Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia

Clinical Kidney Journal, Год журнала: 2024, Номер 17(3)

Опубликована: Фев. 28, 2024

ABSTRACT Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic class for treating anemia in patients with chronic kidney disease. Small molecule analogs of α-ketoglutarate (AKG), an essential substrate 2-oxoglutarate-dependent dioxygenases (2-OGDDs), including domain proteins (PHDs), inhibit PHDs pharmacologically and thereby prevent HIF degradation. stabilization alleviates through several stimulatory effects on erythropoiesis, but it also affects the expression many anemia-unrelated genes whose protein products exert important functions vivo. Therefore, pleiotropic under normoxic conditions deserve to be examined more detail. Specifically, we believe that particular attention should given epigenetic modifications among various AKG-based metabolic systems may altered by HIF-PHIs. It is noteworthy AKG has been reported health-protective actions. include enzymes associated tricarboxylic acid cycle amino metabolism, well 2-OGDD-mediated processes, which play roles biological reactions. In this review, examine multifaceted HIF-PHIs, encompassing not only their on-target effect off-target inhibitory systems. Furthermore, its potential relevance cardiovascular complications, based clinical animal studies suggesting involvement vascular calcification, thrombogenesis heart failure. conclusion, although HIF-PHIs offer promising avenue treatment CKD patients, broader impact multiple raises substantial concerns. The intricate interplay between stabilization, competition complications warrants extensive, long-term investigations ensure safety usefulness practice.

Язык: Английский

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Danshen injection ameliorates unilateral ureteral obstruction-induced renal fibrosis by inhibiting ferroptosis via activating SIRT1/GPX4 pathway

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Янв. 13, 2025

The pathogenesis of renal fibrosis is related to blood stasis, and the method promoting circulation removing stasis often used as treatment principle. Danshen injection (DSI) a commonly drug for in clinic. However, whether DSI slows progression or potential mechanism uncertain. We investigated models using UUO mice TGF-β stimulation HK-2 cells. Our findings revealed that Fer-1 alleviated kidney injury by ameliorating morphology pathological vivo. Besides, inhibited vivo TGF-β-induced Furthermore, ferroptosis was lessened under treatment. More importantly, active ingredients (danshensu, salvianolic acid B, protocatechuic aldehyde, caffeic tanshinone IIA) could bind SIRT1. protein levels SIRT1 GPX4 were downregulated accompanied incremental concentrations Erastin, which repaired intervention. inhibition owing reversed inhibitor EX527. Taken together, our results indicated protect against attenuate activating SIRT1/GPX4 pathway. It expected be agent treat fibrosis.

Язык: Английский

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Targeting Zfp36 to combat cardiac hypertrophy: Insights into ferroptosis pathways

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(3)

Опубликована: Фев. 25, 2025

Cardiac hypertrophy is a precursor to heart failure and represents significant global cause of mortality, thereby necessitating timely effective therapeutic interventions. Zinc finger protein 36 (Zfp36) recognised as critical regulator ferroptosis; however, its role underlying mechanisms in cardiac remain largely unexplored. This study aims investigate the regulatory function Zfp36 ferroptosis within context hypertrophy. Single-cell sequencing analysis demonstrated reduction expression associated with was observed mitigate reduce hypertrophic phenotypes cardiomyocytes subjected Angiotensin II (Ang II) myocardial tissues induced by transverse aortic constriction. The inhibitor Ferrostatin-1 shown alleviate when co-incubated si-Zfp36 Ang II. Mechanistically, binds 3' untranslated region (3'UTR) Ythdc2 mRNA, facilitating degradation. subsequently SLC7A11 enhancing decay, which leads glutathione (GSH) levels, exacerbating Furthermore, overexpression reversed protective effects conferred Zfp36, while silencing counteracted knockdown. elucidates hypertrophy, specifically detailing modulatory mechanism via Ythdc2/SLC7A11/GSH pathway. These insights lay groundwork for innovative approaches understanding pathological clinical initially attenuate through inhibition cardiomyocytes, providing new target strategies targeting ferroptosis. facilitated degradation mRNA binding it, inhibiting Ythdc2-mediated maintaining GSH levels. previously unrecognized pathway

Язык: Английский

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Cell death‑related molecules and targets in the progression of urolithiasis (Review)

International Journal of Molecular Medicine, Год журнала: 2024, Номер 53(6)

Опубликована: Апрель 22, 2024

Urolithiasis is a high‑incidence disease caused by calcium oxalate (mainly), uric acid, phosphate, struvite, apatite, cystine and other stones. The development of kidney stones closely related to renal tubule cell damage crystal adhesion aggregation. Cell death, comprising the core steps damage, can be classified into various types (i.e., apoptosis, ferroptosis, necroptosis pyroptosis). Different types, concentrations, morphologies sizes cause tubular via regulation different forms death. Oxidative stress high or concentrations considered precursor variety In addition, complex crosstalk exists among numerous signaling pathways their key molecules in metabolic disorder, tricarboxylic acid cycle‑related molecules, such as citrate succinate, are death inhibition stone development. However, literature review associations between development, metabolism currently lacking, at least best our knowledge. Thus, present summarizes major advances understanding regulated urolithiasis progression.

