Search Results (4,164)

Diabetic nephropathy is a major challenge in medicine. While a variety of mechanisms underlie the onset and progression of diabetic nephropathy, oxidative stress is critical because it promotes inflammation and creates a vicious cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial–mesenchymal transition, tubular atrophy, and proteinuria. There are various treatments for diabetic nephropathy, and each has its own limitations. Although the exact mechanisms by which polyphenols suppress diabetic nephropathy have not been elucidated, they may have antioxidant, anti-inflammatory, antifibrotic, and/or anti-apoptotic effects. They may also suppress endoplasmic reticulum stress and ameliorate mitochondrial dysfunction and dyslipidemia. Dietary polyphenols may be able to prevent the onset and slow the progression of diabetic nephropathy; they include resveratrol, quercetin, isoflavones, catechins, and anthocyanidins and have antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic effects through multiple molecular targets. Furthermore, they have shown few side effects. However, further research is needed to fully elucidate the molecular mechanisms by which polyphenols exert their effects and to clarify their optimal therapeutic use. In this review, we summarize reports published in the past five years regarding their effects on diabetic nephropathy and provide an overview of the potential of polyphenols. Full article

Soman, an organophosphorus nerve agent, induces neurotoxicity primarily by inhibiting acetylcholinesterase, triggering a series of pathological events including cholinergic crisis, seizures, calcium overload, oxidative stress, mitochondrial dysfunction, and neuronal death. Nevertheless, the mechanisms underlying metabolic dysregulation—especially after repeated exposure—remain poorly characterized. To address this, we used SWATH-based proteomics to analyze changes in the hippocampal proteome following a repeated soman exposure regimen in a model of hippocampal injury. We identified 38 differentially expressed proteins, predominantly enriched in metabolic pathways. KEGG annotation indicated that these were mainly involved in carbohydrate, amino acid, and lipid metabolism, with specific roles in calcium signaling, tryptophan and tyrosine metabolism, alanine, aspartate and glutamate metabolism, and glyoxylate and dicarboxylate metabolism. Overall, our results demonstrate significant disruption of key metabolic pathways, particularly affecting carbohydrate and amino acid metabolism. We suggest that soman-induced hippocampal damage arises not only from acute calcium overload but also from persistent metabolic dysregulation that impairs energy production and biosynthetic processes. All of our preliminary results shed light on the nature of the biological process and target in the metabolism and provide basic research for the treatment, diagnosis, and prevention of nerve-agent-induced brain damage. Full article

Neutrophils are the first line of defense of the human immune system against pathogens. Photobiomodulation, mediated by mitochondrial photoacceptors such as cytochrome c oxidase, has emerged as a method to modulate neutrophil function through targeted light exposure. Despite the extensive characterization of neutrophil extracellular traps (NETs) formation (NETosis), the wavelength-specific modulation of neutrophil photoactivation and the involvement of redox pathways remain poorly defined. In this study, the effects of monochromatic (365 nm, 415 nm, 437 nm, and 625 nm) and dichromatic LED-light irradiation on NETs formation were systematically examined. The highest netotic responses were elicited by UV-A (365 nm) and violet-blue light (415 nm), whereas 437 nm showed the lowest induction and 625 nm stimulated a moderate netotic response. The pharmacological inhibition of NETosis induced by 365 nm and 415 nm irradiation with specific NADPH oxidase inhibitor, apocynin, and mitochondrial reactive oxygen species (mtROS) scavenger, MitoTEMPO, attenuated NETs formation by engaging both enzymatic and mitochondrial oxidative sources. Notably, mtROS played a dominant role under 415 nm stimulation in contrast to 365 nm-induced NETosis as demonstrated by higher sensitivity to MitoTEMPO. Importantly, combined simultaneous irradiation with 415 nm and 625 nm LEDs resulted in a significant suppression of NETs formation by more than 50%, highlighting a potent inhibitory synergy observed for the first time and suggesting a new approach of wavelength pairing to modulate neutrophil activation. These results were further supported by measurements of ROS production using a luminol-amplified chemiluminescence assay. Collectively, these findings delineate a wavelength- and ROS-dependent framework for light-induced neutrophil activation, with mitochondrial pathways exerting central control particularly under short-wavelength irradiation. Full article

