Search Results (3,164)

As life expectancy continues to increase, it becomes increasingly important to extend healthspan by targeting mechanisms associated with aging. Cellular senescence is recognized as a significant contributor to aging and neurodegenerative disorders. This review examines the emerging role of nutraceuticals and functional foods as potential modulators of cellular senescence, which may, in turn, influence the development of neurodegenerative diseases. An analysis of experimental studies indicates that bioactive compounds, including polyphenols, vitamins, and spices, possess substantial antioxidants, anti-inflammatory and epigenetic properties. These nutritional senotherapeutic agents effectively scavenge reactive oxygen species, modulate gene expression, and decrease the secretion of senescence-associated secretory phenotype factors, minimizing cellular damage. Nutraceuticals can enhance mitochondrial function, reduce oxidative stress, and regulate inflammation, key factors in aging and diseases like Alzheimer’s and Parkinson’s. Furthermore, studies reveal that specific bioactive compounds can reduce senescence markers in cellular models, while others exhibit senostatic and senolytic properties, both directly and indirectly. Diets enriched with these nutraceuticals, such as the Mediterranean diet, have been correlated with improved brain health and the deceleration of aging. Despite these promising outcomes, direct evidence linking these compounds to reducing senescent cell numbers remains limited, highlighting the necessity for further inquiry. This review presents compelling arguments for the potential of nutraceuticals and functional foods to promote longevity and counteract neurodegeneration by exploring their molecular mechanisms. The emerging relationship between dietary bioactive compounds and cellular senescence sets the stage for future research to develop effective preventive and therapeutic strategies for age-related diseases. Full article

Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal–lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development. Full article

Background/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds—incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and 1,2,3-oxadiazole scaffolds, as well as N-(1-(4-hydroxy-3-methoxyphenyl)-3-oxo-3-(2-(phenylcarbamothioyl)hydrazineyl) prop-1-en-2-yl)benzamide—was evaluated for antioxidant activity (DPPH assay), PDK-1 and LDHA inhibition, cytotoxic effects against LoVo and HCT-116 colon carcinoma cells, with parallel assessment of safety profiles on normal HUVECs. The underlying anticancer mechanism of the most active compound was investigated through analysis of cell cycle distribution, apoptosis induction, intracellular reactive oxygen species levels, mitochondrial membrane potential disruption, and expression levels of apoptosis-related genes. Molecular docking assessed binding interactions within LDHA and PDK-1 active sites. The physicochemical, drug-likeness, and ADMET properties of the multi-bioactive candidates were predicted in silico. Results: Among the synthesized compounds, thiophenes 3b and 3d exhibited superior PDK-1/LDHA and DPPH/LDHA inhibitions along with significant cytotoxic effects on LoVo and HCT-116 cells (IC₅₀ in µM: 190.3/170.2 and 161.0/156.6), respectively, and minimal cytotoxicity toward HUVECs. Molecular docking revealed favorable interactions with key amino acid residues within the LDHA and/or PDK-1 active sites. Compound 3d notably induced G2/M (LoVo) and G1 (HCT-116) arrest and promoted apoptosis via enhancing ROS generation, modulating Bax/Bcl-2 expressions, disrupting mitochondrial membrane potential, and ultimately activating caspses-3. In silico predictions indicated their promising drug-likeness and pharmacokinetics, though high lipophilicity, poor solubility (especially for 3b), and potential toxicity risks were identified as limitations. Conclusions: Thiophenes 3b and 3d emerged as promising multi-target candidates; however, structural optimization is warranted to enhance their solubility, bioavailability, and safety to support further development as lead anti-colon cancer agents. Full article

Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/ Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca²⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs. Full article

