In Silico molecular docking and dynamic analysis of natural compounds against major non-structural proteins of SARS-COV-2.

COVID-19 has infected millions and significantly affected the global economy and healthcare systems. Despite continuous lockdowns, symptomatic management with currently available medications, and numerous vaccination drives, it is still far more difficult to control. Against COVID-19 infection, the pressure to develop vaccines and drugs has led to using some currently available medications like remdesivir, azithromycin, hydroxychloroquine and ritonavir. Understanding the importance and potential of harmless molecules to tackle SARS-COV-2, we designed the present study to identify potential natural phytocompounds. In the present study, we docked natural compounds and standard drugs against SARS-COV-2 proteins: papain-like protease, main protease and helicase. ADME/T and ProTox-II analyses were used to determine the toxicity of phytocompounds and drugs. The docking analysis revealed that podophyllotoxin gave the highest binding affinity scores of -8.1, -7.1 and -7.4 kcal/mol against PLpro, Mpro and helicase, respectively. Among the control drugs, doxycycline hydrochloride showed the highest binding affinity of -10.5, -8.4 and -8.8 kcal/mol against PLpro, Mpro and helicase. The results of this study revealed that podophyllotoxin and doxycycline hydrochloride could be promising inhibitors against SARS-Cov-2. Molecular dynamic simulations were executed for the best docked (PLpro-podophyllotoxin) complex, and the results displayed stable conformation and convergence. Energy plot results predicted a global minima average energy of -95 kcal/mol and indicated podophyllotoxin's role in stabilizing protein and making it compact and complex. FarPPI server used MM/GBSA approach to determine free binding affinity, and helicase-gallic acid complex showed the highest affinity, respectively. Therefore, it can be concluded that there is still a need for in vitro and in vivo studies to support further and validate these findings and validate these findings.Communicated by Ramaswamy H. Sarma.

Amelioration of hyperglycaemia and modulation of antioxidant status by Alcea rosea seeds in alloxan-induced diabetic rats.

CONTEXT: Alcea rosea L. (Malvaceae) has various medicinal uses including anticancer, anti-inflammatory and analgesic properties. However, there is no report on its antidiabetic activity. OBJECTIVE: Alcea rosea seed extracts were evaluated for antihyperglycaemic and antioxidative potential in diabetic rats. MATERIALS AND METHODS: Single intra-peritoneal injection of alloxan (130 mg/kg b.w.) was used for induction of diabetes in Albino Wistar rats. Antihyperglycaemic and antioxidant activities of methanol and aqueous extracts of Alcea rosea seed (100 and 300 mg/kg b.w.), administered orally on daily basis for 15 days, were assessed in vivo for fasting blood glucose level and antioxidant status of liver and pancreas. Metformin was used as a positive control. RESULTS: Aqueous and methanol extracts (300 mg/kg b.w.) decreased blood glucose level in diabetic rats by 24% and 46%, respectively. Administration of aqueous and methanol extracts at 300 mg/kg b.w. significantly (p < 0.01) modulated the antioxidant status of liver in diabetic rats by increasing levels of GR (22.5 ± 1.0, 24.4 ± 1.02 µg GSSG utilized/min/mg of protein), GPx (20.7 ± 1.2, 23.6 ± 2.04 µg GSH utilized/min/mg of protein), SOD (36.1 ± 1.7, 39.05 ± 1.5 units/mg of protein) and CAT (1744.5 ± 132.5, 1956.6 ± 125.2 nmol H2O2 decomposed/min/mg of protein), respectively. Similar results were observed for pancreas. DISCUSSION AND CONCLUSIONS: Antihyperglycaemic and antioxidative potentials of Alcea rosea seeds suggest its usefulness in management of diabetes and its complications. This is the first report on antidiabetic activity of this plant.

A Current Perspective on the Inhibition of Cholinesterase by Natural and Synthetic Inhibitors.

