Lead optimization of Allium sativum L. compounds for PTP1B inhibition in diabetes treatment: in silico molecular docking and dynamics simulation.

Protein tyrosine phosphatase 1B (PTP1B) has been identified as a promising drug target for the development of diabetes medications via an inhibition mechanism. Using a computational approach, this study investigates the binding mechanism of lead optimized natural compounds from Allium sativum against the human PTP1B. The molecular docking, induced-fit docking, and binding free energy calculations were analyzed using Schrödinger Suite 2021-2. MD simulation, and gene enrichment analysis was achieved via the Desmond module of Schrödinger to identify best compounds as inhibitors against PTP1B in diabetes management. The docking scores of the lead optimized compounds were good; 5280443_121 from apigenin had the best binding score of -9.345 kcal/mol, followed by 5280443_129 with a binding score of -9.200 kcal/mol, and 5280863_177 from kaempferol had a binding score of -8.528 kcal/mol, followed by 5280863_462 with a binding score of -8.338 kcal/mol. The top two lead optimized compounds, docked better than the standard PTP1B inhibitor (-7.155 kcal/mol), suggesting them as potent inhibitors than the standard PTP1B inhibitor. The outcomes of the induced-fit docking were consistent with the increased binding affinity used in the Glide computation of the five conformed poses between the derivatives (5280443_121, 5280443_129, 5280863_177, and 5280863_462) and the protein (PTP1B). Based on the binding fee energies (MM-GBSA), the lead optimized compounds from kaempferol exhibited more stability than those from apigenin. In the pharmacophore development, all the models exhibit good results across the different metrics. The best performing model with five of five matches on a 1.34 and 1.33 phase score was DDRRR_1, DDRRR_2, and DDDRR_1. The average BEDROC value (= 160.9) was 1, while the average EF 1% value across all models was 101. There were no substantial conformational modifications during the MD simulation process, indicating that the apigenin derivatives (5280443_121) was stable in the protein's active site in 100 ns. IGF1R, EGFR, INSR, PTPN1, SRC, JAK2, GRB2, BCAR1, and IRS1 are among the 11 potential targets found in the protein-protein interaction (PPI) of A. sativum against PTP1B that may be important in A. sativum's defense against PTP1B. Sixty-four (64) pathways were found by KEGG pathway enrichment analysis to be potentially involved in the anti-PTP1B of A. sativum. Consequently, data obtained indicates the effectiveness of the in silico studies in identifying potential lead compounds in A. sativum against PTP1B target.Communicated by Ramaswamy H. Sarma.

Therapeutic Study of Cinnamic Acid Derivative for Oxidative Stress Ablation: The Computational and Experimental Answers.

This study aimed to examine the therapeutic activity of the cinnamic acid derivative KAD-7 (N'-(2,4-dichlorobenzylidene)-3-(4-methoxyphenyl) acrylohydrazide) on Fe2+-induced oxidative hepatic injury via experimental and computational models. In addition, the role of ATPase and ectonucleoside triphosphate diphosphohydrolase (ENTPDase) in the coordination of cellular signals is speculated upon to proffer suitable therapeutics for metabolic stress disorder upon their inhibition. While we know little about therapeutics with flexible dual inhibitors for these protein targets, this study was designed to screen KAD-7's (N'-(2,4-dichlorobenzylidene)-3-(4-methoxyphenyl) acrylohydrazide) inhibitory potential for both protein targets. We induced oxidative hepatic damage via the incubation of hepatic tissue supernatant with 0.1 mM FeSO4 for 30 min at 37 °C. We achieved the treatment by incubating the hepatic tissues with KAD-7 under the same conditions. The catalase (CAT), glutathione (GSH), malondialdehyde (MDA), ATPase, and ENTPDase activity were all measured in the tissues. We predicted how the drug candidate would work against ATPase and ENTPDase targets using molecular methods. When hepatic injury was induced, there was a significant decrease in the levels of the GSH, CAT, and ENTPDase (p < 0.05) activities. In contrast, we found a noticeable rise in the MDA levels and ATPase activity. KAD-7 therapy resulted in lower levels of these activities overall (p < 0.05), as compared to the control levels. We found the compound to have a strong affinity for ATPase (-7.1 kcal/mol) and ENTPDase (-7.4 kcal/mol), and a better chemical reactivity than quercetin. It also met all drug-likeness parameters. Our study shows that KAD-7 can protect the liver from damage caused by FeSO4 by reducing oxidative stress and purinergic actions. Our studies indicate that KAD-7 could be developed as a therapeutic option since it can flexibly inhibit both ATPase and ENTPDase.

