Search Results (587)

Background: Acute kidney injury (AKI) remains a condition with limited effective therapeutic options, partly due to challenges in early diagnosis and timely intervention. While lactate accumulation is a hallmark of ischemic and septic AKI, the underlying mechanisms remain unclear. Methods: This study integrated single-cell RNA sequencing data from AKI patients (GEO database) with lactate metabolism-related genes (LMRGs) to identify key therapeutic targets. Results: Collecting duct (CD) cells exhibited the highest LMRG expression. Machine learning algorithms and validation in bilateral ischemia/reperfusion injury (bIRI) and lipopolysaccharide (LPS)-induced AKI mouse models, as well as hypoxia/reoxygenation (H/R)-stimulated renal cells, identified Ldhb as a core gene. Disruption of lactate metabolism via BAY876 (selective GLUT1 inhibitor) or siRNA-mediated Ldhb knockdown significantly attenuated kidney injury, reduced inflammatory cytokines (IL-1β, IL-6, TNF-α), and decreased reactive oxygen species in vitro and in vivo. Conclusions: These findings reveal that lactate metabolism is reprogrammed in AKI, particularly in CD cells, and identify LDHB as a novel potential therapeutic target for this condition, though further mechanistic studies are required to establish causality. Full article

Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated “redox-dead” DRP1-C631A knock-in mutant (Drp1^C/A) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1-like macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1^C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD. Full article

Background/Objectives: Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury and delayed graft function after kidney transplantation. Oxidative stress, mitochondrial dysfunction, and tubular epithelial cell apoptosis are central events in renal IRI. Sophocarpine (SOP), a quinolizidine alkaloid derived from Sophora species, has reported antioxidant and anti-apoptotic activities, but its effects in renal IRI remain unclear. This study investigated the role and function of SOP in renal IRI. Methods: A bilateral renal IRI mouse model and a hypoxia/reoxygenation (H/R) model in HK-2 human proximal tubular epithelial cells were used. Renal function, histological injury, apoptosis, reactive oxygen species, malondialdehyde, superoxide dismutase activity, glutathione, mitochondrial morphology, mitochondrial membrane potential, and mitochondrial dynamics-related proteins were evaluated. SIRT1 dependency was examined using Sirt1 small interfering RNA in HK-2 cells and EX527-mediated SIRT1 inhibition in mice. Results: SOP pretreatment reduced serum creatinine and blood urea nitrogen levels, attenuated tubular injury and apoptosis, decreased oxidative stress, and preserved mitochondrial morphology and function after renal IRI. Similar protective effects were observed in HK-2 cells exposed to H/R. SOP increased SIRT1 and PGC-1α expression, whereas Sirt1 knockdown or pharmacological SIRT1 inhibition weakened the antioxidant and mitochondrial protective effects of SOP. Conclusions: SOP attenuates renal IRI-associated oxidative stress and mitochondrial dysfunction, at least in part through the SIRT1/PGC-1α axis. These findings support further investigation of SOP as a candidate renoprotective compound for ischemic kidney injury. Full article

Background: Renal ischemia–reperfusion injury (RIRI) is a major cause of acute kidney injury (AKI) and contributes to delayed graft function and progression toward chronic kidney disease. In addition to oxidative stress and inflammation, RIRI induces profound metabolic derangements, particularly suppression of tubular fatty-acid β-oxidation (FAO), leading to energetic stress, lipid accumulation, and maladaptive repair. Peroxisome proliferator–activated receptor-α (PPARα) is a key regulator of tubular FAO, but whether Schisandrin B (Sch B) mitigates RIRI through restoration of a PPARα-associated metabolic program remains unclear. Objective: To determine whether Sch B alleviates RIRI in association with restoration of tubular FAO and attenuation of lipid accumulation and fibrotic remodeling. Methods: A unilateral murine renal I/R model and an HK-2 hypoxia/reoxygenation (H/R) model were used. Mice received Sch B (20 or 40 mg/kg/day) before I/R, and a subset was co-treated with the PPARα antagonist GW6471. Renal function, tubular injury, fibrosis, lipid accumulation, and FAO-related proteins were assessed by serum biochemistry, histopathology, Oil Red O staining, transmission electron microscopy, immunohistochemistry, immunofluorescence, and Western blotting. Bulk RNA-seq and public single-cell RNA-seq datasets were integrated to characterize metabolic pathway remodeling and cell-type-associated PPARα changes. Molecular docking and molecular dynamics simulations were performed to explore the potential interaction between Sch B and PPARα. Results: Sch B significantly improved renal function, reduced tubular injury, and attenuated interstitial collagen deposition after I/R. Sch B also reduced lipid droplet accumulation, preserved mitochondrial ultrastructure, and restored the expression of FAO-related proteins, including CPT1A, CPT2, and ACADM. In vivo and in vitro, Sch B decreased α-SMA, COL1A1, and vimentin expression, indicating attenuation of EMT-associated/profibrotic remodeling. Integrated transcriptomic analyses supported marked metabolic reprogramming after I/R, with enrichment of FAO- and PPAR-related pathways and reduced PPARα expression predominantly in tubular compartments. Sch B was associated with restoration of tubular PPARα expression, while docking and molecular dynamics analyses supported a plausible Sch B–PPARα interaction in silico. GW6471 blunted the beneficial effects of Sch B on fibrosis-related and FAO-related readouts. Conclusions: Sch B alleviates RIRI and limits subsequent fibrotic remodeling in association with restoration of a PPARα-related tubular FAO program, reduced lipid accumulation, and preservation of tubular metabolic homeostasis. These findings identify metabolic reprogramming as an important component of Sch B-mediated renoprotection, although the precise mode by which Sch B regulates PPARα requires further investigation. Full article

