Search Results (8,696)

Multiple sclerosis (MS) is characterized by progressive mitochondrial dysfunction affecting complexes I, III, and IV of the electron transport chain, contributing to axonal energy failure and neurodegeneration. This review examines the potential of combining β-hydroxybutyrate (βHB), epigallocatechin-3-gallate (EGCG), and ellagic acid (EA) as a multi-target therapeutic strategy to restore mitochondrial function in patients with MS. Experimental and clinical studies demonstrate that each compound exerts complementary mechanisms. Ketone bodies provide an alternative energy substrate and restore complex I activity via sirtuin-dependent pathways. EGCG acts predominantly at the peripheral level by reducing systemic inflammation and oxidative stress. EA-derived urolithins effectively cross the blood–brain barrier to directly enhance mitochondrial biogenesis and respiratory chain function in the central nervous system. Clinical trials have reported improvements in fatigue, cognition, mood, and muscle function following supplementation with these compounds. The convergence of their actions on energy restoration, reactive oxygen species reduction, and epigenetic modulation of protective pathways suggests their synergistic potential. Optimized delivery strategies, including exogenous ketone salts, liposomal EGCG, and microencapsulated EA, may overcome bioavailability limitations and interindividual variability in the gut microbiota metabolism. Full article

Airborne particulate matter with a diameter of <10 μm (PM₁₀) can damage the corneal epithelium by inducing oxidative stress, disrupting the NRF2 antioxidant pathway, and triggering epithelial barrier dysfunction and inflammation. However, the role of mitochondria in mediating PM₁₀-induced damage remains unexplored. This study investigated the impact of PM₁₀ on mitochondrial homeostasis in both immortalized human corneal epithelial cells (HCE-2) and the mouse corneal epithelium, as well as the protective effects of SKQ1. For in vivo assessment, female C57BL/6 mice were exposed to either control air or PM₁₀ (±SKQ1) in a whole-body exposure chamber for 2 weeks (3 h/day, 5 days/week, with weekends off). In vitro, HCE-2 cells were exposed to 100 μg/mL PM₁₀ (±SKQ1) for 24 h, and mitochondrial function and morphology were evaluated. In vitro, PM₁₀ significantly impaired mitochondrial function by reducing basal, maximal, and ATP-linked respiration; reserve capacity; and coupling efficiency compared to the control and SKQ1 groups. PM₁₀ also downregulated mitofusin1 (MFN1) and optic atrophy1 (OPA1) and upregulated dynamin-related protein1 (DRP1) and mitochondrial fission protein1 (FIS1) in HCE-2 cells. In addition, PM₁₀ exposure significantly decreased the mitochondrial membrane potential; mitochondrial DNA copy number; and cytochrome c oxidase subunit 4 isoform 1 (COX4i1), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels. SKQ1 pre-treatment significantly attenuated these effects. In vivo, PM₁₀ exposure significantly decreased the levels of MFN1, TFAM, COX4i1, and superoxide dismutase (SOD2), whereas SKQ1 treatment significantly reversed these effects. Overall, these findings demonstrate that PM₁₀ exposure induces mitochondrial fragmentation, disrupts mitochondrial biogenesis and quality control, and reduces mitochondrial respiration, resulting in mitochondrial dysfunction. SKQ1 effectively reversed these changes, suggesting its potential as a therapeutic strategy to protect corneal epithelial cells from PM₁₀-induced mitochondrial damage. Full article