This study evaluated the reproductive toxicity and reversibility of gossypol exposure in female Institute of Cancer Research (ICR) mice using the Targeted Risk Assessment of Environmental Chemicals (TRAEC) framework. Mice treated with gossypol (20 mg/kg/day, 30 days) showed reduced body weight (35.90 ± 3.19 g vs. 30.26 ± 0.91 g, p < 0.001), depletion of primordial follicles (46.2 ± 4.8 vs. 27.5 ± 3.6, p < 0.01), and impaired oocyte maturation, with polar body extrusion decreasing from 65.9% to 22.6% at 60 μM (p < 0.0001). In the human granulosa-like tumor cell line (KGN), apoptosis increased to 91.1% at 20 μg/mL compared with 11.46% in controls (p < 0.0001). Proteomic profiling identified 151 differentially expressed proteins, enriched in steroidogenesis, immune regulation, and mitochondrial metabolism. After one-month withdrawal, partial morphological recovery was observed, but endocrine function remained impaired. The TRAEC risk score of 4.68 classified gossypol as a moderate reproductive toxicant. These findings indicate that gossypol damages ovarian reserve and oocyte competence, with only partial reversibility, highlighting the need for caution in its clinical use. Full article

Background/Objectives: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. Methods: In this study, we used a cecal ligation and puncture (CLP) model to induce sepsis in wild-type (WT) and cyclophilin D knockout (CypD KO) mice. Liver tissues were collected at 0, 6, and 18 h post-CLP and analyzed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: Metabolomic profiling revealed that lactate levels significantly increased in the WT mice but remained stable in the KO mice. While AMP levels were preserved in the KO mice, these mice had significantly higher glutathione disulfide (GSSG) and spermidine concentrations than the WT mice at 18 h (p < 0.05). The levels of malondialdehyde (MDA), a marker of oxidative stress, were also significantly lower in the KO mice at 18 h (p < 0.05). These findings suggest that CypD deficiency preserves mitochondrial function, enhances resistance to oxidative stress, and mitigates septic liver injury. Conclusions: Our results highlight the potential of targeting mitochondrial permeability transition as a therapeutic strategy for sepsis. Full article

Depressive disorder is the most prevalent mental illness, and increasing evidence suggests its potential bidirectional relationship with metabolic disorders. Given the limited efficacy of conventional antidepressants (including Selective Serotonin Reuptake Inhibitors; SSRIs) and the growing prevalence of treatment-resistant depression, there is a significant need to identify alternative molecular pathways underlying the pathophysiology of depressive disorder, which may represent novel therapeutic targets for other agents. Emerging evidence indicates that metabolic dysfunction and depressive disorder share a common pathophysiological molecular mechanism and increase each other’s risk. Targeting peripheral metabolic pathways and their interactions with the central nervous system may alleviate depressive symptoms. Glucagon-Like Peptide-1 agonists (GLP-1 RAs) and Sodium–Glucose Cotransporter-2 (SGLT2) inhibitors, widely used in the treatment of type 2 diabetes and obesity, exhibit neurotrophic and anti-inflammatory effects, ameliorate oxidative stress, and enhance mitochondrial function, collectively contributing to the antidepressant-like effects observed in preclinical studies. Peroxisome Proliferator-Activated Receptor (PPAR) α agonists primarily regulate lipid and glucose metabolism, which may potentially improve neuronal plasticity and mood regulation. Moreover, agents such as Angiotensin Receptor Blockers (ARBs) and Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), used in hypertension treatment, exert central anti-inflammatory and neuroprotective effects via the modulation of the renin–angiotensin–aldosterone system (RAAS), implicated in affective disorders. Nevertheless, long-term, head-to-head trials are required to establish their efficacy, safety, and therapeutic positioning within current treatment paradigms. The aim of this review is to summarize current evidence on metabolic modulators as potential antidepressant strategies, focusing on their molecular mechanisms, preclinical and clinical findings, and prospects for integration into future therapies for depression. Full article

