultrasound screening, the hypothesis that patients would be at greatest risk for developing DVT in the subacute post-rupture period was tested. METHODS One hundred ninety-eight patients with aSAH admitted to the Oregon Health & Science University Neurosciences Intensive Care Unit between April 2008 and March 2012 were included in a retrospective analysis. Ultrasound screening was performed every 5.2 ± 3.3 days between admission and discharge. The chi-square test was used to compare DVT incidence during different time periods of interest. Patient baseline characteristics as well as stroke severity and hospital complications were evaluated in univariate and multivariate analyses. RESULTS Forty-two (21%) of 198 patients were diagnosed with DVT, and 3 (2%) of 198 patients were symptomatic. Twenty-nine (69%) of the 42 cases of DVT were first detected between Days 3 and 14, compared with 3 cases (7%) detected between Days 0 and 3 and 10 cases (24%) detected after Day 14 (p < 0.05). The postrupture 5-day window of highest risk for DVT development was between Days 5 and 9 (40%, p < 0.05). In the multivariate analysis, length of hospital stay and use of mechanical prophylaxis alone were significantly associated with DVT formation. CONCLUSIONS DVT formation most commonly occurs in the first 2 weeks following aSAH, with detection in this cohort peaking between Days 5 and 9. Chemoprophylaxis is associated with a significantly lower incidence of DVT. PMID:26162047

Incidence of delayed seizures, delayed cerebral ischemia and poor outcome with the use of levetiracetam versus phenytoin after aneurysmal subarachnoid hemorrhage.

PubMed

Karamchandani, Rahul Ramesh; Fletcher, Jeffrey James; Pandey, Aditya Swarup; Rajajee, Venkatakrishna

2014-09-01

Current guidelines recommend against the use of phenytoin following aneurysmal subarachnoid hemorrhage (aSAH) but consider other anticonvulsants, such as levetiracetam, acceptable. Our objective was to evaluate the risk of poor functional outcomes, delayed cerebral ischemia (DCI) and delayed seizures in aSAH patients treated with levetiracetam versus phenytoin. Medical records of patients with aSAH admitted between 2005-2012 receiving anticonvulsant prophylaxis with phenytoin or levetiracetam for >72 hours were reviewed. The primary outcome measure was poor functional outcome, defined as modified Rankin Scale (mRS) score >3 at first recorded follow-up. Secondary outcomes measures included DCI and the incidence of delayed seizures. The association between the use of levetiracetam and phenytoin and the outcomes of interest was studied using logistic regression. Medical records of 564 aSAH patients were reviewed and 259 included in the analysis after application of inclusion/exclusion criteria. Phenytoin was used exclusively in 43 (17%), levetiracetam exclusively in 132 (51%) while 84 (32%) patients were switched from phenytoin to levetiracetam. Six (2%) patients had delayed seizures, 94 (36%) developed DCI and 63 (24%) had mRS score >3 at follow-up. On multivariate analysis, only modified Fisher grade and seizure before anticonvulsant administration were associated with DCI while age, Hunt-Hess grade and presence of intraparenchymal hematoma were associated with mRS score >3. Choice of anticonvulsant was not associated with any of the outcomes of interest. There was no difference in the rate of delayed seizures, DCI or poor functional outcome in patients receiving phenytoin versus levetiracetam after aSAH. The high rate of crossover from phenytoin suggests that levetiracetam may be better tolerated. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Modification of hydroxyapatite with ion-selective complexants: 1-hydroxyethane-1,1-diphosphonic acid

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

Daniels, Yasmine; Lyczko, Nathalie; Nzihou, Ange

Hydroxyapatite (HAP) was modified with 1-hydroxyethane-1,1-diphosphonic acid (HEDP), and its effect on divalent metal ion binding was determined. HAP was synthesized from calcium hydroxide and phosphoric acid. After calcination, it was modified with HEDP, and the influence of time and temperature on the modification was investigated. HEDP incorporation increased as its initial solution concentration increased from 0.01 to 0.50 M. Unmodified and modified HAP were characterized using Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy, and specific surface area analysis. Ca/P ratios, acid capacities, and phosphorus elemental analyses gave the effect of modification on compositionmore » and surface characteristics. A high reaction temperature produced new phosphonate bands at 993, 1082, and 1144 cm –1 that indicated the presence of HEDP. HAP modification at a high temperature–long reaction time had the highest HEDP loading and gave the sharpest XRD peaks. The emergence of new HAP–HEDP strands was observed in SEM images for treated samples while EDS showed high phosphorus contents in these strands. Modified HAP had a high acid capacity from the additional P–OH groups in HEDP. The P(O)OH groups maintain their ability to bind metal ions within the HAP matrix: contacting the modified HAP with 10–4 N nitrate solutions of five transition metal ions gives an affinity sequence of Pb(II) > Cd(II) > Zn(II) > Ni(II) > Cu(II). Here, this result is comparable to that of commercially available di(2-ethylhexyl)phosphoric acid, a common solvent extractant, and the trend is consistent with the Misono softness parameter of metal ion polarizabilities.« less

Modification of hydroxyapatite with ion-selective complexants: 1-hydroxyethane-1,1-diphosphonic acid

DOE PAGES

Daniels, Yasmine; Lyczko, Nathalie; Nzihou, Ange; ...

2014-12-29

Hydroxyapatite (HAP) was modified with 1-hydroxyethane-1,1-diphosphonic acid (HEDP), and its effect on divalent metal ion binding was determined. HAP was synthesized from calcium hydroxide and phosphoric acid. After calcination, it was modified with HEDP, and the influence of time and temperature on the modification was investigated. HEDP incorporation increased as its initial solution concentration increased from 0.01 to 0.50 M. Unmodified and modified HAP were characterized using Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy, and specific surface area analysis. Ca/P ratios, acid capacities, and phosphorus elemental analyses gave the effect of modification on compositionmore » and surface characteristics. A high reaction temperature produced new phosphonate bands at 993, 1082, and 1144 cm –1 that indicated the presence of HEDP. HAP modification at a high temperature–long reaction time had the highest HEDP loading and gave the sharpest XRD peaks. The emergence of new HAP–HEDP strands was observed in SEM images for treated samples while EDS showed high phosphorus contents in these strands. Modified HAP had a high acid capacity from the additional P–OH groups in HEDP. The P(O)OH groups maintain their ability to bind metal ions within the HAP matrix: contacting the modified HAP with 10–4 N nitrate solutions of five transition metal ions gives an affinity sequence of Pb(II) > Cd(II) > Zn(II) > Ni(II) > Cu(II). Here, this result is comparable to that of commercially available di(2-ethylhexyl)phosphoric acid, a common solvent extractant, and the trend is consistent with the Misono softness parameter of metal ion polarizabilities.« less

Subarachnoid Hemorrhage and Readmissions: National Rates, Causes, Risk Factors, and Outcomes in 16,001 Hospitalized Patients.

PubMed

Rumalla, Kavelin; Smith, Kyle A; Arnold, Paul M; Mittal, Manoj K

2018-02-01

The acute complications of aneurysmal subarachnoid hemorrhage (aSAH) often lead to readmissions, which are linked to hospital reimbursement. The national rates, causes, risk factors, and outcomes associated with 30-day and 90-day readmission after aSAH have not previously been reported. The Nationwide Readmissions Database was queried from January to September 2013 for all patients (age ≥18 years) with a diagnosis of aSAH. Data points included demographics, comorbidities, complications, and discharge outcomes. Causes and risk factors for 30-day and 90-day readmission were identified in univariate and multivariable analysis. In 12,777 patients discharged alive after hospitalization for aSAH, 962 (7.5%) were readmitted within 30 days and 2153 (16.7%) within 90 days. Common causes of readmission included stroke, hydrocephalus, septicemia, and headache. At 30-day and 90-day readmission, 39.7% and 51.2% of patients with diagnosis of hydrocephalus underwent ventriculoperitoneal shunt placement, respectively. In multivariable analysis, cannabis use and diabetes were predictors of both 30-day and 90-day readmission and older patients were uniquely susceptible to 30-day readmissions. Risk factors for 90-day readmission included Medicare insurance, hypothyroidism, initial discharge to skilled nursing facility, and several index complications including bowel obstruction, gastrostomy, acute lung injury, and cerebral edema. Average cost and length of stay were calculated at 30-day ($16.647, 7.1 days) and 90-day readmission ($17,926, 6.7 days). Mortality was 2.8% within 30 days and 3.8% within 90 days. Many readmissions occur outside the 30-day follow-up period in patients subarachnoid hemorrhage and possess unique risk factors, which may help identify high-risk patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Net alkalinity and net acidity 1: Theoretical considerations

USGS Publications Warehouse

Kirby, C.S.; Cravotta, C.A.

2005-01-01

Net acidity and net alkalinity are widely used, poorly defined, and commonly misunderstood parameters for the characterization of mine drainage. The authors explain theoretical expressions of 3 types of alkalinity (caustic, phenolphthalein, and total) and acidity (mineral, CO2, and total). Except for rarely-invoked negative alkalinity, theoretically defined total alkalinity is closely analogous to measured alkalinity and presents few practical interpretation problems. Theoretically defined "CO 2-acidity" is closely related to most standard titration methods with an endpoint pH of 8.3 used for determining acidity in mine drainage, but it is unfortunately named because CO2 is intentionally driven off during titration of mine-drainage samples. Using the proton condition/mass- action approach and employing graphs to illustrate speciation with changes in pH, the authors explore the concept of principal components and how to assign acidity contributions to aqueous species commonly present in mine drainage. Acidity is defined in mine drainage based on aqueous speciation at the sample pH and on the capacity of these species to undergo hydrolysis to pH 8.3. Application of this definition shows that the computed acidity in mg L -1 as CaCO3 (based on pH and analytical concentrations of dissolved FeII, FeIII, Mn, and Al in mg L -1):aciditycalculated=50{1000(10-pH)+[2(FeII)+3(FeIII)]/56+2(Mn)/ 55+3(Al)/27}underestimates contributions from HSO4- and H+, but overestimates the acidity due to Fe3+ and Al3+. However, these errors tend to approximately cancel each other. It is demonstrated that "net alkalinity" is a valid mathematical construction based on theoretical definitions of alkalinity and acidity. Further, it is shown that, for most mine-drainage solutions, a useful net alkalinity value can be derived from: (1) alkalinity and acidity values based on aqueous speciation, (2) measured alkalinity minus calculated acidity, or (3) taking the negative of the value obtained in a

40 CFR 721.3821 - L-Glutamic acid, N-(1-oxododecyl)-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false L-Glutamic acid, N-(1-oxododecyl... Substances § 721.3821 L-Glutamic acid, N-(1-oxododecyl)-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as L-Glutamic acid, N-(1-oxododecyl)- (PMN P...

Korean Clinical Practice Guidelines for Aneurysmal Subarachnoid Hemorrhage

PubMed Central

Cho, Won-Sang; Park, Sukh Que; Ko, Jun Kyeung; Kim, Dae-Won; Park, Jung Cheol; Yeon, Je Young; Chung, Seung Young; Chung, Joonho; Joo, Sung-Pil; Hwang, Gyojun; Kim, Deog Young; Chang, Won Hyuk; Choi, Kyu-Sun; Lee, Sung Ho; Sheen, Seung Hun; Kang, Hyun-Seung; Kim, Byung Moon; Bae, Hee-Joon; Oh, Chang Wan; Park, Hyeon Seon

2018-01-01

Despite advancements in treating ruptured cerebral aneurysms, an aneurysmal subarachnoid hemorrhage (aSAH) is still a grave cerebrovascular disease associated with a high rate of morbidity and mortality. Based on the literature published to date, worldwide academic and governmental committees have developed clinical practice guidelines (CPGs) to propose standards for disease management in order to achieve the best treatment outcomes for aSAHs. In 2013, the Korean Society of Cerebrovascular Surgeons issued a Korean version of the CPGs for aSAHs. The group researched all articles and major foreign CPGs published in English until December 2015 using several search engines. Based on these articles, levels of evidence and grades of recommendations were determined by our society as well as by other related Quality Control Committees from neurointervention, neurology and rehabilitation medicine. The Korean version of the CPGs for aSAHs includes risk factors, diagnosis, initial management, medical and surgical management to prevent rebleeding, management of delayed cerebral ischemia and vasospasm, treatment of hydrocephalus, treatment of medical complications and early rehabilitation. The CPGs are not the absolute standard but are the present reference as the evidence is still incomplete, each environment of clinical practice is different, and there is a high probability of variation in the current recommendations. The CPGs will be useful in the fields of clinical practice and research. PMID:29526058

Oleic acid and linoleic acid from Tenebrio molitor larvae inhibit BACE1 activity in vitro: molecular docking studies.

PubMed

Youn, Kumju; Yun, Eun-Young; Lee, Jinhyuk; Kim, Ji-Young; Hwang, Jae-Sam; Jeong, Woo-Sik; Jun, Mira

2014-02-01

In our ongoing research to find therapeutic compounds for Alzheimer's disease (AD) from natural resources, the inhibitory activity of the BACE1 enzyme by Tenebrio molitor larvae and its major compounds were evaluated. The T. molitor larvae extract and its fractions exhibited strong BACE1 suppression. The major components of hexane fraction possessing both high yield and strong BACE1 inhibition were determined by thin layer chromatography, gas chromatography, and nuclear magnetic resonance analysis. A remarkable composition of unsaturated long chain fatty acids, including oleic acid and linoleic acid, were identified. Oleic acid, in particular, noncompetitively attenuated BACE1 activity with a half-maximal inhibitory concentration (IC₅₀) value of 61.31 μM and Ki value of 34.3 μM. Furthermore, the fatty acids were stably interacted with BACE1 at different allosteric sites of the enzyme bound with the OH of CYS319 and the NH₃ of TYR320 for oleic acid and with the C=O group of GLN304 for linoleic acid. Here, we first revealed novel pharmacophore features of oleic acids and linoleic acid to BACE1 by in silico docking studies. The present findings would clearly suggest potential guidelines for designing novel BACE1 selective inhibitors.

Vibrational spectroscopic study on polymorphism of erucic acid and palmitoleic acid: γ1→α1 and γ→α reversible solid state phase transitions

NASA Astrophysics Data System (ADS)

Kaneko, Fumitoshi; Yamazaki, Kazuhiro; Kobayashi, Masamichi; Sato, Kiyotaka; Suzuki, Masao

1994-08-01

The infrared and Raman spectra of four polymorphic phases (α, α1, γ and γ1) of erucic acid ( cis-13-docosenoic acid) and those of two polymorphic phases (α and γ) of palmitoleic acid ( cis-9-hexadecenoic acid) were investigated. The γ and γ1 phases of erucic acid were analyzed on the basis of crystal structures determined by us. There were large spectral differences between γ and γ1 phases, which could be ascribed to the differences in the conformation of cis-olefin groups and the subcell structure. Two types of reversible solid state phase transitions (γ→α and γ1→α1 transitions) were followed by the infrared and Raman spectra. It was concluded that the mechanism of the γ→α phase transition of erucic and palmitoleic acids is essentially the same as that of oleic acid previously reported by us [ J. Phys. Chem.90, 6371 (1986)], i.e. this phase transition is of order-disorder type accompanied by a conformational disordering at the methyl-terminal chain. Spectral changes on the γ1→α1 transition suggested that a similar structural change took place during this transition but there were large structural differences between α and α1.

Biosynthesis of l-Ascorbic Acid and Conversion of Carbons 1 and 2 of l-Ascorbic Acid to Oxalic Acid Occurs within Individual Calcium Oxalate Crystal Idioblasts1

PubMed Central

Kostman, Todd A.; Tarlyn, Nathan M.; Loewus, Frank A.; Franceschi, Vincent R.

2001-01-01

l-Ascorbic acid (AsA) and its metabolic precursors give rise to oxalic acid (OxA) found in calcium oxalate crystals in specialized crystal idioblast cells in plants; however, it is not known if AsA and OxA are synthesized within the crystal idioblast cell or transported in from surrounding mesophyll cells. Isolated developing crystal idioblasts from Pistia stratiotes were used to study the pathway of OxA biosynthesis and to determine if idioblasts contain the entire path and are essentially independent in OxA synthesis. Idioblasts were supplied with various 14C-labeled compounds and examined by micro-autoradiography for incorporation of 14C into calcium oxalate crystals. [14C]OxA gave heavy labeling of crystals, indicating the isolated idioblasts are functional in crystal formation. Incubation with [1-14C]AsA also gave heavy labeling of crystals, whereas [6-14C]AsA gave no labeling. Labeled precursors of AsA (l-[1-14C]galactose; d-[1-14C]mannose) also resulted in crystal labeling, as did the ascorbic acid analog, d-[1-14C]erythorbic acid. Intensity of labeling of isolated idioblasts followed the pattern OxA > AsA (erythorbic acid) > l-galactose > d-mannose. Our results demonstrate that P. stratiotes crystal idioblasts synthesize the OxA used for crystal formation, the OxA is derived from the number 1 and 2 carbons of AsA, and the proposed pathway of ascorbic acid synthesis via d-mannose and l-galactose is operational in individual P. stratiotes crystal idioblasts. These results are discussed with respect to fine control of calcium oxalate precipitation and the concept of crystal idioblasts as independent physiological compartments. PMID:11161021

Cocrystals of the antimalarial drug 11-azaartemisinin with three alkenoic acids of 1:1 or 2:1 stoichiometry.

PubMed

Nisar, Madiha; Wong, Lawrence W Y; Sung, Herman H Y; Haynes, Richard K; Williams, Ian D

2018-06-01

The stoichiometry, X-ray structures and stability of four pharmaceutical cocrystals previously identified from liquid-assisted grinding (LAG) of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0 4,13 .0 8,13 ]hexadecan-10-one) with trans-cinnamic (Cin), maleic (Mal) and fumaric (Fum) acids are herein reported. trans-Cinnamic acid, a mono acid, forms 1:1 cocrystal 11-Aza:Cin (1, C 15 H 23 NO 4 ·C 9 H 8 O 2 ). Maleic acid forms both 1:1 cocrystal 11-Aza:Mal (2, C 15 H 23 NO 4 ·C 4 H 4 O 4 ), in which one COOH group is involved in self-catenation, and 2:1 cocrystal 11-Aza 2 :Mal (3, 2C 15 H 23 NO 4 ·C 4 H 4 O 4 ). Its isomer, fumaric acid, only affords 2:1 cocrystal 11-Aza 2 :Fum (4). All cocrystal formation appears driven by acid-lactam R 2 2 (8) heterosynthons with short O-H...O=C hydrogen bonds [O...O = 2.56 (2) Å], augmented by weaker C=O...H-N contacts. Despite a better packing efficiency, cocrystal 3 is metastable with respect to 2, probably due to a higher conformational energy for the maleic acid molecule in its structure. In each case, the microcrystalline powders from LAG were useful in providing seeding for the single-crystal growth.

Crystal structures of three co-crystals of 1,2-bis-(pyridin-4-yl)ethane with 4-alk-oxy-benzoic acids: 4-eth-oxy-benzoic acid-1,2-bis-(pyridin-4-yl)ethane (2/1), 4-n-propoxybenzoic acid-1,2-bis(pyridin-4-yl)ethane (2/1) and 4-n-but-oxy-benzoic acid-1,2-bis-(pyridin-4-yl)ethane (2/1).

PubMed

Tabuchi, Yohei; Gotoh, Kazuma; Ishida, Hiroyuki

2015-11-01

The crystal structures of three hydrogen-bonded co-crystals of 4-alk-oxy-benzoic acid-1,2-bis-(pyridin-4-yl)ethane (2/1), namely, 2C9H10O3·C12H12N2, (I), 2C10H12O3·C12H12N2, (II), and 2C11H14O3·C12H12N2, (III), have been determined at 93, 290 and 93 K, respectively. In (I), the asymmetric unit consists of one 4-eth-oxy-benzoic acid mol-ecule and one half-mol-ecule of 1,2-bis-(pyridin-4-yl)ethane, which lies on an inversion centre. In (II) and (III), the asymmetric units each comprise two crystallographically independent 4-alk-oxy-benzoic acid mol-ecules and one 1,2-bis-(pyridin-4-yl)ethane mol-ecule. In each crystal, the two components are linked by O-H⋯N hydrogen bonds, forming a linear hydrogen-bonded 2:1unit of the acid and the base. Similar to the structure of 2:1 unit of (I), the units of (II) and (III) adopt nearly pseudo-inversion symmetry. The 2:1 units of (I), (II) and (III) are linked via C-H⋯O hydrogen bonds, forming tape structures.

No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid.

PubMed

Xiang, Xiaoqiang; Vakkilainen, Juha; Backman, Janne T; Neuvonen, Pertti J; Niemi, Mikko

2011-11-01

To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers. In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1*1A/*1A genotype, seven with the *1B/*1B genotype, and five with the *15/*15 or *5/*15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography-tandem mass spectrometry. The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC(0-12)) in subjects with the SLCO1B1*1B/*1B genotype and in subjects with the SLCO1B1*15/*15 or *5/*15 genotype to the AUC(0-12) in subjects with the SLCO1B1*1A/*1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC(0-24) of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC(0-24) of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC(0-24) of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold (P < 0.05), respectively. Genetic polymorphism in SLCO1B1 does not affect pharmacokinetics of UDCA, suggesting that OATP1B1 is not rate-limiting to the hepatic uptake of therapeutic UDCA. Further studies are required to clarify the mechanisms by which UDCA increases the plasma concentrations of endogenous bile acids.

Agdc1p – a Gallic Acid Decarboxylase Involved in the Degradation of Tannic Acid in the Yeast Blastobotrys (Arxula) adeninivorans

PubMed Central

Meier, Anna K.; Worch, Sebastian; Böer, Erik; Hartmann, Anja; Mascher, Martin; Marzec, Marek; Scholz, Uwe; Riechen, Jan; Baronian, Kim; Schauer, Frieder; Bode, Rüdiger; Kunze, Gotthard

2017-01-01

Tannins and hydroxylated aromatic acids, such as gallic acid (3,4,5-trihydroxybenzoic acid), are plant secondary metabolites which protect plants against herbivores and plant-associated microorganisms. Some microbes, such as the yeast Arxula adeninivorans are resistant to these antimicrobial substances and are able to use tannins and gallic acid as carbon sources. In this study, the Arxula gallic acid decarboxylase (Agdc1p) which degrades gallic acid to pyrogallol was characterized and its function in tannin catabolism analyzed. The enzyme has a higher affinity for gallic acid (Km −0.7 ± 0.2 mM, kcat −42.0 ± 8.2 s−1) than to protocatechuic acid (3,4-dihydroxybenzoic acid) (Km −3.2 ± 0.2 mM, kcat −44.0 ± 3.2 s−1). Other hydroxylated aromatic acids, such as 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid are not gallic acid decarboxylase substrates. A. adeninivorans G1212/YRC102-AYNI1-AGDC1, which expresses the AGDC1 gene under the control of the strong nitrate inducible AYNI1 promoter achieved a maximum gallic acid decarboxylase activity of 1064.4 U/l and 97.5 U/g of dry cell weight in yeast grown in minimal medium with nitrate as nitrogen source and glucose as carbon source. In the same medium, gallic acid decarboxylase activity was not detected for the control strain G1212/YRC102 with AGDC1 expression under the control of the endogenous promoter. Gene expression analysis showed that AGDC1 is induced by gallic acid and protocatechuic acid. In contrast to G1212/YRC102-AYNI1-AGDC1 and G1212/YRC102, A. adeninivorans G1234 [Δagdc1] is not able to grow on medium with gallic acid as carbon source but can grow in presence of protocatechuic acid. This confirms that Agdc1p plays an essential role in the tannic acid catabolism and could be useful in the production of catechol and cis,cis-muconic acid. However, the protocatechuic acid catabolism via Agdc1p to catechol seems to be

WRINKLED1 Rescues Feedback Inhibition of Fatty Acid Synthesis in Hydroxylase-Expressing Seeds1[OPEN

PubMed Central

Browse, John

2016-01-01

Previous attempts at engineering Arabidopsis (Arabidopsis thaliana) to produce seed oils containing hydroxy fatty acids (HFA) have resulted in low yields of HFA compared with the native castor (Ricinus communis) plant and caused undesirable effects, including reduced total oil content. Recent studies have led to an understanding of problems involved in the accumulation of HFA in oils of transgenic plants, which include metabolic bottlenecks and a decrease in the rate of fatty acid synthesis. Focusing on engineering the triacylglycerol assembly mechanisms led to modest increases in the HFA content of seed oil, but much room for improvement still remains. We hypothesized that engineering fatty acid synthesis in the plastids to increase flux would facilitate enhanced total incorporation of fatty acids, including HFA, into seed oil. The transcription factor WRINKLED1 (WRI1) positively regulates the expression of genes involved in fatty acid synthesis and controls seed oil levels. We overexpressed Arabidopsis WRI1 in seeds of a transgenic line expressing the castor fatty acid hydroxylase. The proportion of HFA in the oil, the total HFA per seed, and the total oil content of seeds increased to an average of 20.9%, 1.26 µg, and 32.2%, respectively, across five independent lines, compared with 17.6%, 0.83 µg, and 27.9%, respectively, for isogenic segregants. WRI1 and WRI1-regulated genes involved in fatty acid synthesis were up-regulated, providing for a corresponding increase in the rate of fatty acid synthesis. PMID:27208047

Biosynthesis of Lipoic Acid in Arabidopsis: Cloning and Characterization of the cDNA for Lipoic Acid Synthase1

PubMed Central

Yasuno, Rie; Wada, Hajime

1998-01-01

Lipoic acid is a coenzyme that is essential for the activity of enzyme complexes such as those of pyruvate dehydrogenase and glycine decarboxylase. We report here the isolation and characterization of LIP1 cDNA for lipoic acid synthase of Arabidopsis. The Arabidopsis LIP1 cDNA was isolated using an expressed sequence tag homologous to the lipoic acid synthase of Escherichia coli. This cDNA was shown to code for Arabidopsis lipoic acid synthase by its ability to complement a lipA mutant of E. coli defective in lipoic acid synthase. DNA-sequence analysis of the LIP1 cDNA revealed an open reading frame predicting a protein of 374 amino acids. Comparisons of the deduced amino acid sequence with those of E. coli and yeast lipoic acid synthase homologs showed a high degree of sequence similarity and the presence of a leader sequence presumably required for import into the mitochondria. Southern-hybridization analysis suggested that LIP1 is a single-copy gene in Arabidopsis. Western analysis with an antibody against lipoic acid synthase demonstrated that this enzyme is located in the mitochondrial compartment in Arabidopsis cells as a 43-kD polypeptide. PMID:9808738

A Palmitic Acid Elongase Affects Eicosapentaenoic Acid and Plastidial Monogalactosyldiacylglycerol Levels in Nannochloropsis1

PubMed Central

Dolch, Lina-Juana; Rak, Camille; Broughton, Richard; Leterrier, Marina; Tellier, Frédérique; Faure, Jean-Denis; Falconet, Denis; Jouhet, Juliette

2017-01-01

Nannochloropsis species are oleaginous eukaryotes containing a plastid limited by four membranes, deriving from a secondary endosymbiosis. In Nannochloropsis, thylakoid lipids, including monogalactosyldiacylglycerol (MGDG), are enriched in eicosapentaenoic acid (EPA). The need for EPA in MGDG is not understood. Fatty acids are de novo synthesized in the stroma, then converted into very-long-chain polyunsaturated fatty acids (FAs) at the endoplasmic reticulum (ER). The production of MGDG relies therefore on an EPA supply from the ER to the plastid, following an unknown process. We identified seven elongases and five desaturases possibly involved in EPA production in Nannochloropsis gaditana. Among the six heterokont-specific saturated FA elongases possibly acting upstream in this pathway, we characterized the highly expressed isoform Δ0-ELO1. Heterologous expression in yeast (Saccharomyces cerevisiae) showed that NgΔ0-ELO1 could elongate palmitic acid. Nannochloropsis Δ0-elo1 mutants exhibited a reduced EPA level and a specific decrease in MGDG. In NgΔ0-elo1 lines, the impairment of photosynthesis is consistent with a role of EPA-rich MGDG in nonphotochemical quenching control, possibly providing an appropriate MGDG platform for the xanthophyll cycle. Concomitantly with MGDG decrease, the level of triacylglycerol (TAG) containing medium chain FAs increased. In Nannochloropsis, part of EPA used for MGDG production is therefore biosynthesized by a channeled process initiated at the elongation step of palmitic acid by Δ0-ELO1, thus acting as a committing enzyme for galactolipid production. Based on the MGDG/TAG balance controlled by Δ0-ELO1, this study also provides novel prospects for the engineering of oleaginous microalgae for biotechnological applications. PMID:27895203

Genetics Home Reference: congenital bile acid synthesis defect type 1

MedlinePlus

... type 1 Congenital bile acid synthesis defect type 1 Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Congenital bile acid synthesis defect type 1 ...

Butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1 with high butyric acid yield and selectivity.

PubMed

Kim, Minsun; Kim, Ki-Yeon; Lee, Kyung Min; Youn, Sung Hun; Lee, Sun-Mi; Woo, Han Min; Oh, Min-Kyu; Um, Youngsoon

2016-10-01

The aim of this work was to study the butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1. Results showed that Clostridium sp. S1 produced butyric acid by simultaneously utilizing glucose and mannose in softwood hydrolysate and, more remarkably, it consumed acetic acid in hydrolysate. Clostridium sp. S1 utilized each of glucose, mannose, and xylose as well as mixed sugars simultaneously with partially repressed xylose utilization. When softwood (Japanese larch) hydrolysate containing glucose and mannose as the main sugars was used, Clostridium sp. S1 produced 21.17g/L butyric acid with the yield of 0.47g/g sugar and the selectivity of 1 (g butyric acid/g total acids) owing to the consumption of acetic acid in hydrolysate. The results demonstrate potential of Clostridium sp. S1 to produce butyric acid selectively and effectively from hydrolysate not only by utilizing mixed sugars simultaneously but also by converting acetic acid to butyric acid. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dynamin-dependent amino acid endocytosis activates mechanistic target of rapamycin complex 1 (mTORC1).

PubMed

Shibutani, Shusaku; Okazaki, Hana; Iwata, Hiroyuki

2017-11-03

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis and potential target for modifying cellular metabolism in various conditions, including cancer and aging. mTORC1 activity is tightly regulated by the availability of extracellular amino acids, and previous studies have revealed that amino acids in the extracellular fluid are transported to the lysosomal lumen. There, amino acids induce recruitment of cytoplasmic mTORC1 to the lysosome by the Rag GTPases, followed by mTORC1 activation by the small GTPase Ras homolog enriched in brain (Rheb). However, how the extracellular amino acids reach the lysosomal lumen and activate mTORC1 remains unclear. Here, we show that amino acid uptake by dynamin-dependent endocytosis plays a critical role in mTORC1 activation. We found that mTORC1 is inactivated when endocytosis is inhibited by overexpression of a dominant-negative form of dynamin 2 or by pharmacological inhibition of dynamin or clathrin. Consistently, the recruitment of mTORC1 to the lysosome was suppressed by the dynamin inhibition. The activity and lysosomal recruitment of mTORC1 were rescued by increasing intracellular amino acids via cycloheximide exposure or by Rag overexpression, indicating that amino acid deprivation is the main cause of mTORC1 inactivation via the dynamin inhibition. We further show that endocytosis inhibition does not induce autophagy even though mTORC1 inactivation is known to strongly induce autophagy. These findings open new perspectives for the use of endocytosis inhibitors as potential agents that can effectively inhibit nutrient utilization and shut down the upstream signals that activate mTORC1. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Identification of a novel fatty acid elongase with a wide substrate specificity from arachidonic acid-producing fungus Mortierella alpina 1S-4.

PubMed

Sakuradani, Eiji; Nojiri, Masutoshi; Suzuki, Haruna; Shimizu, Sakayu

2009-09-01

The isolation and characterization of a gene (MALCE1) that encodes a fatty acid elongase from arachidonic acid-producing fungus Mortierella alpina 1S-4 are described. MALCE1 was confirmed to encode a fatty acid elongase by its expression in yeast Saccharomyces cerevisiae, resulting in the accumulation of 18-, 19-, and 20-carbon monounsaturated fatty acids and eicosanoic acid. Furthermore, the MALCE1 yeast transformant efficiently elongated exogenous 9-hexadecenoic acid, 9,12-octadecadienoic acid, and 9,12,15-octadecatrienoic acid. The MALCE1 gene-silenced strain obtained from M. alpina 1S-4 exhibited a low content of octadecanoic acid and a high content of hexadecanoic acid, compared with those in the wild strain. The enzyme encoded by MALCE1 was demonstrated to be involved in the conversion of hexadecanoic acid to octadecanoic acid, its main role in M. alpina 1S-4.

1H NMR-based metabolomics study of liver damage induced by ginkgolic acid (15:1) in mice.

PubMed

Jiang, Lei; Si, Zhi-Hong; Li, Ming-Hui; Zhao, He; Fu, Yong-Hong; Xing, Yue-Xiao; Hong, Wei; Ruan, Ling-Yu; Li, Pu-Min; Wang, Jun-Song

2017-03-20

Ginkgolic acid (15:1) is a major toxic component in extracts obtained from Ginkgo biloba (EGb) that has allergic and genotoxic effects. This study is the first to explore the hepatotoxicity of ginkgolic acid (15:1) using a NMR (nuclear magnetic resonance)-based metabolomics approach in combination with biochemistry assays. Mice were orally administered two doses of ginkgolic acid (15:1), and mouse livers and serum were then collected for NMR recordings and biochemical assays. The levels of activity of alanine aminotransferase (ALT) and glutamic aspartate transaminase (AST) observed in the ginkgolic acid (15:1)-treated mice suggested that it had induced severe liver damage. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) performed to determine the metabolomic profile of mouse liver tissues indicated that many metabolic disturbances, especially oxidative stress and purine metabolism, were induced by ginkgolic acid (15:1). A correlation network analysis combined with information related to structural similarities further confirmed that purine metabolism was disturbed by ginkgolic acid (15:1). This mechanism might represent the link between the antitumour activity and the liver injury-inducing effect of ginkgolic acid (15:1). A SUS (Shared and Unique Structure) plot suggested that a two-dose treatment of ginkgolic acid (15:1) had generally the same effect on metabolic variations but that its effects were dose-dependent, revealing some of the common features of ginkgolic acid (15:1) dosing. This integrated metabolomics approach helped us to characterise ginkgolic acid (15:1)-induced liver damage in mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism*

PubMed Central

Dyachok, Julia; Earnest, Svetlana; Iturraran, Erica N.; Cobb, Melanie H.

2016-01-01

The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cell growth with its nutritional, hormonal, energy, and stress status. Amino acids are critical regulators of mTORC1 that permit other inputs to mTORC1 activity. However, the roles of individual amino acids and their interactions in mTORC1 activation are not well understood. Here we demonstrate that activation of mTORC1 by amino acids includes two discrete and separable steps: priming and activation. Sensitizing mTORC1 activation by priming amino acids is a prerequisite for subsequent stimulation of mTORC1 by activating amino acids. Priming is achieved by a group of amino acids that includes l-asparagine, l-glutamine, l-threonine, l-arginine, l-glycine, l-proline, l-serine, l-alanine, and l-glutamic acid. The group of activating amino acids is dominated by l-leucine but also includes l-methionine, l-isoleucine, and l-valine. l-Cysteine predominantly inhibits priming but not the activating step. Priming and activating steps differ in their requirements for amino acid concentration and duration of treatment. Priming and activating amino acids use mechanisms that are distinct both from each other and from growth factor signaling. Neither step requires intact tuberous sclerosis complex of proteins to activate mTORC1. Concerted action of priming and activating amino acids is required to localize mTORC1 to lysosomes and achieve its activation. PMID:27587390

Cadmium Alters the Concentration of Fatty Acids in THP-1 Macrophages.