Pre-puberty cannabichromene exposure modulates reproductive function via alteration of spermatogenesis, steroidogenesis, and eNOS pathway metabolites.

Background: Cannabis and cannabinoids affect almost every system of the body and exert systemic effects such as alterations in memory and cognitive functions, neurotransmission impediment, as well as obstruction of endocrine and reproductive system functions. Reproduction is a complicated phenomenon that integrates biological, psychological and behavioural aspects, hence susceptible to intracellular and extracellular modulations by numerous chemicals and toxicants like cannabis. Aim: The effects of early-life exposure to cannabis on reproductive function biomarkers and genes were investigated in male and female Wistar rats in this study. Method: An initial computational analysis (molecular docking and induced fit docking) of some cannabinoids with reproductive enzymes; androgen and follicle stimulating hormone receptors was conducted. Overall, cannabichromene (CBC) had the best IFD scores and binding free energies for the two proteins studied and it interacted with notable amino acids within their active sites. Subsequently, forty (40) Wistar rats, 20 male and 20 female (24-28 days old, weighing 20-28 ± 2 g) were divided into two groups each and orally administered CBC for 21 days. Penile tissues, testes and ovaries, were collected for biochemical analysis (hormonal assays, enzyme activities, and metabolite concentrations), gene expressions, and histological evaluations. Results: Activities of arginase and phosphodiesterase-5 in the penile tissue were significantly increased, while nitric oxide and calcium levels were significantly (p < 0.05) decreased in the CBC-exposed groups relative to the control group. Semen analysis showed significantly more abnormalities and decreased concentration of spermatozoa in the CBC-exposed group compared to the control. Activities of 17ß-hydroxysteroid dehydrogenase and cholesterol level were decreased in both testes and ovaries of CBC-exposed groups. Furthermore, levels of testosterone, progesterone, luteinizing, and follicle-stimulating hormones were reduced in the serum of CBC rats. Moreover, relative expressions of androgen receptor and follicle-stimulating hormone receptor genes were significantly downregulated in the CBC-exposed groups. Histological evaluations revealed lesions, tubular necrosis, and cellular congestions in both the testes and ovaries. Conclusion: This study suggests that pre-puberty exposure to cannabis modulates reproductive functions via cannabichromene inhibition of steroidogenesis, stimulation of erectile dysfunction (modulation of intermediates and enzymes of the endothelial nitric oxide synthase (eNOS) pathway in the penile tissue), and downregulation of the expressions of genes associated with reproduction.

Antihypertensive activity of roasted cashew nut in mixed petroleum fractions-induced hypertension: An in vivo and in silico approaches.

Consumption of water polluted by crude oil is a major environmental problem typical in exploration areas. Numerous health complications such as high blood pressure, myocardial infarction, and other heart complications are prevalent and ravaging. These have gradually become age-defiling disease conditions that are usually maintained with lifestyle changes and diet control. The effect of dietary supplementation with 10% and 20% roasted cashew nuts (RCN) on systolic blood pressure and angiotensin converting enzyme I (ACE I) activities in mixed petroleum fraction (MPF) induced toxicity was studied in male Wistar rats through the modulation of the renin-angiotensin system. The phytochemicals in RCN were quantified using the high performance liquid chromatography (HPLC) technique. To predict likely binding affinity and stability, computational methods such as molecular docking, ADME, and molecular dynamic simulation were used. Out of the seven phytochemicals identified, rutin, gallic acid, and quercetin had the greatest quantities. Similarly, rutin had the highest binding affinities with ACE I, -10.7 kcal/mol, followed by quercetin, at -9.1 kcal/mol. During the molecular dynamics simulation, all of the identified phytochemicals demonstrated good pharmacokinetic capabilities and remained stable at their respective binding sites. Subsequent in vivo validation studies revealed that RCN was able to attenuate the effect of MPF by significantly (p < 0.05) lowering the systolic blood pressure and ACE I activity in comparison to the reference medication, atenolol. We recommend that cashew nuts be explored as dietary snacks as well as a low-cost, easily available component of supplements for the treatment of high blood pressure.

Occupational exposure in automobile repair workshops: toxicological effects of contaminated soil in Wistar rats.