MicroRNA 451 (miR-451) is emerging as a pivotal mediator of cardiac damage in experimental models of diabetic cardiomyopathy. Whether miR-451 plays a detrimental role in the human diabetic myocardium is unknown. The present study investigates miR-451’s role in patients with type 2 diabetes (T2D). We show that miR-451 is upregulated in myocardial specimens from T2D patients compared to controls without diabetes and correlates with cardiometabolic parameters, the myocardial triglyceride content and cardiac expression of lipotoxic genes as well as echocardiographic indices of left ventricular dysfunction. Calcium-binding protein 39 (Cab39)—a known target of miR-451 in mouse hearts—was downregulated in T2D patients vs. controls, and its expression negatively correlated with that of miR-451. In cultured human cardiomyocytes (CMs), Ago2 immunoprecipitation confirmed Cab39 to be a direct target of miR-451. Treatment with a high amount of glucose (25mM) and palmitic acid (PA) mimicked miR-451 upregulation and Cab39 downregulation in human CMs. These changes were associated with increased TGs and markers of lipotoxic injury, such as elevated oxidative stress levels, mitochondrial dysfunction and apoptosis. Targeting miR-451 led to restoration of Cab39 levels while rescuing diabetes-induced lipotoxic injury and metabolic dysfunction. By contrast, miR-451 overexpression recapitulated features of lipotoxic damage. Our findings indicate miR-451 to be a potential target for the prevention of myocardial lipotoxic injury in diabetes. Full article

Several microRNAs (miRNAs) are key influencers of tumor microenvironment (TME) cell plasticity, regulating the progression of various tumor types such as glioblastoma (GBM). Differential expressions of miR-27a-3p and miR-155-5p in GBM cells and biopsies have already been described as markers of tumor subtype and progression. We aimed to evaluate the cellular and molecular impacts of inhibiting these two overexpressed miRNAs in GBM cell lines. A172 cells were transfected with miR-27a-3p and miR-155-5p inhibitors, and the effects on cellular processes and the expression of malignancy-related genes were analyzed by flow cytometry and qPCR, respectively. Thus, several cellular characteristics in A172 cells were modulated; however, only the inhibition of miR-27a-3p resulted in apoptosis, reduced glucose uptake, and a decrease in mitochondrial membrane potential. Both inhibitors modulated metabolic and immunological targets, negatively regulating genes in the glycolysis pathway and modulating other metabolic pathways involving glutamine and fatty acids, for example. Additionally, it modulates the TGF-β pathway, which can influence the GBM microenvironment due to its immunosuppressive role in advanced tumors. miR-27a-3p appears to be a pivotal factor in the functional duality of TGF-β and its interaction with HIF1A in the hypoxic tumor environment, modulating SMAD partners or TGF-β pathway inhibitors. Here, we demonstrate the importance of inhibiting overexpressed miRNAs, particularly miR-27a-3p, in modulating key pathways for tumor cell survival. The results of this work provide new insights into potential targets for immune-metabolic interactions in the TME and their implications for tumorigenesis, shedding light on new therapeutic approaches for GBM. Full article

Hypertensive heart disease (HHD) is characterized by pressure overload-induced cardiac remodeling, in which mitochondrial dysfunction has emerged as a central contributor to pathophysiology. Mitochondria occupy roughly one-third of the volume of a cardiomyocyte and serve as the primary source of ATP for the constantly active heart, while also regulating calcium homeostasis, redox balance, and apoptotic signaling. Chronic hypertension imposes energetic and oxidative stress on cardiomyocytes, disrupting mitochondrial structure and function. Key mitochondrial quality control processes including organelle fusion–fission dynamics, biogenesis, and mitophagy become dysregulated in HHD, leading to impaired energy production and heightened cell injury. This unstructured review discusses the physiological roles of mitochondria in cardiac muscle and examines how altered mitochondrial dynamics contribute to hypertensive cardiac damage. We detail mechanisms of mitochondrial dysfunction in HHD, such as excessive fission, cristae disruption, and oxidative stress, and how these changes are exacerbated by aging. Age-related mitochondrial remodeling such as loss of cristae and decreased organelle volume may synergistically worsen hypertensive cardiac injury. We further integrate findings from recent studies in animal and human models, including advanced three-dimensional ultrastructural analyses and molecular investigations that illuminate new aspects of mitochondrial network organization, the mitochondrial contact site and cristae organizing system (MICOS), cristae maintenance complex, and quality control pathways in HHD. Understanding mitochondrial dysfunction in HHD reveals potential therapeutic avenues targeting mitochondrial quality and dynamics to preserve cardiac function in hypertension. Full article

