Search Results (188)

Phosphate is emerging as an active mediator of oxidative stress and vascular injury in chronic kidney disease (CKD). This emerging pathophysiological framework, referred to as “Phosphatopathy”, describes the systemic syndrome driven by chronic phosphate overload and characterized by oxidative stress, inflammation, endothelial dysfunction, vascular calcification, cellular senescence, and metabolic imbalance. Beyond being a biochemical marker, phosphate overload triggers NOX-derived reactive oxygen species (ROS), activates Wnt/β-catenin and TGF-β signaling, and disrupts the FGF23–Klotho axis, promoting endothelial dysfunction, vascular calcification, and left ventricular hypertrophy (LVH). These pathways converge with systemic inflammation and energy imbalance, contributing to the malnutrition–inflammation–atherosclerosis (MIA) syndrome. Experimental and clinical data reveal that the phosphate/urinary urea nitrogen (P/UUN) ratio is a sensitive biomarker of inorganic phosphate load, while emerging regulators such as microRNA-125b and calciprotein particles integrate phosphate-driven oxidative and inflammatory responses. Therapeutic strategies targeting phosphate burden—rather than serum phosphate alone—include dietary restriction of inorganic phosphate, non-calcium binders, magnesium and zinc supplementation, and activation of important pathways related to the activation of antioxidant defense such as AMP-activated protein kinase (AMPK) and SIRT1. This integrative framework redefines phosphate as a modifiable upstream trigger of oxidative and metabolic stress in CKD. Controlling phosphate load and redox imbalance emerges as a convergent strategy to prevent vascular calcification, improve arterial stiffness, and reduce cardiovascular risk through personalized, mechanism-based interventions. Full article

High-altitude exposure poses significant health challenges to mountaineers, military personnel, travelers, and indigenous residents. Altitude-related illnesses encompass acute conditions such as acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE), and chronic manifestations like chronic mountain sickness (CMS). Hypobaric hypoxia induces oxidative stress and inflammatory cascades, causing alterations in multiple organ systems through co-related amplification mechanisms. Therefore, this review aims to systematically discuss the injury mechanisms and comprehensive intervention strategies involved in high-altitude diseases. In summary, these pathologies involve key damage pathways: oxidative stress activates inflammatory pathways through NF-κB and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasomes; energy depletion impairs calcium homeostasis, leading to cellular calcium overload; mitochondrial dysfunction amplifies injury through mitochondrial permeability transition pore (mPTP) opening and apoptotic factor release. These mechanisms could be converged in organ-specific patterns—blood–brain barrier disruption in HACE, stress failure in HAPE, and right heart dysfunction in chronic exposure. Promising strategies include multi-level therapeutic approaches targeting oxygenation (supplemental oxygen, acetazolamide), specific pathway modulation (antioxidants, calcium channel blockers, HIF-1α regulators), and damage repair (glucocorticoids). Notably, functional foods show significant therapeutic potential: dietary nitrates (beetroot) enhance oxygen delivery, tea polyphenols and anthocyanins (black goji berry) provide antioxidant effects, and traditional herbal bioactives (astragaloside, ginsenosides) offer multi-targeted organ protection. Full article

Ischemic heart disease (IHD), the leading causes of cardiovascular morbidity and mortality worldwide, is currently treated though revascularization strategies such as pharmacological thrombolysis, coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI). However, the restoration of blood flow often induces cardiac dysfunction, known as myocardial ischemia–reperfusion injury (MIRI). The pathogenesis of MIRI involves a complex, multifactorial process characterized by the interplay of diverse pathophysiological mechanisms, including oxidative stress, intracellular calcium overload, inflammatory cascade activation, apoptosis, autophagy, and microvascular endothelial dysfunction. In recent years, modified RNA (modRNA) technology has emerged as a novel therapeutic strategy for MIRI due to its enhanced molecular stability, reduced immunogenicity, and controllable transient protein expression. Studies have demonstrated that optimized modRNA delivery systems enable efficient, localized expression of therapeutic genes (e.g., antioxidant, anti-apoptotic, and pro-angiogenic factors) at injury sites, significantly mitigating MIRI-associated pathological damage. Nevertheless, significant challenges remain in clinical translation, such as delivery system targeting, transfection efficiency and cytotoxicity. This review focuses on recent advances in the development and application of modRNA-based delivery systems for MIRI treatment. Understanding the molecular mechanisms of MIRI and the structural characteristics and application of modRNA may encourage researchers to explore promising therapeutic modalities for addressing reperfusion-related cardiac injury. Full article