Majority of the observed cognitive and behavioral changes in Alzheimer's disease are postulated to be due to the deficiencies in cholinergic pathways of the brain. Enhancement of cholinergic transmission may thus stimulate the cholinergic receptors or prolong the availability of acetylcholine in synaptic cleft and hence improve the Alzheimer's disease associated symptoms. Of these two, the inhibition of cholinesterases (Acetylcholinesterase and Butyrylcholinesterase) by cholinesterase inhibitors is suggested to be a promising strategy. In this regard, various agents both natural and non-natural have been evaluated for the inhibition of cholinesterases. Phytochemical studies of some of the medicinal plants have shown the presence of many valuable compounds that show a wide range of pharmacological activity against cholinesterase enzymes. Interestingly, a good number of potent synthetic inhibitors of cholinesterase enzymes reported so far are natural-product based. This article aims to provide a comprehensive overview of both natural and synthetic cholinesterase inhibitors reported so far. Presenting a comparative overview of synthetic and natural cholinesterase inhibitors may provide some leads for the synthesis of new cholinesterase inhibitors from medicinal plants. Structural activity relationship of the active cholinesterase inhibitors is also discussed with some insights from simulation studies. Insights for possible future research have also been highlighted.

Iodine derivatives of chemically modified gum Arabic microspheres.

Acetylated gum Arabic (AGA) derivatives with different degrees of substitution (DS 0.97-2.74) were synthesized using acetyl chloride and a base under varying reaction conditions. The AGA derivatives were obtained in the form of microspheres and thereafter stable iodine products were prepared by doping the microspheres with an iodinating agent, iodine monochloride (ICl). The reaction between electrophilic iodine and polar carbonyl groups was studied by FT-IR, (1)H-NMR, and UV-VIS spectroscopies. The products were also characterized by DSC, TGA and SEM studies. The incorporated iodine was released in aqueous medium as iodide ions (I(-)). A reaction scheme has been proposed for the iodination and de-iodination of the gum derivatives. This work suggests that the iodine derivatives of modified gum Arabic could be used as a source of iodide ions which is the nutritional form of iodine.

Antihyperlipidemic and Antioxidant Potential of Paeonia emodi Royle against High-Fat Diet Induced Oxidative Stress.

The present study was intended to evaluate the effects of Paeonia emodi rhizome extracts on serum triglycerides (TGs), total cholesterol (TC), low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), atherogenic index (AI), superoxide dismutase (SOD), and glutathione peroxidase (GPx). The plant was extensively examined for its in vitro antioxidant activity, and the preliminary phytochemical screening was carried out using standard protocols. Male Wistar rats were induced with hyperlipidemia using high-fat diet and were treated orally with hydroalcoholic and aqueous extracts at the dose of 200 mg/kg bw for 30 days. TGs, TC, LDL-c, and AI were significantly reduced while HDL-c, SOD, and GPx levels rose to a considerable extent. After subjecting to acute toxicity testing, the extracts were found to be safe. The observations suggest antihyperlipidemic and antioxidant potential of P. emodi in high-fat diet induced hyperlipidemic/oxidative stressed rats.

Molecular linkages between diabetes and Alzheimer's disease: current scenario and future prospects.

After the revolutionary Rotterdam study that suggested there was an increased risk of developing Alzheimer's disease (AD) in patients with type-2 diabetes mellitus (T2DM), a number of studies have provided direct evidence for the linkage between AD and T2DM. In recent years, AD is considered as a neuroendocrine disorder, also referred as type-3 diabetes. There is a growing list of evidence to suggest that, in addition to impaired insulin signaling, there are a number of additional factors that may act as mechanistic links between AD and T2DM. These factors mainly include hypercholesterolemia, dyslipidemia, hypercystinemia, inflammation, impaired insulin signaling and impaired central nervous response to the adipose tissue-derived hormone leptin. Increased cholesterol plays a crucial role in the abnormal metabolism of the amyloid precursor protein, leading to the accumulation of ß-amyloid. In addition to impaired insulin signaling, diabetes has been found to accelerate the appearance of cerebrovascular inflammation and ß-amyloid peptide (Aß) deposition. Increased oxidative stress and production of advanced glycation end products are other probable marker linkages. However, the details of many of these molecular links still require extensive investigation. It is possible that a number of common molecular linkages exist between T2DM and AD. Understanding and analyzing the various molecular linkages between AD and T2DM may shed light on new tools that can be used for the early diagnosis and treatment of AD and also accelerate the identification of T2DM patients who are at high risk of AD.