As the hub of energy metabolism and the cell’s fate arbiter, mitochondria are essential for preserving cellular homeostasis and converting it from pathological states. Therefore, through mechanisms that drive metabolic reprogramming, oxidative stress, and apoptosis resistance, mitochondrial dysfunction (including mitochondrial DNA mutations, mitochondrial dynamics imbalance, mitochondrial autophagy abnormalities, mitochondrial permeability abnormalities, and metabolic disorder) can promote the progression of thyroid cancer (TC), resistance to treatment, and reshaping of the immune microenvironment. This article reviews the molecular mechanisms and characteristic manifestations of mitochondrial dysfunction in TC. It focuses on providing a summary of the main strategies currently used to target the mitochondria, such as dietary intervention and targeted medications like curcumin, as well as the clinical translational value of these medications when used in conjunction with current targeted therapies for TC and radioactive iodine (RAI) therapy in patients with advanced or RAI-refractory TC who rely on targeted therapies. The application prospects and existing challenges of emerging therapeutic methods, such as mitochondrial transplantation, are also discussed in depth, aiming to provide new perspectives for revealing the molecular mechanisms by which mitochondrial dysfunction drives the progression of TC, drug resistance, and the reshaping of its immune microenvironment, as well as providing new diagnostic and therapeutic strategies for patients with advanced or RAI-refractory TC who are reliant on targeted therapies. Full article

Unsaturated fatty acids are key contributors to the nutritional and sensory quality of lamb meat. To investigate the molecular basis of intramuscular unsaturated fatty acid variation, we selected lambs with divergent fatty acid profiles and performed integrated transcriptomic and untargeted metabolomic analyses of the longissimus dorsi muscle. The high unsaturated fatty acid group exhibited distinct gene expression patterns in pathways related to lipid metabolism, mitochondrial function, and immune responses. Metabolomic profiling revealed significant enrichment of metabolites involved in both the biosynthesis and degradation of fatty acids. Among the differentially expressed genes, MYH7 was markedly upregulated in lambs with higher unsaturated fatty acid content, suggesting a potential regulatory role in energy metabolism or lipid homeostasis. These findings provide new molecular insights into the mechanisms underlying unsaturated fatty acid deposition in lamb and identify MYH7 and other candidates as potential targets for improving meat quality through breeding or nutritional strategies. Full article

Mitochondrial quality control (MQC) mechanisms, including proteostasis, mitophagy, mitochondrial dynamics, and biogenesis, are essential for maintaining mitochondrial function and overall cellular health. Dysregulation of these systems is a common feature of both neurodegenerative diseases and cancer, but the outcomes differ. Neurons depend strongly on healthy mitochondria and are easily damaged when MQC fails, resulting in organellar dysfunction and oxidative stress. By contrast, cancer cells often adapt by using MQC pathways to sustain survival and resist cell death. The mitochondrial unfolded protein response (mtUPR) and mitophagy are central to these processes, yet their roles are context-dependent. In neurodegeneration, activation of these pathways may help neurons survive, yet persistent stimulation can shift towards harmful effects. In cancer, these same pathways enhance metabolic flexibility, promote resistance to treatment, and support tumor progression. Although therapeutic strategies targeting MQC are being explored, their translation to the clinic is difficult, partly due to opposite effects in different diseases. The observed inverse epidemiological link between cancer and neurodegeneration may also reflect the distinct regulation of MQC pathways. A clearer understanding of these mechanisms is needed to identify new treatment strategies for disorders that are clinically distinct but share common mitochondrial defects. Full article

