Modulation of the miR-122/Sirt-6/ACE2 axis on experimentally-induced myocardial infarction.

Myocardial infarction (MI) is a progressive myocardial necrosis that can lead to a number of life-threatening complications. MiRNAs have a crucial role in the pathogenesis of many cardiovascular diseases. Remarkably, miR-122 targets the sirtuin-6 (Sirt-6) gene, which is an essential regulator of cardiovascular function and is considered a partial angiotensin converting enzyme 2 (ACE2) activator. Modulation of this axis is supposed to contribute to MI pathogenesis. The current study aims to investigate the cardioprotective effects of xanthenone through targeting the miR-122/Sirt-6/ACE2 axis on experimentally-induced MI in rats. Xanthenone was administered for 14 days and isoprenaline was injected in the last 2 days of the experiment. Xanthenone treatment resulted in a significant downregulation of miR-122, which further upregulated Sirt-6 and thus activated the adenosine monophosphate-activated protein kinase (AMPK). AMPK increases ACE2 levels and results in a decrease in the level of its substrate angiotensin II resulting in the normalization of the inflammatory cytokines and the cardiac biomarkers. Finally, by targeting the miR-122/Sirt-6/AMPK/ACE2 axis, xanthenone has the potential to be a promising cardioprotective agent against MI.

Pimitespib, an HSP90 inhibitor, augments nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop in rats with bleomycin-challenged lungs: Evolutionary perspective in managing pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a fatal lung disorder in which the etiology and pathogenesis are still unobvious. Effective treatments are urgently needed considering that lung transplantation is the only treatment that could improve outcomes. This study aimed to investigate the therapeutic significance of the dual administration of pimitespib, an HSP90 inhibitor, and nifuroxazide, a STAT3 inhibitor, against bleomycin-induced pulmonary fibrosis in rats. Our results revealed that pimitespib/nifuroxazide inhibited bleomycin-induced alterations in the structure and the function of the lungs. They demonstrated significant decreases in the BALF total and differential cell counts, LDH activity, and total protein. Concurrently, there was a reduction in the accumulation of collagen as proved by decreased hydroxyproline and the gene expression of COL1A1 accompanied by lower levels of PDGF-BB, TIMP-1, and TGF-ß. The levels of IL-6 were also downregulated. Pimitespib-induced inhibition of HSP90 led to subsequent inhibition of HIF-1α and STAT3 client proteins since the closed HSP90 would not enclose its client proteins. Therefore, pimitespib resulted in the repression of HIF-1α/CREB-p300 HAT as well as the STAT3/CREB-p300 HAT nuclear interactions. On the other hand, nifuroxazide resulted in a notable decline in pSTAT3 and HIF-1α levels. Subsequently, the combined effects of both drugs led to a substantial reduction in ECM deposition. Herein, pimitespib augmented nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop. Our findings also disclose that this novel loop is a promising therapeutic attack site for possible pulmonary fibrosis repression studies. Therefore, the use of pimitespib/nifuroxazide embodies an evolutionary perspective in managing pulmonary fibrosis.

Diacetylrhein, an anthraquinone antiarthritic agent, suppresses dextran sodium sulfate-induced inflammation in rats: A possible mechanism for a protective effect against ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory life-threatening and premalignant disorder with no cure that even might end up with surgical removal of a large section or even all of the colon. It is characterized by relapsing-remitting courses of intestinal inflammation and mucosal damage in which oxidative stress and exaggerated inflammatory response play a significant role. Most of the current medications to maintain remission are symptomatic and have many adverse reactions. Therefore, the potential for improved management of patients with UC continues to increase. Yet, the benefits of using the antiarthritic agent diacetylrhein to counteract inflammation in UC are still obscure. Hence, our study was designed to explore its potential role in UC using a model of dextran sodium sulfate-induced acute colitis in rats. Our results revealed that diacetylrhein targeted the NLRP3 and inhibited the inflammasome assembly. Consequently, caspase-1 activity and the inflammatory cytokines IL-1ß and IL-18 were inhibited leading to a curbed pyroptosis process. Additionally, diacetylrhein revealed a significant antiapoptotic potential as revealed by the levels of pro-apoptotic and anti-apoptotic proteins. Concomitant to these effects, diacetylrhein also interrupted NFκB signals leading to improved microscopic features of inflamed colon and decreased colon weight to length ratio, indices of disease activity, and macroscopic damage. Additionally, a reduction in the myeloperoxidase activity, IL-6, and TGF-ß alongside an increase in the gene expression of Ocln and ZO-1 were detected. To conclude diacetylrhein showed a significant antioxidant and anti-inflammatory potential and therefore might represent a promising agent in the management of acute UC.

