COVID-19 Complications: Oxidative Stress, Inflammation, and Mitochondrial and Endothelial Dysfunction

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(19), С. 14876 - 14876

Опубликована: Окт. 4, 2023

SARS-CoV-2 infection, discovered and isolated in Wuhan City, Hubei Province, China, causes acute atypical respiratory symptoms has led to profound changes our lives. COVID-19 is characterized by a wide range of complications, which include pulmonary embolism, thromboembolism arterial clot formation, arrhythmias, cardiomyopathy, multiorgan failure, more. The disease caused worldwide pandemic, despite various measures such as social distancing, preventive strategies, therapeutic approaches, the creation vaccines, novel coronavirus infection (COVID-19) still hides many mysteries for scientific community. Oxidative stress been suggested play an essential role pathogenesis COVID-19, determining free radical levels patients with may provide insight into severity. generation abnormal oxidants under COVID-19-induced cytokine storm irreversible oxidation macromolecules subsequent damage cells, tissues, organs. Clinical studies have shown that oxidative initiates endothelial damage, increases risk complications post-COVID-19 or long-COVID-19 cases. This review describes radicals mediation mitochondrial dysfunction.

Язык: Английский

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α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Янв. 22, 2024

Abstract Background In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy fibrosis mice HF improved cardiac insufficiency. However, the protective mechanism of AKG remains unclear. We verified hypothesis that improves function by upregulating NAD + levels activating silent information regulator 2 homolog 1 (SIRT1) cardiomyocytes. Methods vivo, 2% was added drinking water undergoing transverse aortic constriction (TAC) surgery. Echocardiography biopsy were performed evaluate pathological changes. Myocardial metabolomics analyzed liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after vitro, expression SIRT1 or PINK1 proteins inhibited selective inhibitors siRNA cardiomyocytes stimulated angiotensin II (AngII) AKG. detected using an test kit. Mitophagy ferroptosis evaluated Western blotting, qPCR, JC-1 staining lipid peroxidation analysis. Results supplementation TAC surgery could alleviate improve mice. Metabolites malate-aspartate shuttle (MAS) increased, but TCA cycle fatty acid metabolism pathway be myocardium supplementation. Decreased protein observed AngII-treated After treatment, these changes reversed, increased mitophagy, ferroptosis, damage observed. When inhibitor siRNA, effect suppressed. Conclusion can hypertrophy, chronic insufficiency caused pressure overload. By increasing level , SIRT-PINK1 SIRT1-GPX4 signaling pathways are activated promote mitophagy inhibit cardiomyocytes, which ultimately alleviates damage.

Язык: Английский

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Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway

Pharmacological Research, Год журнала: 2024, Номер 200, С. 107057 - 107057

Опубликована: Янв. 11, 2024

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial and DCM; however, its effects on mitophagy remain unexplored. The present study aimed to assess the beneficial of nicorandil DCM underlying mechanisms. Cardiac perfusion was assessed using a lectin assay, while via mt-Keima transfection transmission electron microscopy. Ferroptosis examined mRNA sequencing, fluorescence staining, western blotting. localization Parkin, ACSL4, AMPK determined immunofluorescence staining. Following long-term diabetes, treatment improved function remodeling by alleviating injuries, as evidenced structural integrity. mRNA-sequencing biochemical analyses showed that occurred Pink1/Parkin-dependent suppressed cells after diabetes. Nicorandil mitochondria-associated promoting mitophagy. Moreover, increased phosphorylation level AMPKα1 promoted translocation, which further inhibited translocation ACSL4 ultimately ferroptosis. Importantly, overexpression mitochondria-localized (mitoAα1) shared similar benefits with mitophagy, cardiovascular protection injury. In conclusion, demonstrated therapeutic revealed AMPK-Parkin-ACSL4 signaling pathway mediates development dysfunction.

