Dapagliflozin alleviates myocardial ischemia/reperfusion injury by reducing ferroptosis via MAPK signaling inhibition

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 20, 2023

Reperfusion is essential for ischemic myocardium but paradoxically leads to myocardial damage that worsens cardiac functions. Ferroptosis often occurs in cardiomyocytes during ischemia/reperfusion (I/R). The SGLT2 inhibitor dapagliflozin (DAPA) exerts cardioprotective effects independent of hypoglycemia. Here, we investigated the effect and potential mechanism DAPA against injury (MIRI)-related ferroptosis using MIRI rat model hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocytes. Our results show significantly ameliorated injury, reperfusion arrhythmia, function, as evidenced by alleviated ST-segment elevation, biomarkers including cTnT BNP pathological features, prevented H/R-triggered cell viability loss vitro. In vitro vivo experiments showed inhibited upregulating SLC7A11/GPX4 axis FTH inhibiting ACSL4. notably mitigated oxidative stress, lipid peroxidation, ferrous iron overload, reduced ferroptosis. Subsequently, network pharmacology bioinformatics analysis suggested MAPK signaling pathway was a target common treatment phosphorylation vivo, suggesting might protect reducing through pathway.

Language: Английский

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Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(20), P. 15200 - 15200

Published: Oct. 15, 2023

Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to regulation of vascular tone, endothelial function, myocardial haemostasis, thrombosis, amongst many other roles. NO is synthesised through nitric synthase (NOS)-dependent L-arginine-NO pathway, as well nitrate-nitrite-NO pathway. The three isoforms NOS, namely neuronal (NOS1), inducible (NOS2), (NOS3), have different localisation functions human body, are consequently thought differing pathophysiological Furthermore, we continue develop a deepened understanding roles NOS disease, possibility therapeutically modulating activity has emerged. Indeed, impaired (or dysfunctional), overactive dysregulated) attractive therapeutic targets disease. This review aims describe recent advances elucidating physiological within mechanisms dysfunctional dysregulated We then discuss modulation target development novel therapeutics.

Language: Английский

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Protective effects of Pt-N-C single-atom nanozymes against myocardial ischemia-reperfusion injury

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 23, 2024

Effective therapeutic strategies for myocardial ischemia/reperfusion (I/R) injury remain elusive. Targeting reactive oxygen species (ROS) provides a practical approach to mitigate damage following reperfusion. In this study, we synthesize an antioxidant nanozyme, equipped with single-Platinum (Pt)-atom (PtsaN-C), protecting against I/R injury. PtsaN-C exhibits multiple enzyme-mimicking activities ROS scavenging high efficiency and stability. Mechanistic studies demonstrate that the excellent ROS-elimination performance of single Pt atom center precedes cluster center, owing its better synergistic effect metallic electronic property. Systematic in vitro vivo confirm efficiently counteracts ROS, restores cellular homeostasis prevents apoptotic progression after also demonstrates good biocompatibility, making it promising candidate clinical applications. Our study expands scope single-atom nanozyme combating ROS-induced offers avenue treatment

Language: Английский

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Mechanisms of ferroptosis regulating oxidative stress and energy metabolism in myocardial ischemia-reperfusion injury and a novel perspective of natural plant active ingredients for its treatment

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 114706 - 114706

Published: July 1, 2023

Acute myocardial infarction remains the leading cause of death in humans. Timely restoration blood perfusion to ischemic myocardium most effective strategy treatment acute infarction, which can significantly reduce morbidity and mortality. However, after flow reperfusion, injury will aggravate induce apoptosis cardiomyocytes, a process called ischemia-reperfusion injury. Studies have shown that loss cardiomyocytes caused by oxidative stress, iron load, increased lipid peroxidation, inflammation mitochondrial dysfunction, etc., are involved In recent years, with in-depth research on pathology injury, people gradually realized there is new form cell pathological namely ferroptosis. A number studies found tissue patients changes closely related ferroptosis, such as metabolism disorder, reactive oxygen species free radicals. Natural plant products resveratrol, baicalin, cyanidin-3-O-glucoside, naringenin, astragaloside IV also exert therapeutic effects correcting imbalance these ferroptosis-related factors expression levels. Combining our previous studies, this review summarizes regulatory mechanism natural intervening ferroptosis order provide reference information for development targeted inhibitor drugs cardiovascular diseases.

