Panax ginseng ameliorates hepatorenal oxidative alterations induced by commercially used cypermethrin in male rats: experimental and molecular docking approaches.

Cypermethrin (CYP) is a synthetic pyrethroid utilized as an insecticide in agriculture and various pest eradication programs. However, it induces numerous health hazards for animals and humans. Therefore, the current study used Panax ginseng root extract (ginseng) to reduce the hepatorenal damage caused by commercially used CYP. Thirty-two male Wistar albino rats were distributed into control, ginseng (300 mg/kg B.W/day), CYP (4.67 mg/kg B.W.), and Ginseng+CYP (rats received both CYP and ginseng). All treatments were administered orally for 30 consecutive days. Cypermethrin induced harmful effects on hepatic and renal tissues through a substantial decline in body weight in addition to a considerable increase in liver enzymes, functional renal markers, and cholesterol. Also, CYP significantly decreased acetylcholinesterase (AChE) activity and increased pro-inflammatory cytokines (interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α)). Moreover, a marked increase in malondialdehyde level with a significant drop in reduced glutathione level and total superoxide dismutase (T-SOD) and catalase (CAT) activities was reported in the CYP group in kidney and liver tissues. Additionally, CYP exhibited affinities to bind and inhibit AChE and antioxidant enzymes (T-SOD and CAT) in rats following the molecular docking modeling. The apparent hepatorenal oxidative damage was linked with obvious impairments in the liver and kidney histoarchitecture, immunohistochemical staining of B cell lymphoma-2 (Bcl-2), and caspase-3 proteins. Ginseng reduced CYP's oxidative alterations by repairing the metabolic functional markers, improving antioxidant status, reducing the inflammatory response, and enhancing the molecular docking evaluation. It also ameliorated the intensity of the histopathological alterations and improved the immunohistochemical staining of Bcl-2 and caspase-3 proteins in the liver and kidney tissues. Finally, concomitant oral administration of ginseng mitigated CYP-prompted hepatorenal damage through its antioxidant, anti-inflammatory, and anti-apoptotic potentials.

Integrated serum pharmacochemistry and network pharmacology analyses reveal the bioactive metabolites and potential functional mechanism of ground cherry (Physalis pruinosa L.) in treatment of type 2 diabetes mellitus in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Different Physalis plants have been widely employed in traditional medicine for management of diabetes mellitus. Previous studies with respect to the in vivo antidiabetic activity of Physalis plants illustrated that they improved glucose and lipid metabolism in streptozotocin (STZ) -induced diabetic rats yet the mechanism of action of bioactive constituents of the different organs of Physalis plants on diabetes remains obscure. AIM OF STUDY: Our objective is to study the effects of the different organs of ground cherry (P. pruinosa) on diabetes in rat models and elucidate their mechanism of actions through serum pharmacochemistry combined to network pharmacology analyses and in-vivo testing. MATERIALS AND METHODS: Characterization of the constituents in the drug-dosed serum samples relative to the blank serum after treatment with different extracts was performed by UPLC -MS/MS technique. The absorbed metabolites where then subjected to network pharmacology analysis to construct an interaction network linking "compound-target-pathway". In vivo verification was implemented to determine a hypothesized mechanism of action on a STZ and high fat diet induced type II diabetes mellitus (T2DM) model based on functional and enrichment analyses of the Kyoto Encyclopedia of Genes and Genome and Gene Ontology. RESULTS: Identification of a total of 73 compounds (22 prototypes and 51 metabolites) derived from P. pruinosa extracts was achieved through comparison of the serum samples collected from diabetic control group and extracts treated groups. The identified compounds were found to belong to different classes according to their structural type including withanolides, physalins and flavonoids. The absorbed compounds in the analyzed serum samples were considered as the potential bioactive components. The component-target network was found to have 23 nodes with 17 target genes including MAPK8, CYP1A1 and CYP1B1. Quercetin and withaferin A were found to possess the highest combined score in the C-T network. Integrated serum pharmacochemistry and network pharmacology analyses revealed the enrichment of leaves extract with the active constituents, which can be utilized in T2DM treatment. In the top KEGG pathways, lipid and atherosclerosis metabolic pathways in addition to T2DM pathways were found to be highly prioritized. The diabetic rats, which received leaves extract exhibited a substantial increment in GLUT2, INSR, IRS-1, PI3K-p85 and AKT-ser473 proteins by 105%, 142%, 109%, 81% and 73%, respectively relative to the untreated diabetic group. The immunoblotting performed for MAPK and ERK1/2 part of the inflammatory pathway studied in STZ induced diabetic rats revealed that leaves, calyces and stems extracts resulted in a substantial diminish in p38-MAPK, ERK 1/2, NF-κB, and TNF-α. Histopathological examination revealed that the hepatic histoarchitecture was substantially improved in the leaves, stems, and clayces-treated rats in comparison with untreated diabetic rats. Further, pancreatic injuries, which induced by STZ were dramatically altered by the treatment with P. pruinosa leaves, calyces and stems extracts. ß-cells in diabetic rats received leaves extract disclosed moderate insulin immunostaining with a notable increase in the mean insulin area%. CONCLUSIONS: The study in hand offers a comprehensive study to clarify the bioactive metabolites of the different organs of P. pruinosa. The basic pharmacological effects and underlying mechanism of actions in the management of STZ and high fat diet induced T2DM were specifically covered in this paper.

