Cytokine storm modulation using cholecalciferol and low dose gamma radiation in Escherichia coli infected mice.

This work investigates the efficiency of cholecalciferol and low dose gamma radiation in modulating cytokine storm through their impact on inflammatory and anti-inflammatory cytokine and protecting against lung and liver injuries. Male Swiss albino mice were exposed to 0.2 Gy gamma radiation/week for four consecutive weeks then injected intraperitoneally (i.p) with a single dose of 8.3 × 106 CFU Escherichia coli/g b.w. then injected i.p. with 1.0 mg/kg cholecalciferol (Vit D3) for 7 days starting 4 h after E. coli injection. The results revealed that Cholecalciferol and low dose gamma radiation caused significant depletion in the severity of E. coli infection (colony forming unit per milliliter), log10 of E. coli, Tumor necrosis factor alpha, Interleukin 6, VEGF, alanine aminotransferase, and aspartate aminotransferase levels and significant elevation in IL-10, IL-4, and HO-1. Immunohistochemical analysis of caspase-3 expression in lung tissue section showed low caspase-3 expression in cholecalciferol and low dose gamma radiation treated group. Histopathological examinations were performed in both lung and liver tissues which also emphasis the biochemical findings. Our results exhibit the importance of cholecalciferol and low dose gamma radiation in improving liver function and providing anti-inflammatory response in diseases causing cytokine storm.

A new approach of nano-metformin as a protector against radiation-induced cardiac fibrosis and inflammation via CXCL1/TGF-Β pathway.

The present work investigates the potential role of metformin nanoparticles (MTF-NPs) as a radio-protector against cardiac fibrosis and inflammation induced by gamma radiation via CXCL1/TGF-ß pathway. Lethal dose fifty of nano-metformin was determined in mice, then 21 rats (male albino) were equally divided into three groups: normal control (G1), irradiated control (G2), and MTF-NPs + IRR (G3). The possible protective effect of MTF-NPs is illustrated via decreasing cardiac contents of troponin, C-X-C motif Ligand 1 (CXCL1), tumor growth factor ß (TGF-ß), protein kinase B (AKT), and nuclear factor-κB (NF-κB). Also, the positive effect of MTF-NPs on insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) in heart tissues using immunohistochemical technique is illustrated in the present study. Histopathological examination emphasizes the biochemical findings. The current investigation suggests that MTF-NPs might be considered as a potent novel treatment for the management of cardiac fibrosis and inflammation in patients who receive radiotherapy or workers who may be exposed to gamma radiation.

Ipomoea carnea mitigates ethanol-induced ulcers in irradiated rats via Nrf2/HO-1 pathway: an in vivo and in silico study.

The aim of this study was to investigate the potential of Ipomoea carnea flower methanolic extract (ICME) as a natural gastroprotective therapy against ethanol-induced gastric ulcers, particularly in individuals exposed to ionizing radiation (IR). The study focused on the Nrf2/HO-1 signaling pathway, which plays a crucial role in protecting the gastrointestinal mucosa from oxidative stress and inflammation. Male Wistar rats were divided into nine groups, the control group received distilled water orally for one week, while other groups were treated with ethanol to induce stomach ulcers, IR exposure, omeprazole, and different doses of ICME in combination with ethanol and/or IR. The study conducted comprehensive analyses, including LC-HRESI-MS/MS, to characterize the phenolic contents of ICME. Additionally, the Nrf2/HO-1 pathway, oxidative stress parameters, gastric pH, and histopathological changes were examined. The results showed that rats treated with IR and/or ethanol exhibited histopathological alterations, increased lipid peroxidation, decreased antioxidant enzyme activity, and reduced expression levels of Nrf2 and HO-1. However, pretreatment with ICME significantly improved these parameters. Phytochemical analysis identified 39 compounds in ICME, with flavonoids, hydroxybenzoic acids, and fatty acids as the predominant compounds. Virtual screening and molecular dynamics simulations suggested that ICME may protect against gastric ulceration by inhibiting oxidative stress and inflammatory mediators. In conclusion, this study demonstrates the potential of ICME as a natural gastroprotective therapy for preventing gastric ulcers. These findings contribute to the development of novel interventions for gastrointestinal disorders using natural plant extracts particularly in individuals with a history of radiation exposure.