Background: Automobile repair workshops contribute immensely to the generation of soil and water contamination. This study was conducted to compare the soil microbial load, heavy metals, and consequent toxicological effects, in three (3) automobile mechanic sites. Method: Soil samples were randomly collected from 3 different auto mechanic workshop in Abeokuta town of Ogun-State, Nigeria. Bacterial and fungal counts were done via standard procedures. High-performance liquid chromatography was employed for the aflatoxin quantification. Also, 24 Wistar rats were divided into 4 groups (n = 6), group 1-Control animals: orally administered distilled water, Group 2-administered soil sample solution from Ita Oshin mechanic site (I M), Group 3-administered soil sample solution from Ajebo mechanic site (A M), while Group 4-administered soil sample solution from Laderin mechanic site (L M), for two (2) weeks. Conventional methods were used to determine some physical and biochemical parameters in the rat's serum and tissues. Results: Eight bacterial and fungal genera were identified from the soil samples with Bacillus subtilis and Aspergillus niger occurring most frequently. The levels of heavy metals (lead, zinc, chromium, and cadmium) analyzed were higher than the WHO permissible heavy metal limits in all samples. The activity of liver function enzymes ALP, AST, and ALT was significantly increased in the serum of animals exposed to the 3 soil solution samples when compared with the control group, with the highest recorded at Site II. Conclusion: High level of heavy metals and aflatoxins could predispose to several health-related hazards when humans are exposed to contaminated soil solutions around and within automobile mechanic areas.

Antidiabetic Activity of Elephant Grass (Cenchrus Purpureus (Schumach.) Morrone) via Activation of PI3K/AkT Signaling Pathway, Oxidative Stress Inhibition, and Apoptosis in Wistar Rats.

Ethnopharmacological Relevance: The management of diabetes over the years has involved the use of herbal plants, which are now attracting interest. We assessed the antidiabetic properties of aqueous extract of C. purpureus shoots (AECPS) and the mechanism of action on pancreatic ß-cell dysfunction. Methods: This study was conducted using Thirty-six 36) male Wistar rats. The animals were divided into six equal groups (n = 6) and treatment was performed over 14 days. To induce diabetes in the rats, a single dose of 65 mg/kg body weight of alloxan was administered intraperitoneal along with 5% glucose. HPLC analysis was carried out to identified potential compounds in the extract. In vitro tests α-amylase, and α-glucosidase were analyzed. Body weight and fasting blood glucose (FBG) were measured. Biochemical parameters, such as serum insulin, liver glycogen, hexokinase, glucose-6-phosphate (G6P), fructose-1,6-bisphosphatase (F-1,6-BP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-ĸB), were analyzed. Additionally, mRNA expressions of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), B-cell lymphoma 2 (Bcl-2), and proliferating cell nuclear antigen (PCNA) were each evaluated. Results: This in vitro study showed inhibitory potency of Cenchrus purpureus extract (AECPS) as compared with the positive controls. AECPS showed a gradual decrease in alloxan-induced increases in FBG, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL-c), G6P, F-1,6-BP, malondialdehyde (MDA), IL-6, TNF-α, and NF-ĸB and increased alloxan-induced decreases in liver glycogen, hexokinase, and high density lipoprotein (HDL-c). The diabetic control group exhibited pancreatic dysfunction as evidenced by the reduction in serum insulin, homeostasis model assessment of ß-cell function (HOMA-ß), expressions of PI3K/AKT, Bcl-2, and PCNA combined with an elevation in homeostatic model assessment of insulin resistance (HOMA-IR). High performance liquid chromatography (HPLC) revealed 3-O-rutinoside, ellagic acid, catechin, rutin, and kaempferol in AECPS. Conclusion: AECPS showed efficient ameliorative actions against alloxan-induced pancreatic dysfunction, oxidative stress suppression as well as, inflammation, and apoptosis via the activation of PI3K/AKT signaling pathways.

Deciphering the Interactions of Bioactive Compounds in Selected Traditional Medicinal Plants against Alzheimer's Diseases via Pharmacophore Modeling, Auto-QSAR, and Molecular Docking Approaches.