With the intensification of social aging and the improvement of living standards, delaying aging has become a focus of common concern, especially in regard to skin aging. Although collagen peptides have been widely reported as therapeutic agents in relieving skin aging, the molecular mechanisms remain inadequately elucidated. This review emphasizes that the alleviation of skin aging by collagen peptides is a systematic and complex process, including the removal of reactive oxygen species, inhibition of inflammation, inhibition of extracellular matrix (ECM) degradation and melanin deposition, activation of lysosomal and mitochondrial function, and promotion of ECM synthesis. It also highlights that lysosomes and mitochondria may be the key organelles that regulate collagen peptides to alleviate skin aging. Current research on the mechanism of collagen peptides in alleviating skin aging still requires bold breakthroughs and should not be confined to the transforming growth factor (TGF-β)/Smad, mitogen-activated protein kinase, and nuclear factor kappa-B pathways. In addition, many natural antioxidant components have been proven to alleviate skin aging by regulating organelle function. Therefore, the regulatory effects of collagen peptides with antioxidant activity on mitochondrial and lysosome functions in aging skin need more attention and exploration, which is of great significance for further research on precise skin care and targeted anti-skin aging therapy. Full article

Background/Objectives: Stewartia pseudocamellia Maxim. (S. pseudocamellia) has been reported to possess antioxidant and anti-inflammatory properties and contains various bioactive flavonoids and phenolic compounds. These components may contribute to neuroprotective effects relevant to depression and cognitive dysfunction. This study was conducted to evaluate the effects of 20% ethanolic extract from S. pseudocamellia leaves (ESP) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive dysfunction in C57BL/6 mice. Methods: C57BL/6 mice were divided into six groups: normal control (NC), normal sample (NS; ESP 100 mg/kg), CUMS, L-theanine (Thea; 4 mg/kg), ESP 50 mg/kg, and ESP 100 mg/kg groups. Phytochemical profiling of ESP was performed using ultra-performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Depressive-like behaviors and cognitive function were assessed, along with stress-related hormonal regulation and associated cellular signaling pathways. Results: Phytochemical profiling of ESP identified procyanidin B2, epicatechin, rutin, catechin gallate, kaempferol 3-O-glucoside, and quercitrin as major constituents. ESP significantly alleviated CUMS-induced depressive-like behaviors and improved spatial learning and memory. These effects were associated with modulation of stress-related hormones in serum and hypothalamic–pituitary–adrenal (HPA) axis–related proteins in the brain. ESP also enhanced antioxidant defense by activating the Nrf2 signaling pathway and improving mitochondrial function. Furthermore, ESP attenuated neuroinflammation and apoptosis by regulating the TLR4/NF-κB and JNK pathways, and promoted neuroplasticity by modulating cholinergic activity, with enhanced BDNF/TrkB signaling in the cerebral cortex and hippocampus. Conclusions: Collectively, these findings suggest that ESP exerts protective effects against CUMS-induced depressive-like behaviors and cognitive deficits in a preclinical model. Full article

Oxidative stress is a key contributing and convergent pathogenic mechanism linked to retinal and optic nerve diseases including age-related macular degeneration, diabetic retinopathy, and glaucoma. The retina is highly susceptible to redox imbalance due to intense mitochondrial activity, oxygen consumption, and light exposure. While endogenous drivers are well recognized, the contribution of environmental exposure to retinal oxidative injury remains incompletely defined. This review uniquely integrates emerging environmental contaminants with canonical oxidative stress pathways. We examine how cigarette smoke, ultraviolet radiation, heavy metals, microplastics, and per- and polyfluoroalkyl substances (PFASs) promote oxidative injury through mitochondrial dysfunction, inflammatory signaling, impaired antioxidant responses, and ferroptotic pathways. We also highlight therapeutic strategies targeting oxidative pathways and emphasize the importance of exposure-informed retinal and optic nerve disease research. Full article

Mitochondria–endoplasmic reticulum contacts (MERCs) are physical structures formed between mitochondria and the endoplasmic reticulum (ER) through various tethering proteins, playing crucial roles in multiple physiological processes, including Ca²⁺ and lipid exchange between the ER and mitochondria, regulation of mitochondrial morphology and dynamics (fusion and fission), as well as the induction of autophagy and apoptosis. Mitofusin 2 (MFN2), a key mitochondrial fusion protein, has been identified as an essential structural component of MERCs. Our research demonstrates that 16:8 circadian intermittent fasting (CIF) leads to enhanced mitochondrial fusion. The upregulation of MFN2 reinforces MERC stability, thereby facilitating efficient Ca²⁺ transfer between the ER and mitochondria. This process sustains the activity of mitochondrial oxidative phosphorylation (OXPHOS) enzymes, elevates mitochondrial oxygen utilization efficiency, and ultimately augments ATP production. Consequently, these adaptations enhance cardiomyocyte tolerance to hypoxic conditions. This study elucidates a novel mechanism by which MERCs regulate cellular hypoxia resistance and proposes a potential therapeutic strategy for improving acute hypoxia tolerance through the modulation of Ca²⁺ transport at MERCs. Full article