Evaluation of Glycogen Synthase Kinase Pathway for Assessing the Antidepressant-like Effect of Glucosamine as a Radioprotector in Rats: Behavioral and Biochemical Studies.

Radiotherapy is a very important tool in the treatment of cancer; nevertheless, its side effects are a hindrance to its use. The present study is designed to evaluate glucosamine effects against radiation-induced brain oxidative stress and depression-like effect in rats. Four groups of female Wister rats were used as control, irradiated (4 × 2 Gy), glucosamine (1 g/kg P.O), and glucosamine + irradiated group. The behavioral responses are estimated. The brain hippocampi of the rats are separated to evaluate oxidative stress biochemical parameters and glycogen synthase kinase pathway in addition to the biogenic amines. Irradiation exposure led to disturbances in the behavioral assessments (forced swimming test, light-dark box, and open field test) and a significant decrease in brain GSH, neurotransmitters (serotonin, norepinephrine, and dopamine), phosphatidylinositol 3 kinase (PI3K), and phosphorylated protein kinase-B (p-AKT) levels. Additionally, MDA and ROS levels increased significantly post-irradiation along with the phosphorylated glycogen synthase kinase (p-GSK3). Glucosamine administration before irradiation caused improvement in the behavioral valuations and the biochemical parameters in the brain as well. Glucosamine might be used as a radioprotector to improve brain function and as an antidepressant drug. It could be promising as a future therapy in managing depression occurring during radiotherapy.

Novel iodoquinazolinones bearing sulfonamide moiety as potential antioxidants and neuroprotectors.

In a search for new antioxidants, a set of new iodoquinazolinone derivatives bearing benzenesulfonamide moiety and variable acetamide pharmacophores 5-17 were designed and synthesized. The structures of the synthesized compounds were confirmed based on spectral data. Compounds 5-17 were screened using in vitro assay for their antioxidant potential and acetylcholinesterase (AChE) inhibitory activity. The 2-(6-iodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-ylthio)-N-(pyrazin-2-yl) acetamide 14 was the most active scaffold with potent AChE inhibitory activity. Compound 14 showed relative safety with a median lethal dose of 300 mg/kg (LD50 = 300 mg/kg), in an acute toxicity study. The possible antioxidant and neuroprotective activities of 14 were evaluated in irradiated mice. Compound 14 possessed in vivo AChE inhibitory activity and was able to modify the brain neurotransmitters. It was able to cause mitigation of gamma radiation-induced oxidative stress verified by the decline in Myeloperoxidase (MPO) and increase of glutathione (GSH) levels. Also, 14 restored the alterations in behavioral tests. Molecular docking of 14 was performed inside MPO and AChE active sites and showed the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings would support that 14 could be considered a promising antioxidant with a neuromodulatory effect.

Beneficial Effect of Rosuvastatin Therapy on Spleen Injury Induced by Gamma Irradiation in Rats: Targeting Nrf2/EPRE Pathway.

Purpose: The present study investigates the new approach of rosuvastatin (RUV) administration as a drug for the management of spleen injury induced by gamma irradiation. Main Methods: Forty rats were used and divided equally into 4 groups: control group, irradiated group, IRR + rosuvastatin group (10 mg/Kg b. wt), and IRR + rosuvastatin group (20 mg/kg b. wt) for 7 days orally. Results: The possible curative effect can be illustrated via the improvement of hematopoietic cell count (Hb, RBCs, and WBCs) and oxidative stress markers (MDA and GST) in addition to biochemical parameters including [heme oxigenase-1 (HO-1), nuclear erythroid 2-related factor (Nrf2), NOD-, LRR- and pyrin domain- containing protein 3 (NLRP3) inflammasome] and immune assay of nuclear factor kappa beta (NF-kB P65) and inducible nitric oxide synthase (iNOS). Histological pictures emphasize the biochemical findings. Rosuvastatin treatments by using two different doses improve the tested parameters. High-dose administration of RUV (20 mg/kg p.o.) recorded better results than the low dose (10 mg/kg p.o.). Conclusion: Our results suggested that rosuvastatin reversed the radiation-induced spleen-damaging effects. So, RUV can be introduced to the market as a new therapy for the management of spleen damages.