Language: Английский

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Ferroptosis in organ ischemia–reperfusion injuries: recent advancements and strategies

Molecular and Cellular Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: March 31, 2024

Language: Английский

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N-acetylcysteine Protects Against Myocardial Ischemia–Reperfusion Injury Through Anti-ferroptosis in Type 1 Diabetic Mice

Cardiovascular Toxicology, Journal Year: 2024, Volume and Issue: 24(5), P. 481 - 498

Published: April 22, 2024

Abstract The hearts of subjects with diabetes are vulnerable to ischemia–reperfusion injury (IRI). In contrast, experimentally rodent have been shown be more resistant IRI at the very early stages induction than heart non-diabetic control mice, and mechanism is largely unclear. Ferroptosis has recently play an important role in myocardial including that diabetes, while specific mechanisms still Non-diabetic (NC) streptozotocin-induced diabetic (DM) mice were treated antioxidant N-acetylcysteine (NAC) drinking water for 4 week starting 1 after induction. Mice subjected induced by occluding coronary artery 30 min followed 2 h reperfusion, subsequently 1, 2, 5 post-ischemic infarct size DM was smaller NC but greater which associated a significant increase ferroptosis reduction diabetes. NAC significantly attenuated as well oxidative stress reduced Application erastin, inducer, reversed cardioprotective effects NAC. It concluded increased major factors attributable vulnerability attenuation represents whereby confers cardioprotection against

Language: Английский

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WTAP-mediated m6A modification of lncRNA Snhg1 improves myocardial ischemia-reperfusion injury via miR-361-5p/OPA1-dependent mitochondrial fusion

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 25, 2024

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m 6 A) frequent RNA modification and plays a critical role in MIRI. However, it unclear whether lncRNA MIRI was modified m A methylation. Methods Mouse cardiomyocytes HL-1 cells were utilized to construct hypoxia/reoxygenation (H/R) model. cell viability evaluated utilizing CCK-8 method. Cell apoptosis, mitochondrial reactive oxygen species (ROS), membrane potential (MMP) quantitated flow cytometry. immunoprecipitation dual-luciferase reporter assays applied measure methylation interactions between targeted miRNA or target miRNAs its gene. The I/R mouse model constructed with adenovirus expressing Snhg1. HE TUNEL staining used evaluate myocardial tissue damage apoptosis. Results down-regulated H/R injury, overexpressed suppressed H/R-stimulated ROS level polarization. Besides, could miR-361-5p, miR-361-5p OPA1. Overexpressed polarization though miR-361-5p/OPA1 axis. Furthermore, WTAP induced cells. Moreover, enforced repressed I/R-stimulated apoptosis regulated OPA1 levels. Conclusion WTAP-mediated through modulating production, via axis, providing evidence for as prospective alleviating progression.

Language: Английский

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Gastrodin exerts perioperative myocardial protection by improving mitophagy through the PINK1/Parkin pathway to reduce myocardial ischemia-reperfusion injury

Phytomedicine, Journal Year: 2024, Volume and Issue: 133, P. 155900 - 155900

Published: Aug. 1, 2024

Although blood flow is restored after treatment of myocardial infarction (MI), ischemia and reperfusion (I/R) can cause cardiac injury, which a leading heart failure. Gastrodin (GAS) exerts protective effects against brain, heart, kidney I/R. However, its pharmacological mechanism in I/R injury (MIRI) remains unclear. GAS regulates autophagy various diseases, such as acute hepatitis, vascular dementia, stroke. We hypothesized that could repair mitochondrial damage regulate to protect MIRI. Male C57BL/6 mice H9C2 cells were subjected hypoxia-reoxygenation (H/R) administration, respectively, assess the impact on cardiomyocyte phenotypes, structure function. The effect function patients undergoing surgery has been observed clinical practice. function, structure, expression related molecules an animal model MIRI evaluated using immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, western blotting, gene sequencing. Its morphological, molecular, functional phenotypes cardiomyocytes H/R real-time quantitative PCR, blotting. significantly reduces infarct size improves models increases viability cellular models. In practice, was alleviated with better application GAS; improvements mitochondria activation also observed. primarily cardioprotective through PINK1/Parkin pathway, promotes clear damaged mitochondria. promote mitophagy preserve PINK1/Parkin, thus indicating tremendous potential effective perioperative agent.

Language: Английский

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Recent Advances in Alginate-Based Hydrogels for Cell Transplantation Applications

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(4), P. 469 - 469

Published: March 27, 2024

With its exceptional biocompatibility, alginate emerged as a highly promising biomaterial for large range of applications in regenerative medicine. Whether the form microparticles, injectable hydrogels, rigid scaffolds, or bioinks, provides versatile platform encapsulating cells and fostering an optimal environment to enhance cell viability. This review aims highlight recent studies utilizing diverse formulations transplantation, offering insights into efficacy treating various diseases injuries within field

Language: Английский

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The future of cardiac repair: a review on cell-free nanotherapies for regenerative myocardial infarction

Drug Delivery and Translational Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

Abstract Cardiovascular diseases as myocardial infarction (MI) represent a major cause for morbidity and mortality worldwide. Even though, patients who survive MI are susceptible to high risk of heart failure. This is mainly attributed the loss cardiomyocytes limited regenerative potential myocardium. Despite availability various cardiovascular drugs, they fail address main MI. The optimum therapeutic goal should therefore focus on enhancing cardiac regeneration through cellular cell-free approaches. review focused different mechanisms that can be achieved via non-cellular modalities. Passive active targeting infarcted myocardium using nanoparticles loaded with growth factors, drugs or affordable natural products reduce negative ventricular remodeling, infarct size apoptotic rate cardiomyocytes. In addition, injectable biomaterials-based nanocomposite used scaffold support recruit cells. Innovative less invasive approaches implemented enhance post Graphical abstract

Language: Английский

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