Fermented Rooibos tea (Aspalathus linearis) Ameliorates Sodium Fluoride-Induced Cardiorenal Toxicity, Oxidative Stress, and Inflammation via Modulation of NF-κB/IκB/IκKB Signaling Pathway in Wistar Rats.

High dose of fluoride intake is associated with toxic effects on kidney and cardiac tissues. This study evaluated the potential protective effect of fermented rooibos tea (RTE) on sodium fluoride (NaF)-induced cardiorenal toxicity in rats. Male Wistar rats (n = 56) were randomly allocated into one of seven equal groups: control, NaF (100 mg/kg orally), NaF + RTE (2%, w/v), NaF + RTE (4%, w/v), NaF + lisinopril (10 mg/kg orally), 2% RTE, and 4% RTE. The experiment lasted for 14 days and RTE was administered to the rats as their sole source of drinking fluid. NaF induced cardiorenal toxicity indicated by elevated level of urea, creatinine, LDH, creatinine kinase-MB, and cardiac troponin I in the serum, accompanied by altered histopathology of the kidney and heart. Furthermore, levels of H2O2, malondialdehyde, and NO were elevated, while GSH level was depleted in the kidney and heart due to NaF intoxication. Protein levels of c-reactive protein, TNFα, IL-1B, and NF-κB were increased by NaF in the serum, kidney, and heart. RTE at 2% and 4% (w/v) reversed cardiorenal toxicity, resolved histopathological impairment, attenuated oxidative stress and inhibited formation of pro-inflammatory markers. RTE at both concentrations down-regulates the mRNA expression of NF-κB, and upregulates the mRNA expression of both IκB and IκKB, thus blocking the activation of NF-κB signaling pathway. Taken together, these results clearly suggest that the protective potential of rooibos tea against NaF-induced cardiorenal toxicity, oxidative stress, and inflammation may be associated with the modulation of the NF-κB signaling pathway.

Hepatoprotective Effect of Morin Hydrate in Type 2 Diabetic Wistar Rats Exposed to Diesel Exhaust Particles.

Studies have shown that exposure to air pollutants such as diesel exhaust particles (DEP) exacerbate diabetes complications. Morin hydrate (MH), a plant bioflavonoid, provides hepatoprotection due to its diverse pharmacological properties. This study examines the hepatoprotective effects of MH in Wistar rats with type 2 diabetes exposed to diesel exhaust (DE). Procured male Wistar rats (n = 60) were separated into 12 groups of five rat each. Type 2 diabetes was induced following oral therapy with fructose solution and one-time injection of 45 mg/kg of streptozotocin (STZ). The DEP extract was administered by nasal instillation, whereas MH was administered via oral gavage. Biochemical assays were used to determine the effect of MH on diabetic rats and DEP-exposed diabetic rats with respect to liver function indices (AST and ALT), liver antioxidants (SOD, CAT, Gpx, and GSH), lipid profile, and oxidative stress marker (conjugated diene and lipid peroxidation). The mRNA expression of PI3K/AKT/GLUT4 and AMPK/GLUT4 signaling pathways were quantified using RT-PCR. The results show that normal rats, diabetic rats, and diabetic rats exposed to DEP exhibited a substantial decrease in oxidative stress indicators, serum lipid profile, and levels of AST and ALP, as well as an increase in liver natural antioxidants following oral administration of MH. The gene expression study demonstrated that MH promotes the activation of the insulin signaling pathways which facilitates the uptake of glucose from the blood. This study suggests that MH offered hepatoprotection in type 2 diabetic rats and DEP exposed diabetic rats.

Diphenyl diselenide modulates antioxidant status, inflammatory and redox-sensitive genes in diesel exhaust particle-induced neurotoxicity.

This study seeks to determine the influence of diphenyl diselenide (DPDSe) on redox status, inflammatory and redox-sensitive genes in diesel exhaust particle (DEP)-induced neurotoxicity in male albino rats. Male Wistar albino rats were administered nasally with DEP (30 and 60 µg/kg) and treated with intraperitoneal administration of 10 mg/kg DPDSe. Non-enzymatic (lipid peroxidation and conjugated diene concentrations) and enzymatic (catalase, superoxide dismutase, glutathione peroxidase) antioxidant indices and activity of acetylcholinesterase enzyme were evaluated in brain tissues of the rats. Furthermore, the expression of genes linked to oxidative stress (HO-1, Nrf2), pro-inflammatory (NF-KB, IL-8, TNF-α) anti-inflammatory (IL-10) and brain-specific (GFAP, ENO-2) genes were also determined. The results indicated that DPDSe caused a notable reduction in the high levels of thiobarbituric acid reactive substances and conjugated diene observed in the brain of DEP-administered rats. DPDSe also reversed the observed reduction in catalase, superoxide dismutase and glutathione peroxidase enzyme activities in the brain of DEP-administered rats. Lastly, the downregulation of genes associated with redox homeostasis, anti-inflammatory and brain-specific genes and upregulation of pro-inflammatory genes observed in the DEP-treated groups were ameliorated by DPDSe. The immediate restoration of altered biochemical conditions and molecular expression in the brain of DEP-treated rats by DPDSe further validates its use as a promising therapeutic candidate for restoring neurotoxicity linked with DEP-induced oxidative stress.

