Search Results (1,813)

Lipopolysaccharide (LPS) impairs the function of ovine follicular granulosa cells (GCs), representing a primary cause of follicular atresia. Selenium (Se), an essential trace element, possesses anti-inflammatory and cytoprotective properties; however, its effects on GC ultrastructure remain largely unknown. In this study, primary ovine GCs were exposed to LPS (10 µg/mL) and treated with sodium selenite (25 nM). Transmission electron microscopy (TEM), JC-1 staining, enzyme-linked immunosorbent assay (ELISA), reactive oxygen species (ROS) detection, flow cytometry, and quantitative real-time PCR (qRT-PCR) were employed to evaluate cellular ultrastructure, mitochondrial membrane potential (ΔΨm), and downstream physiological processes. LPS induced severe mitochondrial pyknosis, cristae loss, and reduced ΔΨm, accompanied by inflammation, oxidative stress, apoptosis, and impaired steroidogenesis. Se intervention markedly ameliorated these ultrastructural injuries, preserving mitochondrial morphology and ΔΨm. Functionally, Se suppressed the release of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β); enhanced the activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) while attenuating ROS accumulation; inhibited apoptosis by upregulating BCL-2 and downregulating BAX and CASPASE-3; and restored E₂ and P₄ secretion via upregulation of STAR and NR5A1. This study provides direct morphological evidence that Se protects ovine GCs from LPS-induced damage by repairing mitochondrial ultrastructure. This structural restoration is central to its integrated anti-inflammatory, antioxidant, anti-apoptotic, and steroidogenic effects. These in vitro findings suggest that Se may serve as a promising nutritional strategy for mitigating inflammation-driven follicular atresia, pending further in vivo validation. Full article

Neuropathic pain (NP) arises from diverse conditions, including peripheral nerve injury, spinal cord injury (SCI), and painful diabetic neuropathy, yet these disorders share oxidative stress, mitochondrial dysfunction, lipid dysregulation, and altered neuronal excitability. We investigated whether dietary omega-3 polyunsaturated fatty acids modulate ferroptotic stress-associated pathways, defined as lipid peroxidation susceptibility and impaired antioxidant defense rather than overt ferroptotic cell death. Female Sprague–Dawley rats received either a soy oil control diet (SOD) or fish oil omega-3-enriched diet (FOD) before chronic constriction injury (CCI). Behavioral outcomes were assessed using Hargreaves and CatWalk testing, followed by dorsal root ganglion (DRG) RNA sequencing, RT-PCR, and GPX4 ELISA. Previously generated SCI metabolomics and human diabetic serum metabolomic/lipidomic datasets were re-analyzed for shared pathways. FOD attenuated CCI-induced thermal hypersensitivity and improved gait parameters. DRG transcriptomics showed reduced injury-associated transcriptional disruption, enrichment of selenoamino acid metabolism, nonsense-mediated decay, and ribosomal quality-control pathways, and reduced mitochondrial dysfunction pathway activity. Omega-3 increased Gpx1/Gpx4 expression and GPX4 protein, reduced pain-associated genes including Scn10a, Piezo2, Trpa1, and Oprm1, and aligned with selenoamino acid enrichment in SCI and human datasets. Human lipidomics showed MG/DG/PC/PE pathway remodeling. These findings support ferroptotic stress as a plausible shared downstream mechanism modulated by omega-3 supplementation across NP models. Full article

Mastitis is recognized worldwide as one of the most expensive and common bovine diseases, severely affecting bovine health and milk quality. Mitochondria, known to play important roles in bovine mammary epithelial cells (BMECs), not only provide energy for milk synthesis but also participate in the regulation of the intracellular redox balance, inflammatory reactions, calcium signal transduction, and apoptosis. Mastitis destroys the dynamic balance between the intrinsic repair and damage mechanisms of mitochondria, which leads to mitochondrial dysfunction and aggravation of mammary cell injury or apoptosis. Plant extracts are rich in bioactive substances and are promising antibiotic substitutes for alleviating bovine mastitis. This paper reviews the mechanism through which plant extracts promote mitochondrial repair by interfering with mitophagy, dynamic balance and biogenesis, and alleviate mitochondrial damage by inhibiting mitochondrial ROS, calcium homeostasis imbalance and permeability changes, resulting in the regulation of the mitochondrial function of mammary cells under inflammation and oxidative stress. Elucidation of these mechanisms can provide new strategies for the targeted control of bovine mastitis. Full article