PubMed

Olszowski, Tomasz; Gutowska, Izabela; Baranowska-Bosiacka, Irena; Łukomska, Agnieszka; Drozd, Arleta; Chlubek, Dariusz

2018-03-01

Fatty acid composition of human immune cells influences their function. The aim of this study was to evaluate the effects of known toxicant and immunomodulator, cadmium, at low concentrations on levels of selected fatty acids (FAs) in THP-1 macrophages. The differentiation of THP-1 monocytes into macrophages was achieved by administration of phorbol myristate acetate. Macrophages were incubated with various cadmium chloride (CdCl 2 ) solutions for 48 h at final concentrations of 5 nM, 20 nM, 200 nM, and 2 μM CdCl 2 . Fatty acids were extracted from samples according to the Folch method. The fatty acid levels were determined using gas chromatography. The following fatty acids were analyzed: long-chain saturated fatty acids (SFAs) palmitic acid and stearic acid, very long-chain saturated fatty acid (VLSFA) arachidic acid, monounsaturated fatty acids (MUFAs) palmitoleic acid, oleic acid and vaccenic acid, and n-6 polyunsaturated fatty acids (PUFAs) linoleic acid and arachidonic acid. Treatment of macrophages with very low concentrations of cadmium (5-200 nM) resulted in significant reduction in the levels of arachidic, palmitoleic, oleic, vaccenic, and linoleic acids and significant increase in arachidonic acid levels (following exposure to 5 nM Cd), without significant reduction of palmitic and stearic acid levels. Treatment of macrophages with the highest tested cadmium concentration (2 μM) produced significant reduction in the levels of all examined FAs: SFAs, VLSFA, MUFAs, and PUFAs. In conclusion, cadmium at tested concentrations caused significant alterations in THP-1 macrophage fatty acid levels, disrupting their composition, which might dysregulate fatty acid/lipid metabolism thus affecting macrophage behavior and inflammatory state.

Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4).

PubMed

Ziegler, Kerstin; Kerimi, Asimina; Poquet, Laure; Williamson, Gary

2016-06-01

Ferulic acid is released by microbial hydrolysis in the colon, where butyric acid, a major by-product of fermentation, constitutes the main energy source for colonic enterocytes. We investigated how varying concentrations of this short chain fatty acid may influence the absorption of the phenolic acid. Chronic treatment of Caco-2 cells with butyric acid resulted in increased mRNA and protein abundance of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4), previously proposed to facilitate ferulic acid absorption in addition to passive diffusion. Short term incubation with butyric acid only led to upregulation of MCT4 while both conditions increased transepithelial transport of ferulic acid in the apical to basolateral, but not basolateral to apical, direction. Chronic treatment also elevated intracellular concentrations of ferulic acid, which in turn gave rise to increased concentrations of ferulic acid metabolites. Immunofluorescence staining of cells revealed uniform distribution of MCT1 protein in the cell membrane, whereas MCT4 was only detected in the lateral plasma membrane sections of Caco-2 cells. We therefore propose that MCT1 may be acting as an uptake transporter and MCT4 as an efflux system across the basolateral membrane for ferulic acid, and that this process is stimulated by butyric acid. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

40 CFR 721.10122 - 2-Propenoic acid, 2-methyl-, 1,1′-[2-ethyl-2-[[(2-methyl-1-oxo-2-propen-1-yl)oxy]methyl]- 1,3...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false 2-Propenoic acid, 2-methyl-, 1,1â²-[2... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10122 2-Propenoic acid, 2-methyl-, 1,1... new uses subject to reporting. (1) The chemical substance identified as 2-propenoic acid, 2-methyl-, 1...

40 CFR 721.10122 - 2-Propenoic acid, 2-methyl-, 1,1′-[2-ethyl-2-[[(2-methyl-1-oxo-2-propen-1-yl)oxy]methyl]- 1,3...

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false 2-Propenoic acid, 2-methyl-, 1,1â²-[2... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10122 2-Propenoic acid, 2-methyl-, 1,1... new uses subject to reporting. (1) The chemical substance identified as 2-propenoic acid, 2-methyl-, 1...

40 CFR 721.10122 - 2-Propenoic acid, 2-methyl-, 1,1′-[2-ethyl-2-[[(2-methyl-1-oxo-2-propen-1-yl)oxy]methyl]- 1,3...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false 2-Propenoic acid, 2-methyl-, 1,1â²-[2... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10122 2-Propenoic acid, 2-methyl-, 1,1... new uses subject to reporting. (1) The chemical substance identified as 2-propenoic acid, 2-methyl-, 1...

Further Studies on Oxalic Acid Biosynthesis in Oxalate-accumulating Plants 1

PubMed Central

Nuss, Richard F.; Loewus, Frank A.

1978-01-01

l-Ascorbic acid functions as a precursor of oxalic acid in several oxalate-accumulating plants. The present study extends this observation to include Rumex crispus L. (curly dock), Amaranthus retroflexus L. (red root pigweed), Chenopodium album L. (lamb's-quarters), Beta vulgaris L. (sugar beet), Halogeton glomeratus M. Bieb. (halogeton), and Rheum rhabarbarum L. (rhubarb). Several species with low oxalate content are also examined. When l-[1-14C]ascorbic acid is supplied to young seedlings of R. crispus or H. glomeratus, a major portion of the 14C is released over a 24-hour period as 14CO2 and only a small portion is recovered as [14C]oxalate, unlike cuttings from 2- or 4-month-old plants which retain a large part of the 14C as [14C]oxalic acid and release very little 14CO2. Support for an intermediate role of oxalate in the release of 14CO2 from l-[1-14C]ascorbic acid is seen in the rapid release of 14CO2 by R. crispus and H. glomeratus seedlings labeled with [14C]oxalic acid. The common origin of oxalic acid carbon in the C1 and C2 fragment from l-ascorbic acid is demonstrated by comparison of 14C content of oxalic acid in several oxalate-accumulators after cuttings or seedlings are supplied equal amounts of l-[1-14C]- or l-[UL-14C]ascorbic acid. Theoretically, l-[1-14C]ascorbic acid will produce labeled oxalic acid containing three times as much 14C as l-[UL-14C]ascorbic acid when equal amounts of label are provided. Experimentally, a ratio of 2.7 ± 0.5 is obtained in duplicate experiments with six different species. PMID:16660342

A TRPA1-dependent mechanism for the pungent sensation of weak acids

PubMed Central

Wang, Yuanyuan Y.; Chang, Rui B.; Allgood, Sallie D.; Silver, Wayne L.

2011-01-01

Acetic acid produces an irritating sensation that can be attributed to activation of nociceptors within the trigeminal ganglion that innervate the nasal or oral cavities. These sensory neurons sense a diverse array of noxious agents in the environment, allowing animals to actively avoid tissue damage. Although receptor mechanisms have been identified for many noxious chemicals, the mechanisms by which animals detect weak acids, such as acetic acid, are less well understood. Weak acids are only partially dissociated at neutral pH and, as such, some can cross the cell membrane, acidifying the cell cytosol. The nociceptor ion channel TRPA1 is activated by CO2, through gating of the channel by intracellular protons, making it a candidate to more generally mediate sensory responses to weak acids. To test this possibility, we measured responses to weak acids from heterologously expressed TRPA1 channels and trigeminal neurons with patch clamp recording and Ca2+ microfluorometry. Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids. Notably, the degree of channel activation was predicted by the degree of intracellular acidification produced by each acid, suggesting that intracellular protons are the proximate stimulus that gates the channel. Responses to weak acids produced a Ca2+-independent inactivation that precluded further activation by weak acids or reactive chemicals, whereas preactivation by reactive electrophiles sensitized TRPA1 channels to weak acids. Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice. We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to

FAX1, a Novel Membrane Protein Mediating Plastid Fatty Acid Export

PubMed Central

Li, Nannan; Gügel, Irene Luise; Giavalisco, Patrick; Zeisler, Viktoria; Schreiber, Lukas; Soll, Jürgen; Philippar, Katrin

2015-01-01

Fatty acid synthesis in plants occurs in plastids, and thus, export for subsequent acyl editing and lipid assembly in the cytosol and endoplasmatic reticulum is required. Yet, the transport mechanism for plastid fatty acids still remains enigmatic. We isolated FAX1 (fatty acid export 1), a novel protein, which inserts into the chloroplast inner envelope by α-helical membrane-spanning domains. Detailed phenotypic and ultrastructural analyses of FAX1 mutants in Arabidopsis thaliana showed that FAX1 function is crucial for biomass production, male fertility and synthesis of fatty acid-derived compounds such as lipids, ketone waxes, or pollen cell wall material. Determination of lipid, fatty acid, and wax contents by mass spectrometry revealed that endoplasmatic reticulum (ER)-derived lipids decreased when FAX1 was missing, but levels of several plastid-produced species increased. FAX1 over-expressing lines showed the opposite behavior, including a pronounced increase of triacyglycerol oils in flowers and leaves. Furthermore, the cuticular layer of stems from fax1 knockout lines was specifically reduced in C29 ketone wax compounds. Differential gene expression in FAX1 mutants as determined by DNA microarray analysis confirmed phenotypes and metabolic imbalances. Since in yeast FAX1 could complement for fatty acid transport, we concluded that FAX1 mediates fatty acid export from plastids. In vertebrates, FAX1 relatives are structurally related, mitochondrial membrane proteins of so-far unknown function. Therefore, this protein family might represent a powerful tool not only to increase lipid/biofuel production in plants but also to explore novel transport systems involved in vertebrate fatty acid and lipid metabolism. PMID:25646734

Retinoic acid downregulates Rae1 leading to APC(Cdh1) activation and neuroblastoma SH-SY5Y differentiation.

PubMed

Cuende, J; Moreno, S; Bolaños, J P; Almeida, A

2008-05-22

In neuroblastoma cells, retinoic acid induces cell cycle arrest and differentiation through degradation of the F-box protein, Skp2, and stabilization of cyclin-dependent kinase inhibitor, p27. However, the mechanism responsible for retinoic acid-mediated Skp2 destabilization is unknown. Since Skp2 is degraded by anaphase-promoting complex (APC)(Cdh1), here we studied whether retinoic acid promotes differentiation of human SH-SY5Y neuroblastoma cells by modulating Cdh1. We found that retinoic acid induced the nuclear accumulation of Cdh1 that paralleled Skp2 destabilization and p27 accumulation. The mRNA and protein abundance of Rae1-a nuclear export factor that limits APC(Cdh1) activity in mitosis-decreased upon retinoic acid-induced inhibition of neuroblastoma cell proliferation. Furthermore, either Rae1 overexpression or Cdh1 inhibition promoted Skp2 accumulation, p27 destabilization and prevented retinoic acid-induced cell cycle arrest and differentiation. Conversely, inhibition of Rae1 accelerated retinoic acid-induced differentiation. Thus, retinoic acid downregulates Rae1, hence facilitating APC(Cdh1)-mediated Skp2 degradation leading to the arrest of cell cycle progression and neuroblastoma differentiation.

Composition of Fatty Acids and Carbohydrates in Leptospira1

PubMed Central

Kondo, Eiko; Ueta, Nobuo

1972-01-01

The fatty acid and monosaccharide composition of four pathogenic and two saprophytic strains of Leptospira was analyzed by gas chromatography (GC) and GC-mass spectrometry. Among the fatty acids, palmitic acid was most abundant and constituted 30 to 50% of the total fatty acids. Even-numbered unsaturated acids including octadecenoic, hexadecenoic, octadecadienoic, and tetradecadienoic acids comprised 40 to 60% of the total fatty acids. Tetradecanoic acid was about 5% in saprophytic strains, but 1% or less in pathogenic strains. The amount of chloroform-methanol extract of L. biflexa strain Ancona was 14 to 20% of the dry weight of the cell. Tetradecadienoic acid was found in the chloroform-methanol insoluble fraction, suggesting the presence of the acid in a bound form. GC analysis of monosaccharides revealed the existence of arabinose, xylose, rhamnose, mannose, galactose, glucose, glucosamine, and muramic acid in the cells. Among the neutral sugars, glucose was a minor component and was especially low in pathogenic strains. Total pentose content was about two to three times greater than total hexose. PMID:5022167

Crystal structures of 4-meth-oxy-benzoic acid-1,3-bis-(pyridin-4-yl)propane (2/1) and biphenyl-4,4'-di-carb-oxy-lic acid-4-meth-oxy-pyridine (1/2).

PubMed

Gotoh, Kazuma; Ishida, Hiroyuki

2017-07-01

The crystal structures of two hydrogen-bonded compounds, namely 4-meth-oxy-benzoic acid-1,3-bis-(pyridin-4-yl)propane (2/1), C 13 H 14.59 N 2 ·C 8 H 7.67 O 3 ·C 8 H 7.74 O 3 , (I), and biphenyl-4,4'-di-carb-oxy-lic acid-4-meth-oxy-pyridine (1/2), C 14 H 9.43 O 4 ·C 6 H 7.32 NO·C 6 H 7.25 NO, (II), have been determined at 93 K. In (I), the asymmetric unit consists of two crystallographically independent 4-meth-oxy-benzoic acid mol-ecules and one 1,3-bis-(pyridin-4-yl)propane mol-ecule. The asymmetric unit of (II) comprises one biphenyl-4,4'-di-carb-oxy-lic acid mol-ecule and two independent 4-meth-oxy-pyridine mol-ecules. In each crystal, the acid and base mol-ecules are linked by short O-H⋯N/N-H⋯O hydrogen bonds, in which H atoms are disordered over the acid O-atom and base N-atom sites, forming a linear hydrogen-bonded 2:1 or 1:2 unit of the acid and the base. The 2:1 units of (I) are linked via C-H⋯π, π-π and C-H⋯O inter-actions into a tape structure along [101], while the 1:2 units of (II) form a double-chain structure along [-101] through π-π and C-H⋯O inter-actions.

Ursolic Acid Inhibits Adipogenesis in 3T3-L1 Adipocytes through LKB1/AMPK Pathway

PubMed Central

He, Yonghan; Li, Ying; Zhao, Tiantian; Wang, Yanwen; Sun, Changhao

2013-01-01

Background Ursolic acid (UA) is a triterpenoid compound with multiple biological functions. This compound has recently been reported to possess an anti-obesity effect; however, the mechanisms are less understood. Objective As adipogenesis plays a critical role in obesity, the present study was conducted to investigate the effect of UA on adipogenesis and mechanisms of action in 3T3-L1 preadipocytes. Methods and Results The 3T3-L1 preadipocytes were induced to differentiate in the presence or absence of UA for 6 days. The cells were determined for proliferation, differentiation, fat accumulation as well as the protein expressions of molecular targets that regulate or are involved in fatty acid synthesis and oxidation. The results demonstrated that ursolic acid at concentrations ranging from 2.5 µM to 10 µM dose-dependently attenuated adipogenesis, accompanied by reduced protein expression of CCAAT element binding protein β (C/EBPβ), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT element binding protein α (C/EBPα) and sterol regulatory element binding protein 1c (SREBP-1c), respectively. Ursolic acid increased the phosphorylation of acetyl-CoA carboxylase (ACC) and protein expression of carnitine palmitoyltransferase 1 (CPT1), but decreased protein expression of fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4). Ursolic acid increased the phosphorylation of AMP-activated protein kinase (AMPK) and protein expression of (silent mating type information regulation 2, homolog) 1 (Sirt1). Further studies demonstrated that the anti-adipogenic effect of UA was reversed by the AMPK siRNA, but not by the Sirt1 inhibitor nicotinamide. Liver kinase B1 (LKB1), the upstream kinase of AMPK, was upregulated by UA. When LKB1 was silenced with siRNA or the inhibitor radicicol, the effect of UA on AMPK activation was diminished. Conclusions Ursolic acid inhibited 3T3-L1 preadipocyte differentiation and adipogenesis through the LKB1/AMPK pathway

Selective Enrichment of Omega-3 Fatty Acids in Oils by Phospholipase A1

PubMed Central

Puri, Munish; Barrow, Colin; Rao, Nalam Madhusudhana

2016-01-01

Omega fatty acids are recognized as key nutrients for healthier ageing. Lipases are used to release ω-3 fatty acids from oils for preparing enriched ω-3 fatty acid supplements. However, use of lipases in enrichment of ω-3 fatty acids is limited due to their insufficient specificity for ω-3 fatty acids. In this study use of phospholipase A1 (PLA1), which possesses both sn-1 specific activity on phospholipids and lipase activity, was explored for hydrolysis of ω-3 fatty acids from anchovy oil. Substrate specificity of PLA1 from Thermomyces lenuginosus was initially tested with synthetic p-nitrophenyl esters along with a lipase from Bacillus subtilis (BSL), as a lipase control. Gas chromatographic characterization of the hydrolysate obtained upon treatment of anchovy oil with these enzymes indicated a selective retention of ω-3 fatty acids in the triglyceride fraction by PLA1 and not by BSL. 13C NMR spectroscopy based position analysis of fatty acids in enzyme treated and untreated samples indicated that PLA1 preferably retained ω-3 fatty acids in oil, while saturated fatty acids were hydrolysed irrespective of their position. Hydrolysis of structured triglyceride,1,3-dioleoyl-2-palmitoylglycerol, suggested that both the enzymes hydrolyse the fatty acids at both the positions. The observed discrimination against ω-3 fatty acids by PLA1 appears to be due to its fatty acid selectivity rather than positional specificity. These studies suggest that PLA1 could be used as a potential enzyme for selective concentrationof ω-3 fatty acids. PMID:26978518

Selective Enrichment of Omega-3 Fatty Acids in Oils by Phospholipase A1.

PubMed

Ranjan Moharana, Tushar; Byreddy, Avinesh R; Puri, Munish; Barrow, Colin; Rao, Nalam Madhusudhana

2016-01-01

Omega fatty acids are recognized as key nutrients for healthier ageing. Lipases are used to release ω-3 fatty acids from oils for preparing enriched ω-3 fatty acid supplements. However, use of lipases in enrichment of ω-3 fatty acids is limited due to their insufficient specificity for ω-3 fatty acids. In this study use of phospholipase A1 (PLA1), which possesses both sn-1 specific activity on phospholipids and lipase activity, was explored for hydrolysis of ω-3 fatty acids from anchovy oil. Substrate specificity of PLA1 from Thermomyces lenuginosus was initially tested with synthetic p-nitrophenyl esters along with a lipase from Bacillus subtilis (BSL), as a lipase control. Gas chromatographic characterization of the hydrolysate obtained upon treatment of anchovy oil with these enzymes indicated a selective retention of ω-3 fatty acids in the triglyceride fraction by PLA1 and not by BSL. 13C NMR spectroscopy based position analysis of fatty acids in enzyme treated and untreated samples indicated that PLA1 preferably retained ω-3 fatty acids in oil, while saturated fatty acids were hydrolysed irrespective of their position. Hydrolysis of structured triglyceride,1,3-dioleoyl-2-palmitoylglycerol, suggested that both the enzymes hydrolyse the fatty acids at both the positions. The observed discrimination against ω-3 fatty acids by PLA1 appears to be due to its fatty acid selectivity rather than positional specificity. These studies suggest that PLA1 could be used as a potential enzyme for selective concentrationof ω-3 fatty acids.

40 CFR 721.4575 - L-aspartic acid, N,N′- [(1E) - 1,2 - ethenediylbis[(3-sulfo-4, 1-phenylene)imino [6-(phenylamino...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false L-aspartic acid, N,Nâ²- [(1E) - 1,2... Substances § 721.4575 L-aspartic acid, N,N′- [(1E) - 1,2 - ethenediylbis[(3-sulfo-4, 1-phenylene)imino [6... uses subject to reporting. (1) The chemical substance identified as l-aspartic acid, N,N′- [(1E) - 1,2...

40 CFR 721.10457 - 1,2-Benzenedicarboxylic acid, mixed esters with benzyl alc., cyclohexanol, 2-ethyl-1-hexanol...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false 1,2-Benzenedicarboxylic acid, mixed... Substances § 721.10457 1,2-Benzenedicarboxylic acid, mixed esters with benzyl alc., cyclohexanol, 2-ethyl-1... reporting. (1) The chemical substance identified as 1,2-benzenedicarboxylic acid, mixed esters with benzyl...

40 CFR 721.10457 - 1,2-Benzenedicarboxylic acid, mixed esters with benzyl alc., cyclohexanol, 2-ethyl-1-hexanol...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false 1,2-Benzenedicarboxylic acid, mixed... Substances § 721.10457 1,2-Benzenedicarboxylic acid, mixed esters with benzyl alc., cyclohexanol, 2-ethyl-1... reporting. (1) The chemical substance identified as 1,2-benzenedicarboxylic acid, mixed esters with benzyl...

Parenteral diclofenac infusion significantly decreases brain-tissue oxygen tension in patients with poor-grade aneurysmal subarachnoid hemorrhage

PubMed Central

2013-01-01

Introduction Diclofenac, a nonsteroidal antiinflammatory drug, is commonly used as antipyretic therapy in intensive care. The purpose of this study was to investigate the effects of parenteral diclofenac infusion on brain homeostasis, including brain-tissue oxygen tension (PbtO2) and brain metabolism after aneurysmal subarachnoid hemorrhage (aSAH). Methods We conducted a prospective, observational study with retrospective analysis of 21 consecutive aSAH patients with multimodal neuromonitoring. Cerebral perfusion pressure (CPP), mean arterial pressure (MAP), intracranial pressure (ICP), body temperature, and PbtO2 were analyzed after parenteral diclofenac infusion administered over a 34-minute period (20 to 45 IQR). Data are given as mean ± standard error of mean and median with interquartile range (IQR), as appropriate. Time-series data were analyzed by using a general linear model extended by generalized estimation equations (GEEs). Results One-hundred twenty-three interventions were analyzed. Body temperature decreased from 38.3°C ± 0.05°C by 0.8°C ± 0.06°C (P < 0.001). A 10% decrease in MAP and CPP (P < 0.001) necessitated an increase of vasopressors in 26% (n = 32), colloids in 33% (n = 41), and crystalloids in 5% (n = 7) of interventions. PbtO2 decreased by 13% from a baseline value of 28.1 ± 2.2 mm Hg, resulting in brain-tissue hypoxia (PbtO2 <20 mm Hg) in 38% (n = 8) of patients and 35% (n = 43) of interventions. PbtO2 <30 mm Hg before intervention was associated with brain-tissue hypoxia after parenteral diclofenac infusion (likelihood ratio, 40; AUC, 93%; 95% confidence interval (CI), 87% to 99%; P < 0.001). Cerebral metabolism showed no significant changes after parenteral diclofenac infusion. Conclusions Parenteral diclofenac infusion after aSAH effectively reduces body temperature, but may lead to CPP decrease and brain-tissue hypoxia, which were both associated with poor outcome after aSAH. PMID:23663770

Distinctive ribonucleic acid patterns of human rotavirus subgroups 1 and 2.

PubMed Central

Kalica, A R; Greenberg, H B; Espejo, R T; Flores, J; Wyatt, R G; Kapikian, A Z; Chanock, R M

1981-01-01

The ribonucleic acid migration patterns of 7 subgroup 1 and 16 subgroup 2 human rotaviruses recovered from four geographic areas were compared. The subgroup 1 ribonucleic acid patterns had strikingly slower-moving segments 10 and 11, suggesting a correlation between the ribonucleic acid pattern and the subgroup specificity. Images PMID:6270002

The Arabidopsis thaliana REDUCED EPIDERMAL FLUORESCENCE1 gene encodes an aldehyde dehydrogenase involved in ferulic acid and sinapic acid biosynthesis.

PubMed

Nair, Ramesh B; Bastress, Kristen L; Ruegger, Max O; Denault, Jeff W; Chapple, Clint

2004-02-01

Recent research has significantly advanced our understanding of the phenylpropanoid pathway but has left in doubt the pathway by which sinapic acid is synthesized in plants. The reduced epidermal fluorescence1 (ref1) mutant of Arabidopsis thaliana accumulates only 10 to 30% of the sinapate esters found in wild-type plants. Positional cloning of the REF1 gene revealed that it encodes an aldehyde dehydrogenase, a member of a large class of NADP(+)-dependent enzymes that catalyze the oxidation of aldehydes to their corresponding carboxylic acids. Consistent with this finding, extracts of ref1 leaves exhibit low sinapaldehyde dehydrogenase activity. These data indicate that REF1 encodes a sinapaldehyde dehydrogenase required for sinapic acid and sinapate ester biosynthesis. When expressed in Escherichia coli, REF1 was found to exhibit both sinapaldehyde and coniferaldehyde dehydrogenase activity, and further phenotypic analysis of ref1 mutant plants showed that they contain less cell wall-esterified ferulic acid. These findings suggest that both ferulic acid and sinapic acid are derived, at least in part, through oxidation of coniferaldehyde and sinapaldehyde. This route is directly opposite to the traditional representation of phenylpropanoid metabolism in which hydroxycinnamic acids are instead precursors of their corresponding aldehydes.

Nucleic acids encoding mosaic clade M human immunodeficiency virus type 1 (HIV-1) envelope immunogens

DOEpatents

Korber, Bette T; Fischer, William; Liao, Hua-Xin; Haynes, Barton F; Letvin, Norman; Hahn, Beatrice H

2015-04-21

The present invention relates to nucleic acids encoding mosaic clade M HIV-1 Env polypeptides and to compositions and vectors comprising same. The nucleic acids of the invention are suitable for use in inducing an immune response to HIV-1 in a human.

Synthesis oftrans-3-hexadecenoic acid and oftrans-3-hexadecenoic-1-C(14) acid.

PubMed

Knipprath, W G; Stein, R A

1966-01-01

Thetrans-3-hexadecenoic acid has been synthesized. Physical properties and chemical degradation prove its identity with the acid earlier isolated from several plant lipids. In the sequence of the synthesis, the introduction of a terminal triple bond into commercially available 1-tetradecene was performed by bromination and debromination with KOH and NaNH(2). Chain elongation by a Grignard reaction with CO(2) gave a carboxylic acid with a triple bond in the 2-position. Reduction with LiAlH(4) yielded the corresponding alcohol, and reduction of the triple to thetrans double bond was accomplished with Na in ethanol. Bromination of the alcohol with PBr(3) and conversion of the bromide to the nitrile with KCN or KC(14)N elongated the carbon chain to the desired length. Methanolysis with HCl in methanol and saponification with KOH formed the acid with acceptable yields, and in the case of the C(14)-labeled carboxyl, group, with high specific activity.

Bioproduction of L-Aspartic Acid and Cinnamic Acid by L-Aspartate Ammonia Lyase from Pseudomonas aeruginosa PAO1.

PubMed

Patel, Arti T; Akhani, Rekha C; Patel, Manisha J; Dedania, Samir R; Patel, Darshan H

2017-06-01

Aspartase (L-aspartate ammonia lyase, EC 4.3.1.1) catalyses the reversible amination and deamination of L-aspartic acid to fumaric acid which can be used to produce important biochemical. In this study, we have explored the characteristics of aspartase from Pseudomonas aeruginosa PAO1 (PA-AspA). To overproduce PA-AspA, the 1425-bp gene was introduced in Escherichia coli BL21 and purified. A 51.0-kDa protein was observed as a homogenous purified protein on SDS-PAGE. The enzyme was optimally active at pH 8.0 and 35 °C. PA-AspA has retained 56% activity after 7 days of incubation at 35 °C, which displays the hyperthermostablility characteristics of the enzyme. PA-AspA is activated in the presence of metal ions and Mg2+ is found to be most effective. Among the substrates tested for specificity of PA-AspA, L-phenylalanine (38.35 ± 2.68) showed the highest specific activity followed by L-aspartic acid (31.21 ± 3.31) and fumarate (5.42 ± 2.94). K m values for L-phenylalanine, L-aspartic acid and fumarate were 1.71 mM, 0.346 μM and 2 M, respectively. The catalytic efficiency (k cat /K m ) for L-aspartic acid (14.18 s -1  mM -1 ) was higher than that for L-phenylalanine (4.65 s -1  mM -1 ). For bioconversion, from an initial concentration of 1000 mM of fumarate and 30 mM of L-phenylalanine, PA-AspA was found to convert 395.31 μM L-aspartic acid and 3.47 mM cinnamic acid, respectively.

Pseudomonas putida F1 uses energy taxis to sense hydroxycinnamic acids

PubMed Central

Hughes, Jonathan G.; Zhang, Xiangsheng; Parales, Juanito V.; Ditty, Jayna L.; Parales, Rebecca E.

2017-01-01

Soil bacteria such as pseudomonads are widely studied due to their diverse metabolic capabilities, particularly the ability to degrade both naturally occurring and xenobiotic aromatic compounds. Chemotaxis, the directed movement of cells in response to chemical gradients, is common in motile soil bacteria and the wide range of chemicals detected often mirrors the metabolic diversity observed. Pseudomonas putida F1 is a soil isolate capable of chemotaxis toward, and degradation of, numerous aromatic compounds. We showed that P. putida F1 is capable of degrading members of a class of naturally occurring aromatic compounds known as hydroxycinnamic acids, which are components of lignin and are ubiquitous in the soil environment. We also demonstrated the ability of P. putida F1 to sense three hydroxycinnamic acids: p-coumaric, caffeic and ferulic acids. The chemotaxis response to hydroxycinnamic acids was induced during growth in the presence of hydroxycinnamic acids and was negatively regulated by HcaR, the repressor of the hydroxycinnamic acid catabolic genes. Chemotaxis to the three hydroxycinnamic acids was dependent on catabolism, as a mutant lacking the gene encoding feruloyl-CoA synthetase (Fcs), which catalyzes the first step in hydroxycinnamic acid degradation, was unable to respond chemotactically toward p-coumaric, caffeic, or ferulic acids. We tested whether an energy taxis mutant could detect hydroxycinnamic acids and determined that hydroxycinnamic acid sensing is mediated by the energy taxis receptor Aer2. PMID:28954643

Key mediators of intracellular amino acids signaling to mTORC1 activation.

PubMed

Duan, Yehui; Li, Fengna; Tan, Kunrong; Liu, Hongnan; Li, Yinghui; Liu, Yingying; Kong, Xiangfeng; Tang, Yulong; Wu, Guoyao; Yin, Yulong

2015-05-01

Mammalian target of rapamycin complex 1 (mTORC1) is activated by amino acids to promote cell growth via protein synthesis. Specifically, Ras-related guanosine triphosphatases (Rag GTPases) are activated by amino acids, and then translocate mTORC1 to the surface of late endosomes and lysosomes. Ras homolog enriched in brain (Rheb) resides on this surface and directly activates mTORC1. Apart from the presence of intracellular amino acids, Rag GTPases and Rheb, other mediators involved in intracellular amino acid signaling to mTORC1 activation include human vacuolar sorting protein-34 (hVps34) and mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3). Those molecular links between mTORC1 and its mediators form a complicate signaling network that controls cellular growth, proliferation, and metabolism. Moreover, it is speculated that amino acid signaling to mTORC1 may start from the lysosomal lumen. In this review, we discussed the function of these mediators in mTORC1 pathway and how these mediators are regulated by amino acids in details.

Ethylene Production and 1-Aminocyclopropane-1-Carboxylic Acid Conjugation in Thermoinhibited Cicer arietinum L. Seeds 1

PubMed Central

Gallardo, Mercedes; Delgado, María del Mar; Sánchez-Calle, Isabel María; Matilla, Angel Jesús

1991-01-01

The effect of supraoptimal temperatures (30°C, 35°C) on germination and ethylene production of Cicer arietinum (chick-pea) seeds was measured. Compared with a 25°C control, these temperatures inhibited both germination and ethylene production. The effect of supraoptimal temperatures could be alleviated by treating the seeds with ethylene. It was concluded that one effect of high temperature on germination was due to its negative effect on ethylene production. This inhibitory effect of high temperature was due to increased conjugation of 1-aminocyclopropane-1-carboxylic acid to 1-(malonylamino)cyclopropane-1-carboxylic acid and to an inhibition of ethylene-forming enzyme activity. PMID:16668358

The Arabidopsis thaliana REDUCED EPIDERMAL FLUORESCENCE1 Gene Encodes an Aldehyde Dehydrogenase Involved in Ferulic Acid and Sinapic Acid Biosynthesis

PubMed Central

Nair, Ramesh B.; Bastress, Kristen L.; Ruegger, Max O.; Denault, Jeff W.; Chapple, Clint

2004-01-01

Recent research has significantly advanced our understanding of the phenylpropanoid pathway but has left in doubt the pathway by which sinapic acid is synthesized in plants. The reduced epidermal fluorescence1 (ref1) mutant of Arabidopsis thaliana accumulates only 10 to 30% of the sinapate esters found in wild-type plants. Positional cloning of the REF1 gene revealed that it encodes an aldehyde dehydrogenase, a member of a large class of NADP+-dependent enzymes that catalyze the oxidation of aldehydes to their corresponding carboxylic acids. Consistent with this finding, extracts of ref1 leaves exhibit low sinapaldehyde dehydrogenase activity. These data indicate that REF1 encodes a sinapaldehyde dehydrogenase required for sinapic acid and sinapate ester biosynthesis. When expressed in Escherichia coli, REF1 was found to exhibit both sinapaldehyde and coniferaldehyde dehydrogenase activity, and further phenotypic analysis of ref1 mutant plants showed that they contain less cell wall–esterified ferulic acid. These findings suggest that both ferulic acid and sinapic acid are derived, at least in part, through oxidation of coniferaldehyde and sinapaldehyde. This route is directly opposite to the traditional representation of phenylpropanoid metabolism in which hydroxycinnamic acids are instead precursors of their corresponding aldehydes. PMID:14729911

Nucleic Acid Chaperone Activity of the ORF1 Protein from the Mouse LINE-1 Retrotransposon

PubMed Central

Martin, Sandra L.; Bushman, Frederic D.

2001-01-01

Non-LTR retrotransposons such as L1 elements are major components of the mammalian genome, but their mechanism of replication is incompletely understood. Like retroviruses and LTR-containing retrotransposons, non-LTR retrotransposons replicate by reverse transcription of an RNA intermediate. The details of cDNA priming and integration, however, differ between these two classes. In retroviruses, the nucleocapsid (NC) protein has been shown to assist reverse transcription by acting as a “nucleic acid chaperone,” promoting the formation of the most stable duplexes between nucleic acid molecules. A protein-coding region with an NC-like sequence is present in most non-LTR retrotransposons, but no such sequence is evident in mammalian L1 elements or other members of its class. Here we investigated the ORF1 protein from mouse L1 and found that it does in fact display nucleic acid chaperone activities in vitro. L1 ORF1p (i) promoted annealing of complementary DNA strands, (ii) facilitated strand exchange to form the most stable hybrids in competitive displacement assays, and (iii) facilitated melting of an imperfect duplex but stabilized perfect duplexes. These findings suggest a role for L1 ORF1p in mediating nucleic acid strand transfer steps during L1 reverse transcription. PMID:11134335

Studies on the oxidation of hexamethylbenzene 1: Oxidation of hexamethylbenzene with nitric acid

NASA Technical Reports Server (NTRS)

Chiba, K.; Tomura, S.; Mizuno, T.

