Acute and Subchronic Toxicity Study of Flavonoid Rich Extract of Glycyrrhiza glabra (GutGard®) in Sprague Dawley Rats.

Glycyrrhiza glabra (G. glabra) is well known for its health benefits based on the traditional and current scientific evidence. The aim of the present study was to evaluate the safety of GutGard, a standardised-flavonoid rich extract of G. glabra. The study was designed to evaluate the acute and subchronic oral toxicity of GutGard in Sprague Dawley rats according to the procedures and methods of Organisation for Economic Cooperation and Development (OECD) test guidelines for acute and subchronic toxicity. A single dose of GutGard at 5000 mg/kg body weight did not produce treatment related clinical signs of toxicity or mortality in any of the animals tested during the 14-day observation period. Therefore, the median lethal dose was estimated to be more than 5000 mg/kg. A subchronic oral toxicity study for 90 days in rats at the dose levels of 250, 500, and 1000 mg/kg did not show any treatment related adverse clinical signs. The treated animals exhibited normal weight gain and comparable feed intake. Ophthalmoscope examination did not reveal any abnormalities. Further, GutGard administration in rats did not show any clinical evidence of toxicity with respect to urinalysis, haematology, and blood chemistry parameters. The relative organ weight of vital organs did not differ significantly as compared to control. Gross and histopathological findings did not show any remarkable and treatment related changes. Based on the current experimental study findings, the median lethal dose (LD50) of GutGard was found to be >5000 mg/kg b.wt and the no observed adverse effect level (NOAEL) was found to be 1000 mg/kg rat b.wt.

Dipeptidyl peptidase-IV inhibitory action of Calebin A: An in silico and in vitro analysis.

BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, the enhancers of incretin are used for the treatment of diabetes. The non-glycaemic actions of these drugs (under developmental stage) also proved that repurposing of these molecules may be advantageous for other few complicated disorders like cardiovascular diseases, Parkinson's disease, Alzheimer's disease, etc. OBJECTIVE: The present study was aimed to investigate the DPP-IV inhibitory potential of Calebin-A, one of the constituents of Curcuma longa. MATERIAL AND METHODS: The phytoconstituent was subjected for various in silico studies (using Schrödinger Suite) like, Docking analysis, molecular mechanics combined with generalized Born model and solvent accessibility method (MMGBSA) and Induced fit docking (IFD) after validating the protein using Ramachandran plot. Further, the protein-ligand complex was subjected to molecular dynamic simulation studies for 50 nanoseconds. And finally, the results were confirmed through enzyme inhibition study. RESULTS: Insilico results revealed possible inhibitory binding interactions in the catalytic pocket (importantly Glu205, Glu206 and Tyr 662 etc.) and binding affinity in terms of glide g-score and MMGBSA dG bind values were found to be -6.2 kcal/mol and -98.721 kcal/mol. Further, the inhibitory action towards the enzyme was confirmed by an enzyme inhibition assay, in which it showed dose-dependent inhibition, with maximum % inhibition of 55.9 at 26.3 µM. From molecular dynamic studies (50 nanoseconds), it was understood that Calebin A was found to be stable for about 30 nanoseconds in maintaining inhibitory interactions. CONCLUSION: From the in silico and in vitro analysis, the current research emphasizes the consideration of Calebin A to be as a promising or lead compound for the treatment of several ailments where DPP-IV action is culprit.

Anti-diarrhoeal activity of a polyherbal formulation in rats and elucidation of its cellular mechanisms.