Ameliorative Effect of Necrosulfonamide in a Rat Model of Alzheimer's Disease: Targeting Mixed Lineage Kinase Domain-like Protein-Mediated Necroptosis.

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative disorder that has no effective remedy, so far, with available therapeutic modalities being only symptomatic and of modest efficacy. Necroptosis is a form of controlled cell death with a recently emerging link to the pathogenesis of several neurodegenerative diseases. This study investigated the role of necroptosis in the pathogenesis of AD and evaluated the potential beneficial effect of the necroptosis inhibitor, necrosulfonamide (NSA), in a rat model of AD. AD was induced by oral administration of AlCl3 (17 mg/kg/day) for 6 consecutive weeks. Administration of NSA (1.65 mg/kg/day) intraperitoneally for 6 weeks significantly amended AlCl3-induced spatial learning and memory deficits, as demonstrated by enhanced rat performance in Morris water and Y-mazes. NSA alleviated the abnormally high hippocampal expression of tumor necrosis factor-alpha (TNF-α), ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), ß-amyloid, glycogen synthase kinase-3ß (GSK-3ß), phosphorylated tau protein, and acetylcholinesterase with concordant replenishment of acetylcholine. The amendments of AD perturbations achieved by NSA correlated with its inhibitory effect on the phosphorylation of the key necroptotic executioner, mixed lineage kinase domain-like protein (MLKL). Histopathological alterations supported the biochemical findings. In conclusion, NSA treatment represents a promising anti-Alzheimer's approach, mitigating AD neuropathologies via targeting MLKL-dependent necroptosis.

Visfatin -948G/T and resistin -420C/G polymorphisms in Egyptian type 2 diabetic patients with and without cardiovascular diseases.

Diabetes mellitus is one of the main threats to human health in the 21st century. Visfatin/Nampt and resistin are novel adipokines that have been implicated in the pathogenesis of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) complication. Several genetic studies have shown inconsistent results regarding association of visfatin/Nampt gene (NAMPT) and resistin gene (RETN) polymorphisms with T2DM and CVD complications. Here, we investigate whether NAMPT -948G/T and RETN -420C/G polymorphisms are associated with T2DM, its CVD complications, and serum adipokines levels in 90 Egyptian diabetic patients (44 without CVD and 46 with CVD) along with 60 healthy control subjects. Higher frequencies of NAMPT -948G/G and RETN -420G/G were observed among T2DM patients compared with controls. Furthermore, the frequencies of these genotypes were significantly higher in T2DM patients with CVD than those without CVD. Both NAMPT -948G/G and RETN -420G/G genotypes and G alleles were significantly associated with T2DM and CVD in Egyptian diabetic patients. Moreover, serum visfatin/Nampt and resistin levels were markedly elevated in T2DM patients, with the highest values observed in G/G genotypes among T2DM patients with CVD. In addition, positive correlations were observed between plasma adipokines levels and CVD risk factors. In conclusion, our data suggests that genetic variations in NAMPT -948G/T and RETN -420C/G may contribute to the disposition for T2DM and its CVD complications in Egyptian patients. However, further studies with greater sample size should be performed to verify these results.