Search Results (830)

The activation mechanism of the reproductive axis in Kazakh ewes during the non-breeding season was explored by supplementation with glycerol complex (7% glycerol + tyrosine + vitamin B9). The experiment divided 50 ewes into five groups (n = 10). After 90 days of intervention, it was found that significant changes in serum DL-carnitine, N-methyl-lysine and other differential metabolites were observed in the GLY-Tyr-B9 group (p < 0.05, “p < 0.05” means significant difference, “p < 0.01” means “highly significant difference”). The bile acid metabolic pathway was specifically activated (p < 0.01). The group had a 50% estrus rate, ovaries contained 3–5 immature follicles, and HE staining showed intact granulosa cell structure. Serum E2/P4 fluctuated cyclically (p < 0.01), FSH/LH pulse frequency increased (p < 0.01), peak Glu/INS appeared on day 60 (p < 0.05), and LEP was negatively correlated with body fat percentage (p < 0.01). Molecular mechanisms revealed: upregulation of hypothalamic kiss-1/GPR54 expression (p < 0.01) drove GnRH pulses; ovarian CYP11A1/LHR/VEGF synergistically promoted follicular development (p < 0.05); the HSL of subcutaneous fat was significantly increased (p < 0.05), suggesting involvement of lipolytic supply. Glycerol activates the reproductive axis through a dual pathway—L-carnitine-mediated elevation of mitochondrial β-oxidation efficacy synergizes with kisspeptin/GPR54 signalling enhancement to re-establish HPO axis rhythms. This study reveals the central role of metabolic reprogramming in regulating seasonal reproduction in ruminants. Full article

Mitochondria, pivotal organelles in cellular metabolism and energy production, have emerged as critical players in the pathogenesis of cancer. This review outlines the progress in mitochondrial profiling through mass spectrometry-based metabolomics and its applications in cancer research. We provide unprecedented insights into the mitochondrial metabolic rewiring that fuels tumorigenesis, metastasis, and therapeutic resistance. The purpose of this review is to provide a comprehensive guide for the implementation of mitochondrial metabolomics, integrating advanced methodologies—including isolation, detection, and data integration—with insights into cancer-specific metabolic rewiring. We first summarize current methodologies for mitochondrial sample collection and pretreatment. Furthermore, we then discuss the recent advancements in mass spectrometry-based methodologies that facilitate the detailed profiling of mitochondrial metabolites, unveiling significant metabolic reprogramming associated with tumorigenesis. We emphasize how recent technological advancements have addressed longstanding challenges in the field and explore the role of mitochondrial metabolism-driven cancer development and progression for novel drug discovery and translational research applications in cancer. Collectively, this review delineates emerging opportunities for therapeutic discovery and aims to establish a foundation for future investigations into the therapeutic modulation of mitochondrial pathways in cancer, thereby paving the way for innovative diagnostic and therapeutic approaches targeting mitochondrial pathways. Full article

Lymphoma continues to pose a serious challenge to global health, underscoring the urgent need for new therapeutic strategies. Recently, the gut microbiome has been shown to play a potential role in regulating immune responses and influencing cancer progression. However, its molecular mechanisms of action in lymphoma remain poorly understood. This study investigates the antiproliferative and apoptotic activities of gut microbiota-derived metabolites, specifically nisin (N) and urolithin B (UB), individually and in combination 7:3 (5750 μM), against the human lymphoma cell line HKB-11. Comprehensive evaluations were performed using Alamar Blue viability assays, combination index (CI) analyses, reactive oxygen species (ROS) quantification, flow cytometry for apoptosis detection, and advanced bottom-up proteomics analyses. N and UB exhibited potent antiproliferative activity, with the 7:3 combination demonstrating strong synergistic effects (CI < 1), significantly enhancing apoptosis (p < 0.01) and ROS production (p < 0.0001) compared to the untreated control. Proteomics analyses revealed substantial alterations in proteins crucial to ribosomal biogenesis, mitochondrial function, cell cycle control, and apoptosis regulation, including a marked downregulation of ribosomal proteins (RPS27; Log₂FC = −3.47) and UBE2N (Log₂FC = −0.60). These findings highlight the potential of N and UB combinations as a novel and practical therapeutic approach for lymphoma treatment, warranting further in vivo exploration and clinical validation. Full article