Язык: Английский

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Epigenetic regulation of diverse regulated cell death modalities in cardiovascular disease: Insights into necroptosis, pyroptosis, ferroptosis, and cuproptosis

Redox Biology, Год журнала: 2024, Номер 76, С. 103321 - 103321

Опубликована: Авг. 19, 2024

Cell death constitutes a critical component of the pathophysiology cardiovascular diseases. A growing array non-apoptotic forms regulated cell (RCD)-such as necroptosis, ferroptosis, pyroptosis, and cuproptosis-has been identified is intimately linked to various conditions. These RCD are governed by genetically programmed mechanisms within cell, with epigenetic modifications being common crucial regulatory method. Such include DNA methylation, RNA histone acetylation, non-coding RNAs. This review recaps roles modifications, RNAs in diseases, well which regulate key proteins involved death. Furthermore, we systematically catalog existing pharmacological agents targeting novel their action article aims underscore pivotal role precisely regulating specific pathways thus offering potential new therapeutic avenues that may prove more effective safer than traditional treatments.

Язык: Английский

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Role of sirtuin 1 in depression‑induced coronary heart disease: Molecular pathways and therapeutic potential (Review)

Biomedical Reports, Год журнала: 2025, Номер 22(3)

Опубликована: Янв. 14, 2025

Depression and coronary heart disease (CHD) are two interconnected diseases that profoundly impact global health. is both a complex psychiatric disorder an established risk factor for CHD. Sirtuin 1 (SIRT1) enzyme requires the cofactor nicotinamide adenine dinucleotide (NAD+) to perform its deacetylation function, involvement crucial in reducing cardiovascular risks associated with depression. SIRT1 exerts cardioprotective effects via modulating oxidative stress, inflammation metabolic processes, all of which central pathogenesis CHD individuals Through influencing these pathways, helps reduce endothelial dysfunction, prevent formation atherosclerotic plaques stabilize existing plaques, thereby decreasing overall The present review underscores important role serving as therapeutic intervention molecule tackling complications stemming from Furthermore, it highlights need further studies clarify how influences depression at molecular level. ultimate goal this research will be translate findings into practical clinical strategies.

Язык: Английский

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Ferroptosis in organ fibrosis: Mechanisms and therapeutic approaches

International Immunopharmacology, Год журнала: 2025, Номер 151, С. 114341 - 114341

Опубликована: Март 1, 2025

Язык: Английский

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Potential role of SIRT1 in cell ferroptosis

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Март 5, 2025

Ferroptosis is a novel form of cell death that uniquely requires iron and characterized by accumulation, the generation free radicals leading to oxidative stress, formation lipid peroxides, which distinguish it from other forms death. The regulation ferroptosis extremely complex closely associated with spectrum diseases. Sirtuin 1 (SIRT1), NAD + -dependent histone deacetylase, has emerged as pivotal epigenetic regulator potential regulate through wide array genes intricately metabolism, homeostasis, glutathione biosynthesis, redox homeostasis. This review provides comprehensive overview specific mechanisms SIRT1 regulates explores its therapeutic value in context multiple disease pathologies, highlighting significance SIRT1-mediated treatment strategies.

Язык: Английский

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The addition of alpha-ketoglutarate to NT-proBNP improves the prediction of long-term all-cause mortality in acute heart failure patients

Annals of Medicine, Год журнала: 2025, Номер 57(1)

Опубликована: Март 17, 2025

Alpha-ketoglutarate (AKG), is a major intermediate metabolite of the tricarboxylic acid cycle, and closely associated with cardiometabolic disease prognosis. Previous studies indicated that AKG related to myocardial energy expenditure levels reflects adverse short-term outcomes in heart failure (HF) patients. In this prospective cohort study, we examined long-term prognostic value acute HF (AHF) Plasma were assessed patients hospitalized AHF. Hazard ratios (HRs) 95% confidence intervals (CIs) for all-cause mortality calculated via multiple Cox regression. All-cause was compared between NT-proBNP < 1000 pg/ml those ≥ subgroup analysis. Patients 9.83 μg/ml had higher rates lower left ventricular ejection fraction (LVEF) systolic blood pressure (SBP). After adjustment, an increased risk (HR = 1.078, p 0.001). Compared μg/ml, nearly doubled 1.929, 0.001) quadrupled 4.160, pg/ml, respectively. independently greater Higher retained relatively low NT-proBNP.

Язык: Английский

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Cellular and Mitochondrial Pathways Contribute to SGLT2 Inhibitors-mediated Tissue Protection: Experimental and Clinical Data

Current Pharmaceutical Design, Год журнала: 2024, Номер 30(13), С. 969 - 974

Опубликована: Март 29, 2024

Abstract: In metabolic syndrome and diabetes, compromised mitochondrial function emerges as a critical driver of cardiovascular disease, fueling its development persistence, culminating in cardiac remodeling adverse events. this context, angiotensin II - the main interlocutor renin-angiotensin-aldosterone system promotes local systemic oxidative inflammatory processes. To highlight, low activity/expression proteins called sirtuins negatively participates these processes, allowing more significant imbalance, which impacts cellular tissue responses, causing damage, inflammation, vascular remodeling. The reduction energy production mitochondria has been widely described element all types disorders. Additionally, high sirtuin levels AMPK signaling stimulate hypoxia-inducible factor 1 beta promote ketonemia. Consequently, enhanced autophagy mitophagy advance through cells, sweeping away debris silencing orchestra stress ultimately protecting vulnerable from damage. highlight particular interest, SGLT2 inhibitors (SGLT2i) profoundly influence mechanisms. Randomized clinical trials have evidenced compelling picture SGLT2i emerging game-changers, wielding their power to demonstrably improve slash rates renal Furthermore, driven by recent evidence, emerge supermolecules, exerting beneficial actions increase efficiency, alleviate stress, curb severe inflammation. Its strengthen tissues create resilient defense against disease. conclusion, like treasure chest brimming with untold riches, on holds potential for health. Unlocking secrets, map guiding adventurers hidden promises pave way even potent therapeutic strategies.

Язык: Английский

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