Obesity-induced insulin resistance and type 2 diabetes mellitus (T2DM) represent complex systemic disorders marked by chronic inflammation, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. These pathophysiological processes disrupt insulin signaling and β-cell function, leading to impaired glucose homeostasis across multiple organs. Conventional therapies often target isolated pathways, overlooking the intricate molecular crosstalk and organelle-level disturbances driving disease progression. Citrus-derived polyphenols—including hesperidin, naringenin, nobiletin, and tangeretin—have emerged as promising agents capable of orchestrating a multi-targeted “metabolic reprogramming.” These compounds modulate key signaling pathways, including AMPK, PI3K/Akt, NF-κB, and Nrf2, thereby enhancing insulin sensitivity, reducing pro-inflammatory cytokine expression, and restoring redox balance. Furthermore, they improve mitochondrial biogenesis, stabilize membrane potential, and alleviate ER stress by modulating the unfolded protein response (UPR), thus supporting cellular energy homeostasis and protein folding capacity. Evidence from preclinical studies and select clinical trials suggests that citrus polyphenols can significantly improve glycemic control, reduce oxidative and inflammatory markers, and preserve β-cell function. Their pleiotropic actions across molecular and organ-level targets position them as integrative metabolic modulators. This review presents a systems-level synthesis of how citrus polyphenols rewire metabolic signaling networks and organelle resilience, offering a holistic therapeutic strategy to mitigate the root causes of obesity-induced insulin resistance. Full article

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide, arising from complex interactions among metabolic, genetic, and environmental factors. Nicotinamide N-methyltransferase (NNMT) has recently emerged as a key metabolic regulator in CVD pathogenesis. By consuming nicotinamide and methyl groups, NNMT perturbs epigenetic, metabolic, and redox pathways that are critical for cardiovascular health. NNMT-mediated NAD⁺ depletion impairs mitochondrial function, sirtuin (SIRT) activity, redox balance, and energy metabolism, thereby creating a pro-atherogenic environment. NNMT and its product 1-methylnicotinamide (1-MNA) show a complex duality: they modulate SIRT activity—particularly SIRT1 and SIRT3—to influence gluconeogenesis, cholesterol synthesis, lipogenesis, and mitochondrial antioxidant defenses. NNMT upregulation also elevates homocysteine levels, activating pro-inflammatory and pro-oxidative cascades (e.g., TLR4–NF-κB and STAT3–IL-1β). Growing evidence links NNMT to major CVD risk factors, including hyperlipidemia, hypertension, diabetes mellitus, and obesity. Thus, NNMT has a multifaceted role in cardiovascular health: while its enzymatic activity is often pathogenic (via NAD⁺/SAM consumption and homocysteine production), its metabolite 1-MNA can exert protective effects (via NRF2 activation and anti-thrombotic mechanisms). This duality highlights the need to delineate the molecular processes that balance these opposing actions. Experimental studies using small-molecule NNMT inhibitors and RNA interference have shown promising cardiometabolic benefits in preclinical models, including improved insulin sensitivity, reduced atherosclerosis, and attenuated cardiac dysfunction. However, no clinical trials have yet targeted NNMT specifically in CVD. Future research should clarify the tissue-specific functions of NNMT and translate these insights into novel therapeutic strategies. Full article

The cGAS-STING pathway initiates the core cascade of innate immune defense by recognizing pathogen-associated and self-derived abnormal nucleic acids, and key molecules (such as cGAS, STING, downstream IFN-β, IL-6, etc.) may serve as biomarkers in various diseases. The diverse mechanisms by which distinct nucleic acids activate this pathway provide novel insights for therapeutic strategies targeting infectious diseases, cancer, and autoimmune disorders. To prevent aberrant cGAS-STING pathway activation, cells employ multiple regulatory mechanisms, including restricting self-DNA recognition and terminating downstream signaling. Strategies to mitigate pathological activation involve reducing nucleic acid accumulation through nuclease degradation (e.g., of mitochondrial DNA or neutrophil extracellular traps, NETs) or directly inhibiting cGAS or STING. This review elucidates the molecular mechanism of nucleic acid-mediated regulation of cGAS-STING and its role in disease regulation. Full article