Background: Rehmannia glutinosa, a traditional Chinese herb, is commonly used to treat vascular-related disorders. Sepsis-associated vascular endothelial dysfunction is closely associated with mitochondrial damage. This study investigated the protective effects of secondary metabolites from R. glutinosa against LPS-induced mitochondrial dysfunction in endothelial cells, providing potential therapeutic insights into sepsis-related vascular complications. Methods: Phytochemical profiling of fresh R. glutinosa roots was conducted, and the structures of new secondary metabolites (1 and 2) were elucidated through comprehensive spectroscopic analysis and ECD calculations. UPLC-Q-TOF-MS/MS characterized phenylethanoid glycosides. Mitochondrial function was assessed by measuring the membrane potential, ROS levels, and TOM20/DRP1 expression in LPS-injured HUVECs. Results: Two novel eremophilane-type sesquiterpenes, remophilanetriols J (1) and K (2), along with five known phenylethanoid glycosides (3–7), were isolated from the fresh roots of R. glutinosa. UPLC-Q-TOF-MS/MS analysis revealed unique fragmentation pathways for phenylethanoid glycosides (3–7). In LPS-injured HUVECs, all compounds collectively restored the mitochondrial membrane potential, attenuated ROS accumulation, and modulated TOM20/DRP1 expression. In particular, remophilanetriol K (2) exhibited potent protective effects at a low concentration (1.5625 μM). Conclusions: This study identifies R. glutinosa metabolites as potential therapeutics for sepsis-associated vascular dysfunction by preserving mitochondrial homeostasis. This study provides a mechanistic basis for the traditional use of R. glutinosa and offers valuable insights into the development of novel therapeutics targeting mitochondrial dysfunction in sepsis. Full article

Adenosine receptors (ARs) are G protein-coupled receptors that are widely expressed across tissues, traditionally associated with cardiovascular, neurological, and immune regulation. Recent studies, however, have highlighted their non-canonical functions, revealing critical roles in metabolism, immunometabolism, and epigenetic regulation. AR subtypes, particularly A2A and A2B, modulate glucose and lipid metabolism, mitochondrial activity, and energy homeostasis. In immune cells, AR signaling influences metabolic reprogramming and polarization through key regulators such as mTOR, AMPK, and HIF-1α, contributing to immune tolerance or activation depending on the context. Additionally, ARs have been implicated in epigenetic modulation, affecting DNA methylation, histone acetylation, and non-coding RNA expression via metabolite-sensitive mechanisms. Therapeutically, AR-targeting agents are being explored for cancer and chronic inflammatory diseases. While clinical trials with A2A antagonists in oncology show encouraging results, challenges remain due to receptor redundancy, systemic effects, and the need for tissue-specific selectivity. Future strategies involve biased agonism, allosteric modulators, and combination therapies guided by biomarker-based patient stratification. Overall, ARs are emerging as integrative hubs connecting extracellular signals with cellular metabolic and epigenetic machinery. Understanding these non-canonical roles may unlock novel therapeutic opportunities across diverse disease landscapes. Full article

Fumonisin B1, deoxynivalenol (DON), and zearalenone (ZEA) are toxic secondary metabolites produced by Fusarium molds. These mycotoxins are common food and feed pollutants and represent a risk to human and animal health. Although the mycotoxins produced by this genus can cross the blood–brain barrier in many species, their effect on neuronal function remains unclear. We investigated the cell viability effects of these toxins on specified neural cell types, including mouse primary neuronal, astroglial, and mixed-cell cultures 24 or 48 h after mycotoxin administration. DON decreased cell viability in a dose-dependent manner, independent of the culture type. Fumonisin B1 was toxic in pure neuronal cultures only at high doses, but toxicity was attenuated in mixed and pure astroglial cultures. ZEA had significant effects on all culture types in 10 nM by increasing cell viability and network activity, as revealed by multi-electrode array measurements. Since ZEA is a mycoestrogen, we analyzed the effects of ZEA on the expression of estrogen receptor isotypes ERα and ERβ and the mitochondrial voltage-dependent anion channel via qRT-PCR. In neuronal and mixed cultures, ZEA administration decreased ERα expression, while in astroglial cultures, it induced the opposite effect. Thus, our results emphasize that Fusarium mycotoxins act in a cell-specific manner. Full article

