Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants.

The COVID-19 pandemic, which started in Wuhan, China, has spread rapidly over the world with no known antiviral therapy or vaccine. Interestingly, traditional Chinese medicine helped in flattening the pandemic curve in China. In this study, molecules from African medicinal plants were analysed as potential candidates against multiple SARS-CoV-2 therapeutic targets. Sixty-five molecules from the ZINC database subset (AfroDb Natural Products) were virtually screened with some reported repurposed therapeutics against six SARS-CoV-2 and two human targets. Molecular docking, druglikeness, absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the best hits were further simulated. Of the 65 compounds, only three, namely, 3-galloylcatechin, proanthocyanidin B1, and luteolin 7-galactoside found in almond (), grape (), and common verbena (), were able to bind to all eight targets better than the reported repurposed drugs. The findings suggest these molecules may play a role as therapeutic leads in tackling this pandemic due to their multitarget activity

Hesperidin prevents lipopolysaccharide-induced endotoxicity in rats.

CONTEXT Lipopolysaccharide (LPS) is a major trigger of septic shock resulting in multiple organ damage through excessive stimulation of the host's immune cells resulting in the release of cytokines. Previous studies have shown that hesperidin has several beneficial properties against inflammation and oxidative stress. OBJECTIVE The influence of hesperidin on endotoxemia, endothelial dysfunction, inflammation, and oxidative stress was investigated using a murine model of sepsis. MATERIALS AND METHODS Rats were pretreated for 15 d with three doses (50 mg/kg, 100 mg/kg, and 200 mg/kg) of hesperidin prior to LPS administration. Afterwards, the levels of biomarkers of endotoxemia, endothelial dysfunction, and oxidative stress were assessed. Reverse transcriptase PCR technique was used to assess the expression of hepatic proinflammatory cytokines. RESULTS Hesperidin pretreatment significantly (p < 0.05) reduced circulating endotoxin, as well as the levels of bactericidal permeability increasing protein and procalcitonin, and the associated endothelial dysfunction by reducing the levels of plasma soluble intercellular adhesion molecules 1 and inducible nitric oxide (iNO) synthase. There was also down-regulation of the expression of gene for interleukin 1α, interleukin 1β, interleukin 1 receptor, interleukin 6, and tumor necrosis factor α (TNFα) in the liver of rats treated with LPS as a result of hesperidin pretreatment. Hesperidin also showed anti-oxidative properties through the significant (p < 0.05) reduction of NO, hydroperoxides, and thiobarbituric acid reactive substances and increase of glutathione, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase in the organs. CONCLUSION Different doses of hesperidin can prevent endotoxemia-induced oxidative stress as well as inflammatory and endothelial perturbation in rats when administered for as few as 15 d before exposure to endotoxin

Stevioside modulates oxidative damage in the liver and kidney of high fat/low streptozocin diabetic rats

This study investigated the potential of stevioside to prevent oxidative DNA damage in the liver and kidney of type 2 diabetes mellitus (T2DM) using high fat-low streptozocin rat model. Rats were treated daily with 12.5, 25 and 50 mg/kg stevioside orally for 21 days. Levels of biomarkers of T2DM, lipid profile and oxidative stress were assayed spectrophotometrically. The DNA ladder assay method was used to assess DNA fragmentation in the liver and kidney while computational analysis was used to predict the mechanisms of antidiabetic properties of stevioside. Stevioside significantly (p < 0.05) decreased the levels of plasma glucose, insulin, dipeptidyl peptidase IV and activities of kidney angiotensin converting enzyme. Stevioside significantly reduced oxidative stress by decreasing the levels of lipid peroxidation and nitric oxide in the liver and kidney; thereby, reducing the extent of DNA fragmentation in the liver and kidney of the diabetic rats. The in silico analysis showed that the ability of stevioside to exert these effects is linked to its inhibition of beta-adrenergic receptor kinase and G-protein-coupled receptor kinase. The results of this study suggest that the prevention of DNA fragmentation may be an additional benefit of the use of stevioside in the management of T2DM

Gene Expression Profiling Analysis Reveals Putative Phytochemotherapeutic Target for Castration-Resistant Prostate Cancer.