The food industry widely uses dyes from animal and plant sources, but their discharge into water bodies can harm aquatic animals. Red food dyes increase reactive oxygen species (ROS) production, disrupting redox homeostasis in Artemia franciscana nauplii, although the underlying mechanisms are unclear. In this study, we exposed Artemia franciscana cysts for 48 h to three different red dyes: E124 (synthetic), E120 (animal-based) or Vegan red (plant-based) and evaluated the oxidative metabolism and redox status in the hatched nauplii. Only E120 and VEG increased oxygen consumption. E124 and VEG increased mitochondrial Complex I activity, while all dyes enhanced the activity of Complex III. The levels of reactive oxygen species (ROS) and NADPH oxidase activity were increased by all red dyes. E120 and E124 increased antioxidant enzyme activity to a greater extent than VEG. Additionally, only E120 and E124 increased total antioxidant capacity. Nevertheless, E124 exposure induced redox imbalance (increased lipid and protein oxidative damage). Our data, as a whole, allow us to conclude that red dyes can influence the oxidative capacity and redox state of Artemia franciscana nauplii with more harmful effects in the presence of E124, thus drawing attention to their potentially severe influence on aquatic life. Full article

Bcl-2-like protein 13 (Bcl2l13) plays an important role in the cell apoptosis and mitochondrial autophagy of mammals. However, the role of bcl2l13 remains unclear in fish. Therefore, in this study, the function of Megalobrama amblycephala bcl2l13 gene in apoptosis and autophagy was investigated. The results showed that the overexpression of M. amblycephala bcl2l13 under hypoxic condition led to a reduction of reactive oxygen species (ROS), an increase in the expression levels of autophagy-related genes (p62, lc3, pink1), and a disruption of mitochondrial structure. However, deleting its transmembrane (TM) and Bcl-2 homology no (BHNo) domains decreased the P62 protein level, suggesting its essential role in autophagy. Furthermore, bcl2l13 overexpression inhibited cell proliferation and increased apoptosis. Additional studies revealed that the permeability of the mitochondrial permeability transition pore (mPTP) increased after overexpression of bcl2l13, but decreased upon deletion of the TM domain. Additionally, hypoxia led to elevated Bcl2l13 and P62 levels, and caused mitochondrial damage in M. amblycephala liver after 48 h of treatment. In conclusion, bcl2l13 may induce autophagy, inhibit cell proliferation and promote apoptosis, while its TM and BHNo domains play pivotal roles in these processes. Full article

TSGA10, a multifunctional protein critical for mitochondrial coupling and metabolic regulation, plays a paradoxical role in cancer progression and carcinogenesis. Here, we outline a potential mechanism by which TSGA10 mediates metabolism in oncogenesis and thermal modulation. Initially identified in spermatogenesis, TSGA10 interacts with mitochondrial Complex III: it directly binds cytochrome c1 (CytC1). In our model, TSGA10 optimizes electron transport to minimize reactive oxygen species (ROS) and heat production while enhancing Adenosine Triphosphate (ATP) synthesis. In cancer, TSGA10’s expression is context-dependent: Its downregulation in tumors like glioblastoma might disrupt mitochondrial coupling, promoting electron leakage, ROS accumulation, and genomic instability. This dysfunction would be predicted to contribute to a glycolytic shift, facilitating tumor survival under hypoxia. Conversely, TSGA10 overexpression in certain cancers suppresses HIF-1$\alpha$, inhibiting glycolysis and metastasis. TSGA10 and HIF-1$\alpha$ engage in mutual counter-regulation—TSGA10 represses HIF-1$\alpha$ to sustain oxidative phosphorylation (OXPHOS), while HIF-1$\alpha$ suppression of TSGA10 under hypoxia or thermal stress amplifies glycolytic dependency. This interplay is pivotal in tumors adapting to microenvironmental stressors, such as cold-induced mitochondrial uncoupling, which mimics brown adipose tissue thermogenesis to reduce ROS and sustain proliferation. Tissue-specific TSGA10 expression further modulates cancer susceptibility: high levels in the testes and brain may protect against thermal and oxidative damage, whereas low expression in the liver permits HIF-1$\alpha$-driven metabolic plasticity. Altogether, our model suggests that TSGA10 plays a central role in mitochondrial fidelity. We suggest that its crosstalk with oncogenic pathways position it as a metabolic rheostat, whose dysregulation fosters tumorigenesis through ROS-mediated mutagenesis, metabolic reprogramming, and microenvironmental remodeling. Targeting the hypothesized TSGA10-mediated mitochondrial coupling may offer therapeutic potential to disrupt cancer’s adaptive energetics and restore metabolic homeostasis. Full article