Язык: Английский

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Histone acetyltransferase P300 deficiency promotes ferroptosis of vascular smooth muscle cells by activating the HIF-1α/HMOX1 axis

Molecular Medicine, Год журнала: 2023, Номер 29(1)

Опубликована: Июль 6, 2023

Abstract Background E1A-associated 300-kDa protein (P300), an endogenous histone acetyltransferase, contributes to modifications of the chromatin landscape genes involved in multiple cardiovascular diseases. Ferroptosis vascular smooth muscle cells (VSMCs) is a novel pathological mechanism aortic dissection. However, whether P300 regulates VSMC ferroptosis remains unknown. Methods Cystine deprivation (CD) and imidazole ketone erastin (IKE) were used induce ferroptosis. Two different knockdown plasmids targeting A-485 (a specific inhibitor P300) investigate function human (HASMCs). Cell counting kit-8, lactate dehydrogenase flow cytometry with propidium iodide staining performed assess cell viability death under treatment CD IKE. BODIPY-C11 assay, immunofluorescence 4-hydroxynonenal malondialdehyde assay conducted detect level lipid peroxidation. Furthermore, co-immunoprecipitation was utilized explore interaction between HIF-1α, HIF-1α P53. Results Compared normal control, significantly decreased HASMCs treated IKE, which largely nullified by ferrostatin-1 but not autophagy or apoptosis inhibitor. Knockdown short-hairpin RNA inhibition activity promoted CD- IKE-induced HASMC ferroptosis, as evidenced reduction aggravation peroxidation HASMCs. we found that hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase 1 (HMOX1) pathway responsible for impacts on The results demonstrated P53 competitively bound regulate expression HMOX1. Under conditions, interacted inhibit HMOX1 expression, while reduced induced inducers would favor binding trigger overexpression. aggravated effects BAY87-2243. Conclusion Thus, our revealed deficiency inactivation facilitated activating HIF-1α/HMOX1 axis, may contribute development diseases related

Язык: Английский

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SARS-CoV-2 Accessory Protein Orf7b Induces Lung Injury via c-Myc Mediated Apoptosis and Ferroptosis

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 1157 - 1157

Опубликована: Янв. 18, 2024

The pandemic of coronavirus disease 2019 (COVID-19) has been the foremost modern global public health challenge. airway is primary target in severe acute respiratory distress syndrome 2 (SARS-CoV-2) infection, with substantial cell death and lung injury being signature hallmarks exposure. viral factors that contribute to remain incompletely understood. Thus, this study investigated role open reading frame 7b (Orf7b), an accessory protein virus, causing injury. In screening proteins, we identified Orf7b as one major mediates epithelial death. Overexpression leads apoptosis ferroptosis cells, inhibitors ablate Orf7b-induced upregulates transcription regulator, c-Myc, which integral activation pathways. Depletion c-Myc alleviates both apoptotic ferroptotic deaths mouse models. Our suggests a attributable COVID-19 exposure, supporting it potential therapeutic target.

Язык: Английский

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Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells

Cardiovascular Diabetology, Год журнала: 2024, Номер 23(1)

Опубликована: Май 29, 2024

Abstract Background Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target Although association between and vascular reported, the role mechanism of iron overload in are still poorly understood. Specifically, further in-depth research required on whether metalloproteins SLC39a14 SLC39a8 involved induced by overload. Methods R language was employed differential analysis dataset, revealing correlation calcification. The experimental approaches encompassed both vitro vivo studies, incorporating use chelators models Additionally, gain- loss-of-function experiments were conducted to investigate iron’s effects comprehensively. Electron microscopy, immunofluorescence, western blotting, real-time polymerase chain reaction used elucidate how Slc39a14 Slc39a8 mediate promote Results Ferroptosis observed conjunction with (VC); consistently confirmed studies. Our results showed positive VSMCs Iron effective reversing VC exacerbates this process. expression levels metal transport proteins significantly upregulated during calcification; inhibition their alleviated VC. Conversely, overexpression promotes intracellular accumulation VSMCs. Conclusions demonstrates that occurs VC, relieves intercepting overload-induced VSMCs, providing new insights into treatment. Graphical

Язык: Английский

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Beneficial effects of L-Arginine in patients hospitalized for COVID-19: New insights from a randomized clinical trial

Pharmacological Research, Год журнала: 2023, Номер 191, С. 106702 - 106702

Опубликована: Фев. 15, 2023

We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine patients hospitalized for COVID-19. hypothesize that one mechanisms underlying favorable is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels pro-inflammatory and anti-inflammatory cytokines implied pathophysiology COVID-19 to receive oral or placebo. The study was successfully completed by 169 patients. Patients arm had reduced respiratory support evaluated at 10 20 days; moreover, time hospital discharge significantly shorter group. assessment circulating revealed IL-2, IL-6, IFN-γ increased IL-10. Taken together, these findings indicate adding standard therapy markedly reduces need duration in-hospital stay; regulates