1986-01-01

The oxidative reaction of hexamethylbenzene (HMB) with nitric acid was studied, and the hitherto unknown polymethylbenzenepolycarboxylic acids were isolated: tetramethylphthalic anhydride, tetramethylisophthalic acid, 1,3,5-, 1,2,4- and 1,2,3-trimethylbenzenetricarboxylic acids. When HMB was warmed with 50% nitric acid at about 80 C, tetramethylphthalic anhydride and tetramethylisophthalic acid were initially produced. The continued reaction led to the production of trimethylbenzenetricarboxylic acids, but only slight amounts of dimethylbenzenetetracarboxylic acids were detected in the reaction mixture. Whereas tetramethylphthalic anydride and tetramethylisophthalic acid were obtained, pentamethylbenzoic acid, a possible precursor of them, was scarcely produced. On the other hand, a yellow material extracted with ether from the initial reaction mixture contained bis-(nitromethyl)prehnitene (CH3)4C6(CH2NO2)2, which was easily converted into the phthalic anhydride.

78 FR 40099 - 1-Hydroxyethylidene-1, 1-Diphosphonic Acid From India: Final Results of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-03

... DEPARTMENT OF COMMERCE International Trade Administration [A-533-847] 1-Hydroxyethylidene-1, 1... results of the third administrative review of the antidumping duty order on 1-hydroxyethylidene-1, 1-diphosphonic acid (HEDP) from India.\\1\\ The review covers one manufacturer and exporter of the subject...

Supramolecular hydrogen-bonding patterns in 1:1 cocrystals of 5-fluorouracil with 4-methylbenzoic acid and 3-nitrobenzoic acid.

PubMed

Mohana, Marimuthu; Muthiah, Packianathan Thomas; McMillen, Colin D

2017-03-01

The design of a pharmaceutical cocrystal is based on the identification of specific hydrogen-bond donor and acceptor groups in active pharmaceutical ingredients (APIs) in order to choose a `complementary interacting' molecule that can act as an efficient coformer. 5-Fluorouracil (5FU) is a pyrimidine derivative with two N-H donors and C=O acceptors and shows a diversity of hydrogen-bonding motifs. Two 1:1 cocrystals of 5-fluorouracil (5FU), namely 5-fluorouracil-4-methylbenzoic acid (5FU-MBA), C 4 H 3 FN 2 O 2 ·C 8 H 8 O 2 , (I), and 5-fluorouracil-3-nitrobenzoic acid (5FU-NBA), C 4 H 3 FN 2 O 2 ·C 7 H 5 NO 4 , (II), have been prepared and characterized by single-crystal X-ray diffraction. In (I), the MBA molecules form carboxylic acid dimers [R 2 2 (8) homosynthon]. Similarly, the 5FU molecules form two types of base pair via a pair of N-H...O hydrogen bonds [R 2 2 (8) homosynthon]. In (II), 5FU interacts with the carboxylic acid group of NBA via N-H...O and O-H...O hydrogen bonds, generating an R 2 2 (8) ring motif (heterosynthon). Furthermore, the 5FU molecules form base pairs [R 2 2 (8) homosynthon] via N-H...O hydrogen bonds. Both of the crystal structures are stabilized by C-H...F interactions.

Neutralization of acidic drainage by Cryptococcus sp. T1 immobilized in alginate beads.

PubMed

Okai, Masahiko; Suwa, Chisato; Nagaoka, Shintaro; Obara, Nobuo; Mitsuya, Daisuke; Kurihara, Ayako; Ishida, Masami; Urano, Naoto

2017-11-01

We isolated Cryptococcus sp. T1 from Lake Tazawa's acidic water in Japan. Cryptococcus sp. T1 neutralized an acidic casamino acid solution (pH 3.0) and released ammonia from the casamino acids to aid the neutralization. The neutralization volume was estimated to be approximately 0.4 mL/h. The casamino acids' amino acids decreased (1.24→0.15 mM); ammonia increased (0.22→0.99 mM). We neutralized acidic drainage water (1 L) from a Tamagawa River neutralization plant, which was run through the column with the T1-immobilized alginate beads at a flow rate of 0.5 mL/min, and observed that the viscosity, particle size and amounts of the alginate beads affected the acidic drainage neutralization with an increase of the pH value from 5.26 to 6.61 in the last fraction. An increase in the Al concentration decreased Cryptococcus sp. T1's neutralization ability. After 48 h, the pH of acidic water with 50 mg/L Al was apparently lower than that without Al. Almost no pH increase was observed at 75 mg/L.

Acid-Sensing Ion Channel 1a Regulates Fate of Rat Nucleus Pulposus Cells in Acid Stimulus Through Endoplasmic Reticulum Stress.

PubMed

Xie, Zhi-Yang; Chen, Lu; Zhang, Cong; Liu, Lei; Wang, Feng; Cai, Feng; Wang, Xiao-Hu; Shi, Rui; Sinkemani, Arjun; Yu, Hao-Min; Hong, Xin; Wu, Xiao-Tao

2018-01-01

Acid-sensing ion channel 1a (ASIC1a) participates in human intervertebral disc degeneration (IVDD) and regulates the destiny of nucleus pulposus cells (NPCs) in acid stimulus. However, the mechanism of ASIC1a activation and its downstream pathway remain unclear. Endoplasmic reticulum (ER) stress also participates in the acid-induced apoptosis of NPCs. The main purpose of this study was to investigate whether there is any connection between ASIC1a and ER stress in an acid-induced nucleus pulposus degeneration model. The IVDs of Sprague-Dawley rats were stained by immunohistochemical staining to evaluate the expression of ASIC1a in normal and degenerated rat nucleus pulposus. ASIC1a expression was also quantified by quantitative real-time-polymerase chain reaction and Western blotting analysis. NPCs were exposed to the culture media with acidity at pH 7.2 and 6.5 for 24 h, with or without 4-phenylbutyrate (4-PBA, a blocker of the ER stress pathway). Cell apoptosis was examined by Annexin V/Propidium Iodide (PI) staining and was quantified using flow cytometry analysis. ASIC1a-mediated intracellular calcium was determined by Ca 2+ imaging using Fura-2-AM. Acidity-induced changes in ER stress markers were studied using Western blotting analysis. In vivo , ASIC1a expression was upregulated in natural degeneration. In vitro , acid stimulus increased intracellular calcium levels, but this effect was blocked by knockdown of ASIC1a, and this reversal was partly inhibited by 4-PBA. In addition, blockade of ASIC1a reduced expression of ER stress markers, especially the proapoptotic markers. ASIC1a partly regulates ER stress and promotes apoptosis of NPCs under acid stimulus and may be a novel therapeutic target in IVDD.

Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells

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

Zhao Guixiang; Etherton, Terry D.; Department of Dairy and Animal Science, Pennsylvania State University, University Park, PA

2005-10-28

The effects of linoleic acid (LA), {alpha}-linolenic acid (ALA), and docosahexaenoic acid (DHA) were compared to that of palmitic acid (PA), on inflammatory responses in human monocytic THP-1 cells. When cells were pre-incubated with fatty acids for 2-h and then stimulated with lipopolysaccharide for 24-h in the presence of fatty acids, secretion of interleukin (IL)-6, IL-1{beta}, and tumor necrosis factor-{alpha} (TNF{alpha}) was significantly decreased after treatment with LA, ALA, and DHA versus PA (P < 0.01 for all); ALA and DHA elicited more favorable effects. These effects were comparable to those for 15-deoxy-{delta}{sup 12,14}-prostaglandin J2 (15d-PGJ2) and were dose-dependent. Inmore » addition, LA, ALA, and DHA decreased IL-6, IL-1{beta}, and TNF{alpha} gene expression (P < 0.05 for all) and nuclear factor (NF)-{kappa}B DNA-binding activity, whereas peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) DNA-binding activity was increased. The results indicate that the anti-inflammatory effects of polyunsaturated fatty acids may be, in part, due to the inhibition of NF-{kappa}B activation via activation of PPAR{gamma}.« less

78 FR 25699 - 1-Hydroxyethylidene-1, 1-Diphosphonic Acid From India: Preliminary Results of Antidumping Duty...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-02

... DEPARTMENT OF COMMERCE International Trade Administration [A-533-847] 1-Hydroxyethylidene-1, 1... review of the antidumping duty order on 1- hydroxyethylidene-1, 1-diphosphonic acid (HEDP) from India. The period of review (POR) is April 1, 2011, through March 31, 2012. The review covers one producer...

Anti-pandemic influenza A (H1N1) virus potential of catechin and gallic acid.

PubMed

You, Huey-Ling; Huang, Chao-Chun; Chen, Chung-Jen; Chang, Cheng-Chin; Liao, Pei-Lin; Huang, Sheng-Teng

2018-05-01

The pandemic influenza A (H1N1) virus has spread worldwide and infected a large proportion of the human population. Discovery of new and effective drugs for the treatment of influenza is a crucial issue for the global medical community. According to our previous study, TSL-1, a fraction of the aqueous extract from the tender leaf of Toonasinensis, has demonstrated antiviral activities against pandemic influenza A (H1N1) through the down-regulation of adhesion molecules and chemokine to prevent viral attachment. The aim of the present study was to identify the active compounds in TSL-1 which exert anti-influenza A (H1N1) virus effects. XTT assay was used to detect the cell viability. Meanwhile, the inhibitory effect on the pandemic influenza A (H1N1) virus was analyzed by observing plaque formation, qRT-PCR, neuraminidase activity, and immunofluorescence staining of influenza A-specific glycoprotein. Both catechin and gallic acid were found to be potent inhibitors in terms of influenza virus mRNA replication and MDCK plaque formation. Additionally, both compounds inhibited neuraminidase activities and viral glycoprotein. The 50% effective inhibition concentration (EC 50 ) of catechin and gallic acid for the influenza A (H1N1) virus were 18.4 μg/mL and 2.6 μg/mL, respectively; whereas the 50% cytotoxic concentrations (CC 50 ) of catechin and gallic acid were >100 μg/mL and 22.1 μg/mL, respectively. Thus, the selectivity indexes (SI) of catechin and gallic acid were >5.6 and 22.1, respectively. The present study demonstrates that catechin might be a safe reagent for long-term use to prevent influenza A (H1N1) virus infection; whereas gallic acid might be a sensitive reagent to inhibit influenza virus infection. We conclude that these two phyto-chemicals in TSL-1 are responsible for exerting anti-pandemic influenza A (H1N1) virus effects. Copyright © 2017. Published by Elsevier Taiwan LLC.

Conformational characterization of the 1-aminocyclobutane-1-carboxylic acid residue in model peptides.

PubMed

Gatos, M; Formaggio, F; Crisma, M; Toniolo, C; Bonora, G M; Benedetti, Z; Di Blasio, B; Iacovino, R; Santini, A; Saviano, M; Kamphuis, J

1997-01-01

A series of N- and C-protected, monodispersed homo-oligopeptides (to the dodecamer level) from the small-ring alicyclic C alpha, alpha-dialkylated glycine 1-aminocyclobutane-1-carboxylic acid (Ac4c) and two Ala/Ac4c tripeptides were synthesized by solution methods and fully characterized. The conformational preferences of all the model peptides were determined in deuterochloroform solution by FT-IR absorption and 1H-NMR. The molecular structures of the amino acid derivatives Z-Ac4c-OH and Z2-Ac4c-OH, the tripeptides Z-(Ac4c)3-OtBu, Z-Ac4c-(L-Ala)2-OMe and Z-L-Ala-Ac4c-L-Ala-OMe, and the tetrapeptide Z-(Ac4c)4-OtBu were determined in the crystal state by X-ray diffraction. The average geometry of the cyclobutyl moiety of the Ac4c residue was assessed and the tau(N-C alpha-C') bond angle was found to be significantly expanded from the regular tetrahedral value. The conformational data are strongly in favour of the conclusion that the Ac4c residue is an effective beta-turn and helix former. A comparison with the structural propensities of alpha-aminoisobutyric acid, the prototype of C alpha, alpha-dialkylated glycines, and the other extensively investigated members of the family of 1-aminocycloalkane-1-carboxylic acids (Acnc, with n = 3, 5-8) is made and the implications for the use of the Ac4c residue in conformationally constrained peptide analogues are briefly examined.

Butyric acid production from red algae by a newly isolated Clostridium sp. S1.

PubMed

Lee, Kyung Min; Choi, Okkyoung; Kim, Ki-Yeon; Woo, Han Min; Kim, Yunje; Han, Sung Ok; Sang, Byoung-In; Um, Youngsoon

2015-09-01

To produce butyric acid from red algae such as Gelidium amansii in which galactose is a main carbohydrate, microorganisms utilizing galactose and tolerating inhibitors in hydrolysis including levulinic acid and 5-hydroxymethylfurfural (HMF) are required. A newly isolated bacterium, Clostridium sp. S1 produced butyric acid not only from galactose as the sole carbon source but also from a mixture of galactose and glucose through simultaneous utilization. Notably, Clostridium sp. S1 produced butyric acid and a small amount of acetic acid with the butyrate:acetate ratio of 45.4:1 and it even converted acetate to butyric acid. Clostridium sp. S1 tolerated 0.5-2 g levulinic acid/l and recovered from HMF inhibition at 0.6-2.5 g/l, resulting in 85-92% butyric acid concentration of the control culture. When acid-pretreated G. amansii hydrolysate was used, Clostridium sp. S1 produced 4.83 g butyric acid/l from 10 g galactose/l and 1 g glucose/l. Clostridium sp. S1 produces butyric acid from red algae due to its characteristics in sugar utilization and tolerance to inhibitors, demonstrating its advantage as a red algae-utilizing microorganism.

Amino acid N-malonyltransferases from mung beans. Action on 1-aminocyclopropane-1-carboxylic acid and D-phenylalanine.

PubMed

Guo, L; Phillips, A T; Arteca, R N

1993-12-05

1-Aminocyclopropane-1-carboxylate (ACC) N-malonyltransferase from etiolated mung bean hypocotyls was examined for its relationship to D-phenylalanine N-malonyltransferase and other enzymes which transfer malonyl groups from malonyl-CoA to D-amino acids. Throughout a 3600-fold purification the ratio of D-phenylalanine N-malonyltransferase activity to ACC N-malonyltransferase activity was unchanged. Antibodies raised against purified ACC N-malonyltransferase 55-kDa protein were also able to precipitate all D-phenylalanine-directed activity from partially purified mung bean extracts. The irreversible inhibitors phenylglyoxal and tetranitromethane reduced malonyltransferase activity towards D-phenylalanine to the same extent as that for ACC. In addition, several other D-amino acids, particularly D-tryptophan and D-tyrosine, were able to inhibit action towards both ACC and D-phenylalanine. These lines of evidence suggest that a single enzyme is capable of promoting malonylation of both ACC and D-phenylalanine. Km values for D-phenylalanine and malonyl-CoA were found to be 48 and 43 microM, respectively; these values are 10-fold lower than the corresponding values when ACC was substrate. Coenzyme A was a noncompetitive (mixed type) product inhibitor towards malonyl-CoA at both unsaturated and saturated ACC concentrations. The enzyme was also inhibited uncompetitively at high concentrations of malonyl-CoA. We propose that the enzyme follows an Ordered Bi-Bi reaction pathway, with the amino acid substrate being bound initially.

Palmitoleic acid (16:1n7) increases oxygen consumption, fatty acid oxidation and ATP content in white adipocytes.

PubMed

Cruz, Maysa M; Lopes, Andressa B; Crisma, Amanda R; de Sá, Roberta C C; Kuwabara, Wilson M T; Curi, Rui; de Andrade, Paula B M; Alonso-Vale, Maria I C

2018-03-20

We have recently demonstrated that palmitoleic acid (16:1n7) increases lipolysis, glucose uptake and glucose utilization for energy production in white adipose cells. In the present study, we tested the hypothesis that palmitoleic acid modulates bioenergetic activity in white adipocytes. For this, 3 T3-L1 pre-adipocytes were differentiated into mature adipocytes in the presence (or absence) of palmitic (16:0) or palmitoleic (16:1n7) acid at 100 or 200 μM. The following parameters were evaluated: lipolysis, lipogenesis, fatty acid (FA) oxidation, ATP content, oxygen consumption, mitochondrial mass, citrate synthase activity and protein content of mitochondrial oxidative phosphorylation (OXPHOS) complexes. Treatment with 16:1n7 during 9 days raised basal and isoproterenol-stimulated lipolysis, FA incorporation into triacylglycerol (TAG), FA oxidation, oxygen consumption, protein expression of subunits representing OXPHOS complex II, III, and V and intracellular ATP content. These effects were not observed in adipocytes treated with 16:0. Palmitoleic acid, by concerted action on lipolysis, FA esterification, mitochondrial FA oxidation, oxygen consumption and ATP content, does enhance white adipocyte energy expenditure and may act as local hormone.

Phthalazin-1(2H)-one–picric acid (1/1)

PubMed Central

Yathirajan, H. S.; Narayana, B.; Swamy, M. T.; Sarojini, B. K.; Bolte, Michael

2008-01-01

The geometric parameters of the title compound, C8H6N2O·C6H3N3O7, are in the usual ranges. The three nitro groups are almost coplanar with the aromatic picrate ring [dihedral angles 10.2 (2)°, 7.62 (16) and 8.08 (17)°]. The mol­ecular conformation of the picric acid is stabilized by an intra­molecular O—H⋯O hydrogen bond. The phthalazin-1(2H)-one mol­ecules are connected via N—H⋯O hydrogen bonds, forming centrosymmetric dimers. PMID:21200682

Apoptosis-inducing factor (Aif1) mediates anacardic acid-induced apoptosis in Saccharomyces cerevisiae.

PubMed

Muzaffar, Suhail; Chattoo, Bharat B

2017-03-01

Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis.

Serum Paraoxonase 1 Activity Is Associated with Fatty Acid Composition of High Density Lipoprotein

PubMed Central

Boshtam, Maryam; Pourfarzam, Morteza; Ani, Mohsen; Naderi, Gholam Ali; Basati, Gholam; Mansourian, Marjan; Dinani, Narges Jafari; Asgary, Seddigheh; Abdi, Soheila

2013-01-01

Introduction. Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. Methods. One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. Results. Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ω6 fatty acids of HDL. Conclusion. The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health. PMID:24167374

Serum paraoxonase 1 activity is associated with fatty acid composition of high density lipoprotein.

PubMed

Boshtam, Maryam; Razavi, Amirnader Emami; Pourfarzam, Morteza; Ani, Mohsen; Naderi, Gholam Ali; Basati, Gholam; Mansourian, Marjan; Dinani, Narges Jafari; Asgary, Seddigheh; Abdi, Soheila

2013-01-01

Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ω 6 fatty acids of HDL. The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health.

Design, synthesis and activity as acid ceramidase inhibitors of 2-oxooctanoyl and N-oleoylethanolamine analogues.

PubMed

Grijalvo, Santiago; Bedia, Carmen; Triola, Gemma; Casas, Josefina; Llebaria, Amadeu; Teixidó, Jordi; Rabal, Obdulia; Levade, Thierry; Delgado, Antonio; Fabriàs, Gemma

2006-10-01

The synthesis of novel N-acylethanolamines and their use as inhibitors of the aCDase is reported here. The compounds are either 2-oxooctanamides or oleamides of sphingosine analogs featuring a 3-hydroxy-4,5-hexadecenyl tail replaced by ether or thioether moieties. It appears that, within the 2-oxooctanamide family, the C3-OH group of the sphingosine molecule is required for inhibition both in vitro and in cultured cells. Furthermore, although the (E)-4 double bond is not essential for inhibitory activity, the (E) configuration is required, since the analogue with a (Z)-4 unsaturation was not inhibitory. None of the oleamides inhibited the aCDase in vitro. Conversely, with the exception of N-oleoylethanolamine and its analogs with S-decyl and S-hexadecyl substituents, all the synthesized oleamides inhibited the aCDase in cultured cells, although with a relatively low potency. We conclude that novel aCDase inhibitors can evolve from N-acylation of sphingoid bases with electron deficient-acyl groups. In contrast, chemical modification of the N-oleoylsphingosine backbone does not seem to offer an appropriate strategy to obtain aCDase inhibitors.

Apoptosis- and differentiation-inducing activities of jacaric acid, a conjugated linolenic acid isomer, on human eosinophilic leukemia EoL-1 cells.

PubMed

Liu, Wai-Nam; Leung, Kwok-Nam

2014-11-01

Conjugated linolenic acids (CLNAs) are a group of naturally occurring positional and geometrical isomers of the C18 polyunsaturated essential fatty acid, linolenic acid (LNA), with three conjugated double bonds (C18:3). Although previous research has demonstrated the growth-inhibitory effects of CLNA on a wide variety of cancer cell lines in vitro, their action mechanisms and therapeutic potential on human myeloid leukemia cells remain poorly understood. In the present study, we found that jacaric acid (8Z,10E,12Z-octadecatrienoic acid), a CLNA isomer which is present in jacaranda seed oil, inhibited the in vitro growth of human eosinophilic leukemia EoL-1 cells in a time- and concentration-dependent manner. Mechanistic studies showed that jacaric acid triggered cell cycle arrest of EoL-1 cells at the G0/G1 phase and induced apoptosis of the EoL-1 cells, as measured by the Cell Death Detection ELISAPLUS kit, Annexin V assay and JC-1 dye staining. Notably, the jacaric acid-treated EoL-1 cells also underwent differentiation as revealed by morphological and phenotypic analysis. Collectively, our results demonstrated the capability of jacaric acid to inhibit the growth of EoL-1 cells in vitro through triggering cell cycle arrest and by inducing apoptosis and differentiation of the leukemia cells. Therefore, jacaric acid might be developed as a potential candidate for the treatment of certain forms of myeloid leukemia with minimal toxicity and few side effects.

Characterization of Protein Tyrosine Phosphatase 1B Inhibition by Chlorogenic Acid and Cichoric Acid.

PubMed

Lipchock, James M; Hendrickson, Heidi P; Douglas, Bonnie B; Bird, Kelly E; Ginther, Patrick S; Rivalta, Ivan; Ten, Nicholas S; Batista, Victor S; Loria, J Patrick

2017-01-10

Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of the insulin and leptin signaling pathways and is an active target for the design of inhibitors for the treatment of type II diabetes and obesity. Recently, cichoric acid (CHA) and chlorogenic acid (CGA) were predicted by docking methods to be allosteric inhibitors that bind distal to the active site. However, using a combination of steady-state inhibition kinetics, solution nuclear magnetic resonance experiments, and molecular dynamics simulations, we show that CHA is a competitive inhibitor that binds in the active site of PTP1B. CGA, while a noncompetitive inhibitor, binds in the second aryl phosphate binding site, rather than the predicted benzfuran binding pocket. The molecular dynamics simulations of the apo enzyme and cysteine-phosphoryl intermediate states with and without bound CGA suggest CGA binding inhibits PTP1B by altering hydrogen bonding patterns at the active site. This study provides a mechanistic understanding of the allosteric inhibition of PTP1B.

SCD1 Inhibition Causes Cancer Cell Death by Depleting Mono-Unsaturated Fatty Acids

PubMed Central

Mason, Paul; Liang, Beirong; Li, Lingyun; Fremgen, Trisha; Murphy, Erin; Quinn, Angela; Madden, Stephen L.; Biemann, Hans-Peter; Wang, Bing; Cohen, Aharon; Komarnitsky, Svetlana; Jancsics, Kate; Hirth, Brad; Cooper, Christopher G. F.; Lee, Edward; Wilson, Sean; Krumbholz, Roy; Schmid, Steven; Xiang, Yibin; Booker, Michael; Lillie, James; Carter, Kara

2012-01-01

Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway. PMID:22457791

SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids.

PubMed

Mason, Paul; Liang, Beirong; Li, Lingyun; Fremgen, Trisha; Murphy, Erin; Quinn, Angela; Madden, Stephen L; Biemann, Hans-Peter; Wang, Bing; Cohen, Aharon; Komarnitsky, Svetlana; Jancsics, Kate; Hirth, Brad; Cooper, Christopher G F; Lee, Edward; Wilson, Sean; Krumbholz, Roy; Schmid, Steven; Xiang, Yibin; Booker, Michael; Lillie, James; Carter, Kara

2012-01-01

Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway.

The existence and gas phase acidity of the HAlnF3n+1 superacids (n = 1-4)

NASA Astrophysics Data System (ADS)

Czapla, Marcin; Skurski, Piotr

2015-06-01

Novel strong superacids are proposed and investigated on the basis of ab initio calculations. The gas phase acidity of the HAlF4, HAl2F7, and HAl3F10 systems evaluated by the estimation of the Gibbs free energies of their deprotonation reactions were found significant and comparable to the corresponding value characterizing the HTaF6, whereas the strength of the HAl4F13 acid was predicted to exceed that of the HSbF6 acid (the strongest liquid superacid recognized). The deprotonation energies of the HAlnF3n+1 acids (n = 1-4) turned out to be closely related to the electronic stabilities of their corresponding (AlnF3n+1)- anions.

Plant-derived antifungal agent poacic acid targets β-1,3-glucan

DOE PAGES

Piotrowski, Jeff S.; Okada, Hiroki; Lu, Fachuang; ...

2015-03-09

A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole.more » The cellular target was identified; poacic acid localized to the cell wall and inhibited β-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding β-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. In conclusion, the discovery of poacic acid as a natural antifungal agent targeting β-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates.« less

Plant-derived antifungal agent poacic acid targets β-1,3-glucan

PubMed Central

Piotrowski, Jeff S.; Okada, Hiroki; Lu, Fachuang; Li, Sheena C.; Hinchman, Li; Ranjan, Ashish; Smith, Damon L.; Higbee, Alan J.; Ulbrich, Arne; Coon, Joshua J.; Deshpande, Raamesh; Bukhman, Yury V.; McIlwain, Sean; Ong, Irene M.; Myers, Chad L.; Boone, Charles; Landick, Robert; Ralph, John; Kabbage, Mehdi; Ohya, Yoshikazu

2015-01-01

A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole. The cellular target was identified; poacic acid localized to the cell wall and inhibited β-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding β-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. The discovery of poacic acid as a natural antifungal agent targeting β-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates. PMID:25775513

1-(2-aminophenyl)-1H-1,2,3-triazole-4-carboxylic acid: activity against Gram-positive and Gram-negative pathogens including Vibrio cholerae

NASA Astrophysics Data System (ADS)

Maji, Krishnendu; Haldar, Debasish

2017-10-01

We report a new synthetic aromatic ε-amino acid containing a triazole moiety with antimicrobial potential against Gram-positive, Gram-negative and pathogenic bacteria including Vibrio cholerae. Structure-property relationship studies revealed that all the functional groups are essential to enhance the antimicrobial activity. The 1-(2-aminophenyl)-1H-1,2,3-triazole-4-carboxylic acid was synthesized by click chemistry. From X-ray crystallography, the amino acid adopts a kink-like structure where the phenyl and triazole rings are perpendicular to each other and the amine and acid groups maintain an angle of 60°. The agar diffusion test shows that the amino acid has significant antibacterial activity. The liquid culture test exhibits that the minimum inhibitory concentration (MIC) value for Bacillus subtilis and Vibrio cholerae is 59.5 µg ml-1. FE-SEM experiments were performed to study the morphological changes of bacterial shape after treatment with compound 1. The antimicrobial activity of the amino acid was further studied by DNA binding and degradation study, protein binding, dye-binding assay and morphological analysis. Moreover, the amino acid does not have any harmful effect on eukaryotes.

An engineered fatty acid synthase combined with a carboxylic acid reductase enables de novo production of 1-octanol in Saccharomyces cerevisiae.

PubMed

Henritzi, Sandra; Fischer, Manuel; Grininger, Martin; Oreb, Mislav; Boles, Eckhard

2018-01-01

The ideal biofuel should not only be a regenerative fuel from renewable feedstocks, but should also be compatible with the existing fuel distribution infrastructure and with normal car engines. As the so-called drop-in biofuel, the fatty alcohol 1-octanol has been described as a valuable substitute for diesel and jet fuels and has already been produced fermentatively from sugars in small amounts with engineered bacteria via reduction of thioesterase-mediated premature release of octanoic acid from fatty acid synthase or via a reversal of the β-oxidation pathway. The previously engineered short-chain acyl-CoA producing yeast Fas1 R1834K /Fas2 fatty acid synthase variant was expressed together with carboxylic acid reductase from Mycobacterium marinum and phosphopantetheinyl transferase Sfp from Bacillus subtilis in a Saccharomyces cerevisiae Δfas1 Δfas2 Δfaa2 mutant strain. With the involvement of endogenous thioesterases, alcohol dehydrogenases, and aldehyde reductases, the synthesized octanoyl-CoA was converted to 1-octanol up to a titer of 26.0 mg L -1 in a 72-h fermentation. The additional accumulation of 90 mg L -1 octanoic acid in the medium indicated a bottleneck in 1-octanol production. When octanoic acid was supplied externally to the yeast cells, it could be efficiently converted to 1-octanol indicating that re-uptake of octanoic acid across the plasma membrane is not limiting. Additional overexpression of aldehyde reductase Ahr from Escherichia coli nearly completely prevented accumulation of octanoic acid and increased 1-octanol titers up to 49.5 mg L -1 . However, in growth tests concentrations even lower than 50.0 mg L -1 turned out to be inhibitory to yeast growth. In situ extraction in a two-phase fermentation with dodecane as second phase did not improve growth, indicating that 1-octanol acts inhibitive before secretion. Furthermore, 1-octanol production was even reduced, which results from extraction of the intermediate octanoic acid to

Mechanism of Specific Inhibition of Phototropism by Phenylacetic Acid in Corn Seedling 1

PubMed Central

Vierstra, Richard D.; Poff, Kenneth L.

1981-01-01

Using geotropism as a control for phototropism, compounds similar to phenylacetic acid that photoreact with flavins and/or have auxin-like activity were examined for their ability to specifically inhibit phototropism in corn seedlings using geotropism as a control. Results using indole-3-acetic acid, napthalene-1-acetic acid, naphthalene-2-acetic acid, phenylacetic acid, and β-phenylpyruvic acid suggest that such compounds will specifically inhibit phototropism primarily because of their photoreactivity with flavins and not their auxin activity. For example, strong auxins, indole-3-acetic acid and naphthalene-1-acetic acid, affected both tropic responses at all concentrations tested whereas weak auxins, phenylacetic acid and naphthalene-2-acetic acid, exhibited specific inhibition. In addition, the in vivo concentration of phenylacetic acid required to induce specificity was well below that required to stimulate coleoptile growth. Estimates of the percentage of photoreceptor pigment inactivated by phenylacetic acid (>10%) suggest that phenylacetic acid could be used to photoaffinity label the flavoprotein involved in corn seedling phototropism. PMID:16661774

Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration.

PubMed

Zhu, DanHong; Sreekumar, Parameswaran G; Hinton, David R; Kannan, Ram

2010-03-31

Ceramide and its metabolic derivatives are important modulators of cellular apoptosis and proliferation. Dysregulation or imbalance of their metabolic pathways may promote the development of retinal degeneration. The aim of this study was to identify the expression and regulation of key enzymes of the ceramide pathway in retinal pigment epithelial (RPE) cells. RT-PCR was used to screen the enzymes involved in ceramide metabolism that are expressed in RPE. Over-expression of neutral sphingomyelinase-2 (SMPD3) or sphingosine kinase 1 (Sphk1) in ARPE-19 cells was achieved by transient transfection of SMPD3 or Sphk1 cDNA subcloned into an expression vector. The number of apoptotic or proliferating cells was determined using TUNEL and BrdU assays, respectively. Neutral sphingomyelinase-1, neutral sphingomyelinase-2, acidic ceramidase, ceramide kinase, SphK1 and Sphk2 were expressed in both ARPE-19 and early passage human fetal RPE (fRPE) cells, while alkaline ceramidase 2 was only expressed in fRPE cells. Over-expression of SMPD3 decreased RPE cell proliferation and increased cell apoptosis. The percentage of apoptotic cells increased proportionally with the amount of transfected SMPD3 DNA. Over-expression of SphK1 promoted cell proliferation and protected ARPE-19 cells from ceramide-induced apoptosis. The effect of C(2) ceramide on induction of apoptosis was evaluated in polarized vs. non-polarized RPE cultures; polarization of RPE was associated with much reduced apoptosis in response to ceramide. In conclusion, RPE cells possess the synthetic machinery for the production of ceramide, sphingosine, ceramide-1-phosphate (C1P), and sphingosine-1-phosphate (S1P). Over-expression of SMPD3 may increase cellular ceramide levels, leading to enhanced cell death and arrested cell proliferation. The selective induction of apoptosis in non-polarized RPE cultures by C(2) ceramide suggests that increased ceramide levels will preferentially affect non-polarized RPE, as are found in

Structure of five molecular salts assembled from noncovalent associations between organic acids, imidazole, benzimidazole, and 1-(2-(1H-benzimidazol-1-yl)ethyl)-1H-benzimidazole

NASA Astrophysics Data System (ADS)

Chen, Xuchong; Jin, Shouwen; Zhang, Huan; Xiao, Xiao; Liu, Bin; Wang, Daqi

2017-09-01

Cocrystallization of the imidazole derivatives, L1-L3, with a series of organic acids gave a total of five molecular salts with the compositions: (imidazole): (DL-10-camphorsulfonic acid) [(HL1+)·(cpsa-), cpsa- = DL-10-camphorsulfonate] (1), (imidazole): (3,5-dihydroxybenzoic acid) [(HL1+) · (3,5-dba-), 3,5-dba- = 3,5-dihydroxybenzoate] (2), (imidazole): (isophthalic acid): H2O [(HL1)+·(Hmpa)-·H2O, Hmpa- = hydrogenisophthalate] (3), (benzimidazole): (butane-1,2,3,4-tetracarboxylic acid) [(HL2+)·(H3bta -), H3bta- = trihydrogen butane-1,2,3,4-tetracarboxylate] (4), and (benzimidazole)2: 1-(2-(1H-benzimidazol-1-yl)ethyl)-1H-benzimidazole: (5-nitrosalicylic acid)2 [(L2)2·(H2L3)2+·(5-nsa-)2, 5-nsa- = 5-nitrosalicylate], (5). The five salts have been characterized by XRD technique, IR, and EA, and the melting points of all the salts were also reported. And their structural and supramolecular aspects are fully analyzed. The result reveals that among the five investigated crystals the ring N in the imidazole moieties are protonated when the organic acids are ionized, and the crystal packing is interpreted in terms of the strong Nsbnd H⋯O H-bond from the imidazole and the ionized acids. In addition to the Nsbnd H⋯O H-bond, the Osbnd H⋯O H-bonds were also established at the salts 2-5, compound 1 has the additional Nsbnd H⋯S H-bonds. Further analysis of the crystal packing of the salts displayed that a different family of additional CHsbnd O/CH2sbnd O/CH3sbnd O, CHsbnd S, CHsbnd π, NHsbnd π, and πsbnd π associations contribute to the stabilization and expansion of the total 3D framework structures. For the coexistence of the various weak interactions these structures had homo or hetero supramolecular synthons or both. Some classical supramolecular synthons, such as R12(4), R22(7), and R22(8) usually observed in crystals of organic acids with imidazole, were again shown to be involved in constructing most of these hydrogen bonding networks.

l-Type Amino Acid Transporter-1 Overexpression and Melphalan Sensitivity in Barrett's Adenocarcinoma1

PubMed Central

Lin, Jules; Raoof, Duna A; Thomas, Dafydd G; Greenson, Joel K; Giordano, Thomas J; Robinson, Gregory S; Bourner, Maureen J; Bauer, Christopher T; Orringer, Mark B; Beer, David G

2004-01-01

Abstract The L-type amino acid transporter-1 (LAT-1) has been associated with tumor growth. Using cDNA microarrays, overexpression of LAT-1 was found in 87.5% (7/8) of esophageal adenocarcinomas relative to 12 Barrett's samples (33% metaplasia and 66% dysplasia) and was confirmed in 100% (28/28) of Barrett's adenocarcinomas by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry revealed LAT-1 staining in 37.5% (24/64) of esophageal adenocarcinomas on tissue microarray. LAT-1 also transports the amino acid-related chemotherapeutic agent, melphalan. Two esophageal adenocarcinoma and one esophageal squamous cell line, expressing LAT-1 on Western blot analysis, were sensitive to therapeutic doses of melphalan (P < .001). Simultaneous treatment with the competitive inhibitor, BCH [2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid], decreased sensitivity to melphalan (P < .05). In addition, confluent esophageal squamous cultures were less sensitive to melphalan (P < .001) and had a decrease in LAT-1 protein expression. Tumors from two esophageal adenocarcinoma cell lines grown in nude mice retained LAT-1 mRNA expression. These results demonstrate that LAT-1 is highly expressed in a subset of esophageal adenocarcinomas and that Barrett's adenocarcinoma cell lines expressing LAT-1 are sensitive to melphalan. LAT-1 expression is also retained in cell lines grown in nude mice providing a model to evaluate melphalan as a chemotherapeutic agent against esophageal adenocarcinomas expressing LAT-1. PMID:15068672

2,3-Diamino-pyridinium sorbate-sorbic acid (1/1).