Prostate cancer is the leading cause of cancer death among men globally, with castration development resistant contributing significantly to treatment failure and death. By analyzing the differentially expressed genes between castration-induced regression nadir and castration-resistant regrowth of the prostate, we identified soluble guanylate cyclase 1 subunit alpha as biologically significant to driving castration-resistant prostate cancer. A virtual screening of the modeled protein against 242 experimentally-validated anti-prostate cancer phytochemicals revealed potential drug inhibitors. Although, the identified four non-synonymous somatic point mutations of the human soluble guanylate cyclase 1 gene could alter its form and ligand binding ability, our analysis identified compounds that could effectively inhibit the mutants together with wild-type. Of the identified phytochemicals, (8'R)-neochrome and (8'S)-neochrome derived from the Spinach () showed the highest binding energies against the wild and mutant proteins. Our results identified the neochromes and other phytochemicals as leads in pharmacotherapy and as nutraceuticals in management and prevention of castration-resistance prostate cancers

Preadministration of Fermented Sorghum Diet Provides Protection against Hyperglycemia-Induced Oxidative Stress and Suppressed Glucose Utilization in Alloxan-Induced Diabetic Rats

Sorghum bicolor grains are rich in phytochemicals known to considerably impact human health. Several health-promoting products such as flour, staple food, and beverages have been produced from sorghum grains. This study investigated the protective and modulatory effects of a sorghum diet on the genes of some antioxidant and glycolytic enzymes in alloxan-induced diabetic rats. The rats were randomly distributed into six groups: the control group received normal diet, while the other groups were pretreated with 12.5, 25, 50, 75, and 100% of the sorghum diets daily for 8 weeks before the administration of a dose of alloxan (100 mg/kg BW), after which blood was collected and the liver was excised. The effects of the diets on blood glucose levels, liver dysfunction indices, and markers of oxidative stress were assessed spectrophotometrically, while the gene expressions of key glycolytic enzymes and enzymatic antioxidants were assayed using reverse transcriptase polymerase chain reaction. It was observed that the pretreatment of the experimental animals with the diets normalized the blood glucose before and after the administration of alloxan. The sorghum-treated groups also showed statistically significant (p &lt; 0.05) decrease in liver dysfunction indices and markers of oxidative damage compared with the control. In addition, statistically the diets significantly decreased (p &lt; 0.05) the relative expression of superoxide dismutase, glutathione peroxidase, glucokinase, phosphofructokinase, and hexokinase genes in the experimental animals compared with the control. Overall, this study showed that the preadministration of fermented sorghum diet significantly protected against hyperglycemia and suppressed glucose utilization via glycolysis in the liver of alloxan-induced diabetic rats. Thus, the consumption of sorghum diet may protect against hyperglycemia and oxidative damage and may therefore serve as functional food for management of diabetic mellitus

Effects of Stevioside on oxidative DNA damage in liver and kidney of High Fat Diet Induced type 2 diabetes in Rats

Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes and it has been reported to be associated with oxidative stress-induced cellular dysfunction including diabetic nephropathy. Stevioside (STV), a natural non-caloric sweetener refined from the leaves of Stevia rebaudiana Bertoni, has been reported for its insulinotropic and antihyperlipemic effects. In order to investigate the influence of STV on oxidative stress and oxidative DNA damage, high fat-low streptozocin rat model of T2DM were treated orally with 0.125mg/Kg, 0.25mg/Kg and 0.50mg/Kg body weight of STV for 21days. The levels of plasma insulin and dipeptidyl peptidase-4 (DPP IV) were determined using enzyme-linked immunosorbent assay while other biomarkers of T2DM, organ function, oxidative stress and lipid profile were assayed spectrophotometrically. DNA damage in the liver and kidney was determined by assessing the internucleosomal DNA fragmentation pattern on agarose gel electrophoresis. STV treatment resulted in decrease in the levels of fasting plasma glucose, insulin and DPP IV as well as in the activities of plasma amylase and kidney angiotensin-converting enzyme. STV also significantly (p<0.05) improved plasma lipid profile and oxidative stress in the liver and kidney of the diabetic rats, with rats treated with 0.50mg/kg STV having the lowest levels of malondialdehyde and nitric oxide in liver and kidney. There was also a concomitant decrease in the fragmentation of genomic DNA in the liver and kidney of the diabetic rats. This ability of STV, administered orally, to prevent oxidative DNA damage in the liver and kidney of type 2 diabetic rats should contribute to its use in the management of T2DM

Effects of Stevioside on oxidative DNA damage in liver and kidney of High Fat Diet Induced type 2 diabetes in Rats

Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes and it has been reported to be associated with oxidative stress-induced cellular dysfunction including diabetic nephropathy. Stevioside (STV), a natural non-caloric sweetener refined from the leaves of Stevia rebaudiana Bertoni, has been reported for its insulinotropic and antihyperlipemic effects. In order to investigate the influence of STV on oxidative stress and oxidative DNA damage, high fat-low streptozocin rat model of T2DM were treated orally with 0.125mg/Kg, 0.25mg/Kg and 0.50mg/Kg body weight of STV for 21days. The levels of plasma insulin and dipeptidyl peptidase-4 (DPP IV) were determined using enzyme-linked immunosorbent assay while other biomarkers of T2DM, organ function, oxidative stress and lipid profile were assayed spectrophotometrically. DNA damage in the liver and kidney was determined by assessing the internucleosomal DNA fragmentation pattern on agarose gel electrophoresis. STV treatment resulted in decrease in the levels of fasting plasma glucose, insulin and DPP IV as well as in the activities of plasma amylase and kidney angiotensin-converting enzyme. STV also significantly (p<0.05) improved plasma lipid profile and oxidative stress in the liver and kidney of the diabetic rats, with rats treated with 0.50mg/kg STV having the lowest levels of malondialdehyde and nitric oxide in liver and kidney. There was also a concomitant decrease in the fragmentation of genomic DNA in the liver and kidney of the diabetic rats. This ability of STV, administered orally, to prevent oxidative DNA damage in the liver and kidney of type 2 diabetic rats should contribute to its use in the management of T2DM

Protective Role of Seed Extract in High-Fat High-Fructose-Fed Rats.

is a therapeutic herb used in ethnomedicine for the management of several disease conditions including diabetes. This study examined the potential palliative effect of aqueous seed extract of (APN) on dyslipidemia, hyperglycemia, oxidative stress, insulin resistance, and the expression of some metabolic genes in high-fat high-fructose-fed rats. Experimental rats (2 months old) were fed a control diet or a high-fat diet with 25% fructose (HFHF diet) in their drinking water for nine weeks. APN was administered orally during the last four weeks. Anthropometric and antioxidant parameters, lipid profile, plasma glucose, and insulin levels and the relative expression of some metabolic genes were assessed. APN caused a significant decrease ( < 0.05) in weight gained, body mass index, insulin resistance, plasma glucose, and insulin levels. High-density lipoprotein cholesterol level was significantly increased ( < 0.05), while triacylglycerol, cholesterol, low-density lipoprotein, cardiac index, atherogenic index, coronary artery index, and malondialdehyde levels in plasma and liver samples were also significantly decreased ( < 0.05) by APN at all experimental doses when compared to the group fed with an HFHF diet only. APN also significantly ( < 0.05) upregulated the relative expression of glucokinase, carnitine palmitoyltransferase-1 (CPT-1), and leptin at 400 mg/kg body weight when compared to the group fed with an HFHF diet only. This study showed that APN alleviated dyslipidemia, hyperglycemia, and oxidant effect associated with the intake of a high-fat high-fructose diet

Protective Role of Picralima nitida Seed Extract in High-Fat High-Fructose-Fed Rats

Picralima nitida is a therapeutic herb used in ethnomedicine for the management of several disease conditions including diabetes. This study examined the potential palliative effect of aqueous seed extract of Picralima nitida (APN) on dyslipidemia, hyperglycemia, oxidative stress, insulin resistance, and the expression of some metabolic genes in high-fat high-fructose-fed rats. Experimental rats (2 months old) were fed a control diet or a high-fat diet with 25% fructose (HFHF diet) in their drinking water for nine weeks. APN was administered orally during the last four weeks. Anthropometric and antioxidant parameters, lipid profile, plasma glucose, and insulin levels and the relative expression of some metabolic genes were assessed. APN caused a significant decrease (P<0.05) in weight gained, body mass index, insulin resistance, plasma glucose, and insulin levels. High-density lipoprotein cholesterol level was significantly increased (P<0.05), while triacylglycerol, cholesterol, low-density lipoprotein, cardiac index, atherogenic index, coronary artery index, and malondialdehyde levels in plasma and liver samples were also significantly decreased (P<0.05) by APN at all experimental doses when compared to the group fed with an HFHF diet only. APN also significantly (P<0.05) upregulated the relative expression of glucokinase, carnitine palmitoyltransferase-1 (CPT-1), and leptin at 400 mg/kg body weight when compared to the group fed with an HFHF diet only. This study showed that APN alleviated dyslipidemia, hyperglycemia, and oxidant effect associated with the intake of a high-fat high-fructose diet