Hypoxic–ischemic brain injury remains the leading cause of death and neurological disability after cardiac arrest. Although targeted temperature management (TTM) and other neuroprotective strategies have demonstrated promising results in preclinical studies, large randomized controlled trials have largely failed to show consistent clinical benefit. This review examines two major limitations that may contribute to these translational failures: delayed initiation of therapy beyond a time-limited therapeutic window and the lack of baseline injury severity stratification. Evidence from both experimental and clinical studies suggests that the opportunity to modify neurological injury may be confined to the first few hours after return of spontaneous circulation (ROSC). Delayed intervention may occur after irreversible neuronal injury, microvascular dysfunction, and impaired cerebrovascular autoregulation have already become established. In addition, cardiac arrest survivors represent a heterogeneous population. Patients with minimal injury may recover with standard supportive care, whereas those with severe irreversible injury are unlikely to benefit from neuroprotective interventions. Patients with moderate-severity brain injury may represent the subgroup most likely to respond to targeted therapies. Ultra-early stratification using neuroimaging, electroencephalography, circulating biomarkers, and clinical risk scores may help identify patients with therapeutic potential. This review proposes that future post-cardiac arrest research should integrate both time-sensitive intervention strategies and early injury severity stratification. Large prospective studies and randomized controlled trials are needed to determine not only whether interventions are effective, but also when they should be initiated and which patients are most likely to benefit. Full article

Post-exercise release of cardiac biomarkers reflects physiological adaptations of the myocardium to exercise; however, data on their kinetics after exhaustive exercise under hypoxia remain scarce. We determined the kinetics of cardiac biomarker changes following a single bout of exercise to volitional exhaustion under normoxia and moderate normobaric hypoxia (2000 m and 3000 m a.s.l.) in trained (n = 12; VO_2max 64.2 ± 2.9 mL·kg⁻¹·min⁻¹) and untrained (n = 12; VO_2max 44.1 ± 7.4 mL·kg⁻¹·min⁻¹) men. Participants performed a graded exercise test (GXT) followed by a constant-workload exercise test (CXT) at the lactate threshold under three conditions (FiO₂ = 20.9%, 16.5%, 14.4%). Venous blood was sampled at rest, immediately post-exercise, and at 2, 6, and 24 h of recovery for determination of cardiac troponin T (cTnT) and I (cTnI), myoglobin (Mb), creatine kinase MB isoform (CK-MB), heart-type fatty acid-binding protein (H-FABP), ischemia-modified albumin (IMA), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) by ELISA. Exhaustive exercise induced significant elevations in all biomarkers, peaking at 2–6 h post-exercise and largely returning to resting values by 24 h. Moderate normobaric hypoxia did not augment the cardiac biomarker response; rather, it attenuated the increases in Mb, NT-proBNP, and IMA, likely due to earlier peripheral fatigue and lower absolute mechanical work. The inhibitory effect of hypoxia on cTnI release was observed exclusively in trained men, suggesting an interaction between training-related cardiac adaptations and the hypoxic stimulus. These findings support the safety of high-intensity exercise at simulated altitudes of 2000–3000 m a.s.l. Full article