White-Nose Syndrome (WNS) has devastated insectivorous bat populations, particularly in North America, leading to severe ecological and economic consequences. Despite extensive research, many aspects of the evolutionary history, mitochondrial genome organization, and metabolic adaptations of its etiological agent, Pseudogymnoascus destructans, remain unexplored. Here, we present a multi-scale genomic analysis integrating pangenome reconstruction, phylogenetic inference, Bayesian divergence dating, comparative mitochondrial genomics, and refined functional annotation. We show that P. destructans exhibits extensive mitochondrial genome rearrangements absent in its nonpathogenic relatives from the Leotiomycetes class, suggesting a potential link between mitochondrial evolution and pathogenic adaptation. Our divergence dating analysis reveals that P. destructans separated from its Antarctic relatives approximately 141 million years ago, before adapting to bat hibernacula in the Northern Hemisphere. Additionally, our refined functional annotation significantly expands the known functional landscape of P. destructans, revealing an extensive repertoire of previously uncharacterized proteins involved in carbohydrate metabolism and secondary metabolite biosynthesis—key processes that likely contribute to its pathogenic success. By providing new insights into the genomic basis of P. destructans adaptation and pathogenicity, our study refines the evolutionary framework of this fungal pathogen and creates the foundation for future research on WNS mitigation strategies. Full article

Traditionally studied in isolation, the oral and gut microbiota are now being recognized as interconnected through anatomical and physiological pathways forming a dynamic “oral–gut microbiota axis”. Both oral and gut microbiota undergo changes with aging, characterized by a decline in microbial diversity and a shift toward potentially harmful species. The aim of this review is, therefore, to provide an overview of oral–gut communications in mediating frailty and sarcopenia. PubMed, EMBASE and Scopus databases were searched for relevant articles. We limited our search to manuscripts published in the English language. Interactions between oral and gut microbiota occur mainly through three pathways namely the enteral, the bloodstream and the fecal-oral routes. Alterations in the oral–gut microbiota axis contribute to chronic low-grade inflammation (i.e., “inflamm-ageing”) and mitochondrial dysfunction, key mechanisms underlying frailty and sarcopenia. Microbial metabolites, such as short-chain fatty acids and modified bile acids, appear to play an emerging role in influencing microbial homeostasis and muscle metabolism. Furthermore, poor oral health associated with microbial dysbiosis may contribute to altered eating patterns that negatively impact gut microbiota eubiosis, further exacerbating muscle decline and the degree of frailty. Strategies aimed at modulating the microbiota, such as healthy dietary patterns with reduced consumption of ultra-processed foods, refined carbohydrates and alcohol, ensuring an adequate protein intake combined with physical exercise, as well as supplementation with prebiotics, probiotics, and omega-3 polyunsaturated fatty acids, are increasingly recognized as promising interventions to improve both oral and gut microbiota health, with beneficial effects on frailty and sarcopenia. A better understanding of the oral–gut microbiota axis offers promising insights into nutritional interventions and therapeutic strategies for the age-related muscle decline, frailty and systemic health maintenance. Full article

Dietary advanced glycation end-products (dAGEs) contained in high-sugar/fat and ultra-processed foods of the “Western diet” (WD) pattern predispose to several diseases by altering protein function or increasing oxidative stress and inflammation via RAGE (receptor for advanced glycation end-products). Although elevated endogenous AGEs are associated with loss of muscle mass and functionality (i.e., muscle wasting; MW), the impact of dAGEs on MW has not been elucidated. Here, we show that the most common dAGEs or their precursor, methylglyoxal (MGO), induce C2C12 myotube atrophy as endogenous AGE-derived BSA. ROS production, mitochondrial dysfunction, mitophagy, ubiquitin–proteasome activation, and inhibition of myogenic potential are common atrophying mechanisms used by MGO and AGE-BSA. Although of different origins, ROS are mainly responsible for AGE-induced myotube atrophy. However, while AGE-BSA activates the RAGE-myogenin axis, reduces anabolic mTOR, and causes mitochondrial damage, MGO induces glycolytic stress and STAT3 activation without affecting RAGE expression. Among thirty selected natural compounds, Vaccinium macrocarpon (VM), Camellia sinensis, and chlorophyll showed a surprising ability in counteracting in vitro AGE formation. However, only the standardized VM, containing anti-glycative metabolites as revealed by UHPLC-HRMS analysis, abrogates AGE-induced myotube atrophy. Collectively, our data suggest that WD-linked dAGE consumption predisposes to MW, which might be restricted by VM food supplements. Full article

