Search Results (2,561)

Dandruff (DF) is a prevalent, recurrent inflammatory scalp disorder increasingly recognized as a complex state of functional dysbiosis rather than a simple Malassezia overcolonization. The scalp microbiome is predominantly shaped by Malassezia species (M. restricta and M. globosa), Cutibacterium, and Staphylococcus species. Recent multi-omics evidence indicates that DF pathogenesis is driven by the destabilization of microbial interaction networks and strain-level functional heterogeneity, characterized by the disruption of the C. acnes/S. epidermidis balance and the opportunistic expansion of Staphylococcus aureus. Mechanistically, Malassezia utilizes its lipolytic repertoire to hydrolyze host sebum into irritant free fatty acids and peroxides. Concurrently, oxidative metabolites like squalene peroxide (SQOOH) penetrate the stratum corneum to activate the NF-κB and aryl hydrocarbon receptor (AhR) pathways, triggering a pro-inflammatory cascade that overexpresses keratins (K6/16/17) and downregulates filaggrin. This molecular cascade drives abnormal keratinocyte turnover and lipidomic remodeling, establishing a self-perpetuating “metabolism–inflammation–barrier disruption” pathological cycle. This review systematically elucidates the molecular etiology of DF as an ecological disorder driven by a tripartite imbalance among the microbiome, host physiology, and the environmental niche. We propose that next-generation therapeutic paradigms must transcend traditional antifungal eradication, focusing instead on targeted molecular intervention and microecological restoration to recalibrate overall scalp homeostasis. Full article

Adipose tissue expansion in obesity is accompanied by extracellular matrix (ECM) remodeling, regulated by matrix metalloproteinases (MMPs). Visceral adipose tissue (VAT) is metabolically more active than subcutaneous adipose tissue (SAT). However, depot-specific differences in proteolytic activity and protein glycooxidation remain incompletely characterized. In this case–control study, we assessed the activity of six matrix metalloproteinases (MMP-1, -2, -7, -9, -11, and -13) using a fluorescence resonance energy transfer (FRET) assay and quantified advanced glycation- and glycooxidation-related markers in paired VAT, SAT, and plasma samples obtained from 40 patients with obesity and 21 non-obese controls. The activities of all assessed MMPs were greater in patients with obesity than in the control group (p < 0.01 for all MMPs). Direct tissue-compartment comparisons showed that MMP activity and glycooxidation-related markers were most pronounced in VAT, with markedly higher values in obese individuals compared with controls. In VAT of obese individuals, median MMP activity was approximately 50–60% higher compared with controls. Amyloid cross-β-structure, vesperlysine, and pentosidine were significantly elevated in VAT in obesity, whereas plasma levels were markedly lower and showed limited group differences. No significant differences were observed between obese participants with and without metabolic syndrome. Obesity is associated with a depot-specific molecular profile characterized by enhanced proteolytic and glycooxidative activity predominantly within visceral adipose tissue. These findings highlight the importance of tissue-compartment-specific assessment in obesity. Full article

Atrial fibrillation (AF) is the most common tachyarrhythmia worldwide. Accompanying the increasing age of the general population, as well as an increase in underlying cardiovascular disease in the United States, is an explosive rise in the incidence and prevalence of this condition. We reviewed observational cohort studies, systematic reviews, meta-analyses, and randomized controlled trials (RCTs) to determine both underlying risk factors and treatment of AF, with particular focus on comorbid conditions influencing treatment success. Numerous studies have demonstrated a reciprocal relationship between maladaptive cardiac remodeling and AF, with the suggestion that aggressive management of both AF itself and resultant cardiovascular disease can lead to reversal of both conditions. Ultimately, many modifiable risk factors for AF exist, with treatment delays associated with a shift towards these conditions becoming unmodifiable. While a large area of focus for AF research has been on determining the optimal pharmacological strategy (i.e., rate versus rhythm control), results have been mixed, with emerging guidelines now pointing towards a flexible treatment strategy that allows for consideration of patient comorbid conditions, medication ease and affordability, and patient preference. Treatment of AF also includes prevention of thromboembolic events. In recent years, novel strategies for surgical or physical occlusion of the left atrial appendage (LAA) with devices such as the Watchman have arisen. Multiple large RCTs have demonstrated the safety and efficacy of these devices, but consideration must be given towards the patient’s bleeding risk, as short-term courses of blood thinners are still considered the standard of care. Finally, emerging therapies for AF include novel drug combinations, neuromodulation devices, and potentially glucagon-like peptide receptor-1 (GLP-1) agonist medications for reduction in overall metabolic disease. Full article