Studying ferroptosis and pyroptosis as new cell death mechanisms induced by ionizing radiation in Ehrlich solid tumor-bearing mice.

OBJECTIVE: Our objective was to explore the effect of different fractionation schedule on ferroptosis and pyroptosis biomarkers as new cell death mechanisms induced by IR. MATERIALS AND METHODS: This study included 40 tumor bearing mice divided into: Group I: Includes 8 untreated tumor-bearing mice. Group II: Includes 8 tumor bearing mice exposed to single dose 6 Gy of IR. Group III: Includes 8 tumor bearing mice exposed to 12 Gy in 2 fractions (2 × 6 Gy) of IR. Group IV: Includes 8 tumor bearing mice exposed to 12 Gy in 3 fractions (3 × 4 Gy) of IR. Group V: Includes 8 tumor bearing mice exposed to 8 Gy in 4 fractions (4 × 2 Gy) of IR. IL-1ß, IL-18, and GSDMD-CT levels were assessed by ELISA. PTGS2 and ACSL4 expression were assessed by RT-PCR. RESULTS: (2 × 6 Gy) group showed the highest ACSL4 expression followed by (3 × 4 Gy), then (4 × 2 Gy) and finally 6 Gy. (2 × 6 Gy) group resulted in the highest PTGS2 expression followed by (3 × 4 Gy), then 6 Gy, and finally (4 × 2 Gy). MDA significantly increased at (2 × 6 Gy), (3 × 4 Gy), and 6 Gy groups and insignificantly increased at (4 × 2 Gy) group. Iron significantly increased at (2 × 6 Gy), (3 × 4 Gy), and (4 × 2 Gy) groups and insignificantly at 6 Gy. Glutathione was significantly decreased at (2 × 6 Gy), (3 × 4 Gy), and (4 × 2 Gy) groups and insignificantly at 6 Gy. GSDMD-CT, IL-1ß, and IL-18 levels significantly reduced in tumor tissues after exposure to IR at all doses. CONCLUSION: High dose per fraction regimens induce the expression of ferroptosis markers more than low dose per fraction regimen and single dose of IR. IR at all doses induces pyroptotic cell death.

Date palm fruit extract ameliorated pancreatic apoptosis, endocrine dysfunction and regulatory inflammatory cytokines in Streptozotocin-induced diabetes in rats.

The current work studied the mechanism(s) and ability by which date palm (Phoenix dactylifera L.) fruit extract (DPE) inspired a glucose-lowering impact in rats suffering from diabetes. Forty-eight albino rats were divided into six various experimental treatments after induction of diabetes by intraperitoneal infusion of streptozotocin (45 mg/kg bwt) as follows: normal control, DPE, diabetic control, diabetic glibenclamide (GLI), diabetic DPE, and diabetic GLI plus DPE-treated groups. In animals euthanized after 8 weeks, blood and pancreatic tissue samples were assembled to assess different biochemical and histopathological changes. The expressions of insulin, B cell lymphoma-2 (Bcl-2), and cysteine aspartate-specific protease-3 (caspase-3) in islet ß cells were also evaluated using immunohistochemical assessment. Diabetic rats exhibited hyperglycemia; increment of pancreatic malondialdehyde (lipid peroxidation biomarker), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß); and decrement of plasma insulin and pancreatic antioxidants: glutathione, superoxide dismutase, and catalase values. Also, the pancreatic islets exhibited histopathological and morphometric alternations associated with weak positive insulin and Bcl-2 immunoreactivity and strong positive caspase-3 immunoreactivity. DPE and/or GLI, an anti-diabetic drug, improved the pancreatic histoarchitecture and improved ß cell function and structure, which increased insulin levels and improved the insulin, Bcl-2, and caspase-3 immunoreactivity in diabetic rats. Nevertheless, the combined DPE and GLI therapy revealed a significant recovery and restoration of ß cells' structure and function. The date palm fruit has anti-apoptotic, anti-inflammatory, and antioxidant activities and hypoglycemic effects, which in turn play a pivotal role in avoiding the progression of diabetes mellitus. Moreover, it could potentiate the glucose-lowering activity of anti-diabetic drugs.