Aging leads to ovarian degeneration in poultry, reducing egg production and quality. Ellagic acid (EA), a natural plant-derived compound, may help delay ovarian aging, though its precise mechanisms remain unclear. This study investigated the effects of EA on ovarian aging of low-yield laying chickens and explored its underlying mechanism. EA supplementation (100 and 500 mg/kg) significantly increased ovarian weight as well as the number and proportion of small yellow follicles in aging chickens. EA administration elevated serum antioxidant levels and upregulated the expression of glutathione peroxidase 4 (GPX4) expression to reduce oxidative stress. Importantly, EA treatment suppressed the mRNA and protein expression of ferroptosis markers transferrin receptor protein 1 (TFRC) and solute carrier family 7 member 11 (SLC7A11), increased Proliferating Cell Nuclear Antigen (PCNA) expression, and alleviated G1 phase arrest in granulosa cells (GCs), promoting cell proliferation, which improves egg quality and production. Furthermore, in vitro experiments demonstrated that EA treatment decreased reactive oxygen species production, improved mitochondrial function, inhibited ferroptosis, and attenuated GCs aging. In conclusion, this study reveals the critical role of ferroptosis in chicken ovarian aging and suggests that EA may provide a promising approach for delaying ovarian aging and enhancing productivity in low-yield poultry. Full article

Iron deficiency is highly prevalent in patients with idiopathic pulmonary hypertension; nevertheless, its role and clinical significance in hypoxic pulmonary hypertension (HPH) remain elusive. Therefore, this study aims to clarify the role and molecular mechanisms of iron in HPH. By means of a retrospective analysis of clinical data from HPH patients and examinations of HPH animal models, we discovered that both HPH patients and animal models exhibit significant iron deficiency, characterized by reduced hepatic iron storage and elevated hepcidin expression. To further explore iron’s role in HPH, we modulated iron metabolism through pharmacological and dietary interventions in chronic hypoxic animal models. The results showed that iron deficiency exacerbated chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy, while iron supplementation alleviated these conditions. Further investigations revealed that iron regulates HIF2α expression in pulmonary arterial endothelial cells (PAECs) under chronic hypoxia. Therefore, through in vivo and in vitro experiments, we demonstrated that HIF2α inhibition attenuates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Mechanistically, chronic hypoxia-mediated iron deficiency enhances HIF2α activation, subsequently suppressing iron/sulfur cluster assembly enzyme (ISCU) expression. This leads to decreased mitochondrial complexes I and III activity, increased reactive oxygen species (ROS) production, and inhibited oxidative phosphorylation. Consequently, metabolic reprogramming in PAECs results in a proliferation/apoptosis imbalance, ultimately exacerbating hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Collectively, our findings demonstrate that iron supplementation mitigates HPH progression by modulating HIF2α-mediated metabolic reprogramming in PAECs, revealing multiple therapeutic targets for HPH. Full article

Emerging evidence links ferroptosis–mitochondrial dysregulation to depression pathogenesis through an oxidative stress–energy deficit–neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal–hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a “ferroptosis–mitochondrial fragmentation–metabolic maladaptation” triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability—a framework with significant implications for developing neuroprotective antidepressants. Full article