PubMed

Hemamalini, Madhukar; Goh, Jia Hao; Fun, Hoong-Kun

2012-01-01

In the title mol-ecular salt-adduct, C(5)H(8)N(3) (+)·C(6)H(7)O(2) (-)·C(6)H(8)O(2), the 2,3-diamino-pyridinium cation is essentially planar, with a maximum deviation of 0.013 (2) Å, and is protanated at its pyridine N atom. The sorbate anion and sorbic acid mol-ecules exist in extended conformations. In the crystal, the protonated N atom and one of the two amino-group H atoms are hydrogen bonded to the sorbate anion through a pair of N-H⋯O hydrogen bonds, forming an R(1) (2)(6) ring motif. The carboxyl groups of the sorbic acid mol-ecules and the carboxyl-ate groups of the sorbate anions are connected via O-H⋯O hydrogen bonds. Furthermore, the ion pairs and neutral mol-ecules are connected via inter-molecular N-H⋯O hydrogen bonds, forming sheets lying parallel to (100).

40 CFR 721.10020 - Benzoic acid, 5-amino-2-chloro-, 1,1-dimethyl-2-oxo-2-(2-propenyloxy) ethyl ester.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Benzoic acid, 5-amino-2-chloro-, 1,1... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10020 Benzoic acid, 5-amino-2-chloro... subject to reporting. (1) The chemical substance identified as benzoic acid, 5-amino-2-chloro-, 1,1...

40 CFR 721.10020 - Benzoic acid, 5-amino-2-chloro-, 1,1-dimethyl-2-oxo-2-(2-propenyloxy) ethyl ester.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzoic acid, 5-amino-2-chloro-, 1,1... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10020 Benzoic acid, 5-amino-2-chloro... subject to reporting. (1) The chemical substance identified as benzoic acid, 5-amino-2-chloro-, 1,1...

Production of Structured Triacylglycerols Containing Palmitic Acids at sn-2 Position and Docosahexaenoic Acids at sn-1, 3 Positions.

PubMed

Liu, Yanjun; Guo, Yongli; Sun, Zhaomin; Jie, Xu; Li, Zhaojie; Wang, Jingfeng; Wang, Yuming; Xue, Changhu

2015-01-01

Docosahexaenoic acid supplementation has been shown well-established health benefits that justify their use as functional ingredients in healthy foods and nutraceutical products. Structured triacylglycerols rich in 1,3-docosahexenoyl-2-palmitoyl-sn-glycerol were produced from algal oil (Schizochytrium sp) which was prepared by a two-step process. Novozym 435 lipase was used to produce tripalmitin. Tripalmitin was then used to produce the final structured triacylglycerol (STAG) through interesterification reactions using Lipozyme RM IM. The optimum conditions for the enzymatic reaction were a mole ratio of tripalmitin/fatty acid ethyl esters 1:9, 60°C, 10% enzyme load (wt % of substrates), 10 h; the enzymatic product contained 51.6% palmitic acid (PA), 30.13% docosahexaenoic acid (DHA, C22:6 n-3) and 5.33% docosapentanoic acid (DPA, C22:5 n-3), 12.15% oleic acid (OLA). This STAG can be used as a functional ingredient in dietary supplementation to provide the benefits of DHA.

40 CFR 721.10072 - Benzene, 1,1′-methylenebis[4-isocyanato-, polymer with benzenedicarboxylic acid, butyl dialkyl...

Code of Federal Regulations, 2010 CFR

2010-07-01

...-isocyanato-, polymer with benzenedicarboxylic acid, butyl dialkyl ester, poly[oxy(methyl-1,2-ethanediyl)], .alpha.-hydro-.omega.-hydroxy-, oxirane, alkyl-, polymer with oxirane, ether with propanepolyol and...-isocyanato-, polymer with benzenedicarboxylic acid, butyl dialkyl ester, poly[oxy(methyl-1,2-ethanediyl...

Hydrogen bonds in betaine-acid (1:1) crystals revealed by Raman and 13C chemical shift tensors

NASA Astrophysics Data System (ADS)

Ilczyszyn, Marek; Ilczyszyn, Maria M.

2017-06-01

H-bonds of five betaine-acid (1:1) crystals are considered by analysis of tensors based on the Raman scissoring mode and 13C chemical shift of the betaine -CO1O2- carboxylate group. The leading structural factor in these systems is the strongest H-bond linking the betaine and the acidic moieties, (O1⋯H-O)com. The Raman and NMR tensors are strongly related to its character and to the R(O1⋯O)com distance. Very high molecular polarizability variation due to the scissoring vibration was found for the betaine-selenious acid crystal. The probable reason is modest network of H-bonds in this case and relatively high proton polarizability of these bonds.

Ferulic acid reverses ABCB1-mediated paclitaxel resistance in MDR cell lines.

PubMed

Muthusamy, Ganesan; Balupillai, Agilan; Ramasamy, Karthikeyan; Shanmugam, Mohana; Gunaseelan, Srithar; Mary, Beaulah; Prasad, N Rajendra

2016-09-05

Multidrug resistance (MDR) remains a major obstacle in cancer chemotherapy. The use of the dietary phytochemicals as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention as a plausible approach for overcoming the drug resistance. The aim of this study was to investigate whether a naturally occurring diet-based phenolic acid, ferulic acid, could sensitize paclitaxel efficacy in ABCB1 overexpressing (P-glycoprotein) colchicine selected KB Ch(R)8-5 cell line. In vitro drug efflux assays demonstrated that ferulic acid inhibits P-glycoprotein transport function in drug resistant KB Ch(R)8-5 cell lines. However, ferulic acid significantly downregulates ABCB1 expression in a concentration dependent manner. Cytotoxicity assay reveals that ferulic acid decreased paclitaxel resistance in KBCh(R)8-5 and HEK293/ABCB1 cells, which indicates its chemosensitizing potential. Clonogenic cell survival assay and apoptotic morphological staining further confirm the chemosensitizing potential of ferulic acid in drug resistant KB Ch(R)8-5 cell lines. Ferulic acid treatment enhances paclitaxel mediated cell cycle arrest and upregulates paclitaxel-induced apoptotic signaling in KB resistant cells. Hence, it has been concluded that downregulation of ABCB1 and subsequent induction of paclitaxel-mediated cell cycle arrest and apoptotic signaling may be the cause for the chemosensitizing potential of ferulic acid in P-gp overexpressing cell lines. Copyright © 2016 Elsevier B.V. All rights reserved.

Molecular dynamics simulations of the auxin-binding protein 1 in complex with indole-3-acetic acid and naphthalen-1-acetic acid.

PubMed

Grandits, Melanie; Oostenbrink, Chris

2014-10-01

Auxin-binding protein 1 (ABP1) is suggested to be an auxin receptor which plays an important role in several processes in green plants. Maize ABP1 was simulated with the natural auxin indole-3-acetic acid (IAA) and the synthetic analog naphthalen-1-acetic acid (NAA), to elucidate the role of the KDEL sequence and the helix at the C-terminus. The KDEL sequence weakens the intermolecular interactions between the monomers but stabilizes the C-terminal helix. Conformational changes at the C-terminus occur within the KDEL sequence and are influenced by the binding of the simulated ligands. This observation helps to explain experimental findings on ABP1 interactions with antibodies that are modulated by the presence of auxin, and supports the hypothesis that ABP1 acts as an auxin receptor. Stable hydrogen bonds between the monomers are formed between Glu40 and Glu62, Arg10 and Thr97, Lys39, and Glu62 in all simulations. The amino acids Ile22, Leu25, Trp44, Pro55, Ile130, and Phe149 are located in the binding pocket and are involved in hydrophobic interactions with the ring system of the ligand. Trp151 is stably involved in a face to end interaction with the ligand. The calculated free energy of binding using the linear interaction energy approach showed a higher binding affinity for NAA as compared to IAA. Our simulations confirm the asymmetric behavior of the two monomers, the stronger interaction of NAA than IAA and offers insight into the possible mechanism of ABP1 as an auxin receptor. © 2014 Wiley Periodicals, Inc.

Synthesis and mutagenicity of a ring-A-aromatized bile acid, 3-hydroxy-19-nor-1,3,5(10)-cholatrien-24-oic acid.

PubMed

Namba, T; Hirota, T; Hayakawa, S

1988-06-01

It has been presumed that ring-A-aromatized bile acids are produced from biliary bile acids by intestinal flora and the acids thus formed participate in the large bowel carcinogenesis. One of these acids is probably 3-hydroxy-19-nor-1,3,5(10)-cholatrien-24-oic acid, judged from the literatures. Consequently, this acid was synthesized from previously prepared 3-methoxy-19-nor-1,3,5(10)-cholatrien-24-ol. The phenolic ether was successively oxidized with pyridinium chlorochromate and wet silver oxide to give 3-methoxy-19-nor-1,3,5(10)-cholatrien-24-oic acid in high yield, which, after successive treatments with methanol containing a catalytic amount of p-toluenesulfonic acid, a combination of aluminum chloride and ethanethiol, and alkali, gave the desired compound in satisfactory yield. The compound was not mutagenic in Salmonella tester strains TA 98 and TA 100, but it increased the mutagenicity of 2-aminoanthracene when both were applied to plates together. When compared with cholic, deoxycholic, and lithocholic acids, the investigated compound exhibited about two to threefold increase of mutagenicity in the latter assay.

Crystal structure of 1-(3-chloro-phen-yl)piperazin-1-ium picrate-picric acid (2/1).

PubMed

Kavitha, Channappa N; Jasinski, Jerry P; Kaur, Manpreet; Anderson, Brian J; Yathirajan, H S

2014-11-01

The title salt {systematic name: bis-[1-(3-chloro-phen-yl)piperazinium 2,4,6-tri-nitro-phenolate]-picric acid (2/1)}, 2C10H14ClN2 (+)·2C6H5N3O7 (-)·C6H6N3O7, crystallized with two independent 1-(3-chloro-phen-yl)piperazinium cations, two picrate anions and a picric acid mol-ecule in the asymmetric unit. The six-membered piperazine ring in each cation adopts a slightly distorted chair conformation and contains a protonated N atom. In the picric acid mol-ecule, the mean planes of the nitro groups in the ortho-, meta-, and para-positions are twisted from the benzene ring by 31.5 (3), 7.7 (1), and 3.8 (2)°, respectively. In the anions, the dihedral angles between the benzene ring and the ortho-, meta-, and para-nitro groups are 36.7 (1), 5.0 (6), 4.8 (2)°, and 34.4 (9), 15.3 (8), 4.5 (1)°, respectively. The nitro group in one anion is disordered and was modeled with two sites for one O atom with an occupancy ratio of 0.627 (7):0.373 (7). In the crystal, the picric acid mol-ecule inter-acts with the picrate anion through a trifurcated O-H⋯O four-centre hydrogen bond involving an intra-molecular O-H⋯O hydrogen bond and a weak C-H⋯O inter-action. Weak inter-molecular C-H⋯O inter-actions are responsible for the formation of cation-anion-cation trimers resulting in a chain along [010]. In addition, weak C-H⋯Cl and weak π-π inter-actions [centroid-centroid distances of 3.532 (3), 3.756 (4) and 3.705 (3) Å] are observed and contribute to the stability of the crystal packing.

75 FR 22814 - Guidance for Industry: Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-30

... Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV): Testing, Product Disposition, and Donor Deferral... Industry: Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus... Acid Test (NAT) and Hepatitis C Virus (HCV) NAT, on testing individual samples or pooled samples from...

Is Asymptomatic Vasospasm Associated With Poor Outcome in Subarachnoid Hemorrhage?

PubMed Central

Latorre, Julius Gene S.; Lodi, Yahia; El-Zammar, Ziad; Devasenapathy, Ashok

2011-01-01

Background: Vasospasm occurs in up to 70% of aneurysmal subarachnoid hemorrhage (aSAH), but only half becomes symptomatic. It is unclear whether asymptomatic vasospasm (AV) detected by noninvasive testing affects outcome. Prophylactic hemodilutional, hypertensive, and hypervolemic (HHH) therapy is widely used but the benefit remains unproven. We aim to determine whether AV increases the risk of poor outcome and whether HHH is safe. Methods: A total of 175 consecutive patients with aSAH without clinical vasospasm were included. Patients with sonographic (transcranial doppler) or radiologic (computed tomography [CT] Angiography) vasospasm were assigned to AV group, while those without were assigned to no vasospasm (NV) group. Logistic regression was used to determine the association between AV and HHH on poor outcome, defined as modified Rankin scale (mRS) >3 at discharge or 3 to 6 months' follow-up. Results: In all, 106 patients had NV and 25 received HHH. A total of 69 patients had AV and 54 received HHH. Asymptomatic vasospasm compared to NV was not associated with poor outcome (odds ratio [OR] 2.6, 95% confidence interval [CI]: 0.75-8.9; P = .1). Hemodilutional, hypertensive, and hypervolemic use in patients with AV did not improve the outcome (OR 0.16, 95%CI: 0.009-2.84; P = .2). In patients with NV, HHH use showed trend toward poor outcome after multivariable adjustment (OR 12.6, 95%CI: 1.08-146.5 P = .04). Conclusion: Asymptomatic vasospasm does not appear to be associated with poor outcome in aSAH. Hemodilutional, hypertensive, and hypervolemic therapy in AV was not associated with improved outcome and may be harmful to patients who do not have vasospasm. Further research is needed to validate this finding. PMID:23983851

Role of AMACR (α-methylacyl-CoA racemase) and MFE-1 (peroxisomal multifunctional enzyme-1) in bile acid synthesis in mice.

PubMed

Autio, Kaija J; Schmitz, Werner; Nair, Remya R; Selkälä, Eija M; Sormunen, Raija T; Miinalainen, Ilkka J; Crick, Peter J; Wang, Yuqin; Griffiths, William J; Reddy, Janardan K; Baes, Myriam; Hiltunen, J Kalervo

2014-07-01

Cholesterol is catabolized to bile acids by peroxisomal β-oxidation in which the side chain of C27-bile acid intermediates is shortened by three carbon atoms to form mature C24-bile acids. Knockout mouse models deficient in AMACR (α-methylacyl-CoA racemase) or MFE-2 (peroxisomal multifunctional enzyme type 2), in which this β-oxidation pathway is prevented, display a residual C24-bile acid pool which, although greatly reduced, implies the existence of alternative pathways of bile acid synthesis. One alternative pathway could involve Mfe-1 (peroxisomal multifunctional enzyme type 1) either with or without Amacr. To test this hypothesis, we generated a double knockout mouse model lacking both Amacr and Mfe-1 activities and studied the bile acid profiles in wild-type, Mfe-1 and Amacr single knockout mouse line and Mfe-1 and Amacr double knockout mouse lines. The total bile acid pool was decreased in Mfe-1-/- mice compared with wild-type and the levels of mature C24-bile acids were reduced in the double knockout mice when compared with Amacr-deficient mice. These results indicate that Mfe-1 can contribute to the synthesis of mature bile acids in both Amacr-dependent and Amacr-independent pathways.

Changes in the level of cardiac troponine and disorders in pulmonary gas exchange as predictors of short- and long-term outcomes of patients with aneurysm subarachnoid haemorrhage.

PubMed

Burzyńska, Małgorzata; Uryga, Agnieszka; Kasprowicz, Magdalena; Kędziora, Jarosław; Szewczyk, Ewa; Woźniak, Jowita; Jarmundowicz, Włodzimierz; Kübler, Andrzej

2017-12-01

Cardiopulmonary abnormalities are common after aneurysmal subarachnoid haemorrhage (aSAH). However, the relationship between short- and long-term outcome is poorly understood. In this paper, we present how cardiac troponine elevations (cTnI) and pulmonary disorders are associated with short- and long-term outcomes assessed by the Glasgow Outcome Scale (GOS) and Extended Glasgow Outcome Scale (GOSE). A total of 104 patients diagnosed with aSAH were analysed in the study. The non-parametric U Mann-Whitney test was used to evaluate the difference between good (GOS IV-V, GOSE V-VIII) and poor (GOS I-III, GOSE I-IV) outcomes in relation to cTnI elevation and pulmonary disorders. Outcome was assessed at discharge from the hospital, and then followed up 6 and 12 months later. Pulmonary disorders were determined by the PaO 2 /FiO 2 ratio and radiography. The areas under the ROC curves (AUCs) were used to determine the predictive power of these factors. In the group with good short-term outcomes cTnI elevation on the second day after aSAH was significantly lower (p = .00007) than in patients with poor short-term outcomes. The same trend was observed after 6 months, although there were different results 12 months from the onset (p = .024 and n.s., respectively). A higher peak of cTnI was observed in the group with a pathological X-ray (p = .008) and pathological PaO 2 /FiO 2 ratio (p ≪ .001). cTnI was an accurate predictor of short-term outcomes (AUC = 0.741, p ≪ .001) and the outcome after 6 months (AUC = 0.688, p = .015). The results showed that cardiopulmonary abnormalities perform well as predictive factors for short- and long-term outcomes after aSAH.

Interaction of model aryl- and alkyl-boronic acids and 1,2-diols in aqueous solution.

PubMed

Marinaro, William A; Prankerd, Richard; Kinnari, Kaisa; Stella, Valentino J

2015-04-01

The goal of this work was to quantitate ester formation between alkyl and aryl boronic acids and vicinal-diols or 1,2-diols in aqueous solution. As used here, 1,2-diols includes polyols with one or more 1,2-diol pairs. Multiple techniques were used including apparent pKa shifts of the boronic acids using UV spectrophotometry (for aryl acids) and titration (for aryl and alkyl acids). Isothermal microcalorimetry was also used, with all reactions being enthalpically favored. For all the acids and 1,2-diols and the conditions studied, evidence only supported 1:1 ester formation. All the esters formed were found to be significantly more acidic, as Lewis acids, by 3-3.5 pKa units than the corresponding nonesterified boronic acid. The equilibrium constants for ester formation increased with increasing number of 1,2-diol pairs but stereochemistry may also play a role as sorbitol with five possible 1,2-diol pairs and five isomers (taking into account the stereochemistry of the alcohol groups) was twice as efficient at ester formation compared with mannitol, also with five possible 1,2-diol pairs but only three isomers. Alkyl boronic acids formed esters to a greater extent than aryl acids. Although some quantitative differences were seen between the various techniques used, rank ordering of the structure/reactivity was consistent. Formulation implications of ester formation between boronic acids and 1,2-diols are discussed. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Short-Chain Fatty Acids Enhance the Lipid Accumulation of 3T3-L1 Cells by Modulating the Expression of Enzymes of Fatty Acid Metabolism.

PubMed

Yu, Haining; Li, Ran; Huang, Haiyong; Yao, Ru; Shen, Shengrong

2018-01-01

Short-chain fatty acids (SCFA) such as acetic acid, propionic acid, and butyric acid are produced by fermentation by gut microbiota. In this paper, we investigate the effects of SCFA on 3T3-L1 cells and the underlying molecular mechanisms. The cells were treated with acetic acid, propionic acid, or butyric acid when cells were induced to differentiate into adipocytes. MTT assay was employed to detect the viability of 3T3-L1 cells. Oil Red O staining was used to visualize the lipid content in 3T3-L1 cells. A triglyceride assay kit was used to detect the triacylglycerol content in 3T3-L1 cells. qRT-PCR and Western blot were used to evaluate the expression of metabolic enzymes. MTT results showed that safe concentrations of acetic acid, propionic acid, and butyric acid were less than 6.4, 3.2, and 0.8 mM, respectively. Oil Red O staining and triacylglycerols detection results showed that treatment with acetic acid, propionic acid, and butyric acid accelerated the 3T3-L1 adipocyte differentiation. qRT-PCR and Western blot results showed that the expressions of lipoprotein lipase (LPL), adipocyte fatty acid binding protein 4 (FABP4), fatty acid transporter protein 4 (FATP4), and fatty acid synthase (FAS) were significantly increased by acetic acid, propionic acid, and butyric acid treatment during adipose differentiation (p < 0.05). In conclusion, SCFA promoted lipid accumulation by modulating the expression of enzymes of fatty acid metabolism. © 2018 AOCS.

Conditional knock-out of lipoic acid protein ligase 1 reveals redundancy pathway for lipoic acid metabolism in Plasmodium berghei malaria parasite.

PubMed

Wang, Min; Wang, Qiong; Gao, Xiang; Su, Zhong

2017-06-27

Lipoic acid is a cofactor for α-keto acid dehydrogenase system that is involved in the central energy metabolism. In the apicomplexan parasite, Plasmodium, lipoic acid protein ligase 1 (LplA1) and LplA2 catalyse the ligation of acquired lipoic acid to the dehydrogenase complexes in the mitochondrion. The enzymes LipB and LipA mediate lipoic acid synthesis and ligation to the enzymes in the apicoplast. These enzymes in the lipoic acid metabolism machinery have been shown to play important roles in the biology of Plasmodium parasites, but the relationship between the enzymes is not fully elucidated. We used an anhydrotetracycline (ATc)-inducible transcription system to generate transgenic P. berghei parasites in which the lplA1 gene was conditionally knocked out (LplA1-cKO). Phenotypic changes and the lplA1 and lplA2 gene expression profiles of cloned LplA1-cKO parasites were analysed. LplA1-cKO parasites showed severely impaired growth in vivo in the first 8 days of infection, and retarded blood-stage development in vitro, in the absence of ATc. However, these parasites resumed viability in the late stage of infection and mounted high levels of parasitemia leading to the death of the hosts. Although lplA1 mRNA expression was regulated tightly by ATc during the whole course of infection, lplA2 mRNA expression was significantly increased in the late stage of infection only in the LplA1-cKO parasites that were not exposed to ATc. The lplA2 gene can be activated as an alternative pathway to compensate for the loss of LplA1 activity and to maintain lipoic acid metabolism.

Ethylene biosynthesis by 1-aminocyclopropane-1-carboxylic acid oxidase: a DFT study.

PubMed

Bassan, Arianna; Borowski, Tomasz; Schofield, Christopher J; Siegbahn, Per E M

2006-11-24

The reaction catalyzed by the plant enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO) was investigated by using hybrid density functional theory. ACCO belongs to the non-heme iron(II) enzyme superfamily and carries out the bicarbonate-dependent two-electron oxidation of its substrate ACC (1-aminocyclopropane-1-carboxylic acid) concomitant with the reduction of dioxygen and oxidation of a reducing agent probably ascorbate. The reaction gives ethylene, CO(2), cyanide and two water molecules. A model including the mononuclear iron complex with ACC in the first coordination sphere was used to study the details of O-O bond cleavage and cyclopropane ring opening. Calculations imply that this unusual and complex reaction is triggered by a hydrogen atom abstraction step generating a radical on the amino nitrogen of ACC. Subsequently, cyclopropane ring opening followed by O-O bond heterolysis leads to a very reactive iron(IV)-oxo intermediate, which decomposes to ethylene and cyanoformate with very low energy barriers. The reaction is assisted by bicarbonate located in the second coordination sphere of the metal.

40 CFR 721.3820 - L-Glutamic acid, N-(1-oxododecyl)-, disodium salt.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false L-Glutamic acid, N-(1-oxododecyl... Specific Chemical Substances § 721.3820 L-Glutamic acid, N-(1-oxododecyl)-, disodium salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as L-Glutamic...

Effects of a Series of Acidic Drugs on L-Lactic Acid Transport by the Monocarboxylate Transporters MCT1 and MCT4.

PubMed

Leung, Yat H; Belanger, Francois; Lu, Jennifer; Turgeon, Jacques; Michaud, Veronique

2017-01-01

Drug-induced myopathy is a serious side effect that often requires removal of a medication from a drug regimen. For most drugs, the underlying mechanism of drug-induced myopathy remains unclear. Monocarboxylate transporters (MCTs) mediate L-lactic acid transport, and inhibition of MCTs may potentially lead to perturbation of L-lactic acid accumulation and muscular disorders. Therefore, we hypothesized that L-lactic acid transport may be involved in the development of drug-induced myopathy. The aim of this study was to assess the inhibitory potential of 24 acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 and MCT4, respectively. The influx transport of L-lactic acid was minimally inhibited by all drugs tested. The efflux transport was next examined: loratadine (IC50: 10 and 61 µM) and atorvastatin (IC50: 78 and 41 µM) demonstrated the greatest potency for inhibition of L-lactic acid efflux by MCT1 and MCT4, respectively. Acidic drugs including fluvastatin, cerivastatin, simvastatin acid, lovastatin acid, irbesartan and losartan exhibited weak inhibitory potency on L-lactic acid efflux. Our results suggest that some acidic drugs, such as loratadine and atorvastatin, can inhibit the efflux transport of L-lactic acid. This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

1,4-Dihydroxy fatty acids: Artifacts by reduction of di- and polyunsaturated fatty acids with sodium borohydride

NASA Astrophysics Data System (ADS)

Thiemt, Simone; Spiteller, Gerhard

1997-01-01

In an effort to detect lipid peroxidation products in human blood plasma, samples were treated with NaBH4 to reduce the reactive hydroperoxides to hydroxy compounds. After saponification of the lipids, the free fatty acid fraction obtained by extraction was methylated and separated by TLC. The fractions containing polar compounds were trimethylsilylated and subjected to gas chromatography-mass spectrometry (GC/MS). Mass spectra allowed us to detect previously unknown 1,4-dihydroxy fatty acids due to their typical fragmentation pattern. If the reduction was carried out with NaBD4 instead of NaBH4, incorporation of two deuterium atoms was observed (appropriate mass shift). The two oxygen atoms of the hydroxyl groups were incorporated from air as shown by an experiment in 18O2 atmosphere. The reaction required the presence of free acids, indicating that BH3 was liberated, added to a 1,4-pentadiene system, and finally produced 1,4-diols by air oxidation.

Arabidopsis ENHANCED DISEASE SUSCEPTIBILITY1 promotes systemic acquired resistance via azelaic acid and its precursor 9-oxo nonanoic acid

PubMed Central

Wittek, Finni; Hoffmann, Thomas; Kanawati, Basem; Bichlmeier, Marlies; Knappe, Claudia; Wenig, Marion; Schmitt-Kopplin, Philippe; Parker, Jane E.; Schwab, Wilfried; Vlot, A. Corina

2014-01-01

Systemic acquired resistance (SAR) is a form of inducible disease resistance that depends on salicylic acid and its upstream regulator ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1). Although local Arabidopsis thaliana defence responses activated by the Pseudomonas syringae effector protein AvrRpm1 are intact in eds1 mutant plants, SAR signal generation is abolished. Here, the SAR-specific phenotype of the eds1 mutant is utilized to identify metabolites that contribute to SAR. To this end, SAR bioassay-assisted fractionation of extracts from the wild type compared with eds1 mutant plants that conditionally express AvrRpm1 was performed. Using high-performance liquid chromatography followed by mass spectrometry, systemic immunity was associated with the accumulation of 60 metabolites, including the putative SAR signal azelaic acid (AzA) and its precursors 9-hydroperoxy octadecadienoic acid (9-HPOD) and 9-oxo nonanoic acid (ONA). Exogenous ONA induced SAR in systemic untreated leaves when applied at a 4-fold lower concentration than AzA. The data suggest that in planta oxidation of ONA to AzA might be partially responsible for this response and provide further evidence that AzA mobilizes Arabidopsis immunity in a concentration-dependent manner. The AzA fragmentation product pimelic acid did not induce SAR. The results link the C9 lipid peroxidation products ONA and AzA with systemic rather than local resistance and suggest that EDS1 directly or indirectly promotes the accumulation of ONA, AzA, or one or more of their common precursors possibly by activating one or more pathways that either result in the release of these compounds from galactolipids or promote lipid peroxidation. PMID:25114016

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

PubMed Central

Nagahashi, Masayuki; Yuza, Kizuki; Hirose, Yuki; Nakajima, Masato; Ramanathan, Rajesh; Hait, Nitai C.; Hylemon, Phillip B.; Zhou, Huiping; Takabe, Kazuaki; Wakai, Toshifumi

2016-01-01

Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor α, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1-phosphate receptor (S1PR)2. The ligand of S1PR2, sphingosine-1-phosphate (S1P), is a bioactive lipid mediator that regulates various physiological and pathophysiological cellular processes. We have recently reported that conjugated bile acids, via S1PR2, activate and upregulate nuclear sphingosine kinase 2, increase nuclear S1P, and induce genes encoding enzymes and transporters involved in lipid and sterol metabolism in the liver. Here, we discuss the role of bile acids and S1P signaling in the regulation of hepatic lipid metabolism and in hepatobiliary diseases. PMID:27459945

40 CFR 721.10135 - Phosphinic acid, P,P-diethyl-, zinc salt (2:1).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Phosphinic acid, P,P-diethyl-, zinc... Specific Chemical Substances § 721.10135 Phosphinic acid, P,P-diethyl-, zinc salt (2:1). (a) Chemical... acid, P,P-diethyl-, zinc salt (2:1) (PMN P-05-11; CAS No. 284685-45-6) is subject to reporting under...

40 CFR 721.10135 - Phosphinic acid, P,P-diethyl-, zinc salt (2:1).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Phosphinic acid, P,P-diethyl-, zinc... Specific Chemical Substances § 721.10135 Phosphinic acid, P,P-diethyl-, zinc salt (2:1). (a) Chemical... acid, P,P-diethyl-, zinc salt (2:1) (PMN P-05-11; CAS No. 284685-45-6) is subject to reporting under...

Inhibition effects of perfluoroalkyl acids on progesterone production in mLTC-1.

PubMed

Zhao, Wei; Cui, Ruina; Wang, Jianshe; Dai, Jiayin

2017-06-01

Perfluoroalkyl substances (PFASs) are a class of fluorine substituted carboxylic acid, sulfonic acid and alcohol, structurally similar to their corresponding parent compounds. Previous study demonstrated the potential endocrine disruption and reproductive toxicity of perfluorooctane sulfonic acid and perfluorooctanoic acid, two dominant PFASs in animals and humans. We explored the relationship between eleven perfluoroalkyl acids (PFAAs) with different carbon chain length and their ability to inhibit progesterone production in mouse Leydig tumor cells (mLTC-1). We found an obvious dose-response relationship between progesterone inhibition rate and PFAA exposure concentration in mLTC-1. The relative inhibition rate of progesterone by PFAAs was linearly related to the carbon chain length and molar refractivity of PFAAs. Mitochondrial membrane potential (MMP) decreased after PFAA exposure at the half-maximal inhibitory effect concentration (IC 50 ) of progesterone production in mLTC-1, while the reactive oxygen species (ROS) content increased significantly. These results imply that the inhibition effect of PFAAs on progesterone production might be due, in part, to ROS damage and the decrease in MMP in mLTC-1. Copyright © 2016. Published by Elsevier B.V.

ORIGIN OF PALMITIC ACID CARBON IN PALMITATES FORMED FROM HEXADECANE-1-C14 AND TETRADECANE-1-C14 BY MICROCOCCUS CERIFICANS

PubMed Central

Finnerty, W. R.; Kallio, R. E.

1964-01-01

Finnerty, W. R. (University of Iowa, Iowa City), and R. E. Kallio. Origin of palmitic acid carbon in palmitates formed from hexadecane-1-C14 and tetradecane-1-C14 by Micrococcus cerificans. J. Bacteriol. 87:1261–1265. 1964.—Degradation of the palmitic acid moiety of cetyl palmitate and myristyl palmitate formed from hexadecane-1-C14 and tetradecane-1-C14 by Micrococcus cerificans was carried out. The patterns of C14 labeling in palmitic acid from cetyl palmitate showed that hexadecane is oxidized at the C1 position, and cetyl alcohol and palmitic acid thus formed are directly esterified. Palmitic acid arising from tetradecane and esterified to tetradecanol appeared to have been synthesized by the addition of two carbon atoms to an existing 14-carbon atom skeleton. Considerable mixing of C14 occurred in the C1 and C2 positions of palmitic acid thus synthesized. PMID:14188700

An IC-MS/MS Method for the Determination of 1-Hydroxyethylidene-1,1-diphosphonic Acid on Uncooked Foods Treated with Peracetic Acid-Based Sanitizers.

PubMed

Suzuki, Ippei; Kubota, Hiroki; Ohtsuki, Takashi; Tatebe, Chiye; Tada, Atsuko; Yano, Takeo; Akiyama, Hiroshi; Sato, Kyoko

2016-01-01

A rapid, sensitive, and specific analytical method for the determination of 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP) on uncooked foods after treatment with a peracetic acid-based sanitizer (PAS) was developed. The method involves simple sample preparation steps and analysis using ion chromatography (IC) coupled with tandem mass spectrometry (MS/MS). The quantification limits of HEDP on uncooked foods are 0.007 mg/kg for vegetables and fruits and 0.2 mg/kg for meats. The recovery and relative standard deviation (RSD) of HEDP analyses of uncooked foods ranged from 73.9 to 103.8% and 1.9 to 12.6%, respectively. The method's accuracy and precision were evaluated by inter-day recovery tests. The recovery for all samples ranged from 93.6 to 101.2%, and the within-laboratory repeatability and reproducibility were evaluated based on RSD values, which were less than 6.9 and 11.5%, respectively. Analyses of PAS-treated fruits and vegetables using the developed method indicated levels of HEDP ranging from 0.008 to 0.351 mg/kg. Therefore, the results of the present study suggest that the proposed method is an accurate, precise, and reliable way to determine residual HEDP levels on PAS-treated uncooked foods.