Neurodegenerative diseases, for example Alzheimer's, are perceived as driven by hereditary, cellular, and multifaceted biochemical actions. Numerous plant products, for example flavonoids, are documented in studies for having the ability to pass the blood-brain barrier and moderate the development of such illnesses. Computer-aided drug design (CADD) has achieved importance in the drug discovery world; innovative developments in the aspects of structure identification and characterization, bio-computational science, and molecular biology have added to the preparation of new medications towards these ailments. In this study we evaluated nine flavonoid compounds identified from three medicinal plants, namely T. diversifolia, B. sapida, and I. gabonensis for their inhibitory role on acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) activity, using pharmacophore modeling, auto-QSAR prediction, and molecular studies, in comparison with standard drugs. The results indicated that the pharmacophore models produced from structures of AChE, BChE and MAO could identify the active compounds, with a recuperation rate of the actives found near 100% in the complete ranked decoy database. Moreso, the robustness of the virtual screening method was accessed by well-established methods including enrichment factor (EF), receiver operating characteristic curve (ROC), Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC), and area under accumulation curve (AUAC). Most notably, the compounds' pIC50 values were predicted by a machine learning-based model generated by the AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best models achieved for AChE, BChE and MAO were models kpls_radial_17 (R2 = 0.86 and Q2 = 0.73), pls_38 (R2 = 0.77 and Q2 = 0.72), kpls_desc_44 (R2 = 0.81 and Q2 = 0.81) and these externally validated models were utilized to predict the bioactivities of the lead compounds. The binding affinity results of the ligands against the three selected targets revealed that luteolin displayed the highest affinity score of -9.60 kcal/mol, closely followed by apigenin and ellagic acid with docking scores of -9.60 and -9.53 kcal/mol, respectively. The least binding affinity was attained by gallic acid (-6.30 kcal/mol). The docking scores of our standards were -10.40 and -7.93 kcal/mol for donepezil and galanthamine, respectively. The toxicity prediction revealed that none of the flavonoids presented toxicity and they all had good absorption parameters for the analyzed targets. Hence, these compounds can be considered as likely leads for drug improvement against the same.

Oral administration of marijuana produces alterations in serotonin 5-hydroxytryptamine receptor 3A gene (HTR3A) and electrolyte imbalances in brain of male Wistar rats.

The gene expression of serotonin 5-hydroxytryptamine receptor 3A (receptor 3A:HTR3A) as well as the concentration of electrolytes in male Wistar rats after administration of graded doses of marijuana extract was investigated. Twelve groups (3 control and 9 test groups) of 6 animals each were daily exposed to 12.5, 25 and 50 mg/kg b.w doses of petroleum ether extract of marijuana for 4, 8 and 12 weeks. The expressions of the gene were obtained using reverse transcriptase-polymerase chain reaction (RT-PCR) while electrolytes concentrations were determined. An upregulation of over 90% was observed in the expression of HTR3A after exposure to the highest dose throughout the exposure period. There was significant increase in the plasma potassium concentration at all doses while there was a decrease in the brain only at 50 mg/kg dose throughout the exposure period. Sodium concentration in the brain was not affected by the doses over the period of exposure but plasma concentration decreased significantly. All the doses of marijuana extract significantly increased calcium concentration in the brain after prolonged exposure but the plasma concentration remained unchanged. This suggests that different doses of marijuana extract alter the expression of serotonin receptor and electrolyte concentrations over a period of time with possible neurological consequences.

Vitamin K protects against 7,12-dimethylbenz(A)anthracene induced hepatotoxicity in Wistar rats.

Humans are daily exposed to 7,12-dimethylbenz(a)anthracene (DMBA), a well known polycyclic aromatic hydrocarbons (PAH). This study investigated the role of dietary intake of Vitamin K (VK), a polyphenolic compound, with potential antioxidative properties, against DMBA-induced hepatotoxicity. Sixty experimental animals (120-150 g) were divided into six groups (A-F): Control, DMBA (80 mg/kg bw) only, VK (0.00 g/10 kg) diet only, VK (7.5 g/10 kg) diet only, DMBA + VK (0.0 g/10 kg) diet and DMBA + VK (7.5 g/10 kg) diet. Single oral administration of DMBA (80 mg/kg body weight) to Wistar rats resulted in hepatic damage after 16 weeks. DMBA significantly (P < .05) decreased the activities of catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST) and glutathione peroxidase (GPx). Levels of reduced glutathione (GSH) and Vitamin C were significantly decreased with increase in malondialdehyde (MDA) and nitric oxide (NO) levels in serum and liver. Aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), γ-glutamyltransferase (GGT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) activities were significantly (P < .05) elevated in the serum but reduced in the liver of DMBA-administered group. Ingestion of 7.5 g/10 kg VK diet prevented the up regulations in inflammatory biomarkers (granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 17A (IL-17A)) which elicited liver damaged in the DMBA-treated group. DMBA induced hepatic alterations in DMBA-treated group but was restored to near normal in VK (7.5 g/10 kg) diet group. These findings suggest the protective potential of increased dietary intake of vitamin K against DMBA-induced hepatic dysfunction.