The mitochondrial permeability transition pore (mPTP) plays a central role in myocardial injury. Upon reperfusion after myocardial infarction, oxidative stress, calcium overload, and ATP depletion promote mPTP opening, leading to mitochondrial dysfunction, cell death, and infarct expansion. This process affects various cardiac cell types differently, contributing to complex pathological remodelling. Key mitochondrial events, such as disruption of bioenergetics parameters, impaired mitophagy, and oxidative stress, drive regulated cell death. Emerging therapies targeting mitochondrial biology, dynamics, and transplantation offer promising strategies to mitigate damage and improve cardiac outcomes. Considering the potential to improve cardiac outcomes and redefine therapeutic approaches in the management of cardiovascular disease, mPTP modulation represents a compelling therapeutic target in myocardial infarction and ischemia–reperfusion injury management. Full article

Ischemic stroke (IS) is a leading cause of mortality and long-term disability, underpinned by complex molecular mechanisms, such as oxidative stress, neuroinflammation, and apoptosis. The flavonoid Engeletin exhibits promising neuroprotective properties, but its mechanism of action remains largely unknown. In this study, we employed a systems biology approach, combined with artificial intelligence (AI), to uncover the multitarget mechanisms of Engeletin in IS. Potential targets were predicted using SwissTargetPrediction and PharmMapper and were found to intersect with IS-related genes from multiple disease databases. Functional enrichment analyses (GO/KEGG) revealed significant involvement in three classical neuroprotective pathways: PI3K-Akt-mTOR/Caspase/BCL2 (anti-apoptotic), TLR4/NF-κB (anti-inflammatory), and NRF2/KEAP1/HO-1 (antioxidant). Notably, we integrated six machine learning models (RF, SVM, GLM, KNN) to identify robust IS-specific biomarkers from the GSE22255 transcriptomic database. We used CIBERSORTx to characterize immune cell infiltration patterns in IS, revealing elevated populations of CD8⁺ T cells, M0 macrophages, and other PBMC-derived immune cells, suggesting the presence of an immunologically dynamic microenvironment. Molecular docking predicted favorable binding affinities of Engeletin to core targets (e.g., EGFR, IGF1R, KEAP1, JAK2). Finally, in vitro experiments using a Na₂S₂O₄-induced PC12 cell model confirmed Engeletin’s efficacy in reducing oxidative stress, modulating calcium overload, and regulating apoptosis- and inflammation-related genes. Overall, our study establishes a comprehensive pharmacological mechanistic framework for Engeletin in combating IS and reveals the multitarget and multi-pathway neuroprotective mechanisms, thus providing preliminary support for using Engeletin in combating ischemic stroke. Full article

Programmed cell death (PCD), a regulated cell death (RCD) subtype essential for physiological homeostasis, encompasses distinct mechanisms including apoptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and pyroptosis. This evolutionarily conserved process critically regulates disease pathogenesis across degenerative disorders, malignancies, fungal infections, and vascular calcification (VC). VC manifests as pathological calcium deposition in cardiovascular tissues, impairing vascular elasticity and hemodynamics. These structural alterations elevate risks of atherosclerotic events, cerebrovascular accidents, and peripheral vascular dysfunction, while concomitantly inducing vital organ hypoperfusion and cardiac overload that predispose individuals to myocardial ischemia, left ventricular hypertrophy, and heart failure. Despite advances in delineating associated signaling networks, the molecular etiology of VC remains elusive, and effective therapeutic interventions are currently lacking. While systematically examining the pathophysiological contributions of both established and novel PCD mechanisms to VC progression, this review incorporates a discussion of cuproptosis as a novel form of PCD, which may serve as a target for atherosclerosis treatment. The inclusion of cuproptosis, alongside other PCD modalities, allows for a more integrated and updated perspective on the complex regulatory networks governing VC. Our objective is to synthesize the current understanding of how these diverse PCD pathways, both classical and emerging, collectively contribute to the disease pathogenesis and to explore the broader therapeutic potential of targeting PCD in VC. Full article