Induction of apoptosis in human pancreatic MiaPaCa-2 cells through the loss of mitochondrial membrane potential (ΔΨm) by Gentiana kurroo root extract and LC-ESI-MS analysis of its principal constituents.

The objective of the current study was to evaluate the methanolic root extract of Gentiana kurroo for antioxidant and antiproliferative activities as well as to study the effect of the extract on the induction of apoptosis in human pancreatic cancer cell line (MiaPaCa-2). The extract exerted significant antioxidant activity as verified by DPPH, hydroxyl radical, lipid peroxidation and protective oxidative DNA damage assays. The results were comparable to standard antioxidants like α-tocopherol, catechin and BHT used in such experiments. Antioxidant potential of G. kurroo may be attributed to the presence of high phenolic and flavonoid content (73±1.02 and 46±2.05 mg/g extract respectively). The anti-proliferative property of Gentiana kurroo root extract was determined by sulphorhodamine B (SRB) assay against Human colon cancer cell line (HCT-116), Lung carcinoma cell line (A-549), Pancreatic cancer cell line (MiaPaCa-2), Lung cancer cell line (HOP-62) and acute monocytic leukaemia cell line (THP-1). G. kurroo root extract inhibited cancer cell growth depending upon the cell line used and in a dose dependent manner. The extract induced potent apoptotic effects in MiaPaCa-2 cells. The population of apoptotic cells increased from 11.4% in case of control to 49.6% at 100 µg/ml of G. kurroo root extract. The extract also induced a remarkable decrease in mitochondrial membrane potential (ΔΨm) leading to apoptosis of cancer cells used. The main chemical constituents identified by the liquid chromatography-tandem mass spectrometry (LC-ESI-MSMS) were found to be iridoid glucosides (iridoids and secoiridoids), xanthones and flavonoids. Iridoid glucosides are the bitter principles of Gentiana species. Loganic acid, Sweroside, Swertiamarin, Gentiopicroside, Gentisin, Isogentisin, Gentioside, Norswertianolin, Swertianolin, 4″-O-ß-D-glucosyl-6'-O-(4-O-ß-D-glucosylcaffeoyl)-linearoside and Swertisin were the principal compounds present in the methanol root extract of G. kurroo.

Radical scavenging and antibacterial activity of Arnebia benthamii methanol extract.

OBJECTIVE: To evaluate in vitro antioxidant and antibacterial activity of methanolic extract of Arnebia benthamii (A. benthamii) whole plant. METHODS: Plasmid damage was analyzed by agarose gell electrophoresis. Calf thymus DNA was monitored by TBARS formation. DPPH, reducing power and lipid peroxidation was evaluated by using standard procedures. Antibacterial assay was monitored by disc diffusion method. RESULTS: DPPH radical scavenging and hydroxyl radical scavenging potential of the plant revealed that the extract to be active radical scavenger. Reducing (Fe(3+)-Fe(2+)) power and lipid peroxidation inhibition efficiency (TBARS assay) of the extract was also evaluated and the extract showed promising activity in preventing lipid peroxidation and might prevent oxidative damages to biomolecules. The extract offered a significant protection against plasmid and calf thymus DNA damage induced by hydroxyl radicals. The extract was also evaluated on different bacterial strains and the maximum antibacterial activity was exhibited against Escherichia coli (E. coli) when compared with standard drug. CONCLUSIONS: These findings demonstrate that the methanol extract of A. benthamii has excellent anti-oxidant activities and could be considered as a potential source of lead molecules for pharmaceutical industries.