Thirteen new decaline polyketides, namely, zosteropenillines T–W (1–4), 8-hydroxypallidopenilline A (5), 13-epi-zosteropenilline P (6), 11-epi-zosteropenilline N (7), 15-hydroxyzosteropenilline M (8), 8-hydroxyzosteropenilline M (9), 11-epi-zosteropenilline M (10), and zosteropenillines X–Z (11–13), along with 17 known related compounds (14–30) were isolated from the ethyl acetate extract of the marine-derived fungus Penicillium yezoense KMM 4679 cultivated on MgCl₂-containing nutrient medium. The structures of the isolated compounds were established based on spectroscopic methods. The absolute configurations of zosteropenillines T (1) and V (3) were determined using time-dependent density functional theory (TD-DFT) calculations of the ECD spectra. X-ray diffraction analysis data were obtained for the known zosteropenilline S (28). A biogenetic pathway for 1–13 was proposed. The effects of the compounds on Staphylococcus aureus and Candida albicans growth and biofilm formation were observed. Zosteropenillines U (2), Y (12) and Z (13) with higher activity against C. albicans biofilms were nontoxic for normal cardiomyocyte H9c2 cells, making them promising anti-candidal agents. Moreover, zosteropenillines U and Y demonstrated cardioprotective effects in acute ischemia/reperfusion and CoCl₂-mimicking hypoxia in vitro models. Full article

Adenosine has emerged as a central metabolic signal linking cellular stress to systemic physiological adaptation. Under conditions such as hypoxia, ischemia, inflammation, and tissue injury, extracellular adenosine triphosphate (eATP) released from stressed cells is sequentially metabolized by the ectonucleotidases CD39 and CD73, generating adenosine that accumulates in the extracellular microenvironment. This stress-responsive nucleoside activates four G-protein-coupled receptors (A1, A2A, A2B, and A3), triggering intracellular signaling networks including the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), and hypoxia-inducible factor-1 alpha (HIF-1α) pathways. Through these integrated mechanisms, adenosine orchestrates diverse physiological processes such as vascular regulation, metabolic adaptation, immune modulation, and cellular survival. In the cardiovascular system, adenosine promotes coronary vasodilation and ischemic preconditioning, limiting reperfusion injury. In pulmonary tissues, it mediates acute anti-inflammatory responses but may also drive chronic fibrotic remodeling. Within the central nervous system, adenosine functions as a neuromodulator regulating neuronal excitability, sleep–wake homeostasis, and neuroprotection. In the tumor microenvironment, hypoxia-driven adenosine accumulation suppresses cytotoxic T cell and natural killer activity, facilitating immune evasion and tumor progression. Collectively, adenosine signaling represents a central integrative network that links metabolic stress sensing to coordinated cellular adaptation while simultaneously emerging as a clinically actionable therapeutic target across cardiovascular, inflammatory, neurological, and oncological diseases. Full article

Heart failure (HF) and myocardial infarction (MI) are interconnected syndromes with overlapping pathogenic pathways, including ischemia, neurohormonal activation, and maladaptive remodeling. Hypoxia-response genes, lipid-handling genes, and extracellular matrix (ECM) genes each influence these processes. Understanding their integrated roles can uncover biomarkers and targets. A systematic literature search was conducted (PubMed, Web of Science, and Scopus; 2000–2026; English-only, following PRISMA guidelines) to identify studies on key genes in hypoxia signaling, lipid metabolism, and ECM remodeling in MI/HF. Acute hypoxia (via HIFs) orchestrates metabolic adaptation and inflammation, but chronic HIF activation drives fibrosis and dysfunction. In parallel, genes controlling triglyceride and cholesterol handling (e.g., LPL, APOC3) influence energy supply and vascular risk. Variants in these genes modulate plasma lipids and MI/HF risk. For example, genetic loss-of-function in APOC3 lowers triglycerides and reduces coronary risk. ECM-related genes (e.g., COL4A1, LRP1) govern fibrosis and vascular integrity. Mutations in COL4A1 cause cardiomyocyte hypertrophy and severe fibrosis, while LRP1 regulates matrix remodeling and is upregulated in ischemic myocardium. Throughout, gene functions span acute repair versus chronic maladaptation. Findings derive from mixed sources: rodent models and cell studies demonstrate mechanistic links, while human genetics and cohorts link gene variants to HF/MI outcomes. Many promising biomarkers (e.g., circulating ITGA1) are preliminary, lacking large prospective validation. Not all cited therapeutic ideas have been tested in the treatment of human cardiac disease. The literature mix of species, models, and patient cohorts introduces heterogeneity. Full article