Optimization of esterification of dicarboxylic acids and 2-ethyl-1-hexanol

NASA Astrophysics Data System (ADS)

Jafri, Nur Hafifah Nahdirah; Othman, Nor Hamidah Abu; Salimon, Jumat

2018-04-01

Dicarboxylate ester has the potential alternative as plasticizer which environmentally friendly in polymeric formulation especially for poly (vinyl chloride) (PVC). Dicarboxylate ester compounds were synthesized via esterification between dicarboxylic acid and 2-ethyl-1-hexanol by using sulfuric acid as catalyst. The effects of reaction parameters were studied by optimizing temperature, mole ratio of reactants, amount of catalyst and reaction to obtain highest ester conversion. The optimum results showed dicarboxylic acid successfully converted to the dicarboxylate ester at parameters; 4 hours; 120 °C; catalyst amount: 2% w/w of diacid; and mole ratio: 1:2.5. Functional group analysis was conducted by using ATR-FTIR spectroscopy.

Arabidopsis ENHANCED DISEASE SUSCEPTIBILITY1 promotes systemic acquired resistance via azelaic acid and its precursor 9-oxo nonanoic acid.

PubMed

Wittek, Finni; Hoffmann, Thomas; Kanawati, Basem; Bichlmeier, Marlies; Knappe, Claudia; Wenig, Marion; Schmitt-Kopplin, Philippe; Parker, Jane E; Schwab, Wilfried; Vlot, A Corina

2014-11-01

Systemic acquired resistance (SAR) is a form of inducible disease resistance that depends on salicylic acid and its upstream regulator ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1). Although local Arabidopsis thaliana defence responses activated by the Pseudomonas syringae effector protein AvrRpm1 are intact in eds1 mutant plants, SAR signal generation is abolished. Here, the SAR-specific phenotype of the eds1 mutant is utilized to identify metabolites that contribute to SAR. To this end, SAR bioassay-assisted fractionation of extracts from the wild type compared with eds1 mutant plants that conditionally express AvrRpm1 was performed. Using high-performance liquid chromatography followed by mass spectrometry, systemic immunity was associated with the accumulation of 60 metabolites, including the putative SAR signal azelaic acid (AzA) and its precursors 9-hydroperoxy octadecadienoic acid (9-HPOD) and 9-oxo nonanoic acid (ONA). Exogenous ONA induced SAR in systemic untreated leaves when applied at a 4-fold lower concentration than AzA. The data suggest that in planta oxidation of ONA to AzA might be partially responsible for this response and provide further evidence that AzA mobilizes Arabidopsis immunity in a concentration-dependent manner. The AzA fragmentation product pimelic acid did not induce SAR. The results link the C9 lipid peroxidation products ONA and AzA with systemic rather than local resistance and suggest that EDS1 directly or indirectly promotes the accumulation of ONA, AzA, or one or more of their common precursors possibly by activating one or more pathways that either result in the release of these compounds from galactolipids or promote lipid peroxidation. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Na+ Interactions with the Neutral Amino Acid Transporter ASCT1*

PubMed Central

Scopelliti, Amanda J.; Heinzelmann, Germano; Kuyucak, Serdar; Ryan, Renae M.; Vandenberg, Robert J.

2014-01-01

The alanine, serine, cysteine transporters (ASCTs) belong to the solute carrier family 1A (SLC1A), which also includes the excitatory amino acid transporters (EAATs) and the prokaryotic aspartate transporter GltPh. Acidic amino acid transport by the EAATs is coupled to the co-transport of three Na+ ions and one proton, and the counter-transport of one K+ ion. In contrast, neutral amino acid exchange by the ASCTs does not require protons or the counter-transport of K+ ions and the number of Na+ ions required is not well established. One property common to SLC1A family members is a substrate-activated anion conductance. We have investigated the number and location of Na+ ions required by ASCT1 by mutating residues in ASCT1 that correspond to residues in the EAATs and GltPh that are involved in Na+ binding. Mutations to all three proposed Na+ sites influence the binding of substrate and/or Na+, or the rate of substrate exchange. A G422S mutation near the Na2 site reduced Na+ affinity, without affecting the rate of exchange. D467T and D467A mutations in the Na1 site reduce Na+ and substrate affinity and also the rate of substrate exchange. T124A and D380A mutations in the Na3 site selectively reduce the affinity for Na+ and the rate of substrate exchange without affecting substrate affinity. In many of the mutants that reduce the rate of substrate transport the amplitudes of the substrate-activated anion conductances are not substantially affected indicating altered ion dependence for channel activation compared with substrate exchange. PMID:24808181

Polycystic kidney disease among 4,436 intracranial aneurysm patients from a defined population.

PubMed

Nurmonen, Heidi J; Huttunen, Terhi; Huttunen, Jukka; Kurki, Mitja I; Helin, Katariina; Koivisto, Timo; von Und Zu Fraunberg, Mikael; Jääskeläinen, Juha E; Lindgren, Antti E

2017-10-31

To define the association of autosomal dominant polycystic kidney disease (ADPKD) with the characteristics of aneurysmal subarachnoid hemorrhage (aSAH) and unruptured intracranial aneurysm (IA) disease. We fused data from the Kuopio Intracranial Aneurysm database (n = 4,436 IA patients) and Finnish nationwide registries into a population-based series of 53 IA patients with ADPKD to compare the aneurysm- and patient-specific characteristics of IA disease in ADPKD and in the general IA population, and to identify risks for de novo IA formation. In total, there were 33 patients with ADPKD with aSAH and 20 patients with ADPKD with unruptured IAs. The median size of ruptured IAs in ADPKD was significantly smaller than in the general population (6.00 vs 8.00 mm) and the proportion of small ruptured IAs was significantly higher (31% vs 18%). Median age at aSAH was 42.8 years, 10 years younger than in the general IA population. Multiple IAs were present in 45% of patients with ADPKD compared to 28% in the general IA population. Cumulative risk of de novo IA formation was 1.3% per patient-year (vs 0.2% in the general IA population). Hazard for de novo aneurysm formation was significantly elevated in patients with ADPKD (Cox regression hazard ratio 7.7, 95% confidence interval 2.8-20; p < 0.0005). Subarachnoid hemorrhage occurs at younger age and from smaller IAs in patients with ADPKD and risk for de novo IAs is higher than in the general Eastern Finnish population. ADPKD should be considered as an indicator for long-term angiographic follow-up in patients with diagnosed IAs. © 2017 American Academy of Neurology.

Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection.

PubMed

Qing, Song; Tulake, Wuniqiemu; Ru, Mingfang; Li, Xiaohong; Yuemaier, Reziwanguli; Lidifu, Dilare; Rouzibilali, Aierken; Hasimu, Axiangu; Yang, Yun; Rouziahong, Reziya; Upur, Halmurat; Abudula, Abulizi

2017-04-01

It is known that high-risk human papillomavirus infection is the main etiological factor in cervical carcinogenesis. However, human papillomavirus screening is not sufficient for early diagnosis. In this study, we aimed to identify potential biomarkers common to cervical carcinoma and human papillomavirus infection by proteomics for human papillomavirus-based early diagnosis and prognosis. To this end, we collected 76 cases of fresh cervical tissues and 116 cases of paraffin-embedded tissue slices, diagnosed as cervical squamous cell carcinoma, cervical intraepithelial neoplasia II-III, or normal cervix from ethnic Uighur and Han women. Human papillomavirus infection by eight oncogenic human papillomavirus types was detected in tissue DNA samples using a quantitative polymerase chain reaction. The protein profile of cervical specimens from human papillomavirus 16-positive squamous cell carcinoma and human papillomavirus-negative normal controls was analyzed by proteomics and bioinformatics. The expression of candidate proteins was further determined by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. We identified 67 proteins that were differentially expressed in human papillomavirus 16-positive squamous cell carcinoma compared to normal cervix. The quantitative reverse transcriptase-polymerase chain reaction analysis verified the upregulation of ASAH1, PCBP2, DDX5, MCM5, TAGLN2, hnRNPA1, ENO1, TYPH, CYC, and MCM4 in squamous cell carcinoma compared to normal cervix ( p < 0.05). In addition, the transcription of PCBP2, MCM5, hnRNPA1, TYPH, and CYC was also significantly increased in cervical intraepithelial neoplasia II-III compared to normal cervix. Immunohistochemistry staining further confirmed the overexpression of PCBP2, hnRNPA1, ASAH1, and DDX5 in squamous cell carcinoma and cervical intraepithelial neoplasia II-III compared to normal controls ( p < 0.05). Our data suggest that the expression of ASAH1, PCBP2, DDX5

Alpha-lipoic acid improves high-fat diet-induced hepatic steatosis by modulating the transcription factors SREBP-1, FoxO1 and Nrf2 via the SIRT1/LKB1/AMPK pathway.

PubMed

Yang, Yi; Li, Wang; Liu, Yang; Sun, Yuning; Li, Yan; Yao, Qing; Li, Jianning; Zhang, Qian; Gao, Yujing; Gao, Ling; Zhao, Jiajun

2014-11-01

Understanding the mechanism by which alpha-lipoic acid supplementation has a protective effect upon nonalcoholic fatty liver disease in vivo and in vitro may lead to targets for preventing hepatic steatosis. Male C57BL/6J mice were fed a normal diet, high-fat diet or high-fat diet supplemented with alpha-lipoic acid for 24 weeks. HepG2 cells were incubated with normal medium, palmitate or alpha-lipoic acid. The lipid-lowering effects were measured. The protein expression and distribution were analyzed by Western blot, immunoprecipitation and immunofluorescence, respectively. We found that alpha-lipoic acid enhanced sirtuin 1 deacetylase activity through liver kinase B1 and stimulated AMP-activated protein kinase. By activating the sirtuin 1/liver kinase B1/AMP-activated protein kinase pathway, the translocation of sterol regulatory element-binding protein-1 into the nucleus and forkhead box O1 into the cytoplasm was prevented. Alpha-lipoic acid increased adipose triacylglycerol lipase expression and decreased fatty acid synthase abundance. In in vivo and in vitro studies, alpha-lipoic acid also increased nuclear NF-E2-related factor 2 levels and downstream target amounts via the sirtuin 1 pathway. Alpha-lipoic acid eventually reduced intrahepatic and serum triglyceride content. The protective effects of alpha-lipoic acid on hepatic steatosis appear to be associated with the transcription factors sterol regulatory element-binding protein-1, forkhead box O1 and NF-E2-related factor 2. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Activity of glycated chitosan and other adjuvants to PDT vaccines

NASA Astrophysics Data System (ADS)

Korbelik, Mladen; Banáth, Judit; Čiplys, Evaldas; Szulc, Zdzislaw; Bielawska, Alicja; Chen, Wei R.

2015-03-01

Glycated chitosan (GC), a water soluble galactose-conjugated natural polysaccharide, has proven to be an effective immunoadjuvant for treatment of tumors based on laser thermal therapy. It was also shown to act as adjuvant for tumor therapy with high-intensity ultrasound and in situ photodynamic therapy (PDT). In the present study, GC was examined as potential adjuvant to PDT-generated cancer vaccine. Two other agents, pure calreticulin protein and acid ceramidase inhibitor LCL521, were also tested as prospective adjuvants for use in conjunction with PDT vaccines. Single treatment with GC, included with PDT vaccine cells suspension, improved the therapeutic efficacy when compared to vaccine alone. This attractive prospect of GC application remains to be carefully optimized and mechanistically elucidated. Both calreticulin and LCL521 proved also effective adjuvants when combined with PDT vaccine tumor treatment.

Auxin-Induced Ethylene Triggers Abscisic Acid Biosynthesis and Growth Inhibition1

PubMed Central

Hansen, Hauke; Grossmann, Klaus

2000-01-01

The growth-inhibiting effects of indole-3-acetic acid (IAA) at high concentration and the synthetic auxins 7-chloro-3-methyl-8-quinolinecarboxylic acid (quinmerac), 2-methoxy-3,6-dichlorobenzoic acid (dicamba), 4-amino-3,6,6-trichloropicolinic acid (picloram), and naphthalene acetic acid, were investigated in cleavers (Galium aparine). When plants were root treated with 0.5 mm IAA, shoot epinasty and inhibition of root and shoot growth developed during 24 h. Concomitantly, 1-aminocyclopropane-1-carboxylic acid (ACC) synthase activity, and ACC and ethylene production were transiently stimulated in the shoot tissue within 2 h, followed by increases in immunoreactive (+)-abscisic acid (ABA) and its precursor xanthoxal (xanthoxin) after 5 h. After 24 h of treatment, levels of xanthoxal and ABA were elevated up to 2- and 24-fold, relative to control, respectively. In plants treated with IAA, 7-chloro-3-methyl-8-quinolinecarboxylic acid, naphthalene acetic acid, 2-methoxy-3,6-dichlorobenzoic acid, and 4-amino-3,6,6-trichloropicolinic acid, levels of ethylene, ACC, and ABA increased in close correlation with inhibition of shoot growth. Aminoethoxyvinyl-glycine and cobalt ions, which inhibit ethylene synthesis, decreased ABA accumulation and growth inhibition, whereas the ethylene-releasing ethephon promoted ABA levels and growth inhibition. In accordance, tomato mutants defective in ethylene perception (never ripe) did not produce the xanthoxal and ABA increases and growth inhibition induced by auxins in wild-type plants. This suggests that auxin-stimulated ethylene triggers ABA accumulation and the consequent growth inhibition. Reduced catabolism most probably did not contribute to ABA increase, as indicated by immunoanalyses of ABA degradation and conjugation products in shoot tissue and by pulse experiments with [3H]-ABA in cell suspensions of G. aparine. In contrast, studies using inhibitors of ABA biosynthesis (fluridone, naproxen, and tungstate), ABA

75 FR 37738 - 1-Naphthaleneacetic Acid; Time-Limited Tolerance, Technical Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-30

...-Naphthaleneacetic Acid; Time-Limited Tolerance, Technical Correction AGENCY: Environmental Protection Agency (EPA..., ethylene oxide, fenvalerate, et al.; tolerance actions. Today's rule restores the time-limited tolerance...-3) establishing a time-limited tolerance for residues of 1-naphthaleneacetic acid ethyl ester in or...

Mechanism of permeability-enhancing effect of EDTA and boric acid on the corneal penetration of 4-[1-hydroxy-1-methylethyl]-2-propyl-1-[4-[2-[tetrazole-5-yl]phenyl]phenyl] methylimidazole-5-carboxylic acid monohydrate (CS-088).

PubMed

Kikuchi, Takayuki; Suzuki, Masahiko; Kusai, Akira; Iseki, Ken; Sasaki, Hitoshi; Nakashima, Kenichiro

2005-08-11

This study was conducted to clarify the penetration properties of 4-[1-hydroxy-1-methylethyl]-2-propyl-1-[4-[2-[tetrazole-5-yl]phenyl]phenyl]methylimidazole-5-carboxylic acid monohydrate (CS-088), an ophthalmic agent, and the mechanism of the permeability-enhancing effect of EDTA and boric acid (EDTA/boric acid) on the corneal penetration of CS-088. In the absence of additives, corneal permeability decreased with increasing concentration of CS-088 as CS-088 monomers self-associate to form dimers. Presence of EDTA/boric acid caused no significant changes in the physicochemical properties of CS-088, the apparent partition coefficient or the mean particle size of CS-088. EDTA/boric acid induced only a slight change in the zeta potential of liposomes used as a model of the biological membrane. On the other hand, EDTA/boric acid significantly increased membrane fluidity of liposomes, whereas other buffering agents tested did not. This effect was synergistic and concentration-dependent for both EDTA and boric acid as was observed in in vitro corneal penetration of CS-088. In accordance with the result, the rate of CS-088 permeation into the liposomes significantly increased by the addition of EDTA/boric acid. Therefore, it was demonstrated that EDTA/boric acid promotes corneal penetration of CS-088 through the transcellular pathway by increasing membrane fluidity. Conversely, other buffering agents decreased corneal permeability of CS-088 by inducing further self-association of CS-088 aggregates.

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

Higher cord blood levels of fatty acids in pregnant women with type 1 diabetes mellitus.

PubMed

Djelmis, Josip; Ivaniševic, Marina; Desoye, Gernot; van Poppel, Mireille; Berberovic, Edina; Soldo, Dragan; Oreskovic, Slavko

2018-05-01

Type 1 diabetes mellitus is associated with a disturbance of carbohydrate and lipid metabolism. To determine whether type 1 diabetes mellitus (T1DM) alters maternal and neonatal fatty acid levels. Observational study. Academic hospital. Sixty pregnant women (30 women with T1DM with good glycemic control and 30 healthy women) were included in the study. Maternal blood, umbilical vein and artery blood samples were collected immediately upon delivery. Following lipid extraction, the fatty acid profiles of the total fatty acid pool of maternal serum and umbilical vein and artery serum were determined by gas chromatography. Total fatty acid concentration in maternal serum did not differ between the study groups; it was significantly higher in umbilical vein serum of the T1DM group compared with that in the control group, median (interquartile range), T1DM: 2126.2 (1446.4 - 3181.3), control: 1073.8 (657.5 - 2226.0); (P<0.001) and in umbilical artery vein serum T1DM: 1805.7 (1393.1 - 2125.0), control: 990.0 (643.3 - 1668.0); (P<0.001). Composition of fatty acids in umbilical vein serum fatty acids showed significantly higher concentrations of saturated, monounsaturated and polyunsaturated fatty acids in the T1DM group than in compared with those in the control group (P=0.001). Also cord blood levels of leptin (P<0.001), C-peptide (P<0.001), and insulin resistance (P=0.015) were higher in the T1DM group compared to controls. The neonates born to T1DM mothers had higher concentrations of total fatty acids, saturated and monounsaturated fatty acids, as well as polyunsaturated fatty acids, compared to control group newborns.

CPT1{alpha} over-expression increases long-chain fatty acid oxidation and reduces cell viability with incremental palmitic acid concentration in 293T cells

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

Jambor de Sousa, Ulrike L.; Koss, Michael D.; Fillies, Marion

2005-12-16

To test the cellular response to an increased fatty acid oxidation, we generated a vector for an inducible expression of the rate-limiting enzyme carnitine palmitoyl-transferase 1{alpha} (CPT1{alpha}). Human embryonic 293T kidney cells were transiently transfected and expression of the CPT1{alpha} transgene in the tet-on vector was activated with doxycycline. Fatty acid oxidation was measured by determining the conversion of supplemented, synthetic cis-10-heptadecenoic acid (C17:1n-7) to C15:ln-7. CPT1{alpha} over-expression increased mitochondrial long-chain fatty acid oxidation about 6-fold. Addition of palmitic acid (PA) decreased viability of CPT1{alpha} over-expressing cells in a concentration-dependent manner. Both, PA and CPT1{alpha} over-expression increased cell death. Interestingly,more » PA reduced total cell number only in cells over-expressing CPT1{alpha}, suggesting an effect on cell proliferation that requires PA translocation across the mitochondrial inner membrane. This inducible expression system should be well suited to study the roles of CPT1 and fatty acid oxidation in lipotoxicity and metabolism in vivo.« less

Chlorogenic Acid Attenuates High Mobility Group Box 1 (HMGB1) and Enhances Host Defense Mechanisms in Murine Sepsis

PubMed Central

Lee, Chan-Ho; Yoon, Seong-Jin; Lee, Sun-Mee

2012-01-01

Sepsis is a complex, multifactorial, rapidly progressive disease characterized by an overwhelming activation of the immune system and the countervailing antiinflammatory response. In the current study in murine peritoneal macrophages, chlorogenic acid suppressed endotoxin-induced high mobility group box 1 (HMGB1) release in a concentration-dependent manner. Administration of chlorogenic acid also attenuated systemic HMGB1 accumulation in vivo and prevented mortality induced by endotoxemia and polymicrobial sepsis. The mechanisms of action of chlorogenic acid included attenuation of the increase in toll-like receptor (TLR)-4 expression and suppression of sepsis-induced signaling pathways, such as c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB, which are critical for cytokine release. The protection conferred by chlorogenic acid was achieved through modulation of cytokine and chemokine release, suppression of immune cell apoptosis and augmentation of bacterial elimination. Chlorogenic acid warrants further evaluation as a potential therapeutic agent for the treatment of sepsis and other potentially fatal systemic inflammatory disorders. PMID:23168580

Manipulating Membrane Fatty Acid Compositions of Whole Plants with Tween-Fatty Acid Esters 1

PubMed Central

Terzaghi, William B.

1989-01-01

This paper describes a method for manipulating plant membrane fatty acid compositions without altering growth temperature or other conditions. Tween-fatty acid esters carrying specific fatty acids were synthesized and applied to various organs of plants growing axenically in glass jars. Treated plants incorporated large amounts of exogenous fatty acids into all acylated membrane lipids detected. Fatty acids were taken up by both roots and leaves. Fatty acids applied to roots were found in leaves, while fatty acids applied to leaves appeared in both leaves higher on the plant and in roots, indicating translocation (probably in the phloem). Foliar application was most effective; up to 20% of membrane fatty acids of leaves above the treated leaf and up to 40% of root membrane fatty acids were exogenously derived. Plants which took up exogenous fatty acids changed their patterns of fatty acid synthesis such that ratios of saturated to unsaturated fatty acids remained essentially unaltered. Fatty acid uptake was most extensively studied in soybean (Glycine max [L.] Merr.), but was also observed in other species, including maize (Zea mays L.), mung beans (Vigna radiata L.), peas (Pisum sativum L.), petunia (Petunia hybrida L.) and tomato (Lycopersicon esculentum Mill.). Potential applications of this system include studying internal transport of fatty acids, regulation of fatty acid and membrane synthesis, and influences of membrane fatty acid composition on plant physiology. Images Figure 2 PMID:16666997

Molecular cloning and expression analysis of jasmonic acid dependent but salicylic acid independent LeWRKY1.

PubMed

Lu, M; Wang, L F; Du, X H; Yu, Y K; Pan, J B; Nan, Z J; Han, J; Wang, W X; Zhang, Q Z; Sun, Q P

2015-11-30

Various plant genes can be activated or inhibited by phytohormones under conditions of biotic and abiotic stress, especially in response to jasmonic acid (JA) and salicylic acid (SA). Interactions between JA and SA may be synergistic or antagonistic, depending on the stress condition. In this study, we cloned a full-length cDNA (LeWRKY1, GenBank accession No. FJ654265) from Lycopersicon esculentum by rapid amplification of cDNA ends. Sequence analysis showed that this gene is a group II WRKY transcription factor. Analysis of LeWRKY1 mRNA expression in various tissues by qRT-PCR showed that the highest and lowest expression occurred in the leaves and stems, respectively. In addition, LeWRKY1 expression was induced by JA and Botrytis cinerea Pers., but not by SA.

Overexpression of Human Fatty Acid Transport Protein 2/Very Long Chain Acyl-CoA Synthetase 1 (FATP2/Acsvl1) Reveals Distinct Patterns of Trafficking of Exogenous Fatty Acids

PubMed Central

Melton, Elaina M.; Cerny, Ronald L.; DiRusso, Concetta C.; Black, Paul N.

2014-01-01

In mammals, the fatty acid transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in fatty acid transport proceeding through vectorial acylation and in the activation of very long chain fatty acids, branched chain fatty acids and secondary bile acids. FATP1, 2 and 4, for example directly function in fatty acid transport and very long chain fatty acids activation while FATP5 does not function in fatty acid transport but activates secondary bile acids. In the present work, we have used stable isotopically labeled fatty acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in fatty acid transport and intracellular fatty acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4hr. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with transport from their respective exogenous fatty acids. The trafficking of exogenous fatty acids into phosphatidic acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of

Overexpression of human fatty acid transport protein 2/very long chain acyl-CoA synthetase 1 (FATP2/Acsvl1) reveals distinct patterns of trafficking of exogenous fatty acids.

PubMed

Melton, Elaina M; Cerny, Ronald L; DiRusso, Concetta C; Black, Paul N

2013-11-01

In mammals, the fatty acid transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in fatty acid transport proceeding through vectorial acylation and in the activation of very long chain fatty acids, branched chain fatty acids and secondary bile acids. FATP1, 2 and 4, for example directly function in fatty acid transport and very long chain fatty acids activation while FATP5 does not function in fatty acid transport but activates secondary bile acids. In the present work, we have used stable isotopically labeled fatty acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in fatty acid transport and intracellular fatty acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4h. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with transport from their respective exogenous fatty acids. The trafficking of exogenous fatty acids into phosphatidic acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of

Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (1S,3S)-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115)

PubMed Central

2016-01-01

γ-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently, CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5′-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly formed carboxylate produced by hydrolysis of the difluoromethylene group in CPP-115, resulting in a noncovalent, tightly bound complex. This represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general. PMID:25616005

Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (1 S ,3 S )-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115)

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

Lee, Hyunbeom; Doud, Emma H.; Wu, Rui

gamma-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently,more » CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5'-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly formed carboxylate produced by hydrolysis of the difluoromethylene group in CPP-115, resulting in a noncovalent, tightly bound complex. This represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general.« less

Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115).

PubMed

Lee, Hyunbeom; Doud, Emma H; Wu, Rui; Sanishvili, Ruslan; Juncosa, Jose I; Liu, Dali; Kelleher, Neil L; Silverman, Richard B

2015-02-25

γ-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently, CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5'-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly formed carboxylate produced by hydrolysis of the difluoromethylene group in CPP-115, resulting in a noncovalent, tightly bound complex. This represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general.

Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (1 S ,3 S)-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115)

DOE PAGES

Lee, Hyunbeom; Doud, Emma H.; Wu, Rui; ...

2015-01-23

γ-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently,more » CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5'-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly formed carboxylate produced by hydrolysis of the difluoromethylene group in CPP-115, resulting in a noncovalent, tightly bound complex. Ultimately, this represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general.« less

Docosahexaenoic Acid (DHA) and Hepatic Gene Transcription1,3

PubMed Central

Jump, Donald B.; Botolin, Daniela; Wang, Yun; Xu, Jinghua; Demeure, Olivier; Christian, Barbara

2008-01-01

The type and quantity of dietary fat ingested contributes to the onset and progression of chronic diseases, like diabetes and atherosclerosis. The liver plays a central role in whole body lipid metabolism and responds rapidly to changes in dietary fat composition. Polyunsaturated fatty acids (PUFA) play a key role in membrane composition and function, metabolism and the control of gene expression. Certain PUFA, like the n-3 PUFA, enhance hepatic fatty acid oxidation and inhibit fatty acid synthesis and VLDL secretion, in part, by regulating gene expression. Our studies have established that key transcription factors, like PPARα, SREBP-1, ChREBP and MLX, are regulated by n-3 PUFA, which in turn control levels of proteins involved in lipid and carbohydrate metabolism. Of the n-3 PUFA, 22:6,n-3 has recently been established as a key controller of hepatic lipid synthesis. 22:6,n-3 controls the 26S proteasomal degradation of the nuclear form of SREBP-1. SREBP-1 is a major transcription factor that controls the expression of multiple genes involved fatty acid synthesis and desaturation. 22:6,n-3 suppresses nuclear SREBP-1 which, in turn suppresses lipogenesis. This mechanism is achieved, in part, through control of the phosphorylation status of protein kinases. This review will examine both the general features of PUFA-regulated hepatic gene transcription and highlight the unique mechanisms by which 22:6,n-3 impacts gene expression. The outcome of this analysis will reveal that changes in hepatic 22:6,n-3 content has a major impact on hepatic lipid and carbohydrate metabolism. Moreover, the mechanisms involve 22:6,n-3 control of several well-known signaling pathways, such as Akt, Erk1/2, Gsk3β and PKC (novel or atypical). 22:6,n-3 control of these same signaling pathways in non-hepatic tissues may help explain the diverse actions of n-3 PUFA on such complex physiological processes as visual acuity and learning. PMID:18343222

37 CFR 1.821 - Nucleotide and/or amino acid sequence disclosures in patent applications.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Nucleotide and/or amino acid... Biotechnology Invention Disclosures Application Disclosures Containing Nucleotide And/or Amino Acid Sequences § 1.821 Nucleotide and/or amino acid sequence disclosures in patent applications. (a) Nucleotide and...

37 CFR 1.821 - Nucleotide and/or amino acid sequence disclosures in patent applications.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 37 Patents, Trademarks, and Copyrights 1 2011-07-01 2011-07-01 false Nucleotide and/or amino acid... Biotechnology Invention Disclosures Application Disclosures Containing Nucleotide And/or Amino Acid Sequences § 1.821 Nucleotide and/or amino acid sequence disclosures in patent applications. (a) Nucleotide and...

Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation.

PubMed

Wendel, Angela A; Cooper, Daniel E; Ilkayeva, Olga R; Muoio, Deborah M; Coleman, Rosalind A

2013-09-20

Four glycerol-3-phosphate acyltransferase (GPAT) isoforms, each encoded by a separate gene, catalyze the initial step in glycerolipid synthesis; in liver, the major isoforms are GPAT1 and GPAT4. To determine whether each of these hepatic isoforms performs a unique function in the metabolism of fatty acid, we measured the incorporation of de novo synthesized fatty acid or exogenous fatty acid into complex lipids in primary mouse hepatocytes from control, Gpat1(-/-), and Gpat4(-/-) mice. Although hepatocytes from each genotype incorporated a similar amount of exogenous fatty acid into triacylglycerol (TAG), only control and Gpat4(-/-) hepatocytes were able to incorporate de novo synthesized fatty acid into TAG. When compared with controls, Gpat1(-/-) hepatocytes oxidized twice as much exogenous fatty acid. To confirm these findings and to assess hepatic β-oxidation metabolites, we measured acylcarnitines in liver from mice after a 24-h fast and after a 24-h fast followed by 48 h of refeeding with a high sucrose diet to promote lipogenesis. Confirming the in vitro findings, the hepatic content of long-chain acylcarnitine in fasted Gpat1(-/-) mice was 3-fold higher than in controls. When compared with control and Gpat4(-/-) mice, after the fasting-refeeding protocol, Gpat1(-/-) hepatic TAG was depleted, and long-chain acylcarnitine content was 3.5-fold higher. Taken together, these data demonstrate that GPAT1, but not GPAT4, is required to incorporate de novo synthesized fatty acids into TAG and to divert them away from oxidation.

Static and dynamic properties of 1,1'-bi-2-naphthol and its conjugated acids and bases.

PubMed

Alkorta, Ibon; Cancedda, Céline; Cocinero, Emilio José; Dávalos, Juan Z; Ecija, Patrica; Elguero, José; González, Javier; Lesarri, Alberto; Ramos, Rocio; Reviriego, Felipe; Roussel, Christian; Uriarte, Iciar; Vanthuyne, Nicolas

2014-11-03

Several convergent techniques were used to characterize 1,1'-bi-2-naphthol (BINOL) and some of its properties. Its acidity in the gas-phase, from neutral species to monoanion, was measured by mass spectrometry. The conformation and structure of BINOL in the gas phase was determined by microwave rotational spectroscopy. NMR experiments in fluorosulfonic acid established that BINOL was monoprotonated on one of the hydroxyl oxygen atoms. The enantiomerization barriers reported in the literature for BINOL under neutral, basic, and acid conditions were analyzed with regard to the species involved. Finally, DFT calculations allowed all of these results to be gathered in a coherent picture of the BINOL structure. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Application of 1-aminocyclohexane carboxylic acid to protein nanostructure computer design

PubMed Central

Rodríguez-Ropero, Francisco; Zanuy, David; Casanovas, Jordi; Nussinov, Ruth; Alemán, Carlos

2009-01-01

Conformationally restricted amino acids are promising candidates to serve as basic pieces in redesigned protein motifs which constitute the basic modules in synthetic nanoconstructs. Here we study the ability of constrained cyclic amino acid 1-aminocyclohexane-1-carboxylic acid (Ac6c) to stabilize highly regular β-helical motifs excised from naturally occurring proteins. Calculations indicate that the conformational flexibility observed in both the ring and the main chain is significantly higher than that detected for other 1-aminocycloalkane-1-carboxylic acid (Acnc, where n refers to the size of the ring) with smaller cycles. Incorporation of Ac6c into the flexible loops of β-helical motifs indicates that the stability of such excised building blocks as well as the nano-assemblies derived from them is significantly enhanced. Thus, the intrinsic Ac6c tendency to adopt folded conformations combined with the low structural strain of the cyclohexane ring confers the ability to both self-adapt to the β-helix motif and to stabilize the overall structure by absorbing part of its conformational fluctuations. Comparison with other Acnc residues indicates that the ability to adapt to the targeted position improves considerably with the ring size, i.e. when the rigidity introduced by the strain of the ring decreases. PMID:18201062

Gibberellic Acid, Synthetic Auxins, and Ethylene Differentially Modulate α-l-Arabinofuranosidase Activities in Antisense 1-Aminocyclopropane-1-Carboxylic Acid Synthase Tomato Pericarp Discs1

PubMed Central

Sozzi, Gabriel O.; Greve, L. Carl; Prody, Gerry A.; Labavitch, John M.

2002-01-01

α-l-Arabinofuranosidases (α-Afs) are plant enzymes capable of releasing terminal arabinofuranosyl residues from cell wall matrix polymers, as well as from different glycoconjugates. Three different α-Af isoforms were distinguished by size exclusion chromatography of protein extracts from control tomatoes (Lycopersicon esculentum) and an ethylene synthesis-suppressed (ESS) line expressing an antisense 1-aminocyclopropane-1-carboxylic synthase transgene. α-Af I and II are active throughout fruit ontogeny. α-Af I is the first Zn-dependent cell wall enzyme isolated from tomato pericarp tissues, thus suggesting the involvement of zinc in fruit cell wall metabolism. This isoform is inhibited by 1,10-phenanthroline, but remains stable in the presence of NaCl and sucrose. α-Af II activity accounts for over 80% of the total α-Af activity in 10-d-old fruit, but activity drops during ripening. In contrast, α-Af III is ethylene dependent and specifically active during ripening. α-Af I released monosaccharide arabinose from KOH-soluble polysaccharides from tomato cell walls, whereas α-Af II and III acted on Na2CO3-soluble pectins. Different α-Af isoform responses to gibberellic acid, synthetic auxins, and ethylene were followed by using a novel ESS mature-green tomato pericarp disc system. α-Af I and II activity increased when gibberellic acid or 2,4-dichlorophenoxyacetic acid was applied, whereas ethylene treatment enhanced only α-Af III activity. Results suggest that tomato α-Afs are encoded by a gene family under differential hormonal controls, and probably have different in vivo functions. The ESS pericarp explant system allows comprehensive studies involving effects of physiological levels of different growth regulators on gene expression and enzyme activity with negligible wound-induced ethylene production. PMID:12114586

Conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability.

PubMed

Li, Kun; Ma, Tianyi; Cai, Jingjing; Huang, Min; Guo, Hongye; Zhou, Di; Luan, Shenglin; Yang, Jinyu; Liu, Dan; Jing, Yongkui; Zhao, Linxiang

2017-10-15

Twenty-six conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid were designed and synthesized as Pin1 inhibitors. Most of these semi-synthetic compounds showed improved Pin1 inhibitory activity and anti-proliferative effects against prostate cancer cells as compared to 3-(1H-benzo[d]imidazol-2-yl)propanoic acid and GA. Compounds 10a and 12i were the most potent to inhibit growth of prostate cancer PC-3 with GI 50 values of 7.80μM and 3.52μM, respectively. The enzyme inhibition ratio of nine compounds at 10μM was over 90%. Structure-activity relationships indicated that both appropriate structure at ring C of GA and suitable length of linker between GA skeleton and benzimidazole moiety had significant impact on improving activity. Western blot assay revealed that 10a decreased the level of cell cycle regulating protein cyclin D1. Thus, these compounds might represent a novel anti-proliferative agent working through Pin1 inhibition. Copyright © 2017. Published by Elsevier Ltd.

Role of Sphingolipids in Infant Gut Health and Immunity.

