Search Results (6,152)

Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine–metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, and immune factors, including dysregulated adipokine secretion, cytokine-mediated inflammation, oxidative stress (OS), and mitochondrial dysfunction. Current pharmacological therapies, such as metformin, clomiphene, and oral contraceptives, often provide partial benefits and are limited by side effects, necessitating the exploration of safer, multi-target strategies. Flavonoids, a structurally diverse class of plant-derived polyphenols, have gained attention as promising therapeutic candidates in PCOS due to their antioxidant, anti-inflammatory, insulin-sensitizing, and hormone-modulating properties. Preclinical studies in rodent PCOS models consistently demonstrate improvements in insulin sensitivity, normalization of ovarian morphology, restoration of ovulation, and reduction in hyperandrogenism. Human clinical studies, though limited in scale and heterogeneity, report favorable effects of flavonoids such as quercetin, isoflavones, and catechins on glucose metabolism, adipokine balance, inflammatory markers, and reproductive functions. This evidence-based study critically synthesizes mechanistic insights into how flavonoids modulate insulin signaling, adipokine–cytokine crosstalk, OS, and androgen excess, while highlighting translational evidence and emerging delivery systems aimed at overcoming bioavailability barriers. Collectively, flavonoids represent a promising class of nutraceuticals and adjuncts to conventional therapies, offering an integrative strategy for the management of PCOS. Full article

Silymarin, a flavonolignan-rich extract of Silybum marianum, is widely recognized for its hepatoprotective potential. While rodent studies predominate, pigs (Sus scrofa) offer a more translationally relevant model due to their hepatic architecture, bile acid composition, and transporter expression, which closely resemble those of humans. This narrative review synthesises current evidence on the chemistry, pharmacokinetics, biodistribution, and hepatoprotective activity of silymarin in porcine models. Available studies demonstrate that when adequate intrahepatic exposure is achieved, particularly through optimised formulations, silymarin can attenuate oxidative stress, suppress inflammatory signalling, stabilise mitochondria, and modulate fibrogenic pathways. Protective effects have been reported across diverse porcine injury paradigms, including toxin-induced necrosis, ethanol- and diet-associated steatosis, metabolic dysfunction, ischemia–reperfusion injury, and partial hepatectomy. However, the evidence base remains limited, with few long-term studies addressing fibrosis or regeneration, and methodological heterogeneity complicates the comparison of data across studies. Current knowledge gaps in silymarin research include inconsistent chemotype characterization among plant sources, limited reporting of unbound pharmacokinetic parameters, and variability in histological scoring criteria across studies, which collectively hinder cross-study comparability and mechanistic interpretation. Advances in analytical chemistry, transporter biology, and formulation design are beginning to refine the interpretation of exposure–response relationships. Advances in analytical chemistry, transporter biology, and formulation design are beginning to refine the interpretation of exposure–response relationships. In parallel, emerging computational approaches, including machine-learning-assisted chemotype fingerprinting, automated histology scoring, and Bayesian exposure modeling, are being explored as supportive tools to enhance reproducibility and translational relevance; however, these frameworks remain exploratory and require empirical validation, particularly in modeling enterohepatic recirculation. Collectively, current porcine evidence supports silymarin as a context-dependent yet credible hepatoprotective agent, highlighting priorities for future research to better define its therapeutic potential in clinical nutrition and veterinary practice. Full article

Hyaluronic acid (HA) is a major glycosaminoglycan in the hepatic extracellular matrix and pericellular space, playing a critical role in maintaining liver architecture and regulating cell–matrix interactions. In chronic liver disease, regardless of etiology, dysregulated HA metabolism, particularly the generation and accumulation of low-molecular-weight HA (LMW-HA), has been implicated in fibrogenesis, immune dysregulation, and hepatocellular carcinogenesis via receptor-mediated pathways involving lymphocyte homing receptor (CD44), receptor for hyaluronan-mediated motility (RHAMM), and Toll-like receptors (TLRs). This review synthesizes current evidence on HA biosynthesis, turnover, and signaling, emphasizing its dual role as a structural scaffold and as an active modulator of immune responses and tumor progression in chronic liver disease. Given the rising global burden of metabolic liver disease, and in line with our recent findings that small HA fragments are elevated in obesity and promote low-grade, TLR-dependent activation of innate immune cells, we emphasize metabolic dysfunction-associated steatotic liver disease (MASLD) as a highly prevalent and clinically relevant setting to examine HA-driven immunomodulation during progression to advanced fibrosis and hepatocellular carcinoma (HCC) and to consider therapeutic strategies targeting HA synthesis, turnover, or receptor signaling. Full article