Male infertility refers to the inability of a male partner to contribute to pregnancy after 12 months or more of regular unprotected intercourse. It is frequently associated with impaired spermatogenesis, and many cases cannot be completely explained by genetic, inflammatory, endocrine, or environmental factors. Trimethylamine N-oxide (TMAO) is generated when gut bacteria convert dietary choline, L-carnitine, and betaine into trimethylamine (TMA), which is oxidized in the liver mainly by flavin-containing monooxygenase 3 (FMO3). This focused review evaluates current evidence on TMAO and impaired spermatogenesis within the gut–testis axis. The rationale is biologically plausible because sperm motility depends on coordinated glycolytic and mitochondrial energy metabolism, whereas Leydig cell steroidogenesis depends on mitochondrial cholesterol transport and redox balance. Human observational studies associate TMAO with asthenozoospermia and Leydig cell-related markers, particularly insulin-like peptide 3 (INSL3), while mouse studies suggest testicular injury and reduced spermatogenesis after TMAO-related exposure. The Hippo/Yes-associated protein (YAP)–mitochondria–steroidogenic acute regulatory protein (StAR) axis has been proposed as one possible mechanism, but direct reproductive tract exposure, blood–testis barrier kinetics, and human validation remain unresolved. Overall, TMAO should be considered as a candidate metabolic mediator and not a proven causal factor or therapeutic target in male infertility. Full article

Chronic hyperglycemia and excessive reactive oxygen species (ROS) production are defining features of endothelial dysfunction, a key driver of diabetic vascular complications such as diabetic nephropathy. Microvesicles (MV-enriched fraction), a subtype of extracellular vesicles, and the stress-responsive antioxidant protein Sestrin2 (SESN2) have emerged as important contributors to these processes. This study investigated the role of the MV-enriched fraction in endothelial cell communication under diabetic conditions, with a particular focus on oxidative stress signaling. To model diabetic injury, EA.hy926 endothelial cells were treated with methylglyoxal (MGO), and the resulting MV-enriched fraction was isolated and then applied to two recipient models: naïve endothelial cells and SESN2 knockdown (KD) cells. Protein expression of key antioxidant markers, including endothelial nitric oxide synthase (eNOS), was assessed by Western blot. Nitric oxide (NO) bioavailability was quantified via nitrite measurement using 2,3-diaminonaphthalene (DAN), while mitochondrial and cytosolic ROS levels were evaluated using MitoSOX and dihydroethidium (DHE), respectively. Results demonstrated that the MV-enriched fraction derived from diabetic conditions triggers a complex antioxidant response in healthy endothelial cells, characterized by upregulation of SESN2, superoxide dismutase 1 (SOD1), and heme oxygenase-1 (HO-1). This suggests a compensatory mechanism that mitigates oxidative stress. Notably, SESN2 KD cells exhibited increased ROS production and reduced NO levels upon MV treatment, underscoring the essential role of SESN2 in maintaining redox homeostasis. Overall, this study highlights the dual role of the MV-enriched fraction as a mediator of both protective and detrimental redox signaling in diabetic endothelial dysfunction and suggests potential therapeutic targets for managing diabetic vascular complications. Full article

Despite advances in liver machine perfusion (MP), ischemia–reperfusion injury (IRI) remains a major challenge in liver transplantation, with energetic stress and mitochondrial dysfunction recognized as key drivers of damage exacerbation. We investigated whether fractions enriched with extracellular vesicles (EVs) derived from mesenchymal stromal cells can preserve energetic homeostasis in rat livers undergoing normothermic MP (NMP). An established NMP rat model was used (n = 5 per group). After procurement, livers underwent NMP for 4 h, preceded or not by 30 min cold ischemia (CI). EVs (NMP + EVs and CI + NMP + EVs) or saline (NMP and CI + NMP) were randomly administered to the perfusion fluid. Perfusate samples were collected throughout the procedure, and biopsies were taken at the end of NMP. Ischemic livers exhibited succinate accumulation, flavin mononucleotide (FMN) release, activation of reverse electron transport, and adenosine triphosphate (ATP) depletion. EV treatment effectively counteracted these effects, restoring a metabolic profile comparable to that of non-ischemic livers. Moreover, EVs improved adenosine monophosphate/ATP ratios and prevented AMP-activated protein kinase activation, a key energy-stress sensor. Furthermore, EVs reduced oxidative stress markers, cell death mediators, and pro-inflammatory cytokines, indicating a broad cytoprotective and anti-inflammatory effect. These findings support the potential of EVs to preserve mitochondrial function, restore energy balance, and reduce inflammation, thereby improving liver cell viability during NMP. Full article

Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Emerging evidence suggests that epigenetic dysregulation, particularly altered DNA methylation, contributes to DOX-induced cardiac injury. Metformin has been reported to exert cardiometabolic and epigenetic regulatory effects. This study investigated genome-wide DNA methylation changes induced by chronic metformin exposure and their effects on doxorubicin sensitivity in H9c2 cardiomyoblast cells. Methods: Genome-wide DNA methylation changes induced by chronic metformin exposure were investigated in H9c2 cardiomyoblast cells using whole-genome bisulfite sequencing (WGBS). Cells were treated with metformin (0.7–2.8 mM) for four months prior to DOX exposure. Cellular sensitivity to DOX was evaluated using MTT-based dose–response analysis and IC₅₀ estimation. Results: DOX reduced cell viability (IC₅₀ = 0.164 µM). Chronic metformin pre-treatment produced a dose-dependent rightward shift in DOX dose–response curves, increasing IC₅₀ values to 0.21, 0.289, and 0.51 µM at 0.7, 1.4, and 2.8 mM metformin, respectively. WGBS revealed distinct separation between treatment groups in principal component analysis. Significant methylation changes (adjusted p-value < 0.05) were identified in genes related to oxidative stress, mitochondrial function, apoptosis, and chromatin regulation. Conclusions: Chronic metformin exposure induces dose-dependent genome-wide DNA methylation remodeling in cardiac cells and is associated with altered cellular sensitivity to doxorubicin. These findings suggest that metabolic modulation by metformin may influence epigenetic regulation and cellular stress responses relevant to chemotherapy-induced cardiotoxicity. Full article

Background: Neuropathic pain (NP), a debilitating condition resulting from nervous system lesions, is poorly managed by current therapies. The cingulate cortex is crucial for affective pain processing, yet a comprehensive spatiotemporal understanding of its molecular changes in NP is lacking. Methods: We performed RNA sequencing to profile transcriptomic alterations in the anterior cingulate (ACC) and midcingulate (MCC) cortices of mice at two and four weeks after spared nerve injury. Bioinformatics analyses, including differential expression, functional enrichment, weighted gene co-expression network analysis, and protein–protein interaction (PPI) network construction, were employed. Results: We identified widespread, time-dependent transcriptional dysregulation in both regions, with differentially expressed genes increasing over time. Functional analyses confirmed central roles for synaptic plasticity and neuroinflammatory pathways, and further identified pathways related with neurodegeneration and mitochondrial dysregulationin NP pathogenesis. Subregion analysis revealed that the ACC exhibited broader pathway alterations than the MCC, including neuroinflammation (early phase) and mitochondrial dysfunction/neurodegeneration (late phase), indicating a progressive stress response unique to the ACC. PPI analysis identified stage-specific hub genes (e.g., early interferon-stimulated genes and late ribosomal proteins in ACC; persistent extracellular matrix components in MCC). Conclusions: This study provides a detailed transcriptomic atlas of the cingulate cortex in NP, reinforcing known synaptic and neuroinflammatory mechanisms, and suggests a possible role of mitochondrial dysregulation in NP pathogenesis. The findings provide a basis for further mechanistic studies. Full article

Background: Kai-Bi-Bu-Fei Decoction (KBD) is derived from the canonical Traditional Chinese Medicine formulas Xuan-Bai-Cheng-Qi and Ma-Xing-Shi-Gan. It has been employed for decades in the treatment of severe pneumonia with significant clinical efficacy. This study aimed to evaluate the protective effects of KBD against influenza virus-induced severe pneumonia in a murine model and to elucidate the underlying molecular mechanisms. Methods: The chemical profile of KBD was characterized using UPLC-Q-TOF-MS. A severe pneumonia model was established in C57BL/6J mice via intranasal infection with influenza A/Puerto Rico/8/34 (H1N1, PR8). Multiple parameters, including 14-day survival rate, body weight, lung index, histopathological changes, viral load, and pulmonary cytokine/chemokine levels, were assessed. Furthermore, multi-omics analyses were integrated to characterize the gut microbiota and metabolic profiles. Fecal microbiota transplantation (FMT) was subsequently performed to validate the functional role of the gut microbiota and its metabolites. Results: KBD treatment significantly improved the survival rate by 40%, reduced the lung index by 27.85%, and alleviated lung injury. It also markedly lowered the viral load by 80.88%, suppressed pro-inflammatory cytokine levels, and restored intestinal barrier integrity. Mechanistically, KBD restored gut microbiota diversity by increasing the abundance of Firmicutes and Bacteroidetes, enriching beneficial genera such as Bifidobacterium and Faecalibaculum, and reducing Verrucomicrobiota. Integrated transcriptomic and metabolomic analyses revealed that KBD enhanced short-chain fatty acid (SCFA) metabolism and up-regulated pyruvate metabolism. Finally, FMT confirmed that the therapeutic benefits of KBD were transferable via the microbiota to microbiota-depleted mice. Conclusions: KBD exerts robust protection against severe influenza pneumonia, a process primarily mediated by the gut microbiota–SCFA axis. The enhancement of mitochondrial energy metabolism also appears to play a critical role in its therapeutic mechanism. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine. Full article