Momordica charantia silver nanoparticles modulate SOCS/JAK/STAT and P13K/Akt/PTEN signalling pathways in the kidney of streptozotocin-induced diabetic rats.

OBJECTIVES: Diabetes nephropathy (DN) is one of the complications of diabetes mellitus (DM) marked by gradual progressive loss of renal function. SOCS/JAK/STAT and PI3K/Akt/PTEN signalling pathways are among the chain of interactions implicated in the onset, progression and pathology of DN. Momordica charantia (bitter melon) is often used in folk medicine as therapy for DM due to its hypoglycemic properties. This study was designed to evaluate M. charantia silver nanoparticles' therapeutic effect on DN-induced by streptozotocin (STZ) in Wistar rats. METHODS: The M. charantia nanoparticles used was synthesized using the filtrate from the plant methanolic extract added to 1 mM concentration of aqueous silver nitrate. DM was induced in Wistar rats by intraperitoneal injection of STZ (65 mg/kg). The animals' treatment groups were divided into; Diabetic control (65 mg/kg STZ), Control, and groups treated with silver nitrate (10 mg/kg), M. charantia nanoparticles (50 mg/kg), metformin (100 mg/kg), and plant extract (100 mg/kg). Treatment was terminated after 11 days. RT-PCR determined renal mRNA expression of Akt, PI3k, PTEN, TGF-ß, JAK2, STAT3, STAT5, SOCS3, SOCS4 and glucokinase (GCK). Consequently, characterized compounds from M. charantia identified from literatures were docked with PI3K, JAK2 and TGF-ß and STAT3 to retrieve potential hits. RESULTS: Oral administration of M. charantia nanoparticles (50 mg/kg) to STZ-induced diabetic untreated rats significantly ((p < 0.05) down-regulated the mRNA expression of Akt, PI3k, TGF-ß, JAK2, STAT3 and upregulated the mRNA expression of PTEN, SOCS3 and SOCS4, thus establishing the role of M. charantia nanoparticles in alleviating DN in diabetic rats. Additionally, there was a significant up-regulation of glucose metabolizing gene (glucokinase) upon administering M. charantia nanoparticles. Molecular docking results showed 12 compounds from bitter melon with docking score ranging from -6.114 kcal/mol to -8.221 kcal/mol that are likely to exert anti-diabetic properties. CONCLUSION: Observation drawn from this study suggests that M. charantia nanoparticles ameliorate DN through regulation of SOCS/JAK/STAT and PI3K/Akt/PTEN signalling pathways.

Molecular docking studies, molecular dynamics and ADME/tox reveal therapeutic potentials of STOCK1N-69160 against papain-like protease of SARS-CoV-2.

SARS-CoV-2 is a new strain of Coronavirus that caused the pneumonia outbreak in Wuhan, China and has spread to over 200 countries of the world. It has received worldwide attention due to its virulence and high rate of infection. So far, several drugs have experimented against SARS-CoV-2, but the failure of these drugs to specifically interact with the viral protease necessitates urgent measure to boost up researches for the development of effective therapeutics against SARS-CoV-2. Papain-like protease (PLpro) of the viral polyproteins is essential for maturation and infectivity of the virus, making it one of the prime targets explored for SARS-CoV-2 drug design. This study was conducted to evaluate the efficacy of ~ 50,000 natural compounds retrieved from IBS database against COVID-19 PLpro using computer-aided drug design. Based on molecular dock scores, molecular interaction with active catalytic residues and molecular dynamics (MD) simulations studies, STOCK1N-69160 [(S)-2-((R)-4-((R)-2-amino-3-methylbutanamido)-3-(4-chlorophenyl) butanamido) propanoic acid hydrochloride] has been proposed as a novel inhibitor against COVID-19 PLpro. It demonstrated favourable docking score, the free energy of binding, interacted with key amino acid residues necessary for PLpro inhibition and also showed significant moderation for parameters investigated for ADME/tox (Adsorption, distribution, metabolism, excretion and toxicological) properties. The edge of the compound was further established by its stability in MD simulation conducted for 30 ns employing GROMACS software. We propose that STOCK1N-69160 is worth further investigation for preventing SARS-CoV-2.

