The role of miR-433-3p in vascular calcification in type 2 diabetic patients: targeting WNT/ß-Catenin and RANKL/RANK/OPG signaling pathways.

BACKGROUND: Vascular calcification (VC) is a major predictor of cardiovascular diseases that represent the principal cause of mortality among type-2 diabetic patients. Accumulating data suggest the vital role of some microRNAs on vascular calcification as an epigenetic regulator. Thus, we assessed herein, the role of serum miR-433-3p in vascular calcification in type-2 diabetic patients. METHODS: Twenty healthy subjects (control group) and forty diabetic patients (20 without VC and 20 with VC) were involved in the study. miR-433-3p gene expression was measured. Runx2, Dickkopf-1 (DKK1), ß-catenin, Receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) levels in serum were assessed by ELISA technique. RESULTS: Diabetes patients had significantly lower levels of miR-433-3p expression in comparison to the control group, with the lowest levels being found in diabetic patients with VC. Furthermore, Runx2, ß-catenin, and RANKL levels were significantly increased with concomitant lower DKK1 and OPG levels detected in the two diabetic groups especially those with VC. CONCLUSION: Collectively, the study documented that down-regulation of miR-433-3p may contribute to the development of VC through activating WNT/ß-Catenin and RANKL/RANK/OPG signaling pathways.

The Possible Role of Naringenin in the Prevention of Alcohol-Induced Neurochemical and Neurobehavioral Deficits.

Chronic alcohol consumption is associated with progressive/irreversible neurodegeneration. However, there is not a clear understanding of its discrete pathophysiology or therapeutic intervention. The present study aimed to investigate the protective effect of the natural citrus flavonoid, naringenin (NAG), against alcohol-induced neurodegeneration in the brain cerebral cortex. Thirty-two male albino rats were randomly divided into four equal groups (eight rats each): control group (I); NAG-treated group (II); alcohol-intoxicated group (III) and alcohol + NAG co-treated group (IV). Brain nuclear factor erythroid 2-related factor 2 and receptor-interacting protein kinase 3 expression were assessed by real-time polymerase chain reaction. NAD(P)H quinone oxidoreductase 1 activity and malondialdehyde, reduced glutathione, mixed lineage kinase-like protein, phosphorylated glycogen synthase kinase 3 beta, and ciliary neurotrophic factor levels were all measured biochemically. B-cell lymphoma 2 expression was assessed by immunohistochemistry. A histopathological examination and neurobehavioral tests were performed. The alcohol-treated group showed a significant increase in oxidative stress and necroptosis biomarkers with a significant reduction in neuroprotective proteins. NAG co-administration effectively ameliorated cognitive dysfunction with an apparent neuroprotective effect by targeting various signaling pathways, including nuclear factor erythroid 2-related factor/NAD(P)H quinone oxidoreductase 1, anti-oxidant capacity, attenuated necroptosis, and upregulated neuroprotective ciliary neurotrophic factor. The study findings suggest NAG as a possible management strategy for alcohol-induced neurodegeneration.

The prospective effect of fucoidan on splenic dysfunction caused by oxaliplatin in male rats through endoplasmic stress dynamics.

Fucoidans (FUCs) are highly sulfated polysaccharides demonstrating multiple actions in different systems. Oxaliplatin (OXA) is a platinum-containing chemotherapeutic agent with several side effects that restrict its usage. The current study aimed to determine the potential effect of FUC in male rats with splenic dysfunction induced by OXA. Eighty adult male rats aged (8-9 weeks) weighing (190-230 g) were divided into four groups: (Group I: the control group): Rats were administrated normal saline; (Group II: controls treated by FUC): Rats were treated with FUC; (Group III: Splenic dysfunction group): Rats were treated with 8 mg/kg OXA. (IV: Splenic dysfunction treated by FUC): Rats were treated by OXA as Group III, then fucoidan was given. At the end of the experiment, blood was collected to determine red blood cells and white blood cells. Splenic tissues were divided into one part for biochemical assays, oxidative stress markers as MDA and catalase, inflammatory markers (TNF-alpha, IL6), and apoptotic markers (caspase 3) and gene expression of Nrf2, Mapk1 gene expression, and endoplasmic stress parameters and the other part was used for immunohistochemical and histopathological analysis. Compared to the OXA-induced splenic dysfunction group, FUC significantly decreased high levels of MDA, TNF- alpha, IL6, caspase-3, Mapk1, endoplasmic stress induced by OXA, and increased the level of catalase and Nrf2. Fucoidan has corrected the histopathological and immunohistochemical changes compared to the OXA-induced splenic dysfunction group. In conclusion, our findings suggest that fucoidan has a significant role in the treatment of splenic dysfunction induced by OXA.