Umbilical cord mesenchymal stromal cells (UC-MSCs) are a key element of regenerative medicine due to their ability to secrete growth factors that stimulate proliferation and angiogenesis, and modulate the inflammatory response. Despite their widespread use, the influence of the perinatal microenvironment on their biological properties remains poorly understood. The aim of this study was to assess the influence of pH and blood gas parameters in umbilical cord blood on the global transcriptomic profile of UC-MSCs and to analyze the correlation between the metabolic status of the newborn and the expression of key trophic factors: EGF, FGF2, FGFR1, FGFR3, GDNF, HGF, IGF1, NES, NGF, and PGF. Methods: The study was conducted in two stages. In the first phase, transcriptomic screening was performed using Affymetrix HuGene 2.0 ST microarray on cells isolated from three environmental groups defined by cord blood pH: acidic (pH < 7.35), physiological (7.35–7.39), and alkaline (pH ≥ 7.4). In the second phase, the results were validated using qPCR on an expanded study group (N = 50). Gene expression levels (RQ) were related to blood gas parameters (pH, pCO₂, pO₂, cHCO₃) and the presence of clinical features of threatened neonatal asphyxia. Results: Microarray analysis revealed that environmental pH acts as a molecular phenotypic switch. Under low pH conditions (<7.35), a shift in cell profile from proliferative to structural–migratory was observed. Significant overexpression of genes responsible for extracellular matrix (ECM) organization and adhesion (e.g., COMP, DCN, LUM, FMOD) was observed, while pathways related to cell cycle and cell division (↓CDK1, AURKA, TOP2A) were downregulated. qPCR validation confirmed these observations, demonstrating a strong positive correlation between blood pH and the expression of regenerative mediators: FGFR1 (r = 0.28), EGF (r = 0.30), NGF (r = 0.39), and IGF1 (r = 0.30). A negative correlation was also found between carbon dioxide pressure (pCO₂) and the expression of NGF, FGFR1, and EGF. A significant clinical finding was that in newborns diagnosed with threatened asphyxia, EGF, FGFR1, and NGF gene expression was significantly reduced, indicating impaired trophic potential of the cells in response to metabolic stress. Conclusions: These results indicate that cord blood gas parameters are critical regulators of the genetic activity of UC-MSCs. Metabolic and respiratory acidosis not only inhibit the cells’ proliferative potential but also force them into a matrix remodeling mode, permanently modifying their transcriptomic profile. This suggests that the neonatal acid–base status may serve as an objective indicator of the “biological quality” of isolated stromal cells, which has significant implications for their future applications in cell therapies. Full article

Background: The relationship between physical exercise and human longevity constitutes one of the most consequential intersections in contemporary preventive medicine. Although international guidelines recommend 150 min of moderate-intensity exercise weekly, growing evidence suggests that the architecture of optimal exercise is far more complex, encompassing dose, modality, timing across the lifespan, and the paradox risks imposed by extreme endurance. Methods: We included in this narrative review landmark cohort studies, randomized controlled trials, meta-analyses, and expert physiological frameworks published in high-impact cardiovascular, sports medicine, and longevity journals from 1966 to 2024. Results: Cardiorespiratory fitness (CRF), indexed by maximal oxygen uptake (VO₂ max), demonstrates the strongest and most linear dose–response relationship with all-cause mortality identified in preventive medicine, with every 1 metabolic equivalent of task (MET) increment associated with a 12–15% reduction in mortality risk. The optimal dose of vigorous-intensity exercise follows a J-shaped dose–response curve: 3–5 sessions per week generating 1–2.4 h of vigorous activity is associated with the lowest all-cause mortality risk in large prospective cohorts, whereas chronic extreme endurance exercise incurs measurable atrial remodeling, patchy myocardial fibrosis, and a 5.3-fold increase in the risk of atrial fibrillation. The importance of exercise types shifts profoundly across the lifespan, transitioning from aerobic capacity effort in the third decade to resistance training in the seventh decade and neuromuscular stability in the eighth. Based on our interpretation of the available evidence, we propose a structured, personalized four-step exercise pathway integrating CRF assessment, lifespan-adapted prescription, lifestyle co-interventions, and periodic reassessment. Conclusions: Among currently available lifestyle interventions, regular exercise is consistently associated with some of the largest and most reproducible reductions in all-cause and cardiovascular mortality observed in prospective cohort data, while remaining accessible and cost-effective. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global metabolic disorder. As a non-pharmacological intervention, the effects of high-intensity interval training (HIIT) on MASLD and its molecular mechanisms remain poorly understood. This study aimed to investigate whether HIIT could ameliorate high-fat diet (HFD)-induced liver fibrosis by recalibrating the intrahepatic lactate metabolic axis. Methods: An HFD-induced murine MASLD model combined with HIIT intervention