PubMed

Nilsson, Åke

2016-06-01

Sphingomyelin (SM), glycosphingolipids, and gangliosides are important polar lipids in the milk fat globule membrane but are not found in standard milk replacement formulas. Because digestion and absorption of SM and glycosphingolipids generate the bioactive metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P), and because intact gangliosides may have beneficial effects in the gut, this may be important for gut integrity and immune maturation in the neonate. The brush border enzymes that hydrolyze milk SM, alkaline sphingomyelinase (nucleotide phosphodiesterase pyrophosphatase 7), and neutral ceramidase are expressed at birth in both term and preterm infants. Released sphingosine is absorbed, phosphorylated to S1P, and converted to palmitic acid via S1P-lyase in the gut mucosa. Hypothetically, S1P also may be released from absorptive cells and exert important paracrine actions favoring epithelial integrity and renewal, as well as immune function, including secretory IgA production and migration of T lymphocyte subpopulations. Gluco-, galacto-, and lactosylceramide are hydrolyzed to ceramide by lactase-phlorizin hydrolase, which also hydrolyzes lactose. Gangliosides may adhere to the brush border and is internalized, modified, and possibly transported into blood, and may exert protective functions by their interactions with bacteria, bacterial toxins, and the brush border. Copyright © 2016 Elsevier Inc. All rights reserved.

Complex formation equilibria of binary and ternary complexes involving 3,3-bis(1-methylimidazol-2yl)propionic acid and bio-relevant ligands as 1-aminocyclopropane carboxylic acid with reference to plant hormone

NASA Astrophysics Data System (ADS)

Shoukry, Mohamed M.; Hassan, Safaa S.

2014-01-01

The formation equilibria for the binary complexes of Cu(II) with 1-aminocyclopropane carboxylic acid (ACC) and 3,3-bis(1-methylimidazol-2-yl)propionic acid (BIMP) were investigated. ACC and BIMP form the complexes 1 1 0, 1 2 0 and 1 1 -1. The ternary complexes of Cu(II) with BIMP and biorelevant ligands as some selected amino acids, peptides and DNA constituents are formed in a stepwise mechanism. The stability constants of the complexes formed were determined and their distribution diagrams were evaluated. The kinetics of hydrolysis of glycine methyl ester in presence of [Cu(BIMP)]+ was investigated by pH-stat technique and the mechanism was discussed.

Neurodegenerative cerebrospinal fluid biomarkers tau and amyloid beta predict functional, quality of life, and neuropsychological outcomes after aneurysmal subarachnoid hemorrhage.

PubMed

Joswig, Holger; Korte, Wolfgang; Früh, Severin; Epprecht, Lorenz; Hildebrandt, Gerhard; Fournier, Jean-Yves; Stienen, Martin Nikolaus

2018-04-01

Cerebrospinal fluid (CSF) biomarkers might be useful in predicting outcome after aneurysmal subarachnoid hemorrhage (aSAH). It was the aim to determine whether tau and amyloid beta CSF concentrations predict functional, health-related quality of life (hrQoL), and neuropsychological outcomes after aSAH. Ventricular CSF was obtained from n = 24 aSAH patients at admission (D0), day 2 (D2), and day 6 (D6). CSF total (t)Tau, phosphorylated (p)Tau (181P) , and amyloid beta (1-40 and 1-42) (Aβ40/Aβ42) levels were compared between patients with favorable and unfavorable functional (modified Rankin Scale (mRS)), hrQoL (Euro-Qol (EQ-5D)), and neuropsychological outcomes at 3 (3 m) and 12 months (12 m). Patients with unfavorable functional (mRS 4-6) and hrQoL outcome (EQ-5D z-score ≤ - 1.0) at 3 and 12 m had higher CSF tTau/pTau and lower Aβ40/Aβ42 at D0, D2, and D6 with varying degrees of statistical significance. In terms of predicting neuropsychological outcome, CSF pTau showed a statistically significant correlation with the z-scores of executive function (r = - 0.7486, p = 0.008), verbal memory (r = - 0.8101, p = 0.002), attention (r = - 0.6498, p = 0.030), and visuospatial functioning (r = - 0.6944, p = 0.017) at 3 m. At 12 m, CSF pTau had statistically significant correlations with the z-scores of verbal memory (r = - 0.7473, p = 0.008) and visuospatial functioning (r = - 0.6678, p = 0.024). In conclusion, higher tTau/pTau and lower Aβ40/Aβ42 CSF levels predict unfavorable long-term functional and hrQoL outcomes. Neuropsychological deficits correlate with increased CSF tTau and pTau concentrations.

Silverleaf Whitefly Induces Salicylic Acid Defenses and Suppresses Effectual Jasmonic Acid Defenses1[W][OA

PubMed Central

Zarate, Sonia I.; Kempema, Louisa A.; Walling, Linda L.

2007-01-01

The basal defenses important in curtailing the development of the phloem-feeding silverleaf whitefly (Bemisia tabaci type B; SLWF) on Arabidopsis (Arabidopsis thaliana) were investigated. Sentinel defense gene RNAs were monitored in SLWF-infested and control plants. Salicylic acid (SA)-responsive gene transcripts accumulated locally (PR1, BGL2, PR5, SID2, EDS5, PAD4) and systemically (PR1, BGL2, PR5) during SLWF nymph feeding. In contrast, jasmonic acid (JA)- and ethylene-dependent RNAs (PDF1.2, VSP1, HEL, THI2.1, FAD3, ERS1, ERF1) were repressed or not modulated in SLWF-infested leaves. To test for a role of SA and JA pathways in basal defense, SLWF development on mutant and transgenic lines that constitutively activate or impair defense pathways was determined. By monitoring the percentage of SLWF nymphs in each instar, we show that mutants that activate SA defenses (cim10) or impair JA defenses (coi1) accelerated SLWF nymphal development. Reciprocally, mutants that activate JA defenses (cev1) or impair SA defenses (npr1, NahG) slowed SLWF nymphal development. Furthermore, when npr1 plants, which do not activate downstream SA defenses, were treated with methyl jasmonate, a dramatic delay in nymph development was observed. Collectively, these results showed that SLWF-repressed, JA-regulated defenses were associated with basal defense to the SLWF. PMID:17189328

A structural insight into the P1S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

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

Węglarz-Tomczak, Ewelina; Berlicki, Łukasz; Pawełczak, Małgorzata

N0 -substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki ¼ 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-more » diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.« less

75 FR 31713 - 2-Propenoic acid polymer, with 1,3-butadiene and ethenylbenzene; Tolerance Exemption

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-04

... acid polymer, with 1,3-butadiene and ethenylbenzene; Tolerance Exemption AGENCY: Environmental... requirement of a tolerance for residues of 2-propenoic acid polymer, with 1,3- butadiene and ethenylbenzene... residues of 2-propenoic acid polymer, with 1,3-butadiene and ethenylbenzene on food or feed commodities...

Overexpression of human fatty acid transport protein 2/very long chain acyl-CoA synthetase 1 (FATP2/Acsvl1) reveals distinct patterns of trafficking of exogenous fatty acids

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

Melton, Elaina M.; Center for Cardiovascular Sciences, Albany Medical College, Albany, NY; Cerny, Ronald L.

Highlights: •Roles of FATP2 in fatty acid transport/activation contribute to lipid homeostasis. •Use of 13C- and D-labeled fatty acids provide novel insights into FATP2 function. •FATP2-dependent trafficking of FA into phospholipids results in distinctive profiles. •FATP2 functions in the transport and activation pathways for exogenous fatty acids. -- Abstract: In mammals, the fatty acid transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in fatty acid transport proceeding through vectorial acylation and in the activation of very long chain fatty acids, branched chain fatty acids and secondary bile acids. FATP1, 2 and 4,more » for example directly function in fatty acid transport and very long chain fatty acids activation while FATP5 does not function in fatty acid transport but activates secondary bile acids. In the present work, we have used stable isotopically labeled fatty acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in fatty acid transport and intracellular fatty acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4 h. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with transport from their respective exogenous fatty acids. The trafficking of exogenous fatty acids into phosphatidic acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The

Methods of using (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid

DOEpatents

Silverman, Richard B; Dewey, Stephen L; Miller, Steven

2015-03-03

(1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid also known as CPP-115 or its pharmaceutically acceptable salts can be used to treat addiction and neurological disorders such as epilepsy without side effects such as visual field defects caused by vigabatrin (Sabril).

Synthesis of the 1-Monoester of 2-Ketoalkanedioic Acids, e.g., Octyl α-Ketoglutarate

PubMed Central

Jung, Michael E.; Deng, Gang

2012-01-01

Oxidative cleavage of cycloalkene-1-carboxylates, made from the corresponding carboxylic acids, and subsequent oxidation of the resulting ketoaldehyde afforded the important 1-monoesters of 2-ketoalkanedioic acids. Thus ozonolysis of octyl cyclobutene-1-carboxylate followed by sodium chlorite oxidation afforded the 1-monooctyl 2-ketoglutarate. This is a cell-permeable prodrug form of α-ketoglutarate, an important intermediate in the tricarboxylic acid (TCA, Krebs) cycle and a promising therapeutic agent in its own right. PMID:23163977

A Plastidial Lysophosphatidic Acid Acyltransferase from Oilseed Rape1

PubMed Central

Bourgis, Fabienne; Kader, Jean-Claude; Barret, Pierre; Renard, Michel; Robinson, David; Robinson, Colin; Delseny, Michel; Roscoe, Thomas J.

1999-01-01

The biosynthesis of phosphatidic acid, a key intermediate in the biosynthesis of lipids, is controlled by lysophosphatidic acid (LPA, or 1-acyl-glycerol-3-P) acyltransferase (LPAAT, EC 2.3.1.51). We have isolated a cDNA encoding a novel LPAAT by functional complementation of the Escherichia coli mutant plsC with an immature embryo cDNA library of oilseed rape (Brassica napus). Transformation of the acyltransferase-deficient E. coli strain JC201 with the cDNA sequence BAT2 alleviated the temperature-sensitive phenotype of the plsC mutant and conferred a palmitoyl-coenzyme A-preferring acyltransferase activity to membrane fractions. The BAT2 cDNA encoded a protein of 351 amino acids with a predicted molecular mass of 38 kD and an isoelectric point of 9.7. Chloroplast-import experiments showed processing of a BAT2 precursor protein to a mature protein of approximately 32 kD, which was localized in the membrane fraction. BAT2 is encoded by a minimum of two genes that may be expressed ubiquitously. These data are consistent with the identity of BAT2 as the plastidial enzyme of the prokaryotic glycerol-3-P pathway that uses a palmitoyl-ACP to produce phosphatidic acid with a prokaryotic-type acyl composition. The homologies between the deduced protein sequence of BAT2 with prokaryotic and eukaryotic microsomal LAP acytransferases suggest that seed microsomal forms may have evolved from the plastidial enzyme. PMID:10398728

Fatty Acid Biosynthesis Pathways in Methylomicrobium buryatense 5G(B1).

PubMed

Demidenko, Aleksandr; Akberdin, Ilya R; Allemann, Marco; Allen, Eric E; Kalyuzhnaya, Marina G

2016-01-01

Methane utilization by methanotrophic bacteria is an attractive application for biotechnological conversion of natural or biogas into high-added-value products. Haloalcaliphilic methanotrophic bacteria belonging to the genus Methylomicrobium are among the most promising strains for methane-based biotechnology, providing easy and inexpensive cultivation, rapid growth, and the availability of established genetic tools. A number of methane bioconversions using these microbial cultures have been discussed, including the derivation of biodiesel, alkanes, and OMEGA-3 supplements. These compounds are derived from bacterial fatty acid pools. Here, we investigate fatty acid biosynthesis in Methylomicrobium buryatense 5G(B1) . Most of the genes homologous to typical Type II fatty acid biosynthesis pathways could be annotated by bioinformatics analyses, with the exception of fatty acid transport and regulatory elements. Different approaches for improving fatty acid accumulation were investigated. These studies indicated that both fatty acid degradation and acetyl- and malonyl-CoA levels are bottlenecks for higher level fatty acid production. The best strain generated in this study synthesizes 111 ± 2 mg/gDCW of extractable fatty acids, which is ~20% more than the original strain. A candidate gene for fatty acid biosynthesis regulation, farE , was identified and studied. Its deletion resulted in drastic changes to the fatty acid profile, leading to an increased pool of C18-fatty acid methyl ester. The FarE-regulon was further investigated by RNA-seq analysis of gene expression in farE -knockout mutants and farE -overexpressing strains. These gene profiles highlighted a novel set of enzymes and regulators involved in fatty acid biosynthesis. The gene expression and fatty acid profiles of the different farE -strains support the hypothesis that metabolic fluxes upstream of fatty acid biosynthesis restrict fatty acid production in the methanotroph.

Fatty Acid Biosynthesis Pathways in Methylomicrobium buryatense 5G(B1)

PubMed Central

Demidenko, Aleksandr; Akberdin, Ilya R.; Allemann, Marco; Allen, Eric E.; Kalyuzhnaya, Marina G.

2017-01-01

Methane utilization by methanotrophic bacteria is an attractive application for biotechnological conversion of natural or biogas into high-added-value products. Haloalcaliphilic methanotrophic bacteria belonging to the genus Methylomicrobium are among the most promising strains for methane-based biotechnology, providing easy and inexpensive cultivation, rapid growth, and the availability of established genetic tools. A number of methane bioconversions using these microbial cultures have been discussed, including the derivation of biodiesel, alkanes, and OMEGA-3 supplements. These compounds are derived from bacterial fatty acid pools. Here, we investigate fatty acid biosynthesis in Methylomicrobium buryatense 5G(B1). Most of the genes homologous to typical Type II fatty acid biosynthesis pathways could be annotated by bioinformatics analyses, with the exception of fatty acid transport and regulatory elements. Different approaches for improving fatty acid accumulation were investigated. These studies indicated that both fatty acid degradation and acetyl- and malonyl-CoA levels are bottlenecks for higher level fatty acid production. The best strain generated in this study synthesizes 111 ± 2 mg/gDCW of extractable fatty acids, which is ~20% more than the original strain. A candidate gene for fatty acid biosynthesis regulation, farE, was identified and studied. Its deletion resulted in drastic changes to the fatty acid profile, leading to an increased pool of C18-fatty acid methyl ester. The FarE-regulon was further investigated by RNA-seq analysis of gene expression in farE-knockout mutants and farE-overexpressing strains. These gene profiles highlighted a novel set of enzymes and regulators involved in fatty acid biosynthesis. The gene expression and fatty acid profiles of the different farE-strains support the hypothesis that metabolic fluxes upstream of fatty acid biosynthesis restrict fatty acid production in the methanotroph. PMID:28119683

Chiral discrimination of α-hydroxy acids and N-Ts-α-amino acids induced by tetraaza macrocyclic chiral solvating agents by using 1H NMR spectroscopy.

PubMed

Lv, Caixia; Feng, Lei; Zhao, Hongmei; Wang, Guo; Stavropoulos, Pericles; Ai, Lin

2017-02-21

In the field of chiral recognition, reported chiral discrimination by 1 H NMR spectroscopy has mainly focused on various chiral analytes with a single chiral center, regarded as standard chiral substrates to evaluate the chiral discriminating abilities of a chiral auxiliary. Among them, chiral α-hydroxy acids, α-amino acids and their derivatives are chiral organic molecules involved in a wide variety of biological processes, and also play an important role in the area of preparation of pharmaceuticals, as they are part of the synthetic process in the production of chiral drug intermediates and protein-based drugs. In this paper, several α-hydroxy acids and N-Ts-α-amino acids were used to evaluate the chiral discriminating abilities of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a-1d by 1 H NMR spectroscopy. The results indicate that α-hydroxy acids and N-Ts-α-amino acids were successfully discriminated in the presence of TAMCSAs 1a-1d by 1 H NMR spectroscopy in most cases. The enantiomers of the α-hydroxy acids and N-Ts-α-amino acids were assigned based on the change of integration of the 1 H NMR signals of the corresponding protons. The enantiomeric excesses (ee) of N-Ts-α-amino acids 11 with different optical compositions were calculated based on the integration of the 1 H NMR signals of the CH 3 protons (Ts group) of the enantiomers of (R)- and (S)-11 in the presence of TAMCSA 1b. At the same time, the possible chiral discriminating behaviors have been discussed by means of the Job plots of (±)-2 with TAMCSAs 1b and proposed theoretical models of the enantiomers of 2 and 6 with TAMCSA 1a, respectively.

Glycerol-3-phosphate Acyltransferase (GPAT)-1, but Not GPAT4, Incorporates Newly Synthesized Fatty Acids into Triacylglycerol and Diminishes Fatty Acid Oxidation*

PubMed Central

Wendel, Angela A.; Cooper, Daniel E.; Ilkayeva, Olga R.; Muoio, Deborah M.; Coleman, Rosalind A.

2013-01-01

Four glycerol-3-phosphate acyltransferase (GPAT) isoforms, each encoded by a separate gene, catalyze the initial step in glycerolipid synthesis; in liver, the major isoforms are GPAT1 and GPAT4. To determine whether each of these hepatic isoforms performs a unique function in the metabolism of fatty acid, we measured the incorporation of de novo synthesized fatty acid or exogenous fatty acid into complex lipids in primary mouse hepatocytes from control, Gpat1−/−, and Gpat4−/− mice. Although hepatocytes from each genotype incorporated a similar amount of exogenous fatty acid into triacylglycerol (TAG), only control and Gpat4−/− hepatocytes were able to incorporate de novo synthesized fatty acid into TAG. When compared with controls, Gpat1−/− hepatocytes oxidized twice as much exogenous fatty acid. To confirm these findings and to assess hepatic β-oxidation metabolites, we measured acylcarnitines in liver from mice after a 24-h fast and after a 24-h fast followed by 48 h of refeeding with a high sucrose diet to promote lipogenesis. Confirming the in vitro findings, the hepatic content of long-chain acylcarnitine in fasted Gpat1−/− mice was 3-fold higher than in controls. When compared with control and Gpat4−/− mice, after the fasting-refeeding protocol, Gpat1−/− hepatic TAG was depleted, and long-chain acylcarnitine content was 3.5-fold higher. Taken together, these data demonstrate that GPAT1, but not GPAT4, is required to incorporate de novo synthesized fatty acids into TAG and to divert them away from oxidation. PMID:23908354

The DELLA Protein SLR1 Integrates and Amplifies Salicylic Acid- and Jasmonic Acid-Dependent Innate Immunity in Rice1

PubMed Central

De Vleesschauwer, David; Seifi, Hamed Soren; Haeck, Ashley; Huu, Son Nguyen; Demeestere, Kristof

2016-01-01

Gibberellins are a class of tetracyclic plant hormones that are well known to promote plant growth by inducing the degradation of a class of nuclear growth-repressing proteins, called DELLAs. In recent years, GA and DELLAs are also increasingly implicated in plant responses to pathogen attack, although our understanding of the underlying mechanisms is still limited, especially in monocotyledonous crop plants. Aiming to further decipher the molecular underpinnings of GA- and DELLA-modulated plant immunity, we studied the dynamics and impact of GA and DELLA during infection of the model crop rice (Oryza sativa) with four different pathogens exhibiting distinct lifestyles and infection strategies. Opposite to previous findings in Arabidopsis (Arabidopsis thaliana), our findings reveal a prominent role of the DELLA protein Slender Rice1 (SLR1) in the resistance toward (hemi)biotrophic but not necrotrophic rice pathogens. Moreover, contrary to the differential effect of DELLA on the archetypal defense hormones salicylic acid (SA) and jasmonic acid (JA) in Arabidopsis, we demonstrate that the resistance-promoting effect of SLR1 is due at least in part to its ability to boost both SA- and JA-mediated rice defenses. In a reciprocal manner, we found JA and SA treatment to interfere with GA metabolism and stabilize SLR1. Together, these findings favor a model whereby SLR1 acts as a positive regulator of hemibiotroph resistance in rice by integrating and amplifying SA- and JA-dependent defense signaling. Our results highlight the differences in hormone defense networking between rice and Arabidopsis and underscore the importance of GA and DELLA in molding disease outcomes. PMID:26829979

Thermal analysis, X-ray powder diffraction and electron microscopy data related with the production of 1:1 Caffeine:Glutaric Acid cocrystals.

PubMed

Duarte, Íris; Andrade, Rita; Pinto, João F; Temtem, Márcio

2016-09-01

The data presented in this article are related to the production of 1:1 Caffeine:Glutaric Acid cocrystals as part of the research article entitled "Green production of cocrystals using a new solvent-free approach by spray congealing" (Duarte et al., 2016) [1]. More specifically, here we present the thermal analysis and the X-ray powder diffraction data for pure Glutaric Acid, used as a raw material in [1]. We also include the X-ray powder diffraction and electron microscopy data obtained for the 1:1 Caffeine:Glutaric Acid cocrystal (form II) produced using the cooling crystallization method reported in "Operating Regions in Cooling Cocrystallization of Caffeine and Glutaric Acid in Acetonitrile" (Yu et al., 2010) [2]. Lastly, we show the X-ray powder diffraction data obtained for assessing the purity of the 1:1 Caffeine:Glutaric cocrystals produced in [1].

Improvement of lactic acid production in Saccharomyces cerevisiae by a deletion of ssb1.

PubMed

Lee, Jinsuk J; Crook, Nathan; Sun, Jie; Alper, Hal S

2016-01-01

Polylactic acid (PLA) is an important renewable polymer, but current processes for producing its precursor, lactic acid, suffer from process inefficiencies related to the use of bacterial hosts. Therefore, improving the capacity of Saccharomyces cerevisiae to produce lactic acid is a promising approach to improve industrial production of lactic acid. As one such improvement required, the lactic acid tolerance of yeast must be significantly increased. To enable improved tolerance, we employed an RNAi-mediated genome-wide expression knockdown approach as a means to rapidly identify potential genetic targets. In this approach, several gene knockdown targets were identified which confer increased acid tolerance to S. cerevisiae BY4741, of which knockdown of the ribosome-associated chaperone SSB1 conferred the highest increase (52%). This target was then transferred into a lactic acid-overproducing strain of S. cerevisiae CEN.PK in the form of a knockout and the resulting strain demonstrated up to 33% increased cell growth, 58% increased glucose consumption, and 60% increased L-lactic acid production. As SSB1 contains a close functional homolog SSB2 in yeast, this result was counterintuitive and may point to as-yet-undefined functional differences between SSB1 and SSB2 related to lactic acid production. The final strain produced over 50 g/L of lactic acid in under 60 h of fermentation.

Formation of [b3 - 1 + cat]+ ions from metal-cationized tetrapeptides containing beta-alanine, gamma-aminobutyric acid or epsilon-aminocaproic acid residues.

PubMed

Osburn, Sandra M; Ochola, Sila O; Talaty, Erach R; Van Stipdonk, Michael J

2008-11-01

The presence and position of a single beta-alanine (betaA), gamma-aminobutyric acid (gammaABu) or epsilon-aminocaproic acid (Cap) residue has been shown to have a significant influence on the formation of b(n)+ and y(n)+ product ions from a series of model, protonated peptides. In this study, we examined the effect of the same residues on the formation of analogous [b3 - 1 + cat]+ products from metal (Li+, Na+ and Ag+)-cationized peptides. The larger amino acids suppress formation of b3+ from protonated peptides with general sequence AAXG (where X = beta-alanine, gamma-aminobutyric acid or epsilon-aminocaproic acid), presumably because of the prohibitive effect of larger cyclic intermediates in the 'oxazolone' pathway. However, abundant [b3 - 1 + cat]+ products are generated from metal-cationized versions of AAXG. Using a group of deuterium-labeled and exchanged peptides, we found that formation of [b3 - 1 + cat]+ involves transfer of either amide or alpha-carbon position H atoms, and the tendency to transfer the atom from the alpha-carbon position increases with the size of the amino acid in position X. To account for the transfer of the H atom, a mechanism involving formation of a ketene product as [b3 - 1 + cat]+ is proposed.

Crystal structure of 1-(3-chloro­phen­yl)piperazin-1-ium picrate–picric acid (2/1)

PubMed Central

Kavitha, Channappa N.; Jasinski, Jerry P.; Kaur, Manpreet; Anderson, Brian J.; Yathirajan, H. S.

2014-01-01

The title salt {systematic name: bis­[1-(3-chloro­phen­yl)piperazinium 2,4,6-tri­nitro­phenolate]–picric acid (2/1)}, 2C10H14ClN2 +·2C6H5N3O7 −·C6H6N3O7, crystallized with two independent 1-(3-chloro­phen­yl)piperazinium cations, two picrate anions and a picric acid mol­ecule in the asymmetric unit. The six-membered piperazine ring in each cation adopts a slightly distorted chair conformation and contains a protonated N atom. In the picric acid mol­ecule, the mean planes of the nitro groups in the ortho-, meta-, and para-positions are twisted from the benzene ring by 31.5 (3), 7.7 (1), and 3.8 (2)°, respectively. In the anions, the dihedral angles between the benzene ring and the ortho-, meta-, and para-nitro groups are 36.7 (1), 5.0 (6), 4.8 (2)°, and 34.4 (9), 15.3 (8), 4.5 (1)°, respectively. The nitro group in one anion is disordered and was modeled with two sites for one O atom with an occupancy ratio of 0.627 (7):0.373 (7). In the crystal, the picric acid mol­ecule inter­acts with the picrate anion through a trifurcated O—H⋯O four-centre hydrogen bond involving an intra­molecular O—H⋯O hydrogen bond and a weak C—H⋯O inter­action. Weak inter­molecular C—H⋯O inter­actions are responsible for the formation of cation–anion–cation trimers resulting in a chain along [010]. In addition, weak C—H⋯Cl and weak π–π inter­actions [centroid–centroid distances of 3.532 (3), 3.756 (4) and 3.705 (3) Å] are observed and contribute to the stability of the crystal packing. PMID:25484834

The effects of fasting in Ramadan. 1. Serum uric acid and lipid concentrations.

PubMed

Gumaa, K A; Mustafa, K Y; Mahmoud, N A; Gader, A M

1978-11-01

1. The changes in serum levels of uric acid and lipids during 1 month of starvation-refeeding were measured in sixteen male volunteers. 2. Uric acid levels increased linearly with the duration of the experiment. The increase was positively correlated with the increase in serum triglycerides but not with cholesterol or phospholipids. 3. Triglycerides increased at a faster rate than uric acid implying that the increase in uric acid was secondary to that of the lipid. 4. It was concluded that the purine and lipid synthetic pathways are linked through a common small-molecular-weight effector rather than through the sharing of a common enzyme.

Inactivation of the transcription factor mig1 (YGL035C) in Saccharomyces cerevisiae improves tolerance towards monocarboxylic weak acids: acetic, formic and levulinic acid.

PubMed

Balderas-Hernández, Victor E; Correia, Kevin; Mahadevan, Radhakrishnan

2018-06-06

Toxic concentrations of monocarboxylic weak acids present in lignocellulosic hydrolyzates affect cell integrity and fermentative performance of Saccharomyces cerevisiae. In this work, we report the deletion of the general catabolite repressor Mig1p as a strategy to improve the tolerance of S. cerevisiae towards inhibitory concentrations of acetic, formic or levulinic acid. In contrast with the wt yeast, where the growth and ethanol production were ceased in presence of acetic acid 5 g/L or formic acid 1.75 g/L (initial pH not adjusted), the m9 strain (Δmig1::kan) produced 4.06 ± 0.14 and 3.87 ± 0.06 g/L of ethanol, respectively. Also, m9 strain tolerated a higher concentration of 12.5 g/L acetic acid (initial pH adjusted to 4.5) without affecting its fermentative performance. Moreover, m9 strain produced 33% less acetic acid and 50-70% less glycerol in presence of weak acids, and consumed acetate and formate as carbon sources under aerobic conditions. Our results show that the deletion of Mig1p provides a single gene deletion target for improving the acid tolerance of yeast strains significantly.

Effect of arachidonic acid metabolites on CR1 expression by B-lymphocytes.

PubMed

Cook, J M; Guibert, F; Delebassee, S; Gualde, N

1989-01-01

The effect of arachidonic acid metabolites on the expression of the receptor for the C3b/C4b fragment of complement (CR1) by human B-lymphocytes was investigated. Kinetic experiments to determine CR1 expression over time indicated that the maximal receptor number occurred at 2 h, followed by a return to baseline values. Addition of 10(-4) M puromycin to the cells suggested that the increase was due to the expression of an intracellular pool and not de novo synthesis of new receptor molecules. B-lymphocytes were incubated with arachidonic acid, 15-hydroxyeicosatetraenoic acid, leukotrienes B4 or C4 or prostaglandin E2 (PGE2). The quantity of membrane antigenic binding sites was determined before and after incubation. The lipoxygenase metabolites did not alter CR1 numbers. In contrast, PGE2 significantly decreased (P less than 0.05) the quantity of CR1 expressed. In kinetic experiments, PGE2 blocked the maximal expression of CR1 seen at 2 h, indicating that it prevents the appearance of an intracellular pool of receptor. These results show that CR1 number on B-lymphocytes can be altered by at least one arachidonic acid metabolite. This may offer a partial explanation for the inhibitory effects of PGE2 on B-cell proliferation and immunoglobulin secretion since CR1 is implicated in B-lymphocyte differentiation and specific antibody response.

Identification of novel phosphatidic acid binding domain on sphingosine kinase 1 of Arabidopsis thaliana.

PubMed

Pandit, Shatakshi; Dalal, Vikram; Mishra, Girish

2018-07-01

Phosphatidic acid (PA) is an important lipid signaling molecule which interacts with Arabidopsis thaliana Sphingosine kinase1 (AtSPHK1) during several abiotic stresses particularly drought stress as a result of Abscisic acid (ABA) signaling in guard cells. PA molecules respond by generating lipid signal and/or by binding and translocating target proteins to membrane. However, site of interaction and role of PA binding to AtSPHK1 is not clear yet. Owing to the importance of AtSPHK1 during stress signaling it is imperative to decipher the site of PA interaction with AtSPHK1. To identify the PA binding region of AtSPHK1, various deletion fragments from N-terminal and C-terminal region were prepared. Results from protein lipid overlay assay using various truncated proteins of AtSPHK1 suggested the involvement of N-terminal region, between 110 and 205 amino acids, in binding with PA. In-silico analyses performed to build homologous structure of AtSPHK1 revealed that PA docking occurs in the hydrophobic cavity of DAG-Kinase domain. Deletion of amino acids 182 VSGDGI 187 perturbed PA-AtSPHK1 binding, indicating an essential role of these six amino acids in PA-AtSPHK1 binding. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Flow diversion with Pipeline Embolic Device as treatment of subarachnoid hemorrhage secondary to blister aneurysms: dual-center experience and review of the literature.

PubMed

Linfante, Italo; Mayich, Michael; Sonig, Ashish; Fujimoto, Jena; Siddiqui, Adnan; Dabus, Guilherme

2017-01-01

Aneurysmal subarachnoid hemorrhage (aSAH) secondary to blister-type aneurysms (BAs) is associated with high morbidity and mortality. Microsurgical clipping or wrapping and/or use of traditional endovascular techniques to repair the lesion result in frequent regrowth and rebleeds and ultimately high fatality rates. Because of the purely endoluminal nature of arterial reconstruction, flow diversion may represent an ideal option to repair ruptured BAs. We performed a retrospective analysis of our database including all consecutive patients with aSAH secondary to BAs treated with the Pipeline Embolic Device (PED) between November 2013 and November 2015 in two institutions. We collected basic patient demographics, aneurysm size, location, number and sizes of PEDs used, use of coiling, 30-day modified Rankin Scale (mRS) score, and follow-up imaging data. Ten cases of aSAH were found as a result of a ruptured BA. Patients had a mean age of 47.2 years (range 27-68). Mean Hunt and Hess score was 1.6 (range 1-4). Lesions were predominantly left-sided, mostly along the dorsal aspect of the internal carotid artery, either paraclinoid or paraophthalmic (8/10). In two patients the BA was located in the left middle cerebral artery. All lesions were very small (mean 1.4×1.5 mm; range 0.75-2.1 mm). Placement of a single PED resulted in immediate occlusion or near-occlusion of the BA in 9 out of 10 patients. Nine patients did very well; eight had a 90-day mRS score of 0 and one had a 90-day mRS score of 1. Follow-up digital subtraction angiography was performed in all patients (mean 15 months; range 7-24). In the surviving nine patients there was complete occlusion of the BA on long-term follow-up angiography. Repair of ruptured BA with PED may be a safe and durable option. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Computed tomography angiography spot sign predicts intraprocedural aneurysm rupture in subarachnoid hemorrhage.

PubMed

Burkhardt, Jan-Karl; Neidert, Marian Christoph; Stienen, Martin Nikolaus; Schöni, Daniel; Fung, Christian; Roethlisberger, Michel; Corniola, Marco Vincenzo; Bervini, David; Maduri, Rodolfo; Valsecchi, Daniele; Tok, Sina; Schatlo, Bawarjan; Bijlenga, Philippe; Schaller, Karl; Bozinov, Oliver; Regli, Luca

2017-07-01

To analyze whether the computed tomography angiography (CTA) spot sign predicts the intraprocedural rupture rate and outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). From a prospective nationwide multicenter registry database, 1023 patients with aneurysmal subarachnoid hemorrhage (aSAH) were analyzed retrospectively. Descriptive statistics and logistic regression analysis were used to compare spot sign-positive and -negative patients with aneurysmal intracerebral hemorrhage (aICH) for baseline characteristics, aneurysmal and ICH imaging characteristics, treatment and admission status as well as outcome at discharge and 1-year follow-up (1YFU) using the modified Rankin Scale (mRS). A total of 218 out of 1023 aSAH patients (21%) presented with aICH including 23/218 (11%) patients with spot sign. Baseline characteristics were comparable between spot sign-positive and -negative patients. There was a higher clip-to-coil ratio in patients with than without aICH (both spot sign positive and negative). Median aICH volume was significantly higher in the spot sign-positive group (50 ml, 13-223 ml) than in the spot sign-negative group (18 ml, 1-416; p < 0.0001). Patients with a spot sign-positive aICH thus were three times as likely as those with spot sign-negative aICH to show an intraoperative aneurysm rupture [odds ratio (OR) 3.04, 95% confidence interval (CI) 1.04-8.92, p = 0.046]. Spot sign-positive aICH patients showed a significantly worse mRS at discharge (p = 0.039) than patients with spot sign-negative aICH (median mRS 5 vs. 4). Logistic regression analysis showed that the spot sign was an aICH volume-dependent predictor for outcome. Both spot sign-positive and -negative aICH patients showed comparable rates of hospital death, death at 1YFU and mRS at 1YFU. In this multicenter data analysis, patients with spot sign-positive aICH showed higher aICH volumes and a higher rate of intraprocedural aneurysm rupture, but comparable long

Supramolecular assembly of biphenyl dicarboxylic acid on Au(1 1 1)

NASA Astrophysics Data System (ADS)

Zhu, N.; Osada, T.; Komeda, T.

