System biology-based investigation of Silymarin to trace hepatoprotective effect.

Silymarin is used as a hepatoprotective agent since ancient times which could be via its potent anti-oxidant effect. However, the mode of silymarin for the hepatoprotective effect has not been established with the targets involved in hepatic cirrhosis. The present study investigated the multiple interactions of the flavonolignans from Silybum marianum with targets involved in hepatic cirrhosis using a series of system biology approaches. Chemo-informative tools and databases i.e. DIGEP-Pred and DisGeNET were used to predict the targets of flavonolignans and proteins involved in liver cirrhosis respectively. Further, STRING was used to enrich the protein-protein interaction for the flavonolignans-modulated targets. Similarly, molecular docking was performed using AutoDock Vina. Additionally, molecular dynamics simulation and MM-PBSA calculations were carried out for the lead-hit complexes by GROMACS. Thirteen flavonolignans were identified from S. marianum, in which silymonin exhibited the highest drug-likeness score i.e. 1.09. Similarly, CTNNB1 was found to be regulated by the 12 different flavonolignans and was majorly expressed within the compound(s)-protein(s)-pathway(s) network. Further, silymonin had the highest binding affinity; binding energy -9.2 kcal/mol with the CTNNB1 and formed very stable hydrogen bond interactions with Arg332, Ser336, Lys371, and Arg475 throughout 100 ns molecular dynamic production run. The binding free energy of CTNNB1-silymonin complex was found to be -15.83 ± 2.71 kcal/mol. The hepatoprotective property of S. marianum may be due to the presence of silymonin and silychristin; this could majorly modulate CTNNB1, HMOX1, and CASP8 in combination with other flavonolignans. Our findings further suggest designing the in-vitro and in-vivo studies to validate the interaction of flavonolignans with identified targets to strengthen present findings of S. marianum as a hepatoprotective..

Withanolides from Withania somnifera as an immunity booster and their therapeutic options against COVID-19.

Traditionally, Withania somnifera is widely used as an immune booster, anti-viral, and for multiple medicinal purposes. The present study investigated the withanolides as an immune booster and anti-viral agents against the coronavirus-19. Withanolides from Withania somnifera were retrieved from the open-source database, their targets were predicted using DIGEP-Pred, and the protein-protein interaction was evaluated. The drug-likeness score and intestinal absorptivity of each compound were also predicted. The network of compounds, proteins, and modulated pathways was constructed using Cytoscape, and docking was performed using autodock4.0, and selected protein-ligand complexes were subjected to 100 ns Molecular Dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Withanolide_Q was predicted to modulate the highest number of proteins, showed human intestinal absorption, and was predicted for the highest drug-likeness score. Similarly, combined network interaction identified Withanolide_Q to target the highest number of proteins; RAC1 was majorly targeted, and fluid shear stress and atherosclerosis associated pathway were chiefly regulated. Similarly, Withanolide_D and Withanolide_G were predicted to have a better binding affinity with PLpro, Withanolide_M with 3CLpro, and Withanolide_M with spike protein based on binding energy and number of hydrogen bond interactions. MD studies suggested Withanoside_I with the highest binding free energy (ΔGbind-31.56 kcal/mol) as the most promising inhibitor. Among multiple withanolides from W. somnifera, Withanolide_D, Withanolide_G, Withanolide_M, and Withanolide_Q were predicted as the lead hits based on drug-likeness score, modulated proteins, and docking score to boost the immune system and inhibit the COVID-19 infection, which could primarily act against COVID-19. HighlightsWithanolides are immunity boosters.Withanolides are a group of bio-actives with potential anti-viral properties.Withanolide_G, Withanolide_I, and Withanolide_M from Withania somnifera showed the highest binding affinity with PLpro, 3CLpro, and spike protein, respectively.Withanolides from Withania somnifera holds promising anti-viral efficacy against COVID-19.Communicated by Vsevolod Makeev.

Network pharmacology of AYUSH recommended immune-boosting medicinal plants against COVID-19.

