Effects of Bryophyllum pinnatum on Dysfunctional Autophagy in Rats Lungs Exposed to Zinc Oxide Nanoparticles.

Lung inflammation as a result of exposure to toxicants is a major pathological problem. Autophagy (AP) is a process of cell self-digestion and can be disrupted by environmental toxicants, leading to oxidative stress, inflammation and cellular damage. Bryophyllum pinnatum (Lam.) Oken has been used in folklore medicine to manage pathological abnormalities, including inflammation, but mechanisms remain unclear. This work investigated the effects of Bryophyllum pinnatum ethanol leaf extract (BP) on dysfunctional AP in the lungs of Wistar rats exposed to zinc oxide nanoparticles (ZONPs). The experimental rats were orally administered ZONPs for seven days (10 mg/kg). Some exposed rats were post-treated with BP (62.5 and 125 mg/kg) through oral gavage. Oxidative stress, inflammation, and apoptotic and autophagic parameters were assessed using biochemical assay and gene expression methods. Several indices of pulmonary damage were also evaluated. PCR analysis suggested that ZONP downregulated the expression of pro-autophagy-related genes (Beclin 2, ATG5, DAPK, and FOXP3) and upregulated the expression of the TNF-alpha, NF-Kb, LC3 and Bcl2 genes. In contrast, BP significantly (p < 0.0001) reversed ZONP-induced pulmonary toxicity and oxidative stress. It reduced MDA levels and increased SOD, CAT, GSH and GPxD activities. BP significantly (p < 0.0001) downregulated the expressions of proinflammatory genes (IL-6 and JNK) and upregulated the expressions of IL-10, CAT and SOD genes in ZONP-exposed rats. BP restored the lung's histoarchitectural structure after ZNOP-induced distortion. The results suggested that BP has antioxidant and anti-inflammatory properties, and could effectively restore ZNOP-induced dysfunctional AP in the lungs of Wistar rats.

Anacardium occidentale leaves extract and riboceine mitigate hyperglycemia through anti-oxidative effects and modulation of some selected genes associated with diabetes.

Background: Diabetes mellitus (DM) is one of the leading causes of death globally and complications of DM have become a major health concern. Anacardium occidentale is a plant widely recognized for its hypoglycemic properties and traditionally used in developing nations as remedy for DM treatment. Riboceine is a supplement that enhances production of glutathione and known for its vital role in supporting cellular function. This study was designed to evaluate the antidiabetic and antioxidant potential of riboceine and ethanolic extract of A. occidentale leaves in streptozotocin (STZ)-induced diabetic rats. Method: Twenty-nine adult male Wistar rats were induced with DM intraperitoneally using a single dose of STZ (70 mg/kg). The STZ-induced rats were divided into groups and administered the same dose (100 mg/kg) of A. occidentale leaves extract and riboceine via gastric gavage at the dose (100 mg/kg) for seventeen days while metformin (40 mg/kg) was used as positive control. Fasting blood glucose and weight of the model rats were examined periodically. Activities of total protein, creatinine, urea, antioxidants (SOD, GSH and GPX), and level of serum insulin were determined. Expression of diabetes related genes including pancreas (Insulin, pdx-1, P16NK4A, and Mki-67), Liver (FAS, ACC, and GFAT) and KIM-1 genes were also determined. Results: Data showed that treatment of STZ-induced diabetic rats with A. occidentale and riboceine at the same dose significantly (p < 0.05) ameliorated hyperglycemic effects by improving hepatic and renal functions and antioxidants, preventing hepatic fat accumulation by downregulation of ACC, FAS and GFAT expression, improving ß-cell functions through up-regulation of pancreatic insulin, P16NK4A, Mki-67 and pdx-1 expression. Induction of diabetes upregulated mRNA expression of KIM-1, which was ameliorated after treatment of the rats with A. occidentale and riboceine. Conclusion: The results obtained in this study demonstrate significant antidiabetic properties of ethanolic extract of A. occidentale and riboceine.

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.

Newly designed compounds from scaffolds of known actives as inhibitors of survivin: computational analysis from the perspective of fragment-based drug design.

Survivin is an apoptosis suppressing protein linked to different forms of cancer. As it stands, there are no approved drugs for the inhibition of survivin in cancer cells despite a number of promising compounds in clinical trials. This study designed a new set of compounds from fragments of active survivin inhibitors to potentiate their binding with survivin at BIR domain. Three hundred and five (305) fragments made from eight potent inhibitors of survivin were reconstructed to form a new set of compounds. The compounds were optimized using R group enumeration and bioisostere replacement after extensive docking analysis. The optimised compounds were filtered by a validated pharmacophore model to reveal how well they are aligned to the pharmacophore sites. Molecular docking of the well aligned compounds revealed the top-scoring compounds; and these compounds were compared with the eight inhibitors used as template for fragment-based design on the basis of binding affinity (rigid and flexible docking), predicted pIC50 and intermolecular interactions. The electronic behaviours (global descriptors, HOMO/LUMO, molecular electrostatic potential and Fukui functions) of newly designed compounds were calculated to investigate their reactivity and atomic sites prone to neutrophilic/electrophilic attack. The nine newly designed compounds had better rigid and flexible docking scores, free energy of binding and intermolecular interactions with survivin at BIR domain than the eight active inhibitors. Based on frontier molecular orbitals, OPE-3 was found to be the most reactive and less stable compound (0.13194 eV), followed by OPE-4 and OPE-9. The global descriptive parameters showed that OPE-3 had highest softness value (7.5245 eV) while OPE-8 recorded the maximum hardness value (0.08486 eV). The well-validated QSAR model also showed that OPE-3, OPE-7 and OPE-8 had the most significant bioactivity of all the inhibitors. This study thus provides new insight into the design of compounds capable of modulating the activity of survivin. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00108-8.