Myocardial ischemia–reperfusion (I/R) injury remains a major contributor to infarct expansion and adverse cardiac remodeling despite advances in timely reperfusion therapy. Although restoration of blood flow is essential for myocardial salvage, the abrupt transition from ischemia to reperfusion paradoxically exacerbates cardiomyocyte injury through profound metabolic, ionic, and mitochondrial disturbances. Reperfusion should be viewed not simply as restoration of blood flow, but as a critical biological transition that converts ischemic stress into a self-amplifying injury network. Reperfusion induces excessive reactive oxygen species generation, calcium overload, endothelial barrier disruption, and dysregulated innate immune activation, which converge on mitochondrial dysfunction and diverse forms of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Emerging evidence highlights that these pathological processes are tightly interconnected through damage-associated molecular pattern signaling, microvascular leakage, and inflammatory amplification, underscoring the limitations of single-target therapeutic approaches. This review summarizes the molecular and cellular mechanisms underlying myocardial I/R injury with a particular focus on oxidative stress, immune modulation, vascular integrity, and ferroptosis. We further discuss current and emerging cardioprotective strategies, including antioxidant therapies, modulation of neutrophil recruitment, microvascular leakage blockade, and anti-ferroptotic interventions. Finally, we address key translational challenges and future perspectives for developing integrated cardioprotective therapies aimed at improving clinical outcomes in acute myocardial infarction. Full article

Mechanical unloading of skeletal muscle triggers various signaling alterations that result in muscle atrophy and weakness. Mitochondria are essential to muscle health, acting not only as energy suppliers but also as central mediators of molecular regulation. Mitochondrial activity, content, and dynamics are tightly controlled by multiple signaling pathways; conversely, mitochondria-derived messengers, such as reactive oxygen species (ROS), ATP, and mitokines, are involved in the regulation of nearly all aspects of muscle signaling. During mechanical unloading, altered muscle activity leads to mitochondrial dysfunction. However, the initial triggers, underlying mechanisms, and full consequences of this dysfunction remain poorly understood. Nevertheless, mitochondria-targeted therapies have emerged as a promising strategy for mitigating unloading-induced muscle impairments. In this review, we summarize current data regarding the characteristics, causes, and outcomes of unloading-induced mitochondrial dysfunction, specifically focusing on muscle atrophy and functional decline. We highlight novel findings regarding the roles of mitokines and mitochondrial calcium overload, propose a new hypothesis to explain the biphasic dynamics of ATP accumulation during slow-type muscle unloading, and describe emerging therapeutic strategies to counteract these mitochondrial impairments. Full article

The N88S mutation in human seipin causes a dominant motor neuron disease marked by ER stress and inclusion body formation, lipid imbalance, and oxidative damage. However, the metabolic mechanisms connecting these defects remain poorly understood. Previous proteomic profiling in our yeast model of N88S human seipinopathy revealed decreased protein levels of enzymes involved in the tricarboxylic acid cycle, fatty acid and carboxylic acid metabolism, and the glyoxylate cycle, suggesting impaired downstream utilization of peroxisome-derived acetyl-CoA. Guided by these findings, we investigated how peroxisomal function contributes to cellular dyshomeostasis. N88S seipin-expressing cells exhibited increased peroxisome abundance but defective routing of acetyl-CoA into mitochondrial and glyoxylate pathways, resulting in elevated reactive oxygen species (ROS), impaired glyoxylate cycle activation, and reduced metabolic adaptability to non-fermentable carbon sources. Loss of peroxisomes or forced cytosolic redirection of acetyl-CoA further exacerbated ER stress, ROS accumulation, lipid peroxidation, and the growth defect on N88S seipin-expressing cells, whereas inhibition of fatty acid synthesis mitigated oxidative damage. These findings demonstrate that N88S seipin triggers a futile cycle in which misrouted cytosolic acetyl-CoA drives lipogenesis, amplifying oxidative damage and ER stress. We conclude that defective peroxisome–mitochondria metabolic coupling and acetyl-CoA misrouting may represent central pathogenic mechanisms driving cellular dysfunction in N88S-linked seipinopathy. Full article

