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.

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 1ß, 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.

Radiations and biodegradation techniques for detoxifying Carica papaya seed oil for effective dietary and industrial use.

Benzyl isothiocyanate (BITC) is toxic in high concentration. The capacity of Aspergillus niger, microwave and ultraviolet radiations to reduce the BITC levels in Carica papaya Linn seed oil were assessed in vitro. BITC at different concentrations were periodically exposed to microwave and ultraviolet radiations for 30 min and 10 h, respectively; and to identify Aspergillus niger for 4 days. Microwave radiation significantly reduced (p < 0.05) BITC levels (0.0272, 0.0544, and 0.0816 µmol) to 12.19, 8.99 and 27.5 % respectively within 15 min. Ultraviolet radiation significantly reduced (p < 0.05) BITC levels at all the concentrations. A. niger significantly increased (p < 0.05) BITC degradation on days 2 and 4 at 0.816, 1.36 and 2.72 nmol. Glutathione activity was significantly increased (p < 0.05) while glutathione S-transferase activity significantly reduced (p < 0.05) at all concentrations on days 3 and 4 respectively. The three techniques are possible models for improving the dietary consumption of the oil.

Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders.

Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.

Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions.

Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

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.

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 (Terminalia catappa), grape (Vitis vinifera), and common verbena (Verbena officinalis), 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.

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.

Epigenetic modifications associated with in utero exposure to endocrine disrupting chemicals BPA, DDT and Pb.

Endocrine disrupting chemicals (EDCs) are xenobiotics which adversely modify the hormone system. The endocrine system is most vulnerable to assaults by endocrine disruptors during the prenatal and early development window, and effects may persist into adulthood and across generations. The prenatal stage is a period of vulnerability to environmental chemicals because the epigenome is usually reprogrammed during this period. Bisphenol A (BPA), lead (Pb), and dichlorodiphenyltrichloroethane (DDT) were chosen for critical review because they have become serious public health concerns globally, especially in Africa where they are widely used without any regulation. In this review, we introduce EDCs and describe the various modes of action of EDCs and the importance of the prenatal and developmental windows to EDC exposure. We give a brief overview of epigenetics and describe the various epigenetic mechanisms: DNA methylation, histone modifications and non-coding RNAs, and how each of them affects gene expression. We then summarize findings from previous studies on the effects of prenatal exposure to the endocrine disruptors BPA, Pb and DDT on each of the previously described epigenetic mechanisms. We also discuss how the epigenetic alterations caused by these EDCs may be related to disease processes.

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 (Spinacia oleracea) 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.

Naringin enhances reverse cholesterol transport in high fat/low streptozocin induced diabetic rats.

Naringin, a citrus-derived flavonoid with antihyperglycemic, antihyperlipidemic, and antioxidant properties, is reported to be a useful nutraceutical in the management of diabetes and its complications. This study investigated the mechanism of antiatherogenic properties of naringin in type 2 diabetes (T2DM) using high fat-low streptozocin rat model of T2DM. Rats were treated daily with 50, 100 and 200 mg/kg naringin orally for 21days. Levels of biomarkers of T2DM, lipid profile and activity of paraoxonase (PON) were assayed spectrophotometrically. The levels of expression of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr), scavenger receptor class B member 1 (Scarb1), aryl hydrocarbon receptor (Ahr), hepatic Lipase (Lipc), and lecithin-cholesterol acyltransferase (Lcat) were assessed using relative reverse transcriptase polymerase chain reaction technique. Naringin treatment resulted in a dose-dependent significant (p < 0.05) decrease in the levels of plasma cholesterol and triglyceride from 84.84 ±â€¯1.62 to 55.59 ±â€¯1.50 mg/dL and 123.03 ±â€¯15.11 to 55.00 ±â€¯0.86 mg/dL, respectively, at 200 mg/kg naringin. In the liver, Scarb1 and Ahr were significantly (p < 0.05) upregulated at 200 mg/kg naringin while Lipc and Lcat were significantly (p < 0.05) upregulated by 50 mg/kg naringin. T2DM-induced decrease in PON activities in the plasma, liver and HDL was significantly (p < 0.05) reversed by 200 mg/kg naringin treatment. These genes play critical roles in reverse cholesterol transport and hence our results showed that the antiatherogenic property of naringin in T2DM involves enhancement of reverse cholesterol transport and PON activity.

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.

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 < 0.05) decrease in liver dysfunction indices and markers of oxidative damage compared with the control. In addition, statistically the diets significantly decreased (p < 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.

Acute aflatoxin B1 - Induced hepatotoxicity alters gene expression and disrupts lipid and lipoprotein metabolism in rats.

In this study, alterations in lipid metabolism associated with acute aflatoxin B1 (AFB1) induced hepatotoxicity and gene expression changes underlying these effects were investigated. Rats were orally administered three doses (0.25 mg/kg, 0.5 mg/kg and 1.0 mg/kg) of AFB1 for seven days; after which blood was collected and liver excised. Lipid profiles of plasma and liver were determined spectrophotometrically while the expression of genes associated with lipid and lipoprotein metabolism was assayed by reverse transcriptase polymerase chain reaction. Acute exposure to AFB1 increased the levels of plasma and liver cholesterol, triglycerides and phospholipids. AFB1 at 0.5 mg/kg and 1.0 mg/kg resulted in a dose-dependent (1.2 and 1.5 fold, respectively) downregulation of hepatic Cpt1a with a concomitant 1.2 and 1.5 fold increase in the level of plasma FFA, respectively. A similar observation of 1.2 and 1.3 fold increase was also observed in plasma triglyceride concentration, at both respective doses. AFB1 also decreased the relative expression of Ahr, Lipc and Lcat whereas, it upregulated Scarb1 in a dose dependent manner. AFB1-induced dysregulation of the expression of lipid and lipoprotein metabolizing genes may be one mechanism linking AFB1 to altered lipid metabolism and ultimately risk for coronary heart disease.

Inability of legumes to reverse diabetic-induced nephropathy in rats despite improvement in blood glucose and antioxidant status.

Diabetes mellitus has assumed epidemic proportions in most parts of the world, including developing countries, with vascular and renal complications being the major causes of death. Evidence is emerging that legumes play a beneficial role in diabetes and its associated complications. In connection with the above, four groups of alloxan-induced diabetic rats were fed on four different legume-based (Vigna unguiculata ssp. dekindtiana var. dekindtiana, V. unguiculata ssp. unguiculata, Sphenostylis stenocarpa, and Vigna subterranean) diets. Feeding rats with these diets for 5 weeks resulted in reduction of plasma glucose and changes in biomarkers of oxidative stress-namely, superoxide dismutase (SOD), peroxidase (PER), and thiobarbituric acid-reactive substances (TBARS). None of the legumes reversed the increase in plasma total protein associated with diabetes. The legumes increased PER activity and decreased the level of TBARS in the erythrocytes. A decrease in the activities of PER and SOD was observed in the kidneys of the diabetic rats. Nitric oxide (NO) production in the erythrocytes of the diabetic rats (as an index of diabetic endothelial dysfunction) increased for all the legumes in the following order: V. unguiculata ssp. unguiculata, V. unguiculata ssp. dekindtiana var. dekindtiana, V. subterranean, and S. stenocarpa. There was a significant increase (P < .05) in the uric acid concentration in the kidneys of treated rats. It is concluded that while the legumes have beneficial effects on reduction of hyperglycemia and strengthening the antioxidant status of the diabetic animals, the increased kidney uric acid concentration should be of concern.