Hypoxia is a major global health concern, particularly in premature infants and cancer, where it promotes intracellular calcium accumulation and cell death. The transient receptor potential vanilloid 1 (TRPV1) channel has been implicated in calcium dysregulation and oxidative stress under hypoxic conditions, while estrogen (17β-estradiol, E₂) is known to modulate TRPV1 activity and redox balance. This study aimed to investigate the impact of E₂ on TRPV1 expression, hypoxia-inducible factor-1α (HIF-1α), and calcium signaling in MCF-7 breast cancer cells (ERα-positive) and TRPV1-transfected CHO cells (ERα-negative). Four experimental groups were established: normoxia, E₂, hypoxia, and hypoxia + E₂. Hypoxia was induced by CoCl₂ (200 µM, 24 h), while E₂ treatment was applied at 10 nM for 24 h. Western blot analysis revealed that both TRPV1 and HIF-1α expression were upregulated under hypoxia but significantly reduced by E₂. Fura-2 fluorescence assays revealed that hypoxia increased cytosolic Ca²⁺ levels, whereas E₂ reversed this elevation. Moreover, TRPV1 activation by capsaicin induced marked Ca²⁺ influx under hypoxia, which was attenuated by E₂ treatment. These findings demonstrate that E₂ mitigates hypoxia-induced toxicity by modulating TRPV1-mediated Ca²⁺ signaling and HIF-1α expression, underscoring the protective role of E₂ and identifying TRPV1 as a potential therapeutic target in estrogen-responsive tumors. Full article

Type 2 diabetes and gout are both common metabolic disorders that frequently occur together. Research indicates that disturbances in intracellular calcium balance may be a key molecular factor linking the development of these two diseases. Calcium signaling disturbances promote the synergistic progression of both diseases through multiple pathways: In pancreatic β-cells, endoplasmic reticulum (ER) calcium imbalance triggers ER stress, mitochondrial dysfunction, and apoptosis, autophagy, and pyroptosis, leading to impaired insulin secretion. Concurrently, calcium overload exacerbates insulin resistance by disrupting insulin signal transduction in peripheral tissues, while hyperinsulinemia further inhibits uric acid excretion through activation of the renal URAT1 transporter, creating a vicious cycle. Additionally, calcium homeostasis dysregulation activates the NLRP3 inflammasome and promotes the release of pro-inflammatory cytokines, aggravating chronic low-grade inflammation, which further deteriorates β-cell function and peripheral metabolic disorders, collectively driving the pathological link between type 2 diabetes and gout. Although calcium channel modulators show potential in improving β-cell function and reducing inflammation, their clinical application faces challenges such as tissue-specific effects and a lack of high-quality clinical trials. We propose that intracellular calcium dysregulation serves as a central pathological amplifier in the diabetes–gout nexus. Future research on targeted calcium signaling interventions, guided by this integrative concept, may help overcome the therapeutic challenges in managing type 2 diabetes complicated by gout. Full article

Acute myocardial infarction, often associated with ischemia/reperfusion injury (I/R), is a major healthcare issue ranking among the leading causes of death globally. Although kynurenic acid (KYNA), an endogenous tryptophan metabolite, has been previously shown to protect the cardiac tissue against I/R injury, its mechanism of action remains unclear. Therefore, here, we examined whether KYNA administration rescues H9c2 cardiac cells exposed to I/R through the preservation of the structural and functional integrity of the mitochondria. In addition, we assessed whether KYNA-derived agonism on G-protein coupled receptor 35 (GPR35) is involved in the protection of cardiac cells against simulated I/R (SI/R)-induced cellular demise. Our results demonstrated that KYNA attenuated the SI/R-induced calcium overload as well as impairments in the mitochondrial ultrastructure. Furthermore, administration of KYNA was shown to reduce mitochondrial superoxide production and preserve mitochondrial function in cells exposed to SI/R. Activation of the GPR35 receptors using an agonist other than KYNA rescued cardiac cells undergoing SI/R, attenuated the apoptotic activity, and improved various parameters of mitochondrial respiration. The administration of a synthetic GPR35 antagonist in parallel with KYNA attenuated the KYNA-induced cytoprotection. Our findings provide evidence that the protective effect of KYNA against SI/R-induced cardiac cell injury involves mitoprotective mechanisms, acting, at least in part, through the activation of GPR35 receptors. Full article

