ABSTRACT
OBJECTIVE: Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease that has a high rate of morbidity and mortality. It's an acute diffusive lung injury caused by the release of pro-inflammatory cytokines into the lungs. Specific microRNAs have been identified to play a crucial role in the renin-angiotensin system signaling pathways the main pathophysiological pathway responsible for ARDS. Since the ARDS life-threatening complication associated with COVID-19 is an ongoing challenge, this current study aimed to investigate the potential efficacy of xanthenone in the treatment of ARDS induced with LPS in mice through ACE2 activation and modulation of miR-200 and ACE2/Ang 1-7 pathways. MATERIALS AND METHODS: Mice were categorized into three groups randomly. The first set of mice served as the normal control group. The ARDS group was injected with LPS (15 mg/kg; i.p.). The last group was treated with xanthenone (2 mg/kg/day; p.o.) for one week before the LPS injection. RESULTS: Xanthenone treatment resulted in a significant down-regulation of miRNA-200 expression, leading to the activation of ACE2 accompanied with marked inhibition of Angiotensin II as well as increases the levels of Ang 1-7 and SP-A. CONCLUSIONS: Xanthenone has the potential to be a promising therapeutic drug for the treatment of ARDS COVID-19 complication through activation of ACE2/Ang 1-7 pathways.https://www.europeanreview.org/wp/wp-content/uploads/Graphical_abstract.tif.
Subject(s)
Acute Lung Injury , COVID-19 Drug Treatment , MicroRNAs , Respiratory Distress Syndrome , Acute Lung Injury/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Lipopolysaccharides/adverse effects , Mice , Peptidyl-Dipeptidase A/metabolism , Respiratory Distress Syndrome/drug therapy , Signal TransductionABSTRACT
OBJECTIVE: Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality around the world. Nuclear transcription factor kappa B (NF-κB) represents a factor that plays a major role in the pathogenesis of CVDs. The current study aims to investigate the modulatory effects of astaxanthin and its molecular mechanisms in rats with isoprenaline-induced myocardial infarction. MATERIALS AND METHODS: Rats were pretreated with astaxanthin daily for 14 days prior to inducing myocardial infarction with isoprenaline in the final two days. Blood and heart tissue samples were collected 24 hours after the last dose of isoprenaline was injected for biochemical and histological analysis. RESULTS: Isoprenaline-induced myocardial injury was demonstrated with histopathological examination of heart tissue and the significantly elevated serum troponin-I. Isoprenaline caused an increase in oxidative stress and a decrease in antioxidants. Toll-like receptor-4 (TLR4), NF-κB and tumor necrosis factor-α (TNF-α) expression levels were significantly higher in infarcted rats. Astaxanthin pretreatment had a significant preventive effect on all of the biochemical and molecular parameters tested in myocardial infarcted rats. CONCLUSIONS: Astaxanthin's cardioprotective effect has been linked to the inhibition of the TLR4/NF-κB signaling pathway. This inhibits the release of inflammatory cytokines, which can cause myocardial cell death. Because of its antioxidant and anti-inflammatory properties, astaxanthin is a promising cardioprotective agent.
Subject(s)
Cardiotonic Agents/therapeutic use , Myocardial Infarction/drug therapy , Animals , Cardiotonic Agents/pharmacology , Isoproterenol , Male , Malondialdehyde/metabolism , Myocardial Infarction/chemically induced , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardium/metabolism , Myocardium/pathology , NF-kappa B/genetics , NF-kappa B/metabolism , Rats, Wistar , Signal Transduction/drug effects , Superoxide Dismutase/metabolism , Toll-Like Receptor 4/genetics , Troponin I/blood , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Xanthophylls/pharmacology , Xanthophylls/therapeutic useABSTRACT
OBJECTIVE: The current study investigates the effect of the innovative phosphorothioate modified backbone locked nucleic acid (LNA) of microRNA-103 (miR-103) specifically designed for systemic delivery in the silencing of miR-103 in experimentally induced myocardial infarction (MI). MicroRNA-103 is a small non-coding RNA which regulates Fas-associated protein with death domain (FADD) gene expression, which is a negative regulator for necroptosis occurs during the progression of MI. MATERIALS AND METHODS: Experimental male mice were allocated into three groups; the first group received normal saline, the second group was injected with isoprenaline and served as the infarcted control, while the third group was treated with LNA miR-103 power inhibitor before isoprenaline injection. Blood and heart samples were used for biochemical analysis of miR-103, FADD, receptor-interacting protein kinase (RIPK), nuclear factor-κß, tumor necrosis factor-α, interleukin-6, troponin-I and creatine kinase-MB (CK-MB) as well as the histological examination of heart tissue. RESULTS: The treated mice showed marked improvement in the troponin-I and CK-MB levels with almost normal histological structure of heart tissue. Significant inhibition of miR-103 accompanied by increased FADD expression and markedly decreased expression of the other biomarkers were observed in the hearts of the treated mice. CONCLUSIONS: LNA miR-103 inhibitor is a potent cardioprotective agent and can be a promising treatment against MI through targeting FADD/RIPK pathway.