Язык: Английский

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Incidence of type 2 diabetes before and during the COVID-19 pandemic in Naples, Italy: a longitudinal cohort study

EClinicalMedicine, Год журнала: 2023, Номер 66, С. 102345 - 102345

Опубликована: Дек. 1, 2023

BackgroundThe association of COVID-19 with the development new-onset diabetes has been recently investigated by several groups, yielding controversial results. Population studies currently available in literature are mostly focused on type 1 (T1D), comparing patients a SARS-CoV-2 positive test to individuals without COVID-19, especially paediatric populations. In this study, we sought determine incidence 2 (T2D) before and during pandemic.MethodsIn longitudinal cohort analysed followed up over 6-year period using an Interrupted Time Series approach, i.e. 3-years pandemic. We data obtained from >200,000 adults Naples (Italy) January 1st 2017 December 31st 2022. manner, had opportunity compare newly diagnosed T2D (2017–2019) (2020–2022) The key inclusion criteria were age >18-year-old availability for observation; diagnosis excluded. main outcome study was new T2D, as defined International Classification Diseases 10 (ICD-X), including prescription antidiabetic therapies more than 30 days.FindingsA total 234,956 subjects followed-up at least or pandemic included study; among these, 216,498 pre-pandemic years 216,422 years. rate 4.85 (95% CI, 4.68–5.02) per 1000 person-years 2017–2019, vs 12.21 11.94–12.48) 2020–2022, increase about twice half. Moreover, doubling time number diagnoses estimated unadjusted Poisson model 97.12 40.51–153.75) months prepandemic 23.13 16.02–41.59) Interestingly, these findings also confirmed when examining prediabetes.InterpretationOur 200,000 adult participants indicate that significantly higher compared pre-COVID-19 phase. As consequence, epidemiology disease may change terms rates outcomes well public health costs. survivors, prediabetes, require specific clinical programs prevent T2D.FundingThe US National Institutes Health (NIH: NIDDK, NHLBI, NCATS), Diabetes Action Research Education Foundation, Weill-Caulier Hirschl Trusts.

Язык: Английский

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Circ_005077 accelerates myocardial lipotoxicity induced by high-fat diet via CyPA/p47PHOX mediated ferroptosis

Cardiovascular Diabetology, Год журнала: 2024, Номер 23(1)

Опубликована: Апрель 15, 2024

Abstract The long-term high-fat diet (HFD) can cause myocardial lipotoxicity, which is characterized pathologically by hypertrophy, fibrosis, and remodeling clinically cardiac dysfunction heart failure in patients with obesity diabetes. Circular RNAs (circRNAs), a novel class of noncoding RNA ring formation through covalent bonds, play critical role various cardiovascular diseases. However, few studies have been conducted to investigate the mechanism circRNA lipotoxicity. Here, we found that circ_005077, formed exon 2–4 Crmp1, was significantly upregulated myocardium an HFD-fed rat. Furthermore, identified circ_005077 as ferroptosis-related regulator plays palmitic acid (PA) HFD-induced lipotoxicity vitro vivo. Mechanically, interacted Cyclophilin A (CyPA) inhibited its degradation via ubiquitination proteasome system (UBS), thus promoting interaction between CyPA p47phox enhance activity nicotinamide adenine dinucleotide phosphate (NADPH) oxidase responsible for ROS generation, subsequently inducing ferroptosis. Therefore, our results provide new insights into mechanisms potentially leading identification therapeutic target treatment future.

Язык: Английский

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NOX4-mediated astrocyte ferroptosis in Alzheimer’s disease

Cell & Bioscience, Год журнала: 2024, Номер 14(1)

Опубликована: Июль 2, 2024

Abstract This study investigates NADPH oxidase 4 (NOX4) involvement in iron-mediated astrocyte cell death Alzheimer’s Disease (AD) using single-cell sequencing data and transcriptomes. We analyzed AD RNA data, identified marker genes, explored biological processes astrocytes. integrated AD-related chip with ferroptosis-related highlighting NOX4. validated NOX4’s role ferroptosis vitro vivo. Astrocyte genes were enriched AD, emphasizing their role. NOX4 emerged as a crucial player astrocytic AD. Silencing mitigated ferroptosis, improved cognition, reduced Aβ p-Tau levels, alleviated mitochondrial abnormalities. promotes underscoring its significance progression.

Язык: Английский

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