Oxidative stress due to increased reactive oxygen species (ROS) formation and/or inflammation is considered to play an important role in ischemic stroke injury. Leukemia inhibitory factor (LIF) has been shown to protect both oligodendrocytes and neurons from ischemia by upregulating endogenous anti-oxidants, though the effect of ischemia and the protective role of LIF treatment in mitochondrial function have not been studied. The goal of this study was to determine whether LIF protects ischemia-induced altered mitochondrial bioenergetics in reproductively senescent aged rats of both sexes (≥18 months old), approximately equivalent to the average age of human stroke patients. Animals were euthanized at 3 days after permanent middle cerebral artery occlusion (MCAO) surgery. We found that MCAO surgery significantly reduced mitochondrial oxidative phosphorylation in both the ipsilateral striatum and prefrontal cortex in male aged rats compared to their respective contralateral regions of the brain. MCAO injury showed mitochondrial bioenergetic dysfunction only in the striatum in female rats; however, the prefrontal cortex remained unaffected to the injury. LIF-treated rats significantly prevented mitochondrial dysfunction in the striatum in male rats compared to their vehicle-treated counterparts. Collectively, MCAO-induced mitochondrial dysfunction and LIF’s potential as a therapeutic biomolecule exhibited sex- and tissue-specific effects, varying between the striatum and prefrontal cortex in male and female rats. Full article

This study examined branched-chain fatty acids (BCFAs)’ effects on oxidative stress, energy metabolism, inflammation, tight junction disruption, apoptosis, and Toll-like receptor 4/nuclear factor kappa-B (TLR4/NF-κB) signaling in lipopolysaccharide (LPS)-induced calf small intestinal epithelial cells (CSIECs). Eight groups were used: a control group, an LPS-induced group, and six BCFA treatment groups (12-methyltridecanoic acid (iso-C14:0), 13-methyltetradecanoic acid (iso-C15:0), 14-methylpentadecanoic acid (iso-C16:0), 15-methylhexadecanoic acid (iso-C17:0), 12-methyltetradecanoic acid (anteiso-C15:0), and 14-methylhexadecanoic acid (anteiso-C17:0)) with LPS. The BCFA pretreatments significantly increased CSIEC activity compared to the LPS-induced group, with iso-C14:0 showing the highest activity (89.73%). BCFA reduced Reactive Oxygen Species (ROS) generation and malondialdehyde (MDA) levels and improved the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities and glutathione (GSH) levels. Iso-C16:0 optimized total antioxidant capacity (T-AOC). BCFA enhanced the mitochondrial membrane potential, Adenosine Triphosphate (ATP) enzyme activity, and ATP content, with iso-C14:0 increasing ATP by 27.01%. BCFA downregulated interleukin (IL)-1β, IL-8, tumor necrosis factor (TNF)-α, and interferon (INF)-γ gene expression, reduced IL-6 levels, and increased IL-10 expression. Myeloid differentiation factor 88 (MyD88) mRNA levels were reduced. BCFA alleviated Zonula Occludin (ZO-1), Claudin-1, and Claudin-4 decrease and increased Occludin levels. BCFA mitigated LPS-induced increases in Caspase-3 and BCL2-Associated X (BAX) mRNA levels, reduced Caspase-8 and Caspase-9 expression, and increased B-Cell Lymphoma-2 (BCL-2) mRNA levels. The Entropy Weight-TOPSIS method was adopted, and it was discovered that iso-C15:0 has the best effect. In summary, BCFA supplementation mitigated oxidative stress and enhanced mitochondrial function. BCFA inhibited TLR4/NF-κB signaling pathway overactivation, regulated inflammatory cytokine gene expression, reduced cellular apoptosis, preserved tight junction integrity, and supported barrier function. Full article