Background: Obesity is a multifactorial chronic disease resulting from sustained energy imbalance and modulated by environmental and demographic factors, and it is associated with numerous comorbidities. DNA methylation is an epigenetic modification associated with obesity. Modulation of DNA methylation is a viable target for obesity control strategies. The flavanol (-)-epicatechin (EC) exerts beneficial effects in overweight individuals, suggesting that EC may influence gene regulation through signaling pathways and epigenetic mechanisms. We evaluated whether EC modulates obesity-associated DNA methylation changes using complementary in silico, in vitro, and in vivo approaches. Methods. In silico analyses were performed to explore potential EC interactions with the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. DNMT activity was measured in nuclear extracts of 4T1 cells in the presence of EC. Finally, in a C57BL/6 mouse model of diet- induced obesity, we assessed global DNA methylation and the expression of the DNA methyltransferases, as well as metabolism-related genes; peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc-1α), pyruvate dehydrogenase kinase isozyme 4 (Pdk4), and nuclear factor erythroid 2–related factor 2 (Nrf2) and relative mitochondrial DNA content (mtDNA/nDNA ratio) in visceral adipose tissue (VAT) and skeletal muscle. Results. EC showed stable in silico interactions within catalytic/cofactor-binding regions of DNMTs and inhibited DNMT activity in vitro in a concentration-dependent manner. In vivo, the obesogenic diet reduced global DNA methylation and decreased transcript levels of Dnmt1, Dnmt3a, and Dnmt3b in skeletal muscle and adipose tissue. EC counteracted obesity-associated DNA methylation changes in skeletal muscle, restoring global methylation and Dnmt expression toward control levels, whereas effects in VAT were limited. EC increased mitochondrial DNA content. Discussion. In silico and enzymatic data suggest that EC may bind DNMT active sites and inhibit DNMT activity in a concentration-dependent manner, supporting a role for EC in obesity-related epigenetic remodeling, particularly in skeletal muscle. EC also increased relative mitochondrial DNA content in VAT and skeletal muscle despite no obesogenic diet effect on relative mitochondrial abundance, consistent with favorable mitochondrial modulation. In conclusion, EC is an epigenetic modulator and may have positive effects in obesity related dysfunctional tissues. Full article