Apoptosis and astrogliosis perturbations and expression of regulatory inflammatory factors and neurotransmitters in acrylamide-induced neurotoxicity under ω3 fatty acids protection in rats.

This study was aimed to investigate the potential ameliorative effects of omega-3 (ω3) fatty acids against acrylamide (ACR)-induced neurotoxicity. Thirty-two adult male Sprague Dawley rats were randomly assigned into four groups (n = 8) as follows: control, ω3 fatty acids (1000 mg/kg bwt/day orally), ACR-treated (50 mg/kg bwt/day IP) and ACR plus ω3 fatty acids group. Treatments were performed every other day for 21 consecutive days. ACR induced abnormal gait and elevated serum levels of proinflammatory cytokines (IL-6 and TNF-α), brain and spinal cord MDA levels and decreased brain and spinal cord GSH levels. Moreover, it reduced neurotransmitters (acetylcholine, GABA, serotonin and noradrenaline levels) and increased AChE activity in brain tissues. Histopathologically, ACR caused various degenerative changes, necrosis and glial cell activation in the cerebrum, cerebellum, hippocampus, spinal cord and sciatic nerve. Likewise, the histomorphometric analysis was constant with ACR-induced neurotoxicity. The ACR induced axonal atrophy and myelin disruption and decreased g-ratio of the sciatic nerve. Immunohistochemically, strong positive expressions of apoptotic marker caspase-3 and astroglial GFAP in the examined tissues were detected. Contrariwise, concurrent administration of ω3 fatty acids partially attenuated ACR impacts, as it improved the gait performance, reduced oxidative stress and pro-inflammatory cytokines, and modulate the levels of the neurotransmitters. It also ameliorated the intensity of ACR-induced histopathological and histomorphometric alterations within the examined nervous tissues. It could be concluded that ω3 fatty acids have antioxidant, anti-inflammatory and anti-apoptotic potentials against ACR neurotoxicity via suppression of oxidative stress, lipid peroxidation and pro-inflammatory cytokines, and inhibition of AChE activity and downregulation of caspase-3 and GFAP expressions in the nervous tissues.

Partial ameliorative effect of Moringa leaf ethanolic extract on the reproductive toxicity and the expression of steroidogenic genes induced by subchronic cadmium in male rats.

The impact of Moringa oleifera leaf ethanol extract (MOLEE) was assessed on the expression of the steroidogenic genes (steroidogenic acute regulatory protein (StAR) and cytochrome P450c17 subfamily a (CYP17a) and luteinizing hormone receptor (LHR) gene) as well as on the cadmium chloride (CdCl2)-induced reproductive toxicity for 56 days in male rats. Four groups were used: control, Moringa-treated (MOLEE), CdCl2-treated, and CdCl2 + MOLEE groups. The reproductive toxicity of CdCl2 was confirmed; it caused a significant decrease in the accessory sex organ weights, testosterone level, testicular GST level, elevated MDA level (lipid peroxidation indicator), and histopathological alterations in seminiferous tubules, prostate, seminal vesicles, and epididymis as well as sperm characteristics. It also induced downregulation in the expression of StAR and CYP17a genes without change in the expression LHR gene. Eleven active compounds were detected in the GC-MS analysis of MOLEE; six of them have antioxidant properties, and five new compounds presented variable activities. MOLEE alone induced a stimulatory effect on the expression of steroidogenic and LHR genes. It restored the weight of reproductive organs to the control level; however, the recovery in sperm count, motility, abnormalities, percentage of alive sperm, testosterone, and MDA level are still comparable with the control level. Similar findings were also reported at the histological structure of the testes, epididymis, and accessory sex glands. Complete recovery of the GST enzyme activity was observed. Additionally, a restoration in the expression level of the steroidogenic genes was also reported. Our results indicated that the concurrent administration of MOLEE with CdCl2 can partially mitigate its harmful effects on male fertility.