Osteoarthritis (OA) lacks disease-modifying therapies, in part because key features of the joint microenvironment remain underappreciated. One such feature is localized acidosis, characterized by sustained reductions in extracellular pH within the cartilage, meniscus, and the osteochondral interface despite near-neutral bulk synovial fluid. We synthesize current evidence on the origins, sensing, and consequences of joint acidosis in OA. Metabolic drivers include hypoxia-biased glycolysis in avascular cartilage, cytokine-driven reprogramming in the synovium, and limits in proton/lactate extrusion (e.g., monocarboxylate transporters (MCTs)), with additional contributions from fixed-charge matrix chemistry and osteoclast-mediated acidification at the osteochondral junction. Acidic niches shift proteolysis toward cathepsins, suppress anabolic control, and trigger chondrocyte stress responses (calcium overload, autophagy, senescence, apoptosis). In the nociceptive axis, protons engage ASIC3 and sensitize TRPV1, linking acidity to pain. Joint cells detect pH through two complementary sensor classes: proton-sensing GPCRs (GPR4, GPR65/TDAG8, GPR68/OGR1, GPR132/G2A), which couple to G_s, G_q/11, and G_12/13 pathways converging on MAPK, NF-κB, CREB, and RhoA/ROCK; and proton-gated ion channels (ASIC1a/3, TRPV1), which convert acidity into electrical and Ca²⁺ signals. Therapeutic implications include inhibition of acid-enabled proteases (e.g., cathepsin K), pharmacologic modulation of pH-sensing receptors (with emerging interest in GPR68 and GPR4), ASIC/TRPV1-targeted analgesia, metabolic control of lactate generation, and pH-responsive intra-articular delivery systems. We outline research priorities for pH-aware clinical phenotyping and imaging, cell-type-resolved signaling maps, and targeted interventions in ‘acidotic OA’ endotypes. Framing acidosis as an actionable component of OA pathogenesis provides a coherent basis for mechanism-anchored, locality-specific disease modification. Full article

Acute myocardial infarction (AMI) remains the leading cause of death worldwide, with myocardial ischemia/reperfusion injury (MIRI) emerging as a significant factor influencing patient outcomes despite timely reperfusion therapy. MIRI refers to paradoxical myocardial damage that occurs upon restoration of coronary blood flow and is driven by complex inflammatory, oxidative, and metabolic mechanisms, which can exacerbate infarct size (IS), contributing to adverse outcomes. This review explores the molecular and cellular pathophysiology of MIRI, emphasizing both its clinical and forensic relevance. The principal mechanisms discussed include oxidative stress and mitochondrial dysfunction, calcium overload and ion homeostasis imbalance, inflammatory responses, with particular focus on the NLRP3 inflammasome and cytokine pathways, and multiple forms of cell death (apoptosis, necroptosis, pyroptosis, and autophagy). Additionally, the authors present original immunohistochemical findings from autopsy cases of patients who suffered ST-segment elevation myocardial infarction (STEMI) and underwent percutaneous coronary intervention (PCI), but subsequently died. These findings underscore that successful reperfusion does not completely prevent delayed complications, like arrhythmias, ventricular fibrillation (VF), and sudden cardiac death (SCD), often caused by secondary MIRI-related mechanisms. Moreover, the case series highlight the diagnostic value of inflammatory markers for pathologists in identifying MIRI as a contributing factor in such fatalities. Finally, immunotherapeutic strategies—including IL-1 and IL-6 inhibitors such as Canakinumab and Tocilizumab—are reviewed for their potential to reduce cardiovascular events and mitigate the effects of MIRI. The review advocates for continued multidisciplinary research aimed at improving our understanding of MIRI, developing effective treatments, and informing forensic investigations of reperfusion-related deaths. Full article