Background: Although the definition of dietary fibre is complex and constantly evolving, today we can identify it as “carbohydrate polymers with at least 10 monomeric units, which are not hydrolysed in the small intestine of humans”. In addition to the numerous and well-known benefits of dietary fibre for human health, our attention is drawn to its antioxidant properties, achieved through polyphenolic compounds linked to polysaccharide complexes. This study investigated the antioxidant effects of an extract from the fruit of Punica granatum (PUN), particularly rich in polyphenols, fibre, flavonoids, vitamins, organic acids, minerals, amino acids, and alkaloids. Furthermore, these effects were evaluated in two human nervous system cell lines under oxidative stress induced by hydrogen peroxide. Methodology: After examining the fibre composition, some polyphenols present in the extract were identified and quantified by HPLC. Furthermore, the antioxidant power of PUN was measured using the DPPH method, the chelating activity assay, the reducing power test, the ORAC method, the measurement of reactive oxygen species accumulation, the quantification of lipid peroxidation, and the detection of mitochondrial superoxide in cell cultures. Results: The results were consistent, and PUN demonstrated a strong antioxidant potential, justified not only by the high content of easily extractable polyphenols (EPPs) but also by a further addition of these more difficult to identify compounds (NEPPs), indicated as “hidden polyphenols”; therefore, the total polyphenol content in the extract resulted from the sum of EPPs + NEPPs (71 ± 7.9 + 55 ± 6.4 mg = 126 ± 14.3 mg gallic acid equivalent (GAE)/g dry weight). The fraction of hidden polyphenols could therefore explain a mechanism by which the fibre exerts an antioxidant effect. Another important result was achieved by the cell lines used, both of which were significantly protected by PUN following oxidative damage generated by a pro-oxidant treatment. However, astrocytes were found to be more responsive and sensitive than were human neurons. At the same time, PUN mitigated the effects of oxidative damage, and it could be hypothesised that this extract could be used to extinguish the A1 phenotype. Conclusions: We can conclude that the fibrous component of pomegranate is related to the antioxidant property exerted, and the neurodegeneration caused by oxidative stress could be slowed following the intake of Punica granatum. It is possible to identify the pomegranate as a “superfood” or “functional food”, with excellent nutritional characteristics and chemical composition. Full article

Glaucoma is no longer viewed solely as a pressure-mediated optic neuropathy but as a chronic neurodegenerative disease with a strong immune component. Across experimental models and patient samples, convergent inflammatory circuitry complement activation, NLRP3 inflammasome signaling, and microglial reactivity emerge as a central driver of retinal ganglion cell (RGC) dysfunction and death. Local complement upregulation (C1q, C3, C5) in the retina and optic nerve head (ONH) promotes aberrant synaptic tagging, phagoptosis, and membrane attack complex stress. In parallel, biomechanical strain, ischemia, mitochondrial damage, and danger-associated molecular patterns prime and activate the NLRP3 inflammasome in microglia, astrocytes, and ONH cells, leading to caspase-1 activation, IL-1β/IL-18 maturation, and pyroptotic or apoptotic injury. Microglia integrate these cues, shifting from early protective surveillance to chronic maladaptive states that amplify complement and inflammasome outputs. This review synthesizes mechanistic links within the complement NLRP3 microglia axis, considers systemic and adaptive immune contributions, and proposes a translational framework for immune-based clinical stratification. The literature for this review was identified through searches of PubMed, Web of Science, and Scopus using combinations of the terms ‘glaucoma’, ‘complement’, ‘inflammasome’, ‘NLRP3’, ‘microglia’, and ‘neuroinflammation’. Priority was given to recent experimental, translational, and clinical studies. We then evaluate emerging immunomodulatory therapies, complement inhibitors, inflammasome blockers, microglial state reprogrammers, cytokine biologics, and cell-derived immunoregulatory approaches, highlighting biomarkers and trial design needs. An immune systems view of glaucoma enables precision neuroprotection for patients who progress despite controlled intraocular pressure. Full article

Oxidative stress-induced endometrial injury has been shown to contribute to infertility; however, effective strategies that can simultaneously scavenge reactive oxygen species (ROS) and restore mitochondrial and antioxidant homeostasis remain elusive. In this study, we isolated extracellular nanovesicles from Artemisia argyi (A-NVs) and investigated their protective effects on H₂O₂-damaged human endometrial stromal cells (hESCs). We discovered that A-NVs possess a typical lipid bilayer structure and contain a variety of bioactive components. Our metabolomic analysis indicates that A-NVs can be regarded as a “natural drug reservoir”, in which flavonoids account for approximately 10.8%. We demonstrate that A-NVs can be efficiently taken up by cells, improve cell viability, reduce intracellular and mitochondrial ROS levels, enhance superoxide dismutase (SOD) activity, upregulate the expression of catalase (CAT), SOD1, and SOD2, and partially restore mitochondrial membrane potential. Mechanistically, A-NVs exert antioxidant effects by activating the SIRT1/PGC-1α/Nrf2 signaling axis. SIRT1 activation further alleviates H₂O₂-induced premature senescence, as evidenced by a 71.8% reduction in SA-β-Gal-positive cells compared with the H₂O₂ group, together with downregulation of p53 and p21 expression. These positive protective effects can be blocked by the SIRT1 inhibitor EX-527, confirming the central role of this pathway. Collectively, our findings demonstrate that A-NVs can maintain redox and mitochondrial homeostasis while inhibiting oxidative stress-related senescence progression, underscoring their application potential in endometrial repair and functional recovery. Full article