Traditionally, referred to as the “Powerhouse of the Eukaryotic Cell”, mitochondria are essential for host defense in addition to producing ATP. Through processes like mitochondrial antiviral signaling (MAVS), the generation of reactive oxygen species (ROS), and the modification of inflammatory pathways, they respond to bacterial, fungal, viral, and parasitic infections while coordinating immune signaling, controlling cell death, and detecting pathogens. Pathogens, on the other hand, have developed ways to interfere with or harm mitochondrial function, which results in oxidative stress, cell death, altered metabolism, and compromised immune signaling. This type of mitochondrial dysfunction impairs the removal of infections and is linked to tissue damage, chronic inflammation, and long-term health issues. The dual roles of mitochondria in infection are highlighted in this review, which looks at both their defense mechanisms and the ways in which pathogens use them to increase their chances of survival. Full article

Mitochondria play crucial roles in various cellular functions, including ATP production, apoptosis, and calcium homeostasis. Signaling pathways and hormones such as estrogens regulate the mitochondrial network through genetic, epigenetic, and metabolic processes. Estrogens increase the efficiency of mitochondrial oxidative phosphorylation by preventing uncoupling. Upon reaching menopause, when estrogen levels decrease, impaired mitochondrial function (uncoupled oxidative phosphorylation, lower ATP yields) is observed. Like all hormones in the body, estrogens undergo metabolic processing, resulting in estrogenic degradation metabolites (EDMs). These metabolites can form adducts with genomic and mitochondrial DNA and are of particular interest due to their potential role as carcinogens. Given that estradiol influences mitochondrial function, it is possible that EDMs may have an impact on heart mitochondria. To investigate this, we used isolated heart mitochondria from control and oophorectomized (mimicking menopausal stage) female Wistar rats of the same age. We found that mitochondria exposed to EDMs exhibited reduced coupling of oxidative phosphorylation and diminished ATP production, while increasing reactive oxygen species generation. Furthermore, these effects were significantly stronger in mitochondria from oophorectomized rats than in mitochondria from control (intact) rats. In addition, mitochondrial oxidative phosphorylation complex activities were differentially affected: complex I and ATPase activities decreased, while complex IV remained unaffected. We propose that exposure to EDMs promotes mitochondrial dysfunction in rats and that these effects are exacerbated by oophorectomy, a procedure commonly used to model the effects of menopause in women. Full article

Long COVID, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by persistent multi-systemic symptoms such as fatigue, cognitive impairment, and respiratory dysfunction. Accumulating evidence indicates that gut and oral microbiota play an important role in its pathogenesis. Patients with long COVID consistently exhibit reduced microbial diversity, depletion of beneficial short-chain fatty acid (SCFA)-producing species such as Faecalibacterium prausnitzii and Bifidobacterium spp. and enrichment of proinflammatory taxa including Ruminococcus gnavus, Bacteroides vulgatus, and Veillonella. These alterations may disrupt intestinal barrier integrity, sustain low-grade systemic inflammation, and influence host immune and neuroendocrine pathways through the gut–brain and gut–lung axes. Distinct microbial signatures have also been associated with symptom clusters, including neuropsychiatric, respiratory, and gastrointestinal manifestations. Proposed mechanisms linking dysbiosis to long COVID include impaired SCFA metabolism, tryptophan depletion, microbial translocation, and interactions with host immune and inflammatory responses, including autoantibody formation and viral antigen persistence. Preliminary interventional studies using probiotics, synbiotics, and fecal microbiota transplantation suggest that microbiome-targeted therapies may alleviate symptoms, although evidence remains limited and heterogeneous. This review synthesizes current literature on the role of gut and oral microbiota in long COVID, highlights emerging microbial biomarkers, and discusses therapeutic implications. While causality remains to be firmly established, restoring microbial balance represents a promising avenue for diagnosis, prevention, and management of long COVID. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver disorders worldwide and can lead to inflammation, fibrosis, and liver cancer. To better understand the impact of an unbalanced hypercaloric diet on liver phenotype in impaired autophagy, the study compared C57BL/6J wild type (WT) and MAPK15-ERK8 knockout (KO) male mice with C57BL/6J background fed for 17 weeks with “Western-type” (WD) or standard diet (SD). Liver features were monitored in vivo by high-frequency ultrasound (HFUS) using a semi-quantitative and parametric assessment of pathological changes in the parenchyma complemented by computer-aided diagnosis (CAD) methods. Liver histology was considered the reference standard. WD induced liver steatosis in both genotypes, although KO mice showed more pronounced dietary effects than WT mice. Overall, HFUS reliably detected steatosis-related parenchymal changes over time in the two mouse genotypes examined, consistent with histology. Furthermore, this study demonstrated the feasibility of extracting quantitative features from conventional B-mode ultrasound images of the liver in murine models at early clinical stages of MASLD using a computationally efficient and vendor-independent CAD method. This approach may contribute to the non-invasive characterization of genetically engineered mouse models of MASLD according to the principles of replacement, reduction, and refinement (3Rs), with interesting translational implications. Full article