Lymphoma continues to pose a significant global health burden, highlighting the urgent need for novel therapeutic strategies. Recent advances in microbiome research have identified gut-microbiota-derived metabolites, or postbiotics, as promising candidates in cancer therapy. This study investigates the antiproliferative and mechanistic effects of two postbiotics, Nisin (N) and Urolithin B (UB), individually and in combination, against the human lymphoma cell line HKB-11. Moreover, this study evaluated cytotoxic efficacy and underlying molecular pathways using a comprehensive experimental approach, including the Alamar Blue assay, combination index (CI) analysis, flow cytometry, reactive oxygen species (ROS) quantification, and bottom-up proteomics. N and UB displayed notable antiproliferative effects, with IC₅₀ values of 1467 µM and 87.56 µM, respectively. Importantly, their combination at a 4:6 ratio demonstrated strong synergy (CI = 0.09 at IC₉₅), significantly enhancing apoptosis (p ≤ 0.0001) and modulating oxidative stress. Proteomic profiling revealed significant regulation of key proteins related to lipid metabolism, mitochondrial function, cell cycle control, and apoptosis, including upregulation of COX6C (Log₂FC = 2.07) and downregulation of CDK4 (Log₂FC = −1.26). These findings provide mechanistic insights and underscore the translational potential of postbiotics in lymphoma treatment. Further preclinical and clinical investigations are warranted to explore their role in therapeutic regimens. Full article

Nitric oxide (NO) has a dual effect on mitochondria. Incubating liver mitochondria with NO improves oxidative phosphorylation (OXPHOS) efficiency by decreasing state 4 respiration more than ATP synthesis and preventing mitochondrial permeability transition pore (mPTP) opening. We evaluated the effect of L-arginine (L-arg), an NO donor, on isolated liver mitochondrial respiration and mPTP in sepsis. Male mice were subjected to cecal ligation and perforation (CLP) with saline resuscitation or sham. After 8, 24, and 48 h, with and without L-arg, we measured isolated liver mitochondrial respiration and cytochrome c oxidase (COX) activity using polarographic methods and calcium retention capacity (CRC) to assess the mPTP and NO metabolites via the Griess reaction. Mitochondrial NO synthase (mtNOS) was identified by Western blot. CLP decreased state 3 respiration at 24 and 48 h, decreased COX activity at 8, 24, and 48 h, and increased state 4 respiration and decreased the respiratory control ratio (RCR) and CRC at 48 h. L-arg increased NO levels at 8 h, decreased state 4 respiration more than state 3 respiration (−39% versus −12%) at 48 h, decreased the CRC in the CLP groups at 24 and 48 h, but did not improve RCR. Our data suggests that L-arg does not restore liver mitochondrial OXPHOS efficiency or prevent mPTP opening in the late or recovery phases of sepsis. Full article