Background: Low Cardiac Output Syndrome (LCOS) remains a common and clinically significant complication after cardiac surgery, characterized by impaired myocardial performance and inadequate systemic oxygen delivery despite optimized preload, afterload, and rhythm control. Although LCOS has traditionally been attributed to ischemia–reperfusion injury, myocardial stunning, inflammation, and neurohormonal dysregulation, accumulating evidence suggests that subcellular energetic impairment may contribute to postoperative myocardial dysfunction. Objective: This review evaluates mitochondrial dysfunction as a potential pathophysiological substrate that may underlie or exacerbate postoperative LCOS, integrating experimental, translational, and clinical findings relevant to adult cardiac surgery. Methods: A focused narrative review of preclinical and clinical literature was performed, emphasizing mitochondrial bioenergetics, calcium handling, redox signaling, and mitochondrial quality control in the context of cardiopulmonary bypass, ischemia–reperfusion, and postoperative myocardial injury. Results: Cardiomyocytes rely predominantly on mitochondrial oxidative phosphorylation, which supplies approximately 95% of myocardial ATP under physiological conditions. Surgical ischemia–reperfusion, cardioplegia, and systemic inflammatory activation are associated with transient mitochondrial disturbances, including impaired electron transport, increased reactive oxygen species generation, calcium overload, and mitochondrial permeability transition pore opening. These changes may contribute to reduced ATP availability, delayed myocardial recovery, contractile inefficiency, and increased susceptibility to arrhythmias. Emerging evidence suggests that circulating mitochondrial biomarkers, such as cell-free mitochondrial DNA, correlate with postoperative organ dysfunction, supporting the presence of systemic mitochondrial stress after cardiac surgery. Conclusions: Postoperative LCOS may partially reflect a reversible state of myocardial energetic failure. Recognition of mitochondrial involvement complements established hemodynamic and inflammatory models and offers a biologically plausible framework for variability in postoperative cardiac recovery. Full article

The role of gluconeogenesis in kidney disease has increasingly drawn attention. Fructose-1,6-bisphosphatase 1 (FBP1) is a key rate-limiting enzyme in gluconeogenesis that suppresses glycolysis and reduces lactate production. In this study, we first analyzed public transcriptomic datasets of diabetic kidney disease (DKD) and validated the findings in 24-week-old BKS-db mice and in high-glucose-induced human renal tubular epithelial (HK-2) cells. We further constructed tubular-specific FBP1 overexpression/knockdown mouse models via adeno-associated virus serotype 9 (AAV-9) and combined pharmacological inhibition of lactate dehydrogenase B (LDHB) to dissect the underlying mechanism. Analysis of public clinical transcriptomic datasets showed that renal tubular FBP1 expression was positively correlated with estimated glomerular filtration rate (eGFR). In vivo, tubular-specific FBP1 overexpression in BKS-db mice reduced 24-h urinary protein and decreased renal lactate accumulation (p < 0.05) compared with diabetic controls. In vitro, high glucose-induced lactate elevation in HK-2 cells was reversed by FBP1 overexpression, while co-treatment with an LDHB inhibitor abolished this protective effect. Our findings suggest that FBP1 represents a potential experimental therapeutic target associated with alleviation of renal lactic acid accumulation and mitochondrial injury in preclinical DKD models. Full article