2007-04-01

We investigate the structure of submonolayer film of 4,4'-biphenyl dicarboxylic acid (BDA) molecules on Au(1 1 1)-22 × √3 reconstructed surface with the use of scanning tunneling microscopy (STM). The BDA molecules form ordered structures on Au(1 1 1) surface which are commensurate with the substrate. We have concluded that the molecule-molecule interaction is mainly through hydrogen bonding formed by a straight dimer of BDA molecules. The straight dimer can be expressed as 4 s + 2 t or its six crystallographic equivalents using the unit vectors of the gold substrate of s and t. The length of hydrogen bonding (O-H-O) is estimated to be 0.31 nm assuming nearest neighbor distance of gold atoms of 0.275 nm. The ordering shows a clear contrast with the case of BDA on Cu(1 0 0) surface [S. Stepanow, N. Lin, F. Vidal, A. Landa, M. Ruben, J.V. Barth, K. Kern, Nanoletters 5 (2005) 901] in which a square type of ordering of molecules is observed by the formation of hydrogen bonding between a carboxylate (COO) and a benzene ring. The clear difference of the ordered structure on Cu(1 0 0) and Au(1 1 1) surface demonstrates that the absence (presence) of deprotonation of carboxyl group of BDA molecule on Au(1 1 1) (Cu(1 0 0)) switches the straight and square type ordering of BDA molecules.

Effects of berberine and cinnamic acid on palmitic acid-induced intracellular triglyceride accumulation in NIT-1 pancreatic β cells.

PubMed

Zhao, Li; Jiang, Shu-Jun; Lu, Fu-Er; Xu, Li-Jun; Zou, Xin; Wang, Kai-Fu; Dong, Hui

2016-07-01

To investigate the effects of berberine (BBR) and cinnamic acid (CA), the main active components in Jiaotai Pill (, JTP), on palmitic acid (PA)-induced intracellular triglyceride (TG) accumulation in NIT-1 pancreatic β cells. Cells were incubated in culture medium containing PA (0.25 mmol/L) for 24 h. Then treatments with BBR (10 μmol/L), CA (100 μmol/L) and the combination of BBR and CA (BBR+CA) were performed respectively. Intracellular lipid accumulation was assessed by Oil Red O staining and TG content was measured by colorimetric assay. The expression of adenosine monophosphate-activated protein kinase (AMPK) protein and its downstream lipogenic and fatty acid oxidation genes, including fatty acid synthase (FAS), acetyl-coA carboxylase (ACC), phosphorylation acetyl-coA carboxylase (pACC), carnitine acyl transferase 1 (CPT-1) and sterol regulating element binding protein 1c (SREBP-1c) were determined by Western blot or real time polymerase chain reaction. PA induced an obvious lipid accumulation and a significant increase in intracellular TG content in NIT-1 cells. PA also induced a remarkable decrease in AMPK protein expression and its downstream targets such as pACC and CPT-1. Meanwhile, AMPK downstream lipogenic genes including SREBP-1c mRNA, FAS and ACC protein expressions were increased. Treatments with BBR and BBR+CA, superior to CA, significantly reversed the above genes changes in NIT-1 pancreatic β cells. However, the synergistic effect of BBR and CA on intracellular TG content was not observed in the present study. It can be concluded that in vitro, BBR and BBR+CA could inhibit PA-induced lipid accumulation by decreasing lipogenesis and increasing lipid oxidation in NIT-1 pancreatic β cells.

Comparison of efficacy of chemical peeling with 25% trichloroacetic acid and 0.1% retinoic acid for facial rejuvenation.

PubMed

Yildirim, Selda; Gurel, Mehmet Salih; Gungor, Sule; Tekeli, Omur; Canat, Dilek

2016-06-01

Skin aging is a problem which negatively affects the psyche of the person, social relations, as well as work life and health and which compels the patients to find appropriate treatment methods. Numerous treatment methods have been developed in order to delay aging and to reduce the aging effects in addition to having a younger, healthier and more beautiful facial appearance. To compare the efficiency, cosmetic results and possible adverse effects of the peeling treatment with 25% trichloroacetic acid (TCA) and 0.1% retinoic acid for facial rejuvenation in patients presenting with skin aging. Fifty female patients in total presenting with medium and advanced degree skin aging were subject to this study. Two separate treatment groups were formed; the first group underwent chemical skin treatment with 25% TCA while the other group was applied with 0.1% retinoic acid treatment. Following the 4 months' treatment the patients were controlled three times in total for post lesional hypopigmentation, hyperpigmentation, scars, skin irritation and other possible changes per month. The pretreatment and first follow-up visit, and final control images were comparatively evaluated by three observers via specific software. The healing rates of the group subject to retinoic acid were statistically higher (p < 0.05) compared to patients in the TCA group in the final follow-up visit following the treatment according to the first and second observers. On the other hand, according to the third observer, patients applied with retinoic acid presented with higher healing rates compared to those treated with TCA, however; this rate was not statistically significant (p > 0.05). The frequency of TCA- and retinoic acid-associated adverse effects was similar in both groups (p > 0.05). As a result of both treatments, a reduction in the quality of life scores as well as a pronounced recovery (p = 0.001) in the quality of life of those patients with skin aging was observed. The photo aging

Comparison of efficacy of chemical peeling with 25% trichloroacetic acid and 0.1% retinoic acid for facial rejuvenation

PubMed Central

Gurel, Mehmet Salih; Gungor, Sule; Tekeli, Omur; Canat, Dilek

2016-01-01

Introduction Skin aging is a problem which negatively affects the psyche of the person, social relations, as well as work life and health and which compels the patients to find appropriate treatment methods. Numerous treatment methods have been developed in order to delay aging and to reduce the aging effects in addition to having a younger, healthier and more beautiful facial appearance. Aim To compare the efficiency, cosmetic results and possible adverse effects of the peeling treatment with 25% trichloroacetic acid (TCA) and 0.1% retinoic acid for facial rejuvenation in patients presenting with skin aging. Material and methods Fifty female patients in total presenting with medium and advanced degree skin aging were subject to this study. Two separate treatment groups were formed; the first group underwent chemical skin treatment with 25% TCA while the other group was applied with 0.1% retinoic acid treatment. Following the 4 months’ treatment the patients were controlled three times in total for post lesional hypopigmentation, hyperpigmentation, scars, skin irritation and other possible changes per month. The pretreatment and first follow-up visit, and final control images were comparatively evaluated by three observers via specific software. Results The healing rates of the group subject to retinoic acid were statistically higher (p < 0.05) compared to patients in the TCA group in the final follow-up visit following the treatment according to the first and second observers. On the other hand, according to the third observer, patients applied with retinoic acid presented with higher healing rates compared to those treated with TCA, however; this rate was not statistically significant (p > 0.05). The frequency of TCA- and retinoic acid-associated adverse effects was similar in both groups (p > 0.05). As a result of both treatments, a reduction in the quality of life scores as well as a pronounced recovery (p = 0.001) in the quality of life of those patients

Effect of boric acid supplementation of ostrich water on the expression of Foxn1 in thymus.

PubMed

Xiao, Ke; Ansari, Abdur Rahman; Rehman, Zia Ur; Khaliq, Haseeb; Song, Hui; Tang, Juan; Wang, Jing; Wang, Wei; Sun, Peng-Peng; Zhong, Juming; Peng, Ke-Mei

2015-11-01

Foxn1 is essential for thymus development. The relationship between boric acid and thymus development, optimal dose of boric acid in ostrich diets, and the effects of boric acid on the expression of Foxn1 were investigated in the present study. Thirty healthy ostriches were randomly divided into six groups: Group I, II, III, IV, V, VI, and supplemented with boric acid at the concentration of 0 mg/L, 40 mg/L, 80 mg/L, 160 mg/L, 320 mg/L, 640 mg/L, respectively. The histological changes in thymus were observed by HE staining, and the expression of Foxn1 analyzed by immunohistochemistry and western blot. TUNEL method was used to label the apoptotic cells. Ostrich Foxn1 was sequenced by Race method. The results were as following: Apoptosis in ostrich thymus was closely related with boric acid concentrations. Low boric acid concentration inhibited apoptosis in thymus, but high boric acid concentration promoted apoptosis. Foxn1-positive cells were mainly distributed in thymic medulla and rarely in cortex. Foxn1 is closely related to thymus growth and development. The nucleotide sequence and the encoded protein of Foxn1 were 2736 bases and 654 amino acids in length. It is highly conserved as compared with other species. These results demonstrated that the appropriate boric acid supplementation in water would produce positive effects on the growth development of ostrich thymus by promoting Foxn1 expression, especially at 80 mg/L, and the microstructure of the thymus of ostrich fed 80 mg/L boric acid was well developed. The supplementation of high dose boron (>320 mg/L) damaged the microstructure of thymus and inhibited the immune function by inhibiting Foxn1 expression, particularly at 640 mg/L. The optimal dose of boric acid supplementation in ostrich diets is 80 mg/L boric acid. The genomic full-length of African ostrich Foxn1 was cloned for the first time in the study.

Enantioselective Fluorescent Recognition of Chiral Acids by Cyclohexane-1,2-diamine-Based Bisbinaphthyl Molecules

PubMed Central

Li, Zi-Bo; Lin, Jing; Sabat, Michal; Hyacinth, Marilise; Pu, Lin

2008-01-01

The cyclohexane-1,2-diamine-based bisbinaphthyl macrocycles (S)-/(R)-5 and their cyclic and acyclic analogs are synthesized. The interactions of these compounds with various chiral acids are studied. Compounds (S)-/(R)-5 exhibit highly enantioselective fluorescent responses and high fluorescent sensitivity toward α-hydroxycarboxylic acids and N-protected amino acids. Among these interactions, (S)-mandelic acid (10−3 M) led to over 20 fold fluorescence enhancement of (S)-5 (1.0 × 10−5 M in benzene/0.05% DME) at the monomer emission and (S)-hexahydromandelic acid (10−3 M) led to over 80 fold fluorescence enhancement. These results demonstrate that (S)-5 is useful as an enantioselective fluorescent sensor for the recognition of the chiral acids. On the basis of the study of the structures of (S)-5 and the previously reported 1,2-diphenylethylenediamine-based bisbinaphthyl macrocycle (S)-4, the large fluorescence enhancement of (S)-5 with achirality-matched α-hydroxycarboxylic acid is attributed to the formation of a structurally rigidified host-guest complex and the further interaction of this complex with the acid to suppress the photo-induced electron transfer fluorescent quenching caused by the nitrogens in (S)-5. PMID:17530897

Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants.

PubMed

Lee, Jessica M; Ong, Jessica R; Vergnes, Laurent; de Aguiar Vallim, Thomas Q; Nolan, Jonathan; Cantor, Rita M; Walters, Julian R F; Reue, Karen

2018-03-01

Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1 -null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1 -/- mice on the C57BL/6J genetic background. C57BL/6J Diet1 -/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant ( rs12256835 ) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions. Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.

TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status.

PubMed

Guseva, Natalya V; Rokhlin, Oskar W; Glover, Rebecca A; Cohen, Michael B

2011-07-01

A key player in prostate cancer development and progression is the androgen receptor (AR). Tumor-associated lipogenesis can protect cancer cells from carcinogenic- and therapeutic-associated treatments. Increased synthesis of fatty acids and cholesterol is regulated by androgens through induction of several genes in androgen-responsive cancer cells. Acetyl-CoA-carboxylase-α (ACCA) is a key enzyme in the regulation of fatty acids synthesis. Here we show that AR binds in vivo to intron regions of human ACCA gene. We also show that the level of ACCA protein in LNCaP depends on AR expression and that DHT treatment increases ACCA expression and fatty acid synthesis. Inhibition of ACCA by TOFA (5-tetradecyl-oxy-2-furoic acid) decreases fatty acid synthesis and induces caspase activation and cell death in most PCa cell lines. Our data suggest that TOFA can kill cells via the mitochondrial pathway since we found cytochrome c release after TOFA treatment in androgen sensitive cell lines. The results also imply that the pro-apoptotic effect of TOFA may be mediated via a decrease of neuropilin-1(NRP1) and Mcl-1expression. We have previously reported that Mcl-1 is under AR regulation and plays an important role in resistance to drug-induced apoptosis in prostate cancer cells, and NRP1 is known to regulate Mcl-1 expression. Here, we show for the first time that NRP1 expression is under AR control. Taken together, our data suggest that TOFA is a potent cell death inducing agent in prostate cancer cells.

Acidic 1,3-propanediaminetetraacetato lanthanides with luminescent and catalytic ester hydrolysis properties

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

Chen, Mao-Long; Shi, Yan-Ru; Yang, Yu-Chen

2014-11-15

In acidic solution, a serials of water-soluble coordination polymers (CPs) were isolated as zonal 1D-CPs 1,3-propanediaminetetraacetato lanthanides [Ln(1,3-H{sub 3}pdta)(H{sub 2}O){sub 5}]{sub n}·2Cl{sub n}·3nH{sub 2}O [Ln=La, 1; Ce, 2; Pr, 3; Nd, 4; Sm, 5] (1,3-H{sub 4}pdta=1,3-propanediaminetetraacetic acid, C{sub 11}H{sub 18}N{sub 2}O{sub 8}) in high yields. When 1 eq. mol potassium hydroxide was added to the solutions of 1D-CPs, respectively, two 1D-CPs [Ln(1,3-H{sub 2}pdta)(H{sub 2}O){sub 3}]{sub n}·Cl{sub n}·2nH{sub 2}O [Ln=Sm, 6; Gd, 7] were isolated at room temperature and seven 2D-CPs [Ln(1,3-H{sub 2}pdta)(H{sub 2}O){sub 2}]{sub n}·Cl{sub n}·2nH{sub 2}O [Ln=La, 8; Ce, 9; Pr, 10; Nd, 11; Sm, 12; Eu, 13; Gd,more » 14] were isolated at 70 °C. When the crystals of 1–4 were hydrothermally heated at 180 °C with 1–2 eq. mol potassium hydroxide, four 3D-CPs [Ln(1,3-Hpdta)]{sub n}·nH{sub 2}O [Ln=La, 15; Ce, 16; Pr, 17; Nd, 18] were obtained. The two 2D-CPs [Ln(1,3-Hpdta)(H{sub 2}O)]{sub n}·4nH{sub 2}O (Sm, 19; Eu, 20) were isolated in similar reaction conditions. With the increments of pH value in the solution and reaction temperature, the structure becomes more complicated. 1–5 are soluble in water and 1 was traced by solution {sup 13}C({sup 1}H) NMR technique, the water-soluble lanthanides 1 and 5 show catalytic activity to ester hydrolysis reaction respectively, which indicate their important roles in the hydrolytic reaction. The europium complexes 13 and 20 show visible fluorescence at an excitation of 394 nm. The structure diversity is mainly caused by the variation of coordinated ligand in different pH values and lanthanide contraction effect. Acidic conditions are favorable for the isolations of lanthanide complexes in different structures and this may helpful to separate different lanthanides. The thermal stability investigations reveal that acidic condition is favorable to obtain the oxides at a lower temperature. - Graphical abstract: A

Identification of Isn1 and Sdt1 as Glucose- and Vitamin-regulated Nicotinamide Mononucleotide and Nicotinic Acid Mononucleotide 5′-Nucleotidases Responsible for Production of Nicotinamide Riboside and Nicotinic Acid Riboside*

PubMed Central

Bogan, Katrina L.; Evans, Charles; Belenky, Peter; Song, Peng; Burant, Charles F.; Kennedy, Robert; Brenner, Charles

2009-01-01

Recently, we discovered that nicotinamide riboside and nicotinic acid riboside are biosynthetic precursors of NAD+, which are utilized through two pathways consisting of distinct enzymes. In addition, we have shown that exogenously supplied nicotinamide riboside is imported into yeast cells by a dedicated transporter, and it extends replicative lifespan on high glucose medium. Here, we show that nicotinamide riboside and nicotinic acid riboside are authentic intracellular metabolites in yeast. Secreted nicotinamide riboside was detected with a biological assay, and intracellular levels of nicotinamide riboside, nicotinic acid riboside, and other NAD+ metabolites were determined by a liquid chromatography-mass spectrometry method. A biochemical genomic screen indicated that three yeast enzymes possess nicotinamide mononucleotide 5′-nucleotidase activity in vitro. Metabolic profiling of knock-out mutants established that Isn1 and Sdt1 are responsible for production of nicotinamide riboside and nicotinic acid riboside in cells. Isn1, initially classified as an IMP-specific 5′-nucleotidase, and Sdt1, initially classified as a pyrimidine 5′-nucleotidase, are additionally responsible for dephosphorylation of pyridine mononucleotides. Sdt1 overexpression is growth-inhibitory to cells in a manner that depends on its active site and correlates with reduced cellular NAD+. Expression of Isn1 protein is positively regulated by the availability of nicotinic acid and glucose. These results reveal unanticipated and highly regulated steps in NAD+ metabolism. PMID:19846558

Identification of Isn1 and Sdt1 as glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid mononucleotide [corrected] 5'-nucleotidases responsible for production of nicotinamide riboside and nicotinic acid riboside.

PubMed

Bogan, Katrina L; Evans, Charles; Belenky, Peter; Song, Peng; Burant, Charles F; Kennedy, Robert; Brenner, Charles

2009-12-11

Recently, we discovered that nicotinamide riboside and nicotinic acid riboside are biosynthetic precursors of NAD(+), which are utilized through two pathways consisting of distinct enzymes. In addition, we have shown that exogenously supplied nicotinamide riboside is imported into yeast cells by a dedicated transporter, and it extends replicative lifespan on high glucose medium. Here, we show that nicotinamide riboside and nicotinic acid riboside are authentic intracellular metabolites in yeast. Secreted nicotinamide riboside was detected with a biological assay, and intracellular levels of nicotinamide riboside, nicotinic acid riboside, and other NAD(+) metabolites were determined by a liquid chromatography-mass spectrometry method. A biochemical genomic screen indicated that three yeast enzymes possess nicotinamide mononucleotide 5'-nucleotidase activity in vitro. Metabolic profiling of knock-out mutants established that Isn1 and Sdt1 are responsible for production of nicotinamide riboside and nicotinic acid riboside in cells. Isn1, initially classified as an IMP-specific 5'-nucleotidase, and Sdt1, initially classified as a pyrimidine 5'-nucleotidase, are additionally responsible for dephosphorylation of pyridine mononucleotides. Sdt1 overexpression is growth-inhibitory to cells in a manner that depends on its active site and correlates with reduced cellular NAD(+). Expression of Isn1 protein is positively regulated by the availability of nicotinic acid and glucose. These results reveal unanticipated and highly regulated steps in NAD(+) metabolism.

40 CFR 721.1577 - 1,4-Benzenedicarboxylic acid, bis [4-(ethenyloxy) butyl] ester.

Code of Federal Regulations, 2011 CFR

2011-07-01

...-(ethenyloxy) butyl] ester. 721.1577 Section 721.1577 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1577 1,4-Benzenedicarboxylic acid, bis [4-(ethenyloxy) butyl] ester. (a... 1,4-benzenedicarboxylic acid, bis[4-(ethenyloxy) butyl] ester (PMN P-98-1163; CAS No. 117397-31-6...

40 CFR 721.1577 - 1,4-Benzenedicarboxylic acid, bis [4-(ethenyloxy) butyl] ester.

Code of Federal Regulations, 2010 CFR

2010-07-01

...-(ethenyloxy) butyl] ester. 721.1577 Section 721.1577 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1577 1,4-Benzenedicarboxylic acid, bis [4-(ethenyloxy) butyl] ester. (a... 1,4-benzenedicarboxylic acid, bis[4-(ethenyloxy) butyl] ester (PMN P-98-1163; CAS No. 117397-31-6...

40 CFR 721.10057 - Dodecanedioic acid, 1, 12-dihydrazide.

Code of Federal Regulations, 2010 CFR

2010-07-01

... significant new uses subject to reporting. (1) The chemical substance identified as dodecanedioic acid, 1, 12-dihydrazide (PMNs P-01-759 and P-05-555; CAS No. 4080-98-2) is subject to reporting under this section for the... respirators meet the minimum requirement for § 721.63(a)(4): Air-purifying, tight-fitting full-face respirator...

Folic acid protects against arsenic-mediated embryo toxicity by up-regulating the expression of Dvr1

PubMed Central

Ma, Yan; Zhang, Chen; Gao, Xiao-Bo; Luo, Hai-Yan; Chen, Yang; Li, Hui-hua; Ma, Xu; Lu, Cai-Ling

2015-01-01

As a nutritional factor, folic acid can prevent cardiac and neural defects during embryo development. Our previous study showed that arsenic impairs embryo development by down-regulating Dvr1/GDF1 expression in zebrafish. Here, we investigated whether folic acid could protect against arsenic-mediated embryo toxicity. We found that folic acid supplementation increases hatching and survival rates, decreases malformation rate and ameliorates abnormal cardiac and neural development of zebrafish embryos exposed to arsenite. Both real-time PCR analysis and whole in-mount hybridization showed that folic acid significantly rescued the decrease in Dvr1 expression caused by arsenite. Subsequently, our data demonstrated that arsenite significantly decreased cell viability and GDF1 mRNA and protein levels in HEK293ET cells, while folic acid reversed these effects. Folic acid attenuated the increase in subcellular reactive oxygen species (ROS) levels and oxidative adaptor p66Shc protein expression in parallel with the changes in GDF1 expression and cell viability. P66Shc knockdown significantly inhibited the production of ROS and the down-regulation of GDF1 induced by arsenite. Our data demonstrated that folic acid supplementation protected against arsenic-mediated embryo toxicity by up-regulating the expression of Dvr1/GDF1, and folic acid enhanced the expression of GDF1 by decreasing p66Shc expression and subcellular ROS levels. PMID:26537450

Inhibition of carboxylesterase activity of THP1 monocytes/macrophages and recombinant human carboxylesterase 1 by oxysterols and fatty acids

PubMed Central

Crow, J. Allen; Herring, Katye L.; Xie, Shuqi; Borazjani, Abdolsamad; Potter, Philip M.; Ross, Matthew K.

2009-01-01

Summary Two major isoforms of human carboxylesterases (CEs) are found in metabolically active tissues, CES1 and CES2. These hydrolytic enzymes are involved in xenobiotic and endobiotic metabolism. CES1 is abundantly expressed in human liver and monocytes/macrophages, including the THP1 cell line; CES2 is expressed in liver but not in monocytes/macrophages. The cholesteryl ester hydrolysis activity in human macrophages has been attributed to CES1. Here, we report the direct inhibitory effects of several endogenous oxysterols and fatty acids on the CE activity of THP1 monocytes/macrophages and recombinant human CES1 and CES2. Using THP1 whole-cell lysates we found: (1) 27-hydroxycholesterol (27-HC) is a potent inhibitor of carboxylesterase activity (IC50=33 nM); (2) 24(S),25-epoxycholesterol had moderate inhibitory activity (IC50=8.1 μM); and (3) cholesterol, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 25-hydroxycholesterol each had little inhibitory activity. 27-HC was a partially noncompetitive inhibitor of recombinant CES1 (Kiapp=10 nM) and impaired intracellular CES1 activity following treatment of intact THP1 cells. In contrast, recombinant CES2 activity was not inhibited by 27-HC, suggesting isoform-selective inhibition by 27-HC. Furthermore, unsaturated fatty acids were better inhibitors of CES1 activity than saturated fatty acids, while CES2 activity was unaffected by any fatty acid. Arachidonic acid (AA) was the most potent fatty acid inhibitor of recombinant CES1 and acted by a noncompetitive mechanism (Kiapp=1.7 μM); when not complexed to albumin, exogenous AA penetrated intact THP1 cells and inhibited CES1. Inhibition results are discussed in light of recent structural models for CES1 that describe ligand binding sites separate from the active site. In addition, oxysterol-mediated inhibition of CES1 activity was demonstrated by pretreatment of human liver homogenates or intact THP1 cells with exogenous 27-HC, which

[Improvement of acetic acid tolerance and fermentation performance of industrial Saccharomyces cerevisiae by overexpression of flocculent gene FLO1 and FLO1c].

PubMed

Du, Zhaoli; Cheng, Yanfei; Zhu, Hui; He, Xiuping; Zhang, Borun

2015-02-01

Flocculent gene FLO1 and its truncated form FLO1c with complete deletion of repeat unit C were expressed in a non-flocculent industrial strain Saccharomyces cerevisiae CE6 to generate recombinant flocculent strains 6-AF1 and 6-AF1c respectively. Both strains of 6-AF1 and 6-AF1c displayed strong flocculation and better cell growth than the control strain CE6-V carrying the empty vector under acetic acid stress. Moreover, the flocculent strains converted glucose to ethanol at much higher rates than the control strain CE6-V under acetic acid stress. In the presence of 0.6% (V/V) acetic acid, the average ethanol production rates of 6-AF1 and 6-AF1c were 1.56 and 1.62 times of that of strain CE6-V, while the ethanol production rates of 6-AF1 and 6-AF1c were 1.21 and 1.78 times of that of strain CE6-V under 1.0% acetic acid stress. Results in this study indicate that acetic acid tolerance and fermentation performance of industrial S. cerevisiae under acetic acid stress can be improved largely by flocculation endowed by expression of flocculent genes, especially FLO1c.

6-Methyl-1,2,4-benzenetriol, a new intermediate in penicillic acid biosynthesis in Penicillium cyclopium

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

Sekiguchi, J.; Katayama, S.; Yamada, Y.

1987-07-01

Penicillic acid-negative mutants were obtained from a color mutant derived from Penicillium cyclopium NRRL 1888 through N-methyl-N'-nitro-N-nitrosoguanidine treatment. One mutant (SK2N6) accumulated 6-methyl-1,2,4-benzenetriol, which was not previously known to be a metabolite of P. cyclopium, in addition to orsellinic acid and orcinol. The radioactivity of (1-/sup 14/C)acetic acid was rapidly incorporated into 6-methyl-1,2,4-benzenetriol in a culture of P. cyclopium SK2N6. Moreover, the radioactivity of (/sup 14/C)6-methyl-1,2,4-benzenetriol was efficiently incorporated into penicillic acid in a culture of P. cyclopium NRRL 1888. These data indicate that 6-methyl-1,2,4-benzenetriol is a precursor for penicillic acid biosynthesis. The results on the addition of 1,4-dihydroxy-6-methoxy-2-methylbenzene, 6-methoxy-2-methylbenzoquinonemore » (1,4), and 1-O-methylorcinol to a culture of P. cyclopium SK2N6 indicated that only the former two compounds are converted to penicillic acid. Thus, a new portion of the penicillic acid biosynthetic pathway is proposed.« less

1-Aminocyclopropane-1-carboxylic acid oxidase reaction mechanism and putative post-translational activities of the ACCO protein

PubMed Central

Dilley, David R.; Wang, Zhenyong; Kadirjan-Kalbach, Deena K.; Ververidis, Fillipos; Beaudry, Randolph; Padmanabhan, Kallaithe

2013-01-01

1-Aminocyclopropane-1-carboxylic acid (ACC) oxidase (ACCO) catalyses the final step in ethylene biosynthesis converting ACC to ethylene, cyanide, CO2, dehydroascorbate and water with inputs of Fe(II), ascorbate, bicarbonate (as activators) and oxygen. Cyanide activates ACCO. A ‘nest’ comprising several positively charged amino acid residues from the C-terminal α-helix 11 along with Lys158 and Arg299 are proposed as binding sites for ascorbate and bicarbonate to coordinately activate the ACCO reaction. The binding sites for ACC, bicarbonate and ascorbic acid for Malus domestica ACCO1 include Arg175, Arg244, Ser246, Lys158, Lys292, Arg299 and Phe300. Glutamate 297, Phe300 and Glu301 in α-helix 11 are also important for the ACCO reaction. Our proposed reaction pathway incorporates cyanide as an ACCO/Fe(II) ligand after reaction turnover. The cyanide ligand is likely displaced upon binding of ACC and ascorbate to provide a binding site for oxygen. We propose that ACCO may be involved in the ethylene signal transduction pathway not directly linked to the ACCO reaction. ACC oxidase has significant homology with Lycopersicon esculentum cysteine protease LeCp, which functions as a protease and as a regulator of 1-aminocyclopropane-1-carboxylic acid synthase (Acs2) gene expression. ACC oxidase may play a similar role in signal transduction after post-translational processing. ACC oxidase becomes inactivated by fragmentation and apparently has intrinsic protease and transpeptidase activity. ACC oxidase contains several amino acid sequence motifs for putative protein–protein interactions, phosphokinases and cysteine protease. ACC oxidase is subject to autophosphorylaton in vitro and promotes phosphorylation of some apple fruit proteins in a ripening-dependent manner. PMID:24244837

Effectiveness of malic acid 1% in patients with xerostomia induced by antihypertensive drugs

PubMed Central

Guardia, Javier; Aguilar-Salvatierra, Antonio; Cabrera-Ayala, Maribel; Maté-Sánchez de-Val, José E.; Calvo-Guirado, José L.

2013-01-01

Objectives: Assessing the clinical effectiveness of a topical sialogogue on spray (malic acid, 1%) in the treatment of xerostomia induced by antihypertensive drugs. Study Design: This research has been carried out through a randomized double-blind clinical trial. 45 patients suffering from hypertensive drugs-induced xerostomia were divided into 2 groups: the first group (25 patients) received a topical sialogogue on spray (malic acid, 1%) whereas the second group (20 patients) received a placebo. Both of them were administered on demand for 2 weeks. Dry Mouth Questionnaire (DMQ) was used in order to evaluate xerostomia levels before and after product/placebo application. Unstimulated and stimulated salivary flows rates, before and after application, were measured. All the statistical analyses were performed by using SPSS software v17.0. Different DMQ scores at the earliest and final stage of the trial were analysed by using Mann-Whitney U test, whereas Student’s T-test was used to analyse salivary flows. Critical p-value was established at p<0.05. Results: DMQ scores increased significantly (clinical recovery) from 1.21 to 3.36 points (p<0.05) after malic acid (1%) application whereas DMQ scores increased from 1.18 to 1.34 points (p>0.05) after placebo application. After two weeks of treatment with malic acid, unstimulated salivary flow increased from 0.17 to 0.242 mL/min whereas the stimulated one increased from 0.66 to 0.92 mL/min (p<0.05). After placebo application unstimulated flow ranged from 0.152 to 0.146 mL/min and stimulated flow increased from 0.67 to 0.70 mL/min (p>0.05). Conclusions: Malic acid 1% spray improved antihypertensive-induced xerostomia and stimulated the production of saliva. Key words:Xerostomia, hyposialia, malic acid, antihypertensive drugs. PMID:22926481

40 CFR 721.10370 - Phosphonic acid, p-octyl-, lanthanum (3+) salt (2:1).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphonic acid, p-octyl-, lanthanum... New Uses for Specific Chemical Substances § 721.10370 Phosphonic acid, p-octyl-, lanthanum (3+) salt... substance identified as phosphinic acid, p-octyl-, lanthanum (3+) salt (2:1) (PMN P-10-99; CAS No. 1186211...

40 CFR 721.10370 - Phosphonic acid, p-octyl-, lanthanum (3+) salt (2:1).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphonic acid, p-octyl-, lanthanum... New Uses for Specific Chemical Substances § 721.10370 Phosphonic acid, p-octyl-, lanthanum (3+) salt... substance identified as phosphinic acid, p-octyl-, lanthanum (3+) salt (2:1) (PMN P-10-99; CAS No. 1186211...

40 CFR 721.10370 - Phosphonic acid, p-octyl-, lanthanum (3+) salt (2:1).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphonic acid, p-octyl-, lanthanum... New Uses for Specific Chemical Substances § 721.10370 Phosphonic acid, p-octyl-, lanthanum (3+) salt... substance identified as phosphinic acid, p-octyl-, lanthanum (3+) salt (2:1) (PMN P-10-99; CAS No. 1186211...

Deletion of JJJ1 improves acetic acid tolerance and bioethanol fermentation performance of Saccharomyces cerevisiae strains.

PubMed

Wu, Xuechang; Zhang, Lijie; Jin, Xinna; Fang, Yahong; Zhang, Ke; Qi, Lei; Zheng, Daoqiong

2016-07-01

To improve tolerance to acetic acid that is present in lignocellulosic hydrolysates and affects bioethanol production by Saccharomyces cerevisiae. Saccharomyces cerevisiae strains with improved tolerance to acetic acid were obtained through deletion of the JJJ1 gene. The lag phase of the JJJ1 deletion mutant BYΔJJJ1 was ~16 h shorter than that of the parent strain, BY4741, when the fermentation medium contained 4.5 g acetic acid/l. Additionally, the specific ethanol production rate of BYΔJJJ1 was increased (0.057 g/g h) compared to that of the parent strain (0.051 g/g h). Comparative transcription and physiological analyses revealed higher long chain fatty acid, trehalose, and catalase contents might be critical factors responsible for the acetic acid resistance of JJJ1 knockout strains. JJJ1 deletion improves acetic acid tolerance and ethanol fermentation performance of S. cerevisiae.

Characterization of Avt1p as a vacuolar proton/amino acid antiporter in Saccharomyces cerevisiae.

PubMed

Tone, Junichi; Yoshimura, Ayumi; Manabe, Kunio; Murao, Nami; Sekito, Takayuki; Kawano-Kawada, Miyuki; Kakinuma, Yoshimi

2015-01-01

Several genes for vacuolar amino acid transport were reported in Saccharomyces cerevisiae, but have not well been investigated. We characterized AVT1, a member of the AVT vacuolar transporter family, which is reported to be involved in lifespan of yeast. ATP-dependent uptake of isoleucine and histidine by the vacuolar vesicles of an AVT exporter mutant was lost by introducing avt1∆ mutation. Uptake activity was inhibited by the V-ATPase inhibitor: concanamycin A and a protonophore. Isoleucine uptake was inhibited by various neutral amino acids and histidine, but not by γ-aminobutyric acid, glutamate, and aspartate. V-ATPase-dependent acidification of the vesicles was declined by the addition of isoleucine or histidine, depending upon Avt1p. Taken together with the data of the amino acid contents of vacuolar fractions in cells, the results suggested that Avt1p is a proton/amino acid antiporter important for vacuolar compartmentalization of various amino acids.

Fatty acid biosynthesis pathways in Methylomicrobium buryatense 5G(B1)

DOE PAGES

Demidenko, Aleksandr; Akberdin, Ilya R.; Allemann, Marco; ...