Background: Streptococcus pneumonia is the primary etiological agent of community-acquired pneumonia (CAP). Pneumococci promote severe lung injury through the release of virulence factors, including pneumolysin (PLY). Obesity/diabetes increases pneumonia-associated mortality, but the mechanisms remain elusive. We found that obese db/db mice have increased pulmonary barrier disruption to PLY. Previously we showed that upregulation of NOX1 in endothelial cells (EC) of db/db mice drives endothelial dysfunction, but a role for NOX1 in PLY-induced lung injury, especially in diabetic conditions, has not yet been described. Results: Increased NOX1 in lung ECs dose-dependently increased superoxide and EC barrier disruption (p < 0.05). Even at low activity levels, NOX1 greatly potentiated PLY-induced EC barrier disruption, whereas loss of NOX1 activity, either pharmacological or genetic, reduced barrier disruption (p < 0.05). Blockade of calcium entry protected the EC barrier from combined PLY and NOX1, indicating a key role for calcium. Hyperglycemia amplified PLY-enduced EC barrier disruption and intracellular calcium and these effects were mitigated by NOX1 inhibition and silencing (p < 0.05). NOX1-enhanced calcium entry was reduced by knockout of calcium sensor STIM1, and PLY-induced barrier disruption was reduced by STIM1 inhibition. Levels of STIM1, Orai1, TRPV4, or TRPC4 were unchanged by HG, but TRPC1 significantly increased (p < 0.05). NOX1 and HG promoted increased STIM1 and TRPC1 binding, and silencing TRPC1 ameliorated PLY-induced barrier disruption (p < 0.05). Increased calcium promoted mitochondrial permeability transition pore (MPTP) opening and PPIF inhibition protected EC barrier function (p < 0.05). Conclusions: These results suggest that elevated glucose levels in obesity primes EC barrier disruption by amplifying PLY-induced calcium influx via a novel NOX1, STIM1, TRPC1 and MPTP signaling axis. Full article

The aim of this study was to compare the responses of normal human gingival epithelial cells (HGEpiC) and oral squamous cell carcinoma cells (OECM-1) to apigenin, a natural flavonoid, focusing on redox balance, autophagy, and apoptosis. This study is among the first to directly compare apigenin-induced responses in normal and cancerous oral epithelial cells. Cells were exposed to apigenin for 24 or 48 h, with untreated cells as controls. Mitochondrial activity, ATP, ROS (H₂O₂), and GSH were measured. Proliferation and morphology were monitored using HoloMonitor^® M4. Autophagy was assessed by fluorescent vacuole labeling, and apoptosis-related proteins (p-AKT, p-BCL-2, p-p53, p-JNK, caspase-8/9) by Luminex assay. Late apoptosis was evaluated by caspase-3/7 activity. Apigenin elicited a differential response: in HGEpiC cells, it was non-cytotoxic and increased metabolic activity, induced a moderate ROS increase, and activated autophagy as a pro-survival mechanism; in contrast, OECM-1 cells exhibited a significant reduction in metabolic activity, a marked ATP decrease at 24 h, and a pronounced ROS increase. These alterations were associated with reduced autophagy and decreased p-JNK signaling. These findings indicate that apigenin exerted no harmful effects on HGEpiC cells, while inducing redox imbalance in OECM-1 cells, highlighting a context-dependent cellular response. Full article