The Ministry of AYUSH recommended the use of a decoction of the mixture of Ocimum tenuiflorum, Cinnamomum verum, Piper nigrum, Zingiber officinale, and Vitis vinifera as a preventive measure by boosting the immunity against the severity of infection caused by a novel coronavirus (COVID-19). The present study aimed to identify the probable modulated pathways by the combined action of AYUSH recommended herbal tea and golden milk formulation as an immune booster against COVID-19. Reported phytoconstituents of all the medicinal plants were retrieved from the ChEBI database, and their targets were predicted using DIGEP-Pred. STRING database and Cytoscape were used to predict the protein-protein interaction and construct the network, respectively. Likewise, MolSoft and admet SAR2.0 were used to predict the druglikeness score and ADMET profile of phytoconstituents. The study identified the modulation of HIF-1, p53, PI3K-Akt, MAPK, cAMP, Ras, Wnt, NF-kappa B, IL-17, TNF, and cGMP-PKG signaling pathways to boost the immune system. Further, multiple pathways were also identified which are involved in the regulation of pathogenesis of the multiple infections and non-infectious diseases due to the lower immune system. Results indicated that the recommended herbal formulation not only modulated the pathways involved in boosting the immunity but also modulated the multiple pathways that are contributing to the progression of multiple disease pathogenesis which would add the beneficial effect in the co-morbid patients of hypertension and diabetes. The study provides the scientific documentation of the role of the Ayurvedic formulation to combat COVID-19.

Reversal of insulin resistance by Ficus benghalensis bark in fructose-induced insulin-resistant rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Bark of Ficus benghalensis L. (family: Moraceae), commonly known as Banyan is recorded as Nyagrodha in Ayurvedic Pharmacopeia of India to manage burning sensation, obesity, diabetes, bleeding disorders, thirst, skin diseases, wounds, and dysmenorrhoea. However, the effect of F. benghalensis bark over glycolysis, gluconeogenesis, and appetite regulation in insulin-resistant pathogenesis has not been reported yet. AIM OF THE STUDY: The present study aimed to investigate the effect of hydroalcoholic extract of F. benghalensis bark in gluconeogenesis, glycolysis, and appetite regulation in fructose-induced insulin resistance in experimental rats. MATERIALS AND METHODS: Male Wister rats were supplemented with fructose in drinking water (10% w/v for 42 days and 20% w/v for next 12 days; a total of 54 days); insulin resistance was confirmed via the elevated area under the curve of the glucose during oral glucose tolerance test after 54 days and was subjected with extract treatment for next 30 days. After 30 days of treatment, animals were fasted to perform oral glucose and insulin tolerance test to estimate glucose and insulin levels. The blood sample was collected for biochemical estimation and the liver homogenate was prepared to estimate hepatic enzymes and enzymatic and non-enzymatic anti-oxidant biomarkers followed by histopathological evaluation. Also, glycogen content was quantified in gastrocnemius muscle and liver homogenates. Further, reported bioactives from the F. benghalensis were retrieved from the ChEBI database and docked against hexokinase, phosphofructokinase, glucose-6-phosphatase, lactate dehydrogenase, and fructose-1,6-biphosphatase to identify the probable lead hits against the enzymes involved in gluconeogenesis. RESULTS: Treatment with the F. benghalensis bark extract significantly increased the body weight and food intake and significantly decreased fructose supplemented water intake. Further, treatment with extract significantly increased the exogenous glucose clearance and well responded to the exogenous insulin. Further, extract treatment improved lipid metabolism, ameliorated plasma leptin, and multiple enzymatic and non-enzymatic antioxidant biomarkers. Likewise, it also improved gluconeogenesis mediated pathogenesis of non-alcoholic fatty liver injury. Additionally, molecular docking also identified mucusisoflavone A and B as lead hits in downregulating gluconeogenesis. CONCLUSION: Hydroalcoholic extract of F. benghalensis bark may prevent insulin resistance by downregulating gluconeogenesis and improving the appetite in fructose-induced insulin-resistant rats.

Cyperus rotundus L. reverses the olanzapine-induced weight gain and metabolic changes-outcomes from network and experimental pharmacology.