2017-01-10

Methane utilization by methanotrophic bacteria is an attractive application for biotechnological conversion of natural or biogas into high-added-value products. Haloalcaliphilic methanotrophic bacteria belonging to the genus Methylomicrobium are among the most promising strains for methane-based biotechnology, providing easy and inexpensive cultivation, rapid growth, and the availability of established genetic tools. A number of methane bioconversions using these microbial cultures have been discussed, including the derivation of biodiesel, alkanes, and OMEGA-3 supplements. These compounds are derived from bacterial fatty acid pools. Here, we investigate fatty acid biosynthesis in Methylomicrobium buryatense 5G(B1). Most of the genes homologous to typical Type II fattymore » acid biosynthesis pathways could be annotated by bioinformatics analyses, with the exception of FA transport and regulatory elements. Different approaches for improving fatty acid accumulation were investigated. These studies indicated that both fatty acid degradation and acetyl- and malonyl-CoA levels are bottlenecks for higher level fatty acid production. The best strain generated in this study synthesizes 111 ± 2 mg/gDCW of extractable fatty acids, which is ~20% more than the original strain. A candidate gene for FA-biosynthesis regulation, farE, was identified and studied. Its deletion resulted in drastic changes to the FA profile, leading to an increased pool of C18-fatty acid methyl ester. The FarE-regulon was further investigated by RNA-seq analysis of gene expression in farE-knockout mutants and farE-overexpressing strains. These gene profiles highlighted a novel set of enzymes and regulators involved in fatty acid biosynthesis. As a result, the gene expression and fatty acid profiles of the different farE-strains support the hypothesis that metabolic fluxes upstream of fatty acid biosynthesis restrict fatty acid production in the methanotroph.« less

Fatty acid biosynthesis pathways in Methylomicrobium buryatense 5G(B1)

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

Demidenko, Aleksandr; Akberdin, Ilya R.; Allemann, Marco

Methane utilization by methanotrophic bacteria is an attractive application for biotechnological conversion of natural or biogas into high-added-value products. Haloalcaliphilic methanotrophic bacteria belonging to the genus Methylomicrobium are among the most promising strains for methane-based biotechnology, providing easy and inexpensive cultivation, rapid growth, and the availability of established genetic tools. A number of methane bioconversions using these microbial cultures have been discussed, including the derivation of biodiesel, alkanes, and OMEGA-3 supplements. These compounds are derived from bacterial fatty acid pools. Here, we investigate fatty acid biosynthesis in Methylomicrobium buryatense 5G(B1). Most of the genes homologous to typical Type II fattymore » acid biosynthesis pathways could be annotated by bioinformatics analyses, with the exception of FA transport and regulatory elements. Different approaches for improving fatty acid accumulation were investigated. These studies indicated that both fatty acid degradation and acetyl- and malonyl-CoA levels are bottlenecks for higher level fatty acid production. The best strain generated in this study synthesizes 111 ± 2 mg/gDCW of extractable fatty acids, which is ~20% more than the original strain. A candidate gene for FA-biosynthesis regulation, farE, was identified and studied. Its deletion resulted in drastic changes to the FA profile, leading to an increased pool of C18-fatty acid methyl ester. The FarE-regulon was further investigated by RNA-seq analysis of gene expression in farE-knockout mutants and farE-overexpressing strains. These gene profiles highlighted a novel set of enzymes and regulators involved in fatty acid biosynthesis. As a result, the gene expression and fatty acid profiles of the different farE-strains support the hypothesis that metabolic fluxes upstream of fatty acid biosynthesis restrict fatty acid production in the methanotroph.« less

Terson syndrome in aneurysmal subarachnoid hemorrhage-its relation to intracranial pressure, admission factors, and clinical outcome.

PubMed

Joswig, Holger; Epprecht, Lorenz; Valmaggia, Christophe; Leschka, Sebastian; Hildebrandt, Gerhard; Fournier, Jean-Yves; Stienen, Martin Nikolaus

2016-06-01

A large number of reports have not been able to clarify the pathophysiology of Terson syndrome (TS) in aneurysmal subarachnoid hemorrhage (aSAH). Prospective single-center study on aSAH patients. Fundoscopic and radiological signs of TS were assessed. The opening intracranial pressure (ICP) in patients who required a ventriculostomy was recorded with a manometer. Six out of 36 included patients had TS (16.7 %), which was associated with unfavorable admission scores. Twenty-nine patients (80.5 %) required ventriculostomy; TS was associated with higher ICP (median, 40 vs. 15 cm cmH2O, p = .003); all patients with TS had pathological ICP values of >20 cmH2O. Patients with a ruptured aneurysm of the anterior cerebral artery complex were ten times as likely to suffer from TS (OR 10.0, 95 % CI 1.03-97.50). Detection of TS on CT had a sensitivity of 50 %, a specificity of 98.4 %, a positive predictive value of 83.3 %, and a negative predictive value of 92.4 %. Mortality was 45 times as high in patients with TS (OR 45.0, 95 % CI 3.86-524.7) and neurologic morbidity up until 3 months post-aSAH was significantly higher in patients with TS (mRS 4-6; 100 vs. 17 %; p = .001). Our findings demonstrate an association between raised ICP and the incidence of TS. TS should be ruled out in aSAH patients presenting comatose or with raised ICP to ensure upfront ophthalmological follow-up. In alert patients without visual complaints and a TS-negative CT scan, the likelihood for the presence of TS is very low.

Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids.

PubMed

Shabalina, Irina G; Jacobsson, Anders; Cannon, Barbara; Nedergaard, Jan

2004-09-10

Elucidation of the regulation of uncoupling protein 1 (UCP1) activity in its native environment, i.e. the inner membrane of brown-fat mitochondria, has been hampered by the presence of UCP1-independent, quantitatively unresolved effects of investigated regulators on the brown-fat mitochondria themselves. Here we have utilized the availability of UCP1-ablated mice to dissect UCP1-dependent and UCP1-independent effects of regulators. Using a complex-I-linked substrate (pyruvate), we found that UCP1 can mediate a 4-fold increase in thermogenesis when stimulated with the classical positive regulator fatty acids (oleate). After demonstrating that the fatty acids act in their free form, we found that UCP1 increased fatty acid sensitivity approximately 30-fold (as compared with the 1.5-fold increase reported earlier based on nominal fatty acid values). By identifying the UCP1-mediated fraction of the response, we could conclude that the interaction between purine nucleotides (GDP) and fatty acids (oleate) unexpectedly displayed simple competitive kinetics. In GDP-inhibited mitochondria, oleate apparently acted as an activator. However, only a model in which UCP1 is inherently active (i.e."activating" fatty acids cannot be included in the model), where GDP functions as an inhibitor with a K(m) of 0.05 mm, and where oleate functions as a competitive antagonist for the GDP effect (with a K(i) of 5 nm) can fit all of the experimental data. We conclude that, when examined in its native environment, UCP1 functions as a proton (equivalent) carrier in the absence of exogenous or endogenous fatty acids.

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

PubMed Central

Tian, Tian; Bai, Dong; Li, Wen; Huang, Guo-Wei; Liu, Huan

2016-01-01

Alzheimer’s disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase. Herein, we demonstrated that folic acid reduced the deposition of Aβ42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of β-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and γ-secretase complex catalytic component—presenilin 1 (PS1)—in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important α-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of γ-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Aβ deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing β-secretase and increasing α-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression. PMID:27618097

Reactivation of latent HIV-1 by a wide variety of butyric acid-producing bacteria.

PubMed

Imai, Kenichi; Yamada, Kiyoshi; Tamura, Muneaki; Ochiai, Kuniyasu; Okamoto, Takashi

2012-08-01

Latently infected cells harbor human immunodeficiency virus type 1 (HIV-1) proviral DNA copies integrated in heterochromatin, allowing persistence of transcriptionally silent proviruses. It is widely accepted that hypoacetylation of histone proteins by histone deacetylases (HDACs) is involved in maintaining the HIV-1 latency by repressing viral transcription. HIV-1 replication can be induced from latently infected cells by environmental factors, such as inflammation and co-infection with other microbes. It is known that a bacterial metabolite butyric acid inhibits catalytic action of HDAC and induces transcription of silenced genes including HIV-1 provirus. There are a number of such bacteria in gut, vaginal, and oral cavities that produce butyric acid during their anaerobic glycolysis. Since these organs are known to be the major site of HIV-1 transmission and its replication, we explored a possibility that explosive viral replication in these organs could be ascribable to butyric acid produced from anaerobic resident bacteria. In this study, we demonstrate that the culture supernatant of various bacteria producing butyric acid could greatly reactivate the latently-infected HIV-1. These bacteria include Fusobacterium nucleatum (commonly present in oral cavity, and gut), Clostridium cochlearium, Eubacterium multiforme (gut), and Anaerococcus tetradius (vagina). We also clarified that butyric acid in these culture supernatants could induce histone acetylation and HIV-1 replication by inhibiting HDAC. Our observations indicate that butyric acid-producing bacteria could be involved in AIDS progression by reactivating the latent HIV provirus and, subsequently, by eliminating such bacterial infection may contribute to the prevention of the AIDS development and transmission.

Mutant alleles of FAD2-1A and FAD2-1B combine to produce soybeans with the high oleic acid seed oil trait

PubMed Central

2010-01-01

Background The alteration of fatty acid profiles in soybean [Glycine max (L.) Merr.] to improve soybean oil quality is an important and evolving theme in soybean research to meet nutritional needs and industrial criteria in the modern market. Soybean oil with elevated oleic acid is desirable because this monounsaturated fatty acid improves the nutrition and oxidative stability of the oil. Commodity soybean oil typically contains 20% oleic acid and the target for high oleic acid soybean oil is approximately 80% of the oil; previous conventional plant breeding research to raise the oleic acid level to just 50-60% of the oil was hindered by the genetic complexity and environmental instability of the trait. The objective of this work was to create the high oleic acid trait in soybeans by identifying and combining mutations in two delta-twelve fatty acid desaturase genes, FAD2-1A and FAD2-1B. Results Three polymorphisms found in the FAD2-1B alleles of two soybean lines resulted in missense mutations. For each of the two soybean lines, there was one unique amino acid change within a highly conserved region of the protein. The mutant FAD2-1B alleles were associated with an increase in oleic acid levels, although the FAD2-1B mutant alleles alone were not capable of producing a high oleic acid phenotype. When existing FAD2-1A mutations were combined with the novel mutant FAD2-1B alleles, a high oleic acid phenotype was recovered only for those lines which were homozygous for both of the mutant alleles. Conclusions We were able to produce conventional soybean lines with 80% oleic acid in the oil in two different ways, each requiring the contribution of only two genes. The high oleic acid soybean germplasm developed contained a desirable fatty acid profile, and it was stable in two production environments. The presumed causative sequence polymorphisms in the FAD2-1B alleles were developed into highly efficient molecular markers for tracking the mutant alleles. The resources

Mutant alleles of FAD2-1A and FAD2-1B combine to produce soybeans with the high oleic acid seed oil trait.

PubMed

Pham, Anh-Tung; Lee, Jeong-Dong; Shannon, J Grover; Bilyeu, Kristin D

2010-09-09

The alteration of fatty acid profiles in soybean [Glycine max (L.) Merr.] to improve soybean oil quality is an important and evolving theme in soybean research to meet nutritional needs and industrial criteria in the modern market. Soybean oil with elevated oleic acid is desirable because this monounsaturated fatty acid improves the nutrition and oxidative stability of the oil. Commodity soybean oil typically contains 20% oleic acid and the target for high oleic acid soybean oil is approximately 80% of the oil; previous conventional plant breeding research to raise the oleic acid level to just 50-60% of the oil was hindered by the genetic complexity and environmental instability of the trait. The objective of this work was to create the high oleic acid trait in soybeans by identifying and combining mutations in two delta-twelve fatty acid desaturase genes, FAD2-1A and FAD2-1B. Three polymorphisms found in the FAD2-1B alleles of two soybean lines resulted in missense mutations. For each of the two soybean lines, there was one unique amino acid change within a highly conserved region of the protein. The mutant FAD2-1B alleles were associated with an increase in oleic acid levels, although the FAD2-1B mutant alleles alone were not capable of producing a high oleic acid phenotype. When existing FAD2-1A mutations were combined with the novel mutant FAD2-1B alleles, a high oleic acid phenotype was recovered only for those lines which were homozygous for both of the mutant alleles. We were able to produce conventional soybean lines with 80% oleic acid in the oil in two different ways, each requiring the contribution of only two genes. The high oleic acid soybean germplasm developed contained a desirable fatty acid profile, and it was stable in two production environments. The presumed causative sequence polymorphisms in the FAD2-1B alleles were developed into highly efficient molecular markers for tracking the mutant alleles. The resources described here for the creation

STATE ACID RAIN RESEARCH AND SCREENING SYSTEM - VERSION 1.0 USER'S MANUAL

EPA Science Inventory

The report is a user's manual that describes Version 1.0 of EPA's STate Acid Rain Research and Screening System (STARRSS), developed to assist utility regulatory commissions in reviewing utility acid rain compliance plans. It is a screening tool that is based on scenario analysis...

Resistin Regulates Fatty Acid Β Oxidation by Suppressing Expression of Peroxisome Proliferator Activator Receptor Gamma-Coactivator 1α (PGC-1α).

PubMed

He, Fang; Jin, Jie-Qiong; Qin, Qing-Qing; Zheng, Yong-Qin; Li, Ting-Ting; Zhang, Yun; He, Jun-Dong

2018-01-01

Abnormal fatty acid β oxidation has been associated with obesity and type 2 diabetes. Resistin is an adipokine that has been considered as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. However, the effect of resistin on fatty acid β oxidation needs to be elucidated. We detected the effects of resistin on the expression of fatty acid oxidation (FAO) transcriptional regulatory genes, the fatty acid transport gene, and mitochondrial β-oxidation genes using real-time PCR. The rate of FAO was measured using 14C-palmitate. Immunofluorescence assay and western blot analysis were used to explore the underlying molecular mechanisms. Resistin leads to a reduction in expression of the FAO transcriptional regulatory genes ERRα and NOR1, the fatty acid transport gene CD36, and the mitochondrial β-oxidation genes CPT1, MCAD, and ACO. Importantly, treatment with resistin led to a reduction in the rate of cellular fatty acid oxidation. In addition, treatment with resistin reduced phosphorylation of acetyl CoA carboxylase (ACC) (inhibitory). Mechanistically, resistin inhibited the activation of CREB, resulting in suppression of PGC-1α. Importantly, overexpressing PGC-1α can rescue the inhibitory effects of resistin on fatty acid β oxidation. Activating the transcriptional activity of CREB using small molecular chemicals is a potential pharmacological strategy for preventing the inhibitory effects of resistin on fatty acid β oxidation. © 2018 The Author(s). Published by S. Karger AG, Basel.

Phosphatidic acid inhibits ceramide 1-phosphate-stimulated macrophage migration.

PubMed

Ouro, Alberto; Arana, Lide; Rivera, Io-Guané; Ordoñez, Marta; Gomez-Larrauri, Ana; Presa, Natalia; Simón, Jorge; Trueba, Miguel; Gangoiti, Patricia; Bittman, Robert; Gomez-Muñoz, Antonio

2014-12-15

Ceramide 1-phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis. Copyright © 2014 Elsevier Inc. All rights reserved.

Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants.

PubMed

Dang, Zhao; Qian, Keduo; Ho, Phong; Zhu, Lei; Lee, Kuo-Hsiung; Huang, Li; Chen, Chin-Ho

2012-08-15

Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D. Copyright © 2012 Elsevier Ltd. All rights reserved.

ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis.

PubMed

Weber, Thomas J; Magnaldo, Thierry; Xiong, Yijia

2014-09-11

We hypothesize that aldehyde dehydrogenase 1A1 (ALDH1A1) deficiency will result in impaired ataxia-telangiectasia mutated (ATM) activation in a retinoic acid-sensitive fashion. Data supporting this hypothesis include (1) reduced ATM activation in irradiated primary dermal fibroblasts from ALDH1A1-deficient Gorlin syndrome patients (GDFs), relative to ALDH1A1-positive normal human dermal fibroblasts (NHDFs) and (2) increased ATM activation by X-radiation in GDFs pretreated with retinoic acid, however, the impact of donor variability on ATM activation in fibroblasts was not assessed and is a prudent consideration in future studies. Clonogenic survival of irradiated cells showed differential responses to retinoic acid as a function of treatment time. Long-term (5 Day) retinoic acid treatment functioned as a radiosensitizer and was associated with downregulation of ATM protein levels. Short-term (7 h) retinoic acid treatment showed a trend toward increased survival of irradiated cells and did not downregulate ATM protein levels. Using a newly developed IncubATR technology, which defines changes in bulk chemical bond patterns in live cells, we can discriminate between the NHDF and GDF phenotypes, but treatment of GDFs with retinoic acid does not induce reversion of bulk chemical bond patterns associated with GDFs toward the NHDF phenotype. Collectively, our preliminary investigation of the Gorlin phenotype has identified deficient ALDH1A1 expression associated with deficient ATM activation as a possible susceptibility factor that is consistent with the high incidence of spontaneous and radiation-induced carcinogenesis in these patients. The IncubATR technology exhibits sufficient sensitivity to detect phenotypic differences in live cells that may be relevant to radiation health effects.

40 CFR 180.155 - 1-Naphthaleneacetic acid; tolerances for residues.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific... established for the combined residues of the plant growth regulator 1-naphthaleneacetic acid and its...

40 CFR 180.155 - 1-Naphthaleneacetic acid; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific... established for the combined residues of the plant growth regulator 1-naphthaleneacetic acid and its...

Milk fatty acid unsaturation: genetic parameters and effects of stearoyl-CoA desaturase (SCD1) and acyl CoA: diacylglycerol acyltransferase 1 (DGAT1).

PubMed

Schennink, A; Heck, J M L; Bovenhuis, H; Visker, M H P W; van Valenberg, H J F; van Arendonk, J A M

2008-05-01

With regard to human health aspects of milk fat, increasing the amount of unsaturated fatty acids in milk is an important selection objective. The cow's diet has an influence on the degree of unsaturation, but literature suggests that genetics also plays a role. To estimate genetic variation in milk fatty acid unsaturation indices, milk fatty acid composition of 1,933 Dutch Holstein Friesian heifers was measured and unsaturation indices were calculated. An unsaturation index represents the concentration of the unsaturated product proportional to the sum of the unsaturated product and the saturated substrate. Intraherd heritabilities were moderate, ranging from 0.23 +/- 0.07 for conjugated linoleic acid (CLA) index to 0.46 +/- 0.09 for C16 index. We genotyped the cows for the SCD1 A293V and DGAT1 K232A polymorphisms, which are known to alter milk fatty acid composition. Both genes explain part of the genetic variation in unsaturation indices. The SCD1 V allele is associated with lower C10, C12, and C14 indices, and with higher C16, C18, and CLA indices in comparison to the SCD1 A allele, with no differences in total unsaturation index. In comparison to the DGAT1 K allele, the DGAT1 A allele is associated with lower C10, C12, C14, and C16 indices and with higher C18, CLA, and total indices. We conclude that selective breeding can contribute to higher unsaturation indices, and that selective breeding can capitalize on genotypic information of both the SCD1 A293V and the DGAT1 K232A polymorphism.

Effect of 1,4-cyclohexanediol on percutaneous absorption and penetration of azelaic acid.

PubMed

Li, Nan; Su, Qian; Tan, Fengping; Zhang, Jerry

2010-03-15

The objective of this study is to investigate the effect of 1,4-cyclohexanediol as a retardant on the percutaneous absorption and penetration of azelaic acid. Hairless rat skin was mounted on Franz diffusion cells and treated with topical formulations containing solubilized azelaic acid with and without 1,4-cyclohexanediol. The skin was separated into stratum corneum and the deeper skin layers. The azelaic acid collected in receptor medium and each layer at the end of each time point was extracted and quantified. A significant decrease in flux across the skin suggests a penetration retardation effect of 1,4-cyclohexanediol (42.50 microg/cm(2)/h in the presence of vs. 76.25 microg/cm(2)/h in the absence of) at active loading level of 1.13 mg/cm(2). The penetration retardation effect was also observed at higher active loading level (2.82 mg/cm(2)). Furthermore, presence of 1,4-cyclohexanediol in the topical formulation did not reduce the skin and epidermal retention of azelaic acid, suggesting its potential use in the development of superior topical formation for reducing potential systematic side effect while maintaining therapeutic efficiency. 2009 Elsevier B.V. All rights reserved.

Terminal sialic acid linkages determine different cell infectivities of human parainfluenza virus type 1 and type 3.

PubMed

Fukushima, Keijo; Takahashi, Tadanobu; Ito, Seigo; Takaguchi, Masahiro; Takano, Maiko; Kurebayashi, Yuuki; Oishi, Kenta; Minami, Akira; Kato, Tatsuya; Park, Enoch Y; Nishimura, Hidekazu; Takimoto, Toru; Suzuki, Takashi

2014-09-01

Human parainfluenza virus type 1 (hPIV1) and type 3 (hPIV3) initiate infection by sialic acid binding. Here, we investigated sialic acid linkage specificities for binding and infection of hPIV1 and hPIV3 by using sialic acid linkage-modified cells treated with sialidases or sialyltransferases. The hPIV1 is bound to only α2,3-linked sialic acid residues, whereas hPIV3 is bound to α2,6-linked sialic acid residues in addition to α2,3-linked sialic acid residues in human red blood cells. α2,3 linkage-specific sialidase treatment of LLC-MK2 cells and A549 cells decreased the infectivity of hPIV1 but not that of hPIV3. Treatment of A549 cells with α2,3 linkage-specific sialyltransferase increased infectivities of both hPIV1 and hPIV3, whereas α2,6 linkage-specific sialyltransferase treatment increased only hPIV3 infectivity. Clinical isolates also showed similar sialic acid linkage specificities. We concluded that hPIV1 utilizes only α2,3 sialic acid linkages and that hPIV3 makes use of α2,6 sialic acid linkages in addition to α2,3 sialic acid linkages as viral receptors. Copyright © 2014. Published by Elsevier Inc.

Strong-acid, carboxyl-group structures in fulvic acid from the Suwannee River, Georgia. 1. Minor structures

USGS Publications Warehouse

Leenheer, J.A.; Wershaw, R. L.; Reddy, M.M.

1995-01-01

An investigation of the strong-acid characteristics (pKa 3.0 or less) of fulvic acid from the Suwannee River, Georgia, was conducted. Quantitative determinations were made for amino acid and sulfur-containing acid structures, oxalate half-ester structures, malonic acid structures, keto acid structures, and aromatic carboxyl-group structures. These determinations were made by using a variety of spectrometric (13C-nuclear magnetic resonance, infrared, and ultraviolet spectrometry) and titrimetric characterizations on fulvic acid or fulvic acid samples that were chemically derivatized to indicate certain functional groups. Only keto acid and aromatic carboxyl-group structures contributed significantly to the strong-acid characteristics of the fulvic acid; these structures accounted for 43% of the strong-acid acidity. The remaining 57% of the strong acids are aliphatic carboxyl groups in unusual and/or complex configurations for which limited model compound data are available.

Self-perceived health status following aneurysmal subarachnoid haemorrhage: a cohort study

PubMed Central

Quinn, Audrey C; Bhargava, Deepti; Al-Tamimi, Yahia Z; Clark, Matthew J; Ross, Stuart A; Tennant, Alan

2014-01-01

Objective The objective of the study was to assess the long-term self-reported health status and quality of life (QoL) of patients following an aneurysmal subarachnoid haemorrhage (ASAH) using a self-completed questionnaire booklet. Design A two-cohort study. Setting A regional tertiary neurosurgical centre. Participants 2 cohorts of patients with ASAH treated between 1998 and 2008 and followed up at approximately 1 year. Interventions Routine care. Primary and secondary outcomes A range of standardised scales included: AKC Short Sentences Test, the Barthel Index, the Self-Report Dysexecutive Questionnaire, the Everyday Memory Questionnaire, Stroke Symptom Checklist, Wimbledon Self-Report Scale, Modified Rankin Score (MRS) and a new Stroke-QoL. The data from summated scales were fit to the Rasch measurement model to validate the summed score. Results 214 patients (48%) returned the questionnaires; the majority (76%) had a World Federation of Neurosurgeons grade of 1 or 2. The most frequent aneurysm type was that of the anterior communicating artery (28%) with approximately 90% of aneurysms of the anterior circulation. Of those previously in full or part-time employment, 48.9% were unemployed at follow-up. All summated scales satisfied the Rasch measurement model requirements, such that their summed scores were a sufficient statistic. Given this, one-third of patients were noted to have a significant mood disorder and 25% had significant dysexecutive function. Patients with an MRS of 3, 4 or 5 had significantly worse scores on most outcome measures, but a significant minority of those with a score of zero had failed to return to work and displayed significant mood disorder. Conclusions A range of self-reported cognitive and physical deficits have been highlighted in a cohort of patients with ASAH. While the MRS has been shown to provide a reasonable indication of outcome, in routine clinical follow-up it requires supplementation by instruments assessing

Wide Tolerance to Amino Acids Substitutions In The OCTN1 Ergothioneine Transporter

PubMed Central

Frigeni, Marta; Iacobazzi, Francesco; Yin, Xue; Longo, Nicola

2016-01-01

Background Organic cation transporters transfer solutes with a positive charge across the plasma membrane. The novel organic cation transporter 1 (OCTN1) and 2 (OCTN2) transport ergothioneine and carnitine, respectively. Mutations in the SLC22A5 gene encoding OCTN2 cause primary carnitine deficiency, a recessive disorders resulting in low carnitine levels and defective fatty acid oxidation. Variations in the SLC22A4 gene encoding OCTN1 are associated with rheumatoid arthritis and Crohn disease. Methods Here we evaluate the functional properties of the OCTN1 transporter using chimeric transporters constructed by fusing different portion of the OCTN1 and OCTN2 cDNAs. Their relative abundance and subcellular distribution was evaluated through western blot analysis and confocal microscopy. Results Substitutions of the C-terminal portion of OCTN1 with the correspondent residues of OCTN2 generated chimeric OCTN transporters more active than wild-type OCTN1 in transporting ergothioneine. Additional single amino acid substitutions introduced in chimeric OCTN transporters further increased ergothioneine transport activity. Kinetic analysis indicated that increased transport activity was due to an increased Vmax, with modest changes in Km toward ergothioneine. Conclusions Our results indicate that the OCTN1 transporter is tolerant to extensive amino acid substitutions. This is in sharp contrast to the OCTN2 carnitine transporter that has been selected for high functional activity through evolution, with almost all substitutions reducing carnitine transport activity. General significance The widespread tolerance of OCTN1 to amino acid substitutions suggests that the corresponding SLC22A4 gene may have derived from a recent duplication of the SLC22A5 gene and might not yet have a defined physiological role. PMID:26994919

Molecular Characterization of the Elaeis guineensis Medium-Chain Fatty Acid Diacylglycerol Acyltransferase DGAT1-1 by Heterologous Expression in Yarrowia lipolytica.

PubMed

Aymé, Laure; Jolivet, Pascale; Nicaud, Jean-Marc; Chardot, Thierry

2015-01-01

Diacylglycerol acyltransferases (DGAT) are involved in the acylation of sn-1,2-diacylglycerol. Palm kernel oil, extracted from Elaeis guineensis (oil palm) seeds, has a high content of medium-chain fatty acids mainly lauric acid (C12:0). A putative E. guineensis diacylglycerol acyltransferase gene (EgDGAT1-1) is expressed at the onset of lauric acid accumulation in the seed endosperm suggesting that it is a determinant of medium-chain triacylglycerol storage. To test this hypothesis, we thoroughly characterized EgDGAT1-1 activity through functional complementation of a Yarrowia lipolytica mutant strain devoid of neutral lipids. EgDGAT1-1 expression is sufficient to restore triacylglycerol accumulation in neosynthesized lipid droplets. A comparative functional study with Arabidopsis thaliana DGAT1 highlighted contrasting substrate specificities when the recombinant yeast was cultured in lauric acid supplemented medium. The EgDGAT1-1 expressing strain preferentially accumulated medium-chain triacylglycerols whereas AtDGAT1 expression induced long-chain triacylglycerol storage in Y. lipolytica. EgDGAT1-1 localized to the endoplasmic reticulum where TAG biosynthesis takes place. Reestablishing neutral lipid accumulation in the Y. lipolytica mutant strain did not induce major reorganization of the yeast microsomal proteome. Overall, our findings demonstrate that EgDGAT1-1 is an endoplasmic reticulum DGAT with preference for medium-chain fatty acid substrates, in line with its physiological role in palm kernel. The characterized EgDGAT1-1 could be used to promote medium-chain triacylglycerol accumulation in microbial-produced oil for industrial chemicals and cosmetics.

Molecular Characterization of the Elaeis guineensis Medium-Chain Fatty Acid Diacylglycerol Acyltransferase DGAT1-1 by Heterologous Expression in Yarrowia lipolytica

PubMed Central

Aymé, Laure; Jolivet, Pascale; Nicaud, Jean-Marc; Chardot, Thierry

2015-01-01

Diacylglycerol acyltransferases (DGAT) are involved in the acylation of sn-1,2-diacylglycerol. Palm kernel oil, extracted from Elaeis guineensis (oil palm) seeds, has a high content of medium-chain fatty acids mainly lauric acid (C12:0). A putative E. guineensis diacylglycerol acyltransferase gene (EgDGAT1-1) is expressed at the onset of lauric acid accumulation in the seed endosperm suggesting that it is a determinant of medium-chain triacylglycerol storage. To test this hypothesis, we thoroughly characterized EgDGAT1-1 activity through functional complementation of a Yarrowia lipolytica mutant strain devoid of neutral lipids. EgDGAT1-1 expression is sufficient to restore triacylglycerol accumulation in neosynthesized lipid droplets. A comparative functional study with Arabidopsis thaliana DGAT1 highlighted contrasting substrate specificities when the recombinant yeast was cultured in lauric acid supplemented medium. The EgDGAT1-1 expressing strain preferentially accumulated medium-chain triacylglycerols whereas AtDGAT1 expression induced long-chain triacylglycerol storage in Y. lipolytica. EgDGAT1-1 localized to the endoplasmic reticulum where TAG biosynthesis takes place. Reestablishing neutral lipid accumulation in the Y. lipolytica mutant strain did not induce major reorganization of the yeast microsomal proteome. Overall, our findings demonstrate that EgDGAT1-1 is an endoplasmic reticulum DGAT with preference for medium-chain fatty acid substrates, in line with its physiological role in palm kernel. The characterized EgDGAT1-1 could be used to promote medium-chain triacylglycerol accumulation in microbial-produced oil for industrial chemicals and cosmetics. PMID:26581109

Properties of kojic acid and curcumin: Assay on cell B16-F1

NASA Astrophysics Data System (ADS)

Sugiharto, Ariff, Arbakariya; Ahmad, Syahida; Hamid, Muhajir

2016-03-01

Ultra violet (UV) exposure and oxidative stress are casually linked to skin disorders. They can increase melanin synthesis, proliferation of melanocytes, and hyperpigmentation. It is possible that antioxidants or inhibitors may have a beneficial effect on skin health to reduce hyperpigmentation. In the last few years, a huge number of natural herbal extracts have been tested to reduce hyperpigmentation. The objective of this study was to determine and to compare of kojic acid and curcumin properties to viability cell B16-F1. In this study, our data showed that the viability of cell B16-F1 was 63.91% for kojic acid and 64.12% for curcumin at concentration 100 µg/ml. Further investigation assay of antioxidant activities, indicated that IC50 for kojic acid is 63.8 µg/ml and curcumin is 16.05 µg/ml. Based on the data, kojic acid and curcumin have potential antioxidant properties to reduce hyperpigmentation with low toxicity effect in cell B16-F1.

Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay

NASA Astrophysics Data System (ADS)

Hariono, Maywan; Abdullah, Nurshariza; Damodaran, K. V.; Kamarulzaman, Ezatul E.; Mohamed, Nornisah; Hassan, Sharifah Syed; Shamsuddin, Shaharum; Wahab, Habibah A.

2016-12-01

We report the computational and experimental efforts in the design and synthesis of novel neuraminidase (NA) inhibitors from ferulic acid and vanillin. Two proposed ferulic acid analogues, MY7 and MY8 were predicted to inhibit H1N1 NA using molecular docking. From these two analogues, we designed, synthesised and evaluated the biological activities of a series of ferulic acid and vanillin derivatives. The enzymatic H1N1 NA inhibition assay showed MY21 (a vanillin derivative) has the lowest IC50 of 50 μM. In contrast, the virus inhibition assay showed MY15, a ferulic acid derivative has the best activity with the EC50 of ~0.95 μM. Modelling studies further suggest that these predicted activities might be due to the interactions with conserved and essential residues of NA with ΔGbind values comparable to those of oseltamivir and zanamivir, the two commercial NA inhibitors.

Thermokinetic profile of NDM-1 and its inhibition by small carboxylic acids

PubMed Central

Wang, Qian; He, Yuan; Lu, Rui; Wang, Wen-Ming; Yang, Ke-Wu; Fan, Hai Ming; Jin, Yi; Blackburn, G. Michael

2018-01-01

The New Delhi metallo-β-lactamase (NDM-1) is an important clinical target for antimicrobial research, but there are insufficient clinically useful inhibitors and the details of NDM-1 enzyme catalysis remain unclear. The aim of this work is to provide a thermodynamic profile of NDM-1 catalysed hydrolysis of β-lactams using an isothermal titration calorimetry (ITC) approach and to apply this new method to the identification of new low-molecular-weight dicarboxylic acid inhibitors. The results reveal that hydrolysis of penicillin G and imipenem by NDM-1 share the same thermodynamic features with a significant intrinsic enthalpy change and the release of one proton into solution, while NDM-1 hydrolysis of cefazolin exhibits a different mechanism with a smaller enthalpy change and the release of two protons. The inhibitory constants of four carboxylic acids are found to be in the micromolar range. The compounds pyridine-2,6-dicarboxylic acid and thiazolidine-2,4-dicarboxylic acid show the best inhibitory potency and are confirmed to inhibit NDM-1 using a clinical strain of Escherichia coli. The pyridine compound is further shown to restore the susceptibility of this E. coli strain to imipenem, at an inhibitor concentration of 400 μM, while the thiazoline compound also shows a synergistic effect with imipenem. These results provide valuable information to enrich current understanding on the catalytic mechanism of NDM-1 and to aid the future optimisation of β-lactamase inhibitors based on these scaffolds to tackle the problem of antibiotic resistance. PMID:29507059

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection.

PubMed

LoRicco, Josephine G; Xu, Changmingzi Sherry; Neidleman, Jason; Bergkvist, Magnus; Greene, Warner C; Roan, Nadia R; Makhatadze, George I

2016-07-01

Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248-286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86-107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection*

PubMed Central

LoRicco, Josephine G.; Xu, Changmingzi Sherry; Neidleman, Jason; Bergkvist, Magnus; Greene, Warner C.; Roan, Nadia R.; Makhatadze, George I.

2016-01-01

Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248–286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86–107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection. PMID:27226574

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

PubMed Central

Bi, Xinyun; Li, Fanghong; Liu, Shanshan; Jin, Yan; Zhang, Xin; Yang, Tao; Dai, Yifan; Li, Xiaoxi; Zhao, Allan Zijian

2017-01-01

Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, mfat-1, normalized blood glucose and insulin levels for at least 182 days, blocked the development of autoimmunity, prevented lymphocyte infiltration into regenerated islets, and sharply elevated the expression of the β cell markers pancreatic and duodenal homeobox 1 (Pdx1) and paired box 4 (Pax4). The findings suggest that ω-3 PUFAs could potentially serve as a therapeutic modality for T1D. PMID:28375156

Citric acid production in Yarrowia lipolytica SWJ-1b yeast when grown on waste cooking oil.

PubMed

Liu, Xiaoyan; Lv, Jinshun; Xu, Jiaxing; Zhang, Tong; Deng, Yuanfang; He, Jianlong

2015-03-01

In this study, citric acid was produced from waste cooking oil by Yarrowia lipolytica SWJ-1b. To get the maximal yield of citric acid, the compositions of the medium for citric acid production were optimized, and our results showed that extra nitrogen and magnesium rather than vitamin B1 and phosphate were needed for CA accumulation when using waste cooking oil. The results also indicated that the optimal initial concentration of the waste cooking oil in the medium for citric acid production was 80.0 g/l, and the ideal inoculation size was 1 × 10(7) cells/l of medium. We also reported that during 10-l fermentation, 31.7 g/l of citric acid, 6.5 g/l of isocitric acid, 5.9 g/l of biomass, and 42.1 g/100.0 g cell dry weight of lipid were attained from 80.0 g/l of waste cooking oil within 336 h. At the end of the fermentation, 94.6 % of the waste cooking oil was utilized by the cells of Y. lipolytica SWJ-1b, and the yield of citric acid was 0.4 g/g waste cooking oil, which suggested that waste cooking oil was a suitable carbon resource for citric acid production.