Objective: Cerebral ischemia–reperfusion (I/R) injury constitutes a pivotal pathological driver in cerebrovascular disorders such as stroke, yet effective therapeutic interventions remain scarce. This study explored whether hydrogen sulfide (H₂S) mitigates endothelial cell damage in the cerebral vasculature during I/R by modulating nicotinamide phosphoribosyltransferase (NAMPT) activity and its S-sulfhydration status, consequently restoring mitochondrial integrity and energetic homeostasis. Methods: Primary cerebrovascular endothelial cells (ECs) were subjected to hypoxia/reoxygenation (H/R) conditions in vitro, while rats experienced middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo. The H₂S donor sodium hydrosulfide (NaHS) was administered, and outcomes were evaluated through Western blot analysis, S-sulfhydration assays, mitochondrial functional tests, autophagy profiling, and neurobehavioral assessments. The contributions of NAMPT and S-sulfhydration were validated using FK866 and dithiothreitol (DTT), respectively. LC-MS/MS was employed to identify candidate S-sulfhydration sites on NAMPT triggered by H₂S. Results: In cellular models, NaHS substantially boosted NAMPT enzymatic activity, elevated NAD⁺ and ATP levels, and enhanced cell survival. These protective benefits were nullified upon NAMPT inhibition with FK866 or reversal of S-sulfhydration via DTT. In animal studies, NaHS treatment significantly diminished infarct volume and ameliorated neurological deficits in MCAO/R rats; however, pretreatment with FK866 or DTT attenuated these benefits. Mechanistic investigations revealed that NaHS promoted S-sulfhydration of NAMPT, thereby activating autophagy of dysfunctional mitochondria. LC-MS/MS analysis confirmed enhanced S-sulfhydration at Cys39 and Cys397 residues of NAMPT following H₂S exposure. Conclusions: H₂S exerts neuroprotection against cerebral I/R injury in rats through S-sulfhydration-mediated activation of NAMPT, which improves mitochondrial performance and stimulates autophagy in cerebrovascular ECs. Full article

Introduction: This study explored how illness severity scores correspond to hypoxic-ischemic brain injury (HIBI) after cardiac arrest. Methods: This study included cardiac arrest survivors with sufficient data to calculate the Pittsburgh Cardiac Arrest Category (PCAC) and revised post-cardiac arrest syndrome for therapeutic hypothermia (rCAST) scores who underwent brain magnetic resonance imaging and cerebrospinal fluid neuron–specific enolase (CSF-NSE) measurement within 6 h after return of spontaneous circulation. The primary outcome was the association of PCAC and rCAST with quantitative brain injury markers assessed using whole brain mean apparent diffusion coefficient (mean ADC), low ADC volume fractions (PV600, 650, and 700), and CSF-NSE. Results: In total, 81 patients were included. PCAC was not significantly associated with CSF-NSE, mean ADC, or PVs. The rCAST score was significantly associated with higher CSF-NSE, lower mean ADC, and higher PV700. The neurologic sub-score of PCAC was independently associated with all evaluated brain injury markers, whereas the systemic sub-score was not. Of the individual rCAST components, anoxic time was independently associated with CSF-NSE, whereas no other single component was associated with these markers. Conclusions: rCAST was significantly associated with degree of HIBI, whereas PCAC was not. The neurologic sub-score of PCAC showed independent associations with HIBI. Full article

Trained immunity refers to the enduring functional reprogramming of innate immune cells after particular stimuli, driven by epigenetic and metabolic alterations that augment non-specific responses upon subsequent exposure. Neutrophils and monocytes/macrophages, as essential innate effectors, are crucial for the induction and control of trained immunity, which is the primary emphasis of this review. Neutrophils, the predominant circulating leukocytes, were historically considered incapable of memory owing to their brief lifespan. Emerging evidence indicates that trained immunity functions at the bone marrow progenitor level, influencing granulopoiesis to produce neutrophils with lasting functional modifications. This research offers new insights into neutrophil functions in infection, cancer, and inflammation. Monocytes and macrophages, characterized by phenotypic plasticity and tissue residence, function as conventional models of trained immunity. They experience direct peripheral reprogramming or emerge as primed descendants of trained bone marrow precursors, performing pro-inflammatory or reparative roles in malignancies, infections, and ischemia lesions. This study comprehensively outlines the regulatory mechanisms of trained immunity in these cells, clarifies their functions in various clinical situations, and examines therapeutic applications. Comprehending these pathways is crucial for elucidating the cellular foundation of innate immunological memory, uncovering its multiple functions in disease, and guiding innovative therapeutics aimed at granulopoiesis and monocyte-macrophage polarization. Full article