Nrf2 and NF-қB interplay in tamoxifen-induced hepatic toxicity: A promising therapeutic approach of sildenafil and low-dose γ radiation.

Tamoxifen-induced hepatotoxicity is an inevitable side effect during breast cancer treatment. Low-dose gamma irradiation (IRR) shows many beneficial effects by stimulating various biological processes. This study evaluates the possible effect of sildenafil and low-dose gamma radiation on liver damages as new treatment strategies. Group I (control), group II: (tamoxifen), group III: (tamoxifen + Sildenafil), group IV: (tamoxifen+ irradiation) and group V: (tamoxifen +Sildenafil + irradiation). Rats were sacrificed after 5 h from tamoxifen injection. Results showed that tamoxifen caused elevation in serum AST, ALT and ALP as well hepatic ROS, iNOS, MDA, Keap-1 and NF-Kb, in addition to diminution in hepatic Nrf2 and HO-1. Exposure to low-dose gamma radiation and sildenafil amended the alterations in the measured parameters in serum and tissue. Moreover, all results were confirmed by histopathological examination. In conclusion, sildenafil and low-dose gamma radiation can mitigate the toxicity induced by tamoxifen in liver tissues. Hence, this treatment could be further evaluated as a new approach for alleviating various liver disorders.

Modulation of PTZ-induced convulsions in rats using topiramate alone or combined with low dose gamma irradiation: involving AKT/m-TOR pathway.

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine' score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral changes, brain mediators, m-TOR pathway, oxidative stress, and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ-treated rats exhibited necrosis, pyknosis, and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Effect of valproic acid alone or combined with low dose gamma irradiation in modulating PTZ-induced convulsions in rats involving AKT/m-TOR pathway.

AIM: The current study evaluates the anticonvulsant effect of valproic acid (VPA) alone or combined with low dose γ-irradiation (LDR) against pentylenetetrazol-induced convulsions in rats. MATERIAL AND METHODS: Five groups of rats were used, group I served as normal control, group II served as PTZ- control and the other three groups were pretreated with single LDR(o.5 Gy), VPA(150 mg/kg i.p.5 days) and VPA with LDR respectively before PTZ injection. Racine score, latency and duration of convulsions were assessed. Evaluation of brain neurotransmitters (glutamate and GABA) as well as AKT/m-TOR pathway (protein kinase B [AKT], mammalian target of rapamycin [m-TOR], protein S6 and caspase 3). Measurement of oxidative stress (Malondialdehyde, glutathione and nitric oxide) was carried out. Histopathological examinations of hippocampi were done. KEY FINDINGS: PTZ resulted in behavioural changes (high Racine score, long seizure duration and short latency).PTZ enhanced oxidative stress state (high MDA and NO, as well as low GSH) compared to normal control. VPA alone or combined with LDR ameliorated, the convulsions and caused significant improvement in behavioural changes and other tested parameters compared to normal control. Histopathological examination of hippocampi was carried out to adjoin the biochemical changes. Certain changes were observed after PTZ injection. However, normal pictures of the other tested groups. SIGNIFICANCE: The previously mentioned findings support that LDR purveyed novel anticonvulsant activity which could offer a possible contributor in the basic treatment of convulsions. This effect might be due to modulation of AkT/m-TOR pathway, reduction of oxidative stress and modulation of neurotransmitters.