(1) Background: This article reviews the biological characteristics of phenolic acid compounds, focusing on their mechanisms of action in various liver diseases. (2) Methods: The review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We utilized PubMed and Web of Science databases to search for relevant studies on the use of phenolic acids in liver diseases from 2015 to 2025. (3) Results: Phenolic acids can improve different types of liver diseases, including drug-induced liver injury (DILI), alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancer. Their beneficial effects are attributed to mechanisms such as anti-inflammatory properties, antioxidant activity, regulation of lipid metabolism, inhibition of cell apoptosis, and modulation of gut microbiota. (4) Conclusion: Phenolic acids exhibit a good protective effect against various liver diseases and are associated with multiple signaling pathways. However, the primary target cells and specific molecular targets of phenolic acids remain unclear, necessitating further research to elucidate their protective mechanisms in liver diseases. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide and is attributed to complex pathophysiological mechanisms that surpass the traditional risk factors. Emerging evidence indicates that mitochondrial dysfunction plays a central role in CVD progression, linking impaired bioenergetics, oxidative stress imbalance, and defective mitochondrial quality control to endothelial dysfunction, myocardial injury, and adverse cardiac remodeling. However, the mechanistic interplay between mitochondrial dysfunction and CVD pathogenesis remains unclear. This review provides a comprehensive synthesis of recent knowledge, focusing on the dysregulation of mitochondrial energy metabolism, alterations in mitochondrial membrane potential, and disruptions in mitochondrial dynamics, including the balance of fusion and fission, mitophagy, and biogenesis. Furthermore, we critically evaluated emerging mitochondria-targeted therapeutic strategies, including pharmacological agents, gene therapies, and regenerative approaches. By bridging fundamental mitochondrial biology with clinical cardiology, this review underscores the critical translational challenges and opportunities in developing mitochondria-focused interventions. A deeper understanding of the mitochondrial mechanisms in CVD pathophysiology will offer novel diagnostic biomarkers and precision-targeted therapeutics, thereby transforming CVD management. Full article

Pediatric type 1 diabetes (T1D) disrupts musculoskeletal development during critical windows of growth, puberty, and peak bone mass accrual. Beyond classic micro- and macrovascular complications, accumulating evidence shows a dual burden of diabetic bone disease—reduced bone mineral density, microarchitectural deterioration, and higher fracture risk—and diabetic myopathy, characterized by loss of muscle mass, diminished strength, and metabolic dysfunction. Mechanistically, chronic hyperglycemia, absolute or functional insulin deficiency, and glycemic variability converge to suppress PI3K–AKT–mTOR signaling, activate FoxO-driven atrogenes (atrogin-1, MuRF1), and impair satellite-cell biology; advanced glycation end-products (AGEs) and RAGE signaling stiffen extracellular matrix and promote low-grade inflammation (IL-6, TNF-α/IKK/NF-κB), while oxidative stress and mitochondrial dysfunction further compromise the bone–muscle unit. In vitro, ex vivo, and human studies consistently link these pathways to lower BMD and trabecular/cortical quality, reduced muscle performance, and increased fractures—associations magnified by poor metabolic control and longer disease duration. Prevention prioritizes tight, stable glycemia, daily physical activity with weight-bearing and progressive resistance training, and optimized nutrition (adequate protein, calcium, vitamin D). Treatment is individualized: supervised exercise-based rehabilitation (including neuromuscular and flexibility training) is the cornerstone of skeletal muscle health. This review provides a comprehensive analysis of the mechanisms underlying the impact of type 1 diabetes on musculoskeletal system. It critically appraises evidence from in vitro studies, animal models, and clinical research in children, it also explores the effects of prevention and treatment. Full article