Possible protective effects of CO Q10 against vincristine-induced peripheral neuropathy: Targeting oxidative stress, inflammation, and sarmoptosis.

Vincristine is a chemotherapy drug that belongs to the vinca alkaloids group. It is used for treatment of hematologic malignancies and several solid tumors. Vincristine-induced peripheral neuropathy is a major dose-limiting side effect. Coenzyme Q10 (Co Q10), an essential component of the mitochondrial electron transport chain, participates in energy production. It is a powerful fat-soluble antioxidant and also exerts anti-inflammatory effects. Therefore, this study was aimed to focus on the mechanistic insights of vincristine-induced peripheral neuropathy in addition to shedding the light on the modulatory effect of Co Q10. Twenty-eight rats were randomly divided into four groups. Peripheral neuropathy was induced by intraperitoneal injection of vincristine (0.1 mg/kg body weight). Co Q10 was injected intraperitoneally (10 mg/kg body weight) for 24 days. Sciatic nerve MDA, TAC, GSH, 8-OHdG, TNF-α, IL-1ß, and NF-κB levels were assessed. Gene expression of SARM1 and Nrf2 was also assessed. Serum neurofilament light chain was immunoassayed, in addition to the behavioral assessment. Co Q10 significantly improved oxidative stress and inflammatory biomarkers. It also decreased serum NFL levels. It enhanced Nrf2 and decreased SARM1 gene expression. Histopathological findings proved the biochemical and molecular findings. Our results support Co Q10 as a potential protective agent against vincristine-induced peripheral neuropathy.

Unraveling the biomechanistic role of Rac1/TWEAK/Fn14/NF-κB intricate network in experimentally doxorubicin-induced cardiotoxicity in rats: The role of curcumin.

Doxorubicin (DOX) is an important chemotherapeutic drug. Cardiotoxicity diminishes its clinical efficacy. We aimed to focus on the mechanism of DOX-induced cardiotoxicity, in addition, to evaluate curcumin's protective effect against it. Twenty-eight rats were divided into the normal control group I, curcumin-treated (200 mg/kg body weight [b.w.]) group II, DOX-treated (4 mg/kg b.w.) group III, and DOX + curcumin group IV. Cardiac injury markers, heart tissue oxidative stress indices, interferon-gamma (INF-γ), tumor necrosis factor-like weak inducer of apoptosis (TWEAK), upregulated modulator of apoptosis (PUMA), p53 and nuclear factor kappa-B p65 (NF-κB p65) levels as well as messenger RNA gene expression of Rac1 and fibroblast growth factor-inducible protein 14 (Fn14) were assayed, besides the assay of DNA damage, histopathological changes, survivin immunohistochemistry and electron microscopic examination. Curcumin significantly downregulated Rac1 and Fn14 gene expression and significantly decreased p53, NF-κB p65, INF-γ, and PUMA levels in the cardiac tissue. In addition, curcumin improved oxidative stress indices, DNA damage, and cardiac toxicity markers in the form of lactate dehydrogenase (LD), creatine kinase isoenzyme-MB (CK-MB), and cardiac troponin-I (cTn-I). Meanwhile, upregulated antiapoptotic marker survivin was observed. Light and electron microscopic findings confirmed our biochemical and molecular outcomes. The current study established the antioxidant, anti-inflammatory, and antiapoptotic roles of curcumin against DOX cardiotoxicity.