Involvement of fat mass and obesity gene (FTO) in the anti-obesity action of Annona muricata Annonaceae: in silico and in vivo studies.

Background: Annona muricata (Annonaceae) known as soursop is a common tropical plant species known for its numerous medicinal properties including obesity. The underlying mechanism of anti-obesity effect of A. muricata was investigated. The fat mass and obesity associated protein (FTO) is a validated potential target for anti-obesity drugs. Methods: The interaction of compounds previously characterized from A. muricata was investigated against FTO using Autodock Vina. Also, modulation of FTO and STAT-3 mRNA expression by A. muricata was investigated in high fat diet induced obese rats (HFDR) using RT-PCR. Results: A significant up-regulation of FTO gene was observed in HFDR when compared to control rats, while administration of A. muricata (200 mg/kg) significantly (p < 0.05) down-regulated FTO gene expression when compared to HFDR group. The effect of obesity on STAT-3 gene expression was also reversed by A. muricata (200 mg/kg). In silico study revealed annonaine and annonioside (-9.2 kcal/mol) exhibited the highest binding affinity with FTO, followed by anonaine and isolaureline (-8.6 kcal/mol). Arg-96 is a critical amino acid enhancing anonaine, isolaureline-FTO binding. Conclusion: This study suggests the possible anti-obesity mechanism of A. muricata is via down-regulation of FTO with concomitant up-regulation of STAT-3 genes. This study confirmed the use of this plant in the management of obesity and the probable compounds responsible for its antiobesity effect are annonaine and annonioside.

Potential use of bitter melon (Momordica charantia) derived compounds as antidiabetics: In silico and in vivo studies.

Momordica charantia (bitter lemon) belongs to the cucurbitaceae family which has been extensively used in traditional medicines for the cure of various ailments such as cancer and diabetes. The underlying mechanism of M. charantia to maintain glycemic control was investigated. GLP-1 and DPP-4 gene modulation by M. charantia (5-20% inclusion in rats diet) was investigated in vivo by RT-PCR and possible compounds responsible for diabetic action predicted through in silico approach. Phytochemicalss previously characterized from M. charantia were docked into glucacon like peptide-1 receptor (GLP-1r), dipeptidyl peptidase (DPP4) and Takeda-G-protein-receptor-5 (TGR5) predicted using Autodock Vina. The results of the in silico suggests momordicosides D (ligand for TGR5), cucurbitacin (ligand for GLP-1r) and charantin (ligand for DPP-4) as the major antidiabetic compounds in bitter lemon leaf. M. charantia increased the expression of GLP-1 by about 295.7% with concomitant decreased in expression of DPP-4 by 87.2% with 20% inclusion in rat's diet. This study suggests that the mechanism underlying the action of these compounds is through activation of TGR5 and GLP-1 receptor with concurrent inhibition of DPP4. This study confirmed the use of this plant in diabetes management and the possible bioactive compounds responsible for its antidiabetic property are charantin, cucurbitacin and momordicoside D and all belong to the class of saponins.

Differential sensitivity and responsiveness of three human cell lines HepG2, 1321N1 and HEK 293 to cadmium.

Cadmium (Cd) is a toxic heavy metal with no uniform mechanism of toxicity. In this the present study, the toxic effect of 5, 10 and 50 microM of Cd chloride was compared in three human cell lines; a human hepatoma cell line HepG2, a human astrocytoma cell line 1321N1, and a human embryonic kidney cell HEK 293. The results indicate a decrease in the viability of all three cell lines following exposure to Cd with HepG2 cells (IC50=13.96 microM) showing the most sensitivity when measured using the MTT assay. There was significant increase in lactate dehydrogenase leakage, DNA damage, malondialdeyde and antioxidant enzymes activities in all three cell lines especially at 50 microM Cd. Significant decreases in ATP production were also observed at all Cd concentrations in HepG2 and HEK 293 cell lines. ROS levels significantly increase and GSH/GSSG ratio significantly decrease in all the three cell lines after Cd exposure, but these effects were attenuated by the presence of N-acetylcysteine (NAC). The present study therefore shows that ROS production and glutathione (GSH) depletion may play a role in Cd-induced toxicity in all the three cell lines. The endogenous levels of protective enzymes as well as their responsiveness are likely to determine a cell's susceptibility to Cd.