Endothelial dysfunction plays a central role in the pathogenesis of cardiovascular diseases, driven by a complex interplay of oxidative stress, metabolic imbalances, and adipokine dysregulation. Excessive reactive oxygen species reduce nitric oxide bioavailability by impairing endothelial nitric oxide synthase function, leading to vascular inflammation and impaired vasodilation. Adipose tissue-derived hormones such as leptin, adiponectin, and resistin exert opposing effects on vascular homeostasis, influencing inflammation and oxidative stress in obesity and metabolic syndrome. Dyslipidemia, particularly through oxidized LDL, initiates endothelial injury and foam cell formation, accelerating atherosclerosis. Furthermore, hypertension and obesity exacerbate vascular dysfunction by disrupting the balance between vasodilators and vasoconstrictors, enhancing oxidative stress, and altering perivascular adipose tissue function. These interrelated mechanisms contribute to the progression of atherosclerotic cardiovascular disease and diabetic vascular complications. A deeper understanding of these processes is essential for developing targeted interventions to restore endothelial health and reduce cardiometabolic risk. Full article

Frozen shoulder (FS), traditionally regarded as an idiopathic musculoskeletal disorder characterized by pain, stiffness, and capsular fibrosis, is increasingly recognized as the clinical manifestation of systemic endocrine, metabolic, vascular, and immunological dysfunctions. This narrative review reframes FS within a broader neuro–endocrine–immunometabolic model, emphasizing the central role of estrogen deficiency, resistance, and receptor-level disruption, together with their interactions with thyroid dysfunction, endothelial health, and lifestyle-related low-grade inflammation (LGI). Evidence from epidemiological, clinical, and mechanistic studies shows that estrogen signaling failure weakens anti-inflammatory, antifibrotic, and antioxidant defenses, predisposing peri- and postmenopausal women to more severe FS phenotypes. Thyroid dysfunction, particularly hypothyroidism, further contributes to fibrosis and pain sensitization. Endothelial dysfunction—driven by poor diet, advanced glycation end-products (AGEs), and oxidative stress—impairs vascular integrity and promotes local microvascular inflammation. In parallel, lifestyle factors such as sedentarism, circadian misalignment, psychosocial stress, and environmental exposures sustain systemic LGI and hormonal resistance. Together, these interconnected mechanisms suggest that FS is not merely a localized joint pathology but a systemic disorder requiring integrative clinical strategies that combine orthopedic management with endocrine evaluation, metabolic monitoring, dietary interventions, circadian health, and stress regulation. In addition, this review outlines specific clinical implications, highlighting how an integrative, personalized approach that targets hormonal, metabolic, vascular, and lifestyle dimensions may improve pain, function, and long-term prognosis in FS. This paradigm shift underscores the need for future research to focus on stratified patient profiling and interventional trials targeting hormonal, vascular, and lifestyle axes to improve outcomes, particularly in women who remain disproportionately affected by FS. Full article