We examined neocortical pathology and interneuron degeneration in neonatal hypoxia-ischemic encephalopathy (HIE). Piglets in two age groups (2–3 or 7–10 days old, n = 4–12/group) underwent global cerebral hypoxia–ischemia (HI) or sham treatment. Piglets (2–3 days old) had epidural electrodes for continuous electroencephalography (cEEG) and were treated with hypothermia (HT) or remained at normothermia (NT). Older piglets, all NT, had scalp EEG. Piglets at both ages had seizures and survived for 1–7 days. Cortical damage was assessed by hematoxylin & eosin staining and immunohistochemistry; calretinin (CR), parvalbumin (PV), and vasoactive intestinal peptide (VIP) interneurons (INs) were counted. Cell injury was assessed by DNA fragmentation and protein nitration. TAR DNA binding protein-43 (TDP43) and the DNA repair scaffold protein X-ray repair cross complementing-1 (XRCC1) were examined for degeneration mechanisms. Cortical layers 3 and 4 showed high vulnerability; damage emerged as isolated cells, focal and laminar, and distributed as panlaminar throughout different cortical regions that correlated with seizure burden. HT protected strongly against cortical damage. CR- and PV-INs were severely depleted in HI-NT piglets compared to sham. VIP INs appeared invulnerable. HT partially rescued the loss of INs. CR and PV formed nuclear and cytoplasmic inclusions that colocalized with TDP43 and XRCC1; co-immunoprecipitation identified interactions among these proteins, and tyrosine nitration of CR. CR and PV INs accumulated DNA single- and double-strand breaks and appeared as attritional apoptosis variants with proteinopathy. This cell death is identified as aggreosis. IN loss correlated with seizure presence. Postmortem human neonatal HIE cases had a similar loss of CR and PV INs and nuclear depletion of TDP43 in the neocortex. Thus, neonatal HIE causes the loss of neocortical inhibitory IN subtypes with vulnerabilities instructed by their intrinsic calcium-binding protein signature and by mechanisms consistent with toxic sequestration and the nuclear depletion of XRCC1 and TDP43 underlying DNA damage accumulation. Early inhibitory IN deletion could drive seizure evolution in HIE; TDP43 and XRCC1 could be therapeutic targets for neonatal HIE. Full article

Severe accidental hypothermia represents a unique and potentially reversible cause of cardiac arrest in which prolonged resuscitation may still result in favorable neurological recovery. Unlike normothermic cardiac arrest, hypothermic cardiac arrest (HCA) is characterized by profound metabolic suppression and temperature-mediated myocardial instability, requiring a fundamentally different therapeutic paradigm. Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) provides not only circulatory support but also controlled reperfusion and rewarming, positioning it as the cornerstone of modern management. Recent international guidelines have clarified indications for extracorporeal life support (ECLS) in HCA and have contributed to improved standardization of care. Building upon these recommendations, this narrative review focuses on physiological principles underlying extracorporeal rewarming and their implications for bedside management. We examine mechanisms of ischemia–reperfusion injury, rewarming-associated hemodynamic instability and myocardial stunning, discuss dynamic risk assessment beyond statistical thresholds such as the HOPE score and summarize practical considerations regarding cannulation strategies, differential hypoxia, left ventricular unloading and neurologic evaluation. By integrating current evidence with pathophysiological insight and organizational considerations, this review proposes a clinically oriented framework to support decision-making in hypothermic cardiac arrest and to optimize meaningful neurological recovery. Full article

Myocardial ischemia–reperfusion injury (MIRI) significantly limits the clinical benefits of reperfusion therapy, underscoring a pressing need for effective interventions. This study examines the cardioprotective effects and underlying mechanisms of the natural amide alkaloid N-p-trans-Coumaroyltyramine (p-CT). Using hypoxia/reoxygenation (H/R) models in neonatal rat cardiomyocytes and in vivo rat MIRI models, we assessed p-CT pretreatment on cell viability, cardiac function, serum injury markers (lactate dehydrogenase, creatine kinase-MB, cardiac troponin T, and myoglobin), myocardial histopathology, ultrastructural alterations, and infarct size. The systematic screening and validation of potential targets were conducted via label-free quantitative proteomics, molecular docking, and Western blot. The results demonstrated that p-CT pretreatment dose-dependently mitigated H/R-induced cellular injury, improved cardiac function in MIRI rats, reduced serum markers of myocardial damage, alleviated pathological and ultrastructural injury in myocardial tissue, and significantly diminished infarct size. Proteomic analysis revealed 19 differentially expressed proteins specifically reversed by p-CT, with Titin-cap (Tcap) exhibiting the most pronounced downregulation in the MIRI model—a change effectively restored by p-CT pretreatment. Molecular docking indicated strong binding affinity between p-CT and Tcap protein. In summary, p-CT represents a promising cardioprotective agent, likely exerting its effects by targeting Tcap protein and upregulating its expression, thereby helping preserve cardiomyocyte structural and functional integrity. Full article