Estrogen levels are the core factor influencing postmenopausal osteoporosis (PMOP). Estrogen can affect the progression of PMOP by regulating bone metabolism, influencing major signaling pathways related to bone metabolism, and modulating immune responses. When estrogen levels decline, the activity of Sirtuins (SIRTs) is reduced. SIRTs are enzymes that function as NAD+-dependent deacetylases. SIRTs can modulate osteocyte function, sustain mitochondrial homeostasis, and modulate relevant signaling pathways, thereby improving bone metabolic imbalances, reducing bone resorption, and promoting bone formation. In PMOP, SIRT1, SIRT3, and SIRT6 are primarily affected. Oxidative stress (OS) is a crucial factor in PMOP, as it generates excessive reactive oxygen species (ROS) that exacerbate PMOP. There is a certain interplay between SIRTs and OS. The reduced activity of SIRTs leads to intensified OS and the excessive accumulation of ROS. In return, ROS suppresses the AMPK signaling pathway and the synthesis of NAD+, which consequently diminishes the function of SIRTs. Natural SIRT activators and natural antioxidants, which are characterized by high safety, convenience, and minimal side effects, represent a potential therapeutic strategy for PMOP. This study aims to investigate the mechanisms of SIRTs and OS in PMOP and summarize potential therapeutic strategies to assist in the improvement of PMOP. Full article

The role of ferroptosis—a novel iron-dependent programmed cell death pathway—in infectious spleen and kidney necrosis virus (ISKNV) infection remains poorly understood. Here, we demonstrate that ISKNV infection induces ferroptosis in CPB cells. Following ISKNV challenge, CPB cells exhibited hallmark morphological alterations including mitochondrial shrinkage, increased membrane density, and cristae reduction. Biochemical assays confirmed significant time-dependent elevations in ferroptosis markers: malondialdehyde (MDA, 1.7-fold), reactive oxygen species (ROS, 3.14-fold), and ferrous iron (Fe²⁺, 1.42-fold) compared to controls (p < 0.05). Mechanistic studies revealed that ISKNV downregulated glutathione peroxidase 4 (GPx4) while upregulating acyl-CoA synthetase long-chain family member 4 (ACSL4), as validated by quantitative real-time PCR (qRT-PCR) and immunoblotting. Ferroptosis induction with erastin enhanced ISKNV replication, whereas inhibition with liproxstatin-1 suppressed viral yield. These findings establish that ISKNV exploits ferroptosis to facilitate its replication, and pharmacological blockade of this pathway significantly suppresses viral propagation, providing a new strategy and intervention approach for controlling ISKNV infection. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignant tumor globally with a poor prognosis. Despite continuous advancements in treatment modalities, the molecular mechanisms underlying its progression and chemotherapy resistance remain unclear. In previous studies, cisplatin drug induction was performed on HNSCC patient-derived tumor organoids (HNSCC-PDOs), successfully establishing a cisplatin-resistant organoid model (HNSCC-PDO^cisR). This study conducted RNA sequencing on cisplatin-resistant HNSCC-PDO^cisR and their parental PDOs. Bioinformatic analysis revealed that the oncoprotein olfactomedin 4 (OLFM4) was significantly upregulated in the drug-resistant model. Combined analysis of TCGA and CPTAC databases demonstrated that OLFM4 expression correlates with poor clinical prognosis in HNSCC. In vitro cellular experiments verified that OLFM4 overexpression significantly enhanced HNSCC cell proliferation, migration, and invasion capabilities (p < 0.05), while OLFM4 knockdown inhibited these phenotypes. Additionally, OLFM4 was found to mediate cisplatin resistance by regulating levels of reactive oxygen species (ROS), malondialdehyde (MDA), and ferrous ions (Fe²⁺), suppressing cisplatin-induced oxidative stress and ferroptosis while maintaining mitochondrial membrane potential. This study confirms that OLFM4 enhances tumor cell proliferation, migration, and resistance to cisplatin-induced cell death, thereby promoting HNSCC progression. These findings suggest OLFM4 may serve as a prognostic biomarker for HNSCC and a potential therapeutic target to reverse cisplatin resistance in HNSCC. Full article