Cold seawater immersion is a critical lethal risk in maritime accidents and military operations, frequently inducing fatal myocardial dysfunction. However, the mechanisms underlying this seawater immersion hypothermia-induced cardiac injury remain poorly defined. This study aimed to elucidate the pathological progression and underlying mechanisms of myocardial injury induced by cold seawater immersion. A male SD rat model was immersed in 15 °C seawater for 2 h. Echocardiography, transmission electron microscopy, transcriptomics, and Western blot were performed to assess cardiac function, mitochondrial ultrastructure, and molecular mechanisms. Cold stress triggered progressive bradycardia (~480 to ~100 bpm) with initial Frank–Starling compensation, followed by decompensation with reduced cardiac output and impaired diastolic function. Mitochondrial ultrastructural damage preceded histological lesions and was accompanied by elevated cardiac injury markers (cTnT, CK-MB, BNP). Cardiac tissue exhibited upregulated TNF-α, IL-1β, and IL-6, while transcriptomic analysis revealed enrichment of inflammatory pathways (TNF, NF-κB) and coordinated upregulation of pattern recognition receptors including scavenger receptor, Toll-like receptor, and NOD-like receptor families. The Western blot confirmed NF-κB activation, NLRP3 inflammasome assembly, and the N-terminal fragment of gasdermin D (GSDMD-NT) accumulation, indicating pyroptotic cell death. These findings demonstrate that cold seawater stress disrupts mitochondrial homeostasis and activates the NF-κB/NLRP3/pyroptosis cascade, contributing to inflammatory cardiomyocyte death and cardiac decompensation. This mechanistic insight may inform therapeutic strategies for seawater immersion hypothermia. Full article

Myocardial ischemia–reperfusion injury (MIRI) represents a major contributor to morbidity and mortality in patients undergoing reperfusion therapy after acute myocardial infarction. Although timely restoration of coronary blood flow is essential for myocardial salvage, reperfusion paradoxically initiates a complex cascade of molecular and cellular events that may aggravate myocardial injury. Oxidative stress is considered one of the central mechanisms underlying MIRI, primarily through excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to mitochondrial dysfunction, calcium overload, endothelial injury, inflammatory activation, and cardiomyocyte death. This review summarizes the current understanding of the pathophysiological mechanisms involved in oxidative stress-mediated reperfusion injury, with emphasis on mitochondrial permeability transition pore opening, inflammasome activation, cytokine release, neutrophil extracellular trap formation, macrophage polarization, and interconnected cell death pathways including PANoptosis. Emerging evidence regarding immunometabolic regulation and epigenetic modulation in MIRI is also discussed. In addition, current pharmacological and non-pharmacological cardioprotective strategies targeting oxidative stress, mitochondrial dysfunction, and inflammatory signaling are reviewed, highlighting both promising experimental findings and the persistent challenges in clinical translation. A deeper understanding of the molecular interplay between oxidative stress and inflammatory pathways may facilitate the development of integrated therapeutic approaches aimed at improving myocardial recovery and long-term cardiovascular outcomes following reperfusion therapy. Full article

Cisplatin (CP) chemotherapy is limited by nephrotoxicity, primarily involving tubular epithelial cell apoptosis. αB-crystallin (CryAB) is a small heat shock protein that plays a cytoprotective role in stressed kidneys but can also promote tumor progression. Its precise role and molecular mechanisms in CP-induced kidney injury remain largely unclear. This study highlighted the function of CryAB and its regulatory pathways in CP nephrotoxicity by employing in vitro models of rat renal tubular epithelial cells (NRK-52E) with CryAB gene knockdown/overexpression, and in vivo models of CryAB knockout/wild-type mice, followed by CP treatment. Apoptosis and key signaling pathways (NF-κB, MAPK, AKT) were evaluated in this study. The results indicated that CP treatment (20 µM) significantly upregulated CryAB expression in renal cells (p < 0.01) and triggered both apoptosis and MAPK activation. CryAB deficiency sensitized cells and mice to CP, exacerbating renal dysfunction, tubular injury, and apoptosis, as evidenced by increased Bax, cyt c release, and caspase-3 cleavage. Conversely, CryAB overexpression attenuated these effects. Furthermore, our findings suggest that the lack of CryAB favors the cytoplasmic retention of NF-κB, and that CryAB status can influence MAPK signaling, pointing to a potential regulatory loop. Additionally, CP-induced AKT phosphorylation was diminished in CryAB-deficient models. Therefore, CryAB may exert a cytoprotective role in CP nephrotoxicity, potentially mitigating tubular apoptosis by modulating the mitochondrial apoptotic pathway, supporting NF-κB-mediated survival signaling, and cross-talking with MAPK and AKT pathways. Our findings suggest that CryAB serves as an important regulator of renal cell fate and a potential therapeutic target for mitigating CP-induced kidney injury. Full article