Oxidative stress and mitochondrial dysfunction play a key role in the early stage of Doxorubicin (Doxo)-induced cardiotoxicity. Our study investigated the potential cardioprotective role of Simvastatin (Sim), widely known for its antioxidant properties, in an in vitro model of Doxo-induced acute cardiotoxicity. Human Cardiomyocytes (HCMs) were treated with Sim (10 µM, 4 h) and then co-exposed to Doxo (1 µM) and Sim for 20 h. Our data showed that Sim co-treatment significantly (p < 0.05) reduced both cytosolic and mitochondrial Doxo-induced reactive oxygen species overproduction. In Sim co-treated cells, significant reductions in nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression (p < 0.01) and catalase (CAT), heme-oxygenase 1 (HO-1), and superoxide dismutase 2 (SOD2) levels (p < 0.05) compared to Doxo-treated cells were also demonstrated, suggesting a decreased need for compensatory antioxidant defense responses. Moreover, significant reductions in Doxo-induced mitochondrial calcium overload, mitochondrial membrane depolarization (p < 0.005), and apoptosis (p < 0.005) confirmed the protective effects of Sim co-treatment on cardiomyocytes. These data confirm that Sim could be a valuable therapeutic strategy for reducing Doxo-induced HCM damage, preventing the development of dilated cardiomyopathy and long-term heart damage, which are the main limitations of anthracycline use. Finally, real-time PCR analysis revealed that Sim co-treatment significantly reduced (p < 0.001) the Doxo-induced overexpression of MAP4K4, a mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) involved in oxidative stress-induced cell death, thus suggesting the involvement of other molecular mechanisms in Sim-mediated cardioprotection. Full article

Na⁺/Ca²⁺ exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of NCX isoforms (NCX1, NCX2, and NCX3) has emerged as a potential therapeutic strategy for disorders such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). However, the identification of selective modulators directed at specific NCX isoforms, or even different splice variants, remains challenging and limits their clinical validation. This Review aims to provide an updated overview of small-molecule NCX modulators, described over the last two decades. Chemical structures, mechanisms of action, and isoform specificity are discussed, along with the most commonly used biological assays for their functional evaluation. Full article

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration and fibrosis. A key pathological feature of DMD is mitochondrial dysfunction driven by calcium overload, which disrupts oxidative phosphorylation and triggers cell death pathways. This study shows the therapeutic potential of VBIT-4, a novel inhibitor of the mitochondrial voltage-dependent anion channel (VDAC), in two dystrophin-deficient mouse models: the mild mdx and the severe D2.DMDel8-34 strains. VBIT-4 administration (20 mg/kg) reduced mitochondrial calcium overload, enhanced resistance to permeability transition pore induction, and improved mitochondrial ultrastructure in D2.DMDel8-34 mice, while showing negligible effects in mdx mice. VBIT-4 suppressed mitochondrial and total calpain activity and reduced endoplasmic reticulum stress markers, suggesting a role in mitigating proteotoxic stress. However, it did not restore oxidative phosphorylation or reduce oxidative stress. Functional assays revealed limited improvements in muscle strength and fibrosis reduction, exclusively in the severe model. These findings underscore VDAC as a promising target for severe DMD and highlight the critical role of mitochondrial calcium homeostasis in DMD progression. Full article

Soman, an organophosphorus nerve agent, induces neurotoxicity primarily by inhibiting acetylcholinesterase, triggering a series of pathological events including cholinergic crisis, seizures, calcium overload, oxidative stress, mitochondrial dysfunction, and neuronal death. Nevertheless, the mechanisms underlying metabolic dysregulation—especially after repeated exposure—remain poorly characterized. To address this, we used SWATH-based proteomics to analyze changes in the hippocampal proteome following a repeated soman exposure regimen in a model of hippocampal injury. We identified 38 differentially expressed proteins, predominantly enriched in metabolic pathways. KEGG annotation indicated that these were mainly involved in carbohydrate, amino acid, and lipid metabolism, with specific roles in calcium signaling, tryptophan and tyrosine metabolism, alanine, aspartate and glutamate metabolism, and glyoxylate and dicarboxylate metabolism. Overall, our results demonstrate significant disruption of key metabolic pathways, particularly affecting carbohydrate and amino acid metabolism. We suggest that soman-induced hippocampal damage arises not only from acute calcium overload but also from persistent metabolic dysregulation that impairs energy production and biosynthetic processes. All of our preliminary results shed light on the nature of the biological process and target in the metabolism and provide basic research for the treatment, diagnosis, and prevention of nerve-agent-induced brain damage. Full article