The mitochondrial regulator MNRR1 is reduced in several pathologies, including the mitochondrial heteroplasmic disease MELAS, and genetic restoration of its level normalizes the pathological phenotype. Here, we investigate the upstream mechanism that reduces MNRR1 levels. We have identified the hypoxic regulator HIF2α to bind the MNRR1 promoter and inhibit transcription by competing with RBPJκ. In MELAS cells, there is a pseudohypoxic state that transcriptionally induces HIF2α and stabilizes HIF2α protein. MELAS cybrids harboring the m.3243A > G mutation display reduced levels of prolyl hydroxylase 3 (PHD3), which contributes to the HIF2α stabilization. These results prompted a search for compounds that could increase MNRR1 levels pharmacologically. The screening of a 2400-compound library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as enhancers of MNRR1 transcription. We show that treating MELAS cybrids with tizoxanide restores cellular respiration, enhances mitophagy, and, importantly, shifts heteroplasmy toward wild-type mtDNA. Furthermore, in fibroblasts from MELAS patients, the compound improves mitochondrial biogenesis, enhances autophagy, and protects from LPS-induced inflammation. Mechanistically, nitazoxanide reduces HIF2α levels by increasing PHD3. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Finally, our data suggests a broader physiological pathway wherein two proteins, induced under severe (1% O2; HIF2α) and moderate (4% O2; MNRR1) hypoxic conditions, regulate each other inversely. Full article

Burnout syndrome is characterized mainly by three criteria (emotional exhaustion, depersonalization, and low personal accomplishment), and further exacerbated by night shift work, with profound implications for individual and societal well-being. The Maslach Burnout Inventory survey applied to 97 medical care professionals (with day and night work) revealed different scores for these criteria. Blood metabolic profiles were obtained by UHPLC-QTOF-ESI⁺-MS untargeted metabolomics and multivariate statistics using the Metaboanalyst 6.0 platform. The Partial Least Squares Discrimination scores and VIP values, Random Forest graphs, and Heatmaps, based on 99 identified metabolites, were complemented with Biomarker Analysis (AUC ranking) and Pathway Analysis of metabolic networks. The data obtained reflected the biochemical implications of night shift work and correlated with each criterion’s burnout scores. Four main metabolic pathways with important consequences in burnout were affected, namely lipid metabolism, especially steroid hormone synthesis and cortisol, the energetic mitochondrial metabolism involving acylated carnitines, fatty acids, and phospholipids as well polar metabolites’ metabolism, e.g., catecholamines (noradrenaline, acetyl serotonin), and some amino acids (tryptophan, tyrosine, aspartate, arginine, valine, lysine). These metabolic profiles suggest potential strategies for managing burnout levels in healthcare professionals, based on validated criteria, including night shift work management. Full article

The poll gland, a specialized tissue of male Bactrian camels, undergoes seasonal enlargement and marked metabolic activation during the rutting season. However, the metabolic mechanisms of the poll gland and its role in rutting activities and inducing estrus are still not fully understood. This study aimed to investigate the contribution of fatty acid metabolic pathways, specifically those mediated by carnitine palmitoyltransferase 1A (CPT1A), in poll gland activity during the breeding season; poll gland tissue, neck mane, and urine samples were systematically collected from healthy male Bactrian camels stratified into breeding and non-breeding season groups for integrated proteomic, metabolomic, and biochemical assays. Histological and immunohistochemical analyses revealed reduced adipocytes but elevated ATP production in rutting camels, suggesting increased mitochondrial activity and enhanced oxidative phosphorylation. Proteomic analyses identified 119 differentially expressed proteins (DEPs) linked to fatty acid metabolism, with CPT1A, a key regulator of mitochondrial fatty acid oxidation, emerging as a central hub. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further confirmed enrichment in fatty acid biosynthesis, degradation, and PPAR/AMPK signaling. The metabolomic analysis identified 14 metabolites, including acetylcarnitine and glycine, that were closely correlated with CPT1A expression, suggesting their potential involvement in regulating fatty acid metabolism during the breeding season. Quantitative expression analyses revealed that CPT1A in glandular acini was significantly upregulated in the breeding group compared to the non-breeding group across all assays: qPCR (2.53-fold, p < 0.05), Western blot (3.5-fold, p < 0.05), and immunohistochemistry (1.5-fold, p < 0.05). This demonstrated that CPT1A-mediated fatty acid metabolism plays a pivotal role in energy provision for reproductive activities. The results suggested that CPT1A-mediated fatty acid oxidation sustains poll gland function and reproductive behaviors in male Bactrian camels. This study provided a theoretical basis for understanding the role of CPT1A-mediated fatty acid oxidation in maintaining poll gland function and supporting reproductive activities in male Bactrian camels. Full article

Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut–brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF’s capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience. Full article