Cyperus rotundus L. is used to treat multiple clinical conditions like inflammation, diarrhea, pyrosis, and metabolic disorders including diabetes and obesity. The present study aimed to predict the interaction of reported bioactives from Cyperus rotundus against obesity via network pharmacology and to evaluate the efficacy of hydroalcoholic extract of Cyperus rotundus against the olanzapine-induced weight gain and metabolic disturbances in experimental animals. Reported phytochemicals of Cyperus rotundus were retrieved from the open-source database(s) and published literature and their targets were predicted using SwissTargetPrediction, enriched in STRING, and bioactives-proteins-pathways network was constructed using Cytoscape. Further, the hydroalcoholic extract of Cyperus rotundus (100, 200, and 400 mg/kg/day, p.o.) was co-administered with olanzapine (2 mg/kg, i.p.) for 21 days in Sprague Dawley rats. During treatment, body weight and food intake were recorded; after the successful completion of 21 days of treatment, animals were fasted to perform oral glucose and insulin tolerance tests. Further, the animals were euthanized; blood and abdominal fat were collected for lipid profiling and histopathological examination respectively. Herein, network pharmacology predicted neuroactive ligand-receptor interaction as a primarily modulated pathway and protein tyrosine phosphatase 1b as a majorly triggered protein via the combined action of bioactives. Further, Cyperus rotundus significantly reversed weight gain, cumulative food intake, ameliorated the lipid and glucose metabolism, and promoted energy expenditure.

Consolidation of network and experimental pharmacology to divulge the antidiabetic action of Ficus benghalensis L. bark.

A total of 21 different bioactives were identified from F. benghalensis in which 3 molecules, i.e., apigenin, 3',4',5,7-tetrahydroxy-3-methoxyflavone, and kaempferol were predicted to target the highest number of proteins involved in diabetic pathogenesis in which protein tyrosine phosphatase 1b was primarily targeted. Similarly, a docking study identified ursolic acid to have the highest binding affinity with protein tyrosine phosphatase 1b. The combined synergic network analysis identified PI3K/Akt signaling pathway to be primarily modulated followed by the calcium signaling pathway. Similarly, in oral glucose tolerance test, we observed the efficacy of hydroalcoholic extract of F. benghalensis to lower the total area under the curve of glucose and increase total area under curve of insulin for 2 hours. Likewise, hydroalcoholic extract reversed the altered homeostatic hepatic enzymes after 28 days of treatments. Similarly, the extract also enhanced the antioxidant enzymes level like catalase and superoxide dismutase in liver homogenate. In summary, hydroalcoholic extract of F. benghalensis bark may act as an antidiabetic agent by enhancing the glycolysis, decreasing gluconeogenesis, promoting glucose uptake, enhancing insulin secretion, and maintaining pancreatic ß-cell mass via PI3K/Akt signaling pathway and downregulating the function of  protein tyrosine phosphatase 1b. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02788-7.

Effect of Moringa oleifera bark extracts on dexamethasone-induced insulin resistance in rats.

BACKGROUND: Experimental study has revealed the antidiabetic potentials of ethanolic extract of the bark of Moringa oleifera Lam., (Moringaceae), a multipurpose tree of south Asia. OBJECTIVE: To investigate the effects of alcoholic and petroleum ether extracts of Moringa oleifera bark on acute and chronic insulin resistance induced by dexamethasone in rats. MATERIALS AND METHODS: Dexamethasone (dexa) was administered for 11 days (1 mg/kg, s. c., once daily) and single dose (1 mg/kg, i. p.) to induce chronic and acute insulin resistance respectively. 2 doses each of alcoholic (AE125 and AE250 mg/kg) and petroleum ether extracts (PEE30 and PEE60 mg/kg) and single dose each of alcoholic (AE250 mg/kg) and petroleum ether extract (PEE 60 mg/kg) of Moringa oleifera bark were tested in chronic and acute studies. At the end of the studies fasting plasma glucose, triglyceride levels and oral glucose tolerance were measured. RESULTS: In chronic study, treatment of rats with AE125 and AE250 prevented dexamethasone-induced hypertriglyceridemia and oral glucose intolerance but not fasting hyperglycemia, whereas both PEE30 and PEE60 had no effects on any of these parameters measured except that significant reduction of triglyceride level was observed in PEE60 treated rats. Oral glucose intolerance induced by single dose administration of dexamethasone was prevented by AE250 but not by PEE60. In normal rats AE250 treatment improved the glucose tolerance, where as PEE60 had no effect on this parameter. CONCLUSION: The present study indicates that AE of Moringa oleifera prevents dexamethasone-induced insulin resistance in peripheral tissues.