Renin–angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), have been associated with improved outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess the differential impact of ACEIs versus ARBs on survival and cardiovascular outcomes in individuals with MASLD. Using data from the UK Biobank, we identified 52,143 participants with exclusive use of either an ACEI or ARB. Individuals with viral, autoimmune, cholestatic, or alcohol-related liver disease were excluded. MASLD was defined as fatty liver index ≥ 60 with ≥1 cardiometabolic risk factor. Inverse probability of treatment weighting (IPTW) was used to adjust for confounders. Outcomes included all-cause mortality, cardiovascular events, hepatic decompensation, and hepatocellular carcinoma (HCC), analyzed using Cox proportional hazards models. Among MASLD participants, ARB use was associated with significantly lower all-cause mortality compared to ACEI use (HR, 0.94; 95% CI, 0.90–1.00; p = 0.031) after IPTW adjustment. Cardiovascular risk was also lower with ARBs (HR, 0.92; 95% CI, 0.89–0.96; p < 0.001), particularly in subgroups with BMI ≥ 25 kg/m², no diabetes, and advanced fibrosis. No differences in hepatic decompensation or HCC incidence were observed. Benefits of ARBs were not significant in participants without steatotic liver disease. ARB use was associated with improved survival and reduced cardiovascular events in individuals with MASLD, whereas ACEIs expressed no comparable benefit. These findings suggest that ARBs might be a more effective RAS inhibitor subclass in MASLD and support their preferential use in patients with steatotic liver disease requiring antihypertensive therapy. Full article

We hypothesize that a unified mitochondrial perspective on aging, HIV, and long COVID reveals shared pathogenic mechanisms and specific therapeutic vulnerabilities that are overlooked when these conditions are treated independently. Mitochondrial dysfunction is increasingly recognized as a common factor driving aging, HIV, and long COVID. Shared mechanisms—including oxidative stress, impaired mitophagy and dynamics, mtDNA damage, and metabolic reprogramming—contribute to ongoing energy failure and chronic inflammation. Recent advancements highlight new therapeutic strategies such as mitochondrial transfer, transplantation, and genome-level correction of mtDNA variants, with early preclinical and clinical studies providing proof-of-concept. This review summarizes current evidence on mitochondrial changes across aging and post-viral syndromes, examines emerging organelle-based therapies, and discusses key challenges related to safety, durability, and translation. Full article

Background/Objectives: Mitochondrial damage is implicated in metabolic dysfunction and may contribute to inflammation and insulin resistance, key features of type 2 diabetes. This study examined the relationship among inflammatory markers, mtDNA DAMPs, and insulin sensitivity/resistance, and evaluated their response to three dietary interventions in type 2 diabetes. Methods: Data was pooled from two clinical trials involving adults aged 35 to 75 with type 2 diabetes (n = 39). Participants followed one of three 12-week diet interventions aimed at enhancing glucose metabolism without causing weight loss. The sample was 74% female and 64% African American with a mean age of 55.6 ± 7.7 years, and 92.3% (n = 36) had overweight/obesity. Participants were assigned to either a carbohydrate-restricted, low-fat, or fruit-rich Mediterranean diet. Primary outcomes included insulin resistance (HOMA-IR), insulin sensitivity (Matsuda index), mtDNA DAMPs (ND1, ND6), pro/anti-inflammatory cytokines (IFN-γ, IL-10, IL-6, IL-8, TNF-α), CRP, and cortisol. Associations among mtDNA DAMPs, inflammation, and insulin sensitivity/resistance were examined using regression analysis Results: The carbohydrate-restricted diet led to the greatest improvements in insulin sensitivity (72.7%) and reductions in HOMA-IR (41.3%) (p = 0.03). All diets increased mtDNA DAMPs, with most observed in the fruit-rich Mediterranean diet and low-fat diet groups and the smallest in the carbohydrate-restricted group. Total mtDNA DAMPs were associated with lower insulin sensitivity (Matsuda index: β = –0.77; SE = 0.31; p = 0.02), and ND6 mtDNA DAMP levels were associated with greater insulin resistance (HOMA-IR: β = 0.90; SE = 0.40; p = 0.03) and lower insulin sensitivity (Matsuda index: β = –0.86; SE = 0.33; p = 0.01), independent of BMI and race. Proinflammatory cytokines were associated with increased HOMA-IR (β = 0.45; p = 0.007) and reduced Matsuda index (β = –0.43; p = 0.009) and moderated effects of mtDNA DAMPs on insulin sensitivity/resistance. Conclusions: These findings highlight mtDNA DAMPs in metabolic dysfunction in the context of inflammation. Full article