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Coenzyme Q10 (CoQ10) is a lipid soluble, endogenous antioxidant present at highest levels in the heart followed by the kidney and liver. The reduced CoQ10 ubiquinol is well known for its chemical instability and low bioavailability. The present study was designed to synthesize ubiquinol acetate, which is more stable and biologically active, and further evaluate its safety and genotoxic potential. Synthesized ubiquinol acetate showed better stability than that of ubiquinol at the end of 3 months. In vitro genotoxicity studies (AMES test, in vitro micronucleus and chromosomal aberration) showed ubiquinol acetate as nongenotoxic with no clastogenic or aneugenic effects at high dose of 5000 and 62.5 μg/mL, respectively. In subchronic toxicity study, ubiquinol acetate was administered orally to Sprague Dawley rats at 150, 300, and 600 mg/kg/day for 90 days. No treatment related adverse effects were observed in males at 600 mg/kg/day; however, females showed treatment related increase in AST and ALT with small focal irregular white-yellow spots in liver on gross necropsy examination. Histopathological evaluation revealed hepatocellular necrosis in high dose females which was considered as adverse. Based on the results, the No-Observed-Adverse-Effect Level (NOAEL) of ubiquinol acetate in males and females was determined as 600 and 300 mg/kg/day, respectively. [ABSTRACT FROM AUTHOR]

Abstract: African Bush Mango from Irvingia gabonensis is a West African culinary fruit and the mucilage from this fruit seed is used to make traditional soups and sauces. Extract from the kernel (IGOB131) has been claimed for its health benefits. In the present investigations, potential adverse effects, if any, of IGOB131 were investigated in dose–response 90-day study and genotoxicity studies. In the subchronic study, Sprague Dawley rats (20/sex/group) were gavaged with I. gabonensis extract (IGOB131) at dose levels of 0, 100, 1000 and 2500mg/kg body weight (bw)/day for 90-days. No treatment-related changes in clinical signs, functional observations, mortality, ophthalmologic observations, body weights, body weight gain or feed consumption were noted. Similarly, hematological, clinical chemistry, urine analysis parameters, and organ weights did not reveal any toxicologically significant treatment-related changes. No treatment-related macroscopic and microscopic abnormalities were noted at the end of treatment period. The mutagenicity as evaluated by Ames assay, in vitro and in vivo chromosomal aberration test and in vivo micronucleus assay did not reveal any genotoxicity of IGOB131. The results of subchronic toxicity study suggest the no-observed-adverse-effect level (NOAEL) for I. gabonensis extract (IGOB131) as ⩾2500mg/kg bw/day, the highest dose tested. [Copyright &y& Elsevier]

Abstract: Cissus quadrangularis has been used for centuries for therapeutic and culinary purposes. Extract from this plant (CQR-300) has been claimed for its health benefits. The objective of present investigation was to delineate adverse effects, if any, of CQR-300 in subchronic toxicity, and gentotoxicity studies. In the subchronic study, Sprague Dawley rats (20/sex/group) were administered (gavage) C. quadrangularis extract (CQR-300) at dose levels of 0, 100, 1000, and 2500mg/kg body weight (bw)/day for 90days. No treatment related clinical signs of toxicity, mortality or changes in body weights, body weight gain or food consumption were noted. Functional observation tests and ophthalmological examination did not reveal any changes. No toxicologically significant treatment related changes in hematological, clinical chemistry, urine analysis parameters, and organ weights were noted. No treatment related macroscopic and microscopic abnormalities were noted at the end of treatment period. The results of mutagenicity studies as evaluated by Ames assay, in vitro chromosomal aberration and in vivo micronucleus assay did not reveal any genotoxicity of CQR-300. Based on the subchronic study, the no-observed-adverse-effect level (NOAEL) for C. quadrangularis extract (CQR-300) determined as 2500mg/kgbw/day, the highest dose tested. [Copyright &y& Elsevier]

Graphical abstract A new series of quinoline carrying 1,2,4-oxadiazole moiety have been synthesized and evaluated for their antituberculosis studies. Majority of them showed moderate to good antituberculosis activity. Highlights • Compound QD-18, QD-19, QD-20 and QD-21 are potent against Mtb WT H37Rv with encouraging MIC values. • Four identified compounds are tuberculosis specific, orally bioavailable, non-cytotoxic and metabolically stable. • Compound QD-20 and QD-21 exhibited an excellent pharmacokinetic profile. • A series of quinoline hybrids synthesized are a new class of anti-tubercular molecules. Abstract Tuberculosis is the infectious disease caused by mycobacterium tuberculosis (Mtb), responsible for the utmost number of deaths annually across the world. Herein, twenty-one new substituted 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl-quinoline derivatives were designed and synthesized through multistep synthesis followed by in vitro evaluation of their antitubercular potential against Mtb WT H37Rv. The compound QD-18 was found to be promising with MIC value of 0.5 µg/ml and QD-19 to QD-21 were also remarkable with MIC value of 0.25 µg/ml. Additionally, we have carried out experiments to confirm the metabolic stability, cytotoxicity and pharmacokinetics of these compounds along with kill kinetics of QD-18. These compounds were found to be orally bioavailable and highly effective. Altogether, these results indicate that QD-18 , QD-19 , QD-20 and QD-21 are promising lead compounds for the development of a novel chemical class of antitubercular drugs. [ABSTRACT FROM AUTHOR]

Nutritional abundance associated with chronic inflammation and dyslipidemia impairs the functioning of endoplasmic reticulum (ER) thereby hampering cellular responses to insulin. PHLPP1 was identified as a phosphatase which inactivates Akt, the master regulator of insulin mediated glucose homeostasis. Given the suggestive role of PHLPP1 phosphatase in terminating insulin signalling pathways, deeper insights into its functional role in inducing insulin resistance are warranted. Here, we show that PHLPP1 expression is enhanced in skeletal muscle of insulin resistant rodents which also displayed ER stress, an important mediator of insulin resistance. Using cultured cells and PHLPP1 knockdown mice, we demonstrate that PHLPP1 facilitates the development of ER stress. Importantly, shRNA mediated ablation of PHLPP1 significantly improved glucose clearance from systemic circulation with enhanced expression of glucose transporter 4 (GLUT-4) in skeletal muscle. Mechanistically, we show that endogenous PHLPP1 but not PP2Cα interacts with and directly dephosphorylates AMPK Thr 172 in myoblasts without influencing its upstream kinase, LKB1. While the association between endogenous PHLPP1 and AMPK was enhanced in ER stressed cultured cells and soleus muscle of high fat diet fed mice, the basal interaction between PP2Ac and AMPK was minimally altered. Further, we show that PHLPP1α is phosphorylated by ERK1/2 at Ser 932 under ER stress which is required for its ability to interact with and dephosphorylate AMPK and thereby induce ER stress. Taken together, our data position PHLPP1 as a key regulator of ER stress. [ABSTRACT FROM AUTHOR]