OBJECTIVE: The present study was aimed to study anti-diarrhoeal activity of a polyherbal formulation (PHF) in rats and elucidate its mechanism of action. MATERIALS AND METHODS: Anti-diarrhoeal activity of PHF was investigated using castor oil-induced diarrhoea, small intestinal transit and enteropooling models in rats. PHF was tested at 75, 150 and 300 mg/kg rat body weight. Loperamide was used as a reference control for in vivo studies. Anti-secretory action was evaluated against heat labile enterotoxin (from Escherichia coli) induced secretion in rat ileal loop model. The effect of PHF (12.5-100 µg/ml) on cAMP-dependent secretory activity was investigated against forskolin-induced cAMP release in HT-29 cells. RESULTS: PHF demonstrated significant (p≤0.05) anti-diarrhoeal activity by increasing the time for first faecal drop and inhibited diarrhoeal episodes by 43, 58 and 60% at 75, 150 and 300 mg/kg body weight, respectively in a dose-dependent manner. Also, the intestinal transit was inhibited upto 33% and the weight of secretory contents induced by castor oil was significantly reduced by PHF, approximately 29% in enteropooling assay. On the other hand, the intestinal loop instilled with PHF and enterotoxin from E. coli demonstrated 61% inhibition of fluid accumulation as compared to loop instilled with enterotoxin only. In vitro studies indicated that PHF inhibits cAMP release in HT-29 cells corroborating the anti-secretory effects observed in aforesaid studies. CONCLUSION: The results suggest that the PHF possesses anti-diarrhoeal activity, evident through reduced faecal output, decreased intestinal transit and anti-secretory activities.

Aminoglycosides can be a better choice over macrolides in COVID-19 regimen: Plausible mechanism for repurposing strategy.

In the current COVID-19 pandemic, prioritizing the immunity enhancers is equally important to anti-virals. Defensins are the forgotten molecules that enhance the innate immunity against various microbes. Although macrolides like azithromycin and clarithromycin etc., have been reported to act against respiratory infections but they lack the ability of immunity enhancement through defensins. The aminoglycosides were proved to have defensin mediated antiviral activity, that could enhance the immunity. So, Consideration of aminoglycosides can be a double edge sword viz., against respiratory infection as well as Immunity enhancer (along with anti-virals) for COVID-19 regimen.

Possible role of DPP4 inhibitors to promote hippocampal neurogenesis in Alzheimer's disease.

As well-known to the scientific community, Alzheimer's disease (AD) is an irreversible neurodegenerative disease that ends up with impairment of memory and cognition. Patient quality of life can be enhanced by targeting neurogenesis as a therapeutic paradigm. Preserving functional activity of SDF-1α and GLP-1 by DPPIV inhibition will enhance the homing of stem cells and modulate cell signalling pathways. The non-invasive approach presented in this article is a major advantage for managing AD, as regular/conventional stem-cell therapy necessarily relies on the application of regenerative stem cells exogenously. Using DPP-4 inhibitors to achieve the SDF-1α/CXCR4 axis stabilisation and augmenting GLP-1 levels, will enhance the homing/recruitment of brain resident and non-resident circulating stem cells/progenitor cells towards the sites of lesion to increase synaptic plasticity, a promising approach and also a novel one as well.

DPP4 Inhibitors Can Be a Drug of Choice for Type 3 Diabetes: A Mini Review.

As well known to the scientific community, Alzheimer's disease (AD) is an irreversible neurodegenerative disease that ends up with impairment of memory and cognition due to neuronal and synapse loss. Patient's quality of life can be enhanced by targeting neurogenesis as a therapeutic paradigm. Moreover, several research evidences support the concept that AD is a type of metabolic disorder mediated by impairment in brain insulin responsiveness and energy metabolism. Growing evidence suggests that endogenous peptides such as glucagon-like peptide-1 (GLP-1) and stromal-derived factor-1α (SDF-1α) provide neuroprotection across a range of experimental models of AD. So, preserving functional activity of SDF-1α and GLP-1 by dipeptidyl peptidase-4 inhibition will enhance the homing/recruitment of brain resident and nonresident circulating stem cells/progenitor cells, a noninvasive approach for promoting neurogenesis. So, herewith we provide this in support of dipeptidyl peptidase-4 inhibitors as a new target of attention for treating AD.