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Shakiru O. Alapafuja Michael S. Malamas Vidyanand Shukla Alexander Zvonok Sally Miller Laura Daily Girija Rajarshi Christina Yume Miyabe Honrao Chandrashekhar JodiAnne Wood Sergiy Tyukhtenko Alex Straiker Alexandros Makriyannis 《Bioorganic & medicinal chemistry》2019,27(1):55-64
Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6?h. This interconversion process “intrinsic reversibility” was exploited by modifications of the ligand’s size (length and bulkiness) to generate analogs with “tunable’ adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ~4.5?mmHg in a sustained manner for at least 12?h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma. 相似文献
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Shukla Geeta Sharma Anuj Bhatia Ruchika Sharma Mridul 《Probiotics and antimicrobial proteins》2019,11(1):165-174
Probiotics and Antimicrobial Proteins - Giardiasis is a re-emerging infectious disease with outbreaks reported globally specially in children and malnourished individuals leading to malabsorption,... 相似文献
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Patel C Patel M Rani S Nivsarkar M Padh H 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2007,850(1-2):356-360
Atomoxetine is the first, non-stimulant alternative to other stimulant medications used for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). Reported methods for the determination of atomoxetine include expensive liquid chromatography tandem mass spectrometry (LCMS) and high performance liquid chromatography (HPLC) with liquid scintillation counting (LSC) detection. Till date, no method has been reported in literature to determine atomoxetine using HPLC with UV detection. In this paper, we describe a new HPLC method for the determination of atomoxetine using liquid-liquid extraction with tertiary butyl methyl ether and UV detector. This method was found to be linear over the concentration range of 0.05-3.0 microg/ml. The limit of quantification was 0.05 microg/ml. Intra- and inter-day precision was <15% and accuracy was in the range of 95.67-108.80%. Stability studies showed that atomoxetine was stable in human plasma for short- and long-term period for sample preparation and analysis. This method was used for sample analysis in a pharmacokinetic study of atomoxetine (25mg) in five healthy adult female volunteers. The observed mean+/-S.D. pharmacokinetic parameters Cmax, Tmax and AUC(0-t) were 0.40+/-0.06 microg/ml, 3.40+/-0.42 h and 1.34+/-0.52 microg h/ml, respectively. 相似文献
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Pranjal Kumar Seema Khadirnaikar Sudhanshu Kumar Shukla 《Journal of cellular physiology》2019,234(9):16021-16031
The prognostic signatures play an essential role in the era of personalised therapy for cancer patients including lung adenocarcinoma (LUAD). Long noncoding RNA (LncRNA), a relatively novel class of RNA, has shown to play a crucial role in all the areas of cancer biology. Here, we developed and validated a robust LncRNA-based prognostic signature for LUAD patients using three different cohorts. In the discovery cohort, four LncRNAs were identified with 10% false discovery rate and a hazard ratio of >10 using univariate Cox regression analysis. A risk score, generated from the four LncRNAs’ expression, was found to be a significant predictor of survival in the discovery and validation cohort (p = 9.97 × 10 −8 and 1.41 × 10 −3, respectively). Further optimisation of four LncRNAs signature in the validation cohort, generated a three LncRNAs prognostic score (LPS), which was found to be an independent predictor of survival in both the cohorts ( p = 1.00 × 10 −6 and 7.27 × 10 −4, respectively). The LPS also significantly divided survival in clinically important subsets, including Stage I ( p = 9.00 × 10 −4 and 4.40 × 10 −2, respectively), KRAS wild-type (WT), KRAS mutant ( p = 4.00 × 10 −3 and 4.30 × 10 −2, respectively) and EGFR WT ( p = 2.00 × 10 −4). In multivariate analysis LPS outperformed, eight previous prognosticators. Further, individual members of LPS showed a significant correlation with survival in microarray data sets. Mutation analysis showed that high-LPS patients have a higher mutation rate and inactivation of the TP53 pathway. In summary, we identified and validated a novel LncRNA signature LPS for LUAD. 相似文献
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Shukla Pawan Reddy Ramesha A. Ponnuvel Kangayam M. Rohela Gulab Khan Shabnam Aftab A. Ghosh M. K. Mishra Rakesh Kumar 《Molecular biology reports》2019,46(2):1809-1817
Molecular Biology Reports - Mulberry (Morus alba L.) is the sole food source for the mulberry silkworm, Bombyx mori and therefore important for sericulture industry. Different abiotic stress... 相似文献
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Mishra Aradhana Singh Satyendra Pratap Mahfooz Sahil Shukla Richa Mishra Nishtha Pandey Shipra Dwivedi Sanjay Pandey Vivek Shirke Pramod Arvind Nautiyal Chandra Shekhar 《Plant Molecular Biology Reporter》2019,37(5-6):499-499
Plant Molecular Biology Reporter - The original version of this article unfortunately contained missing information at author’s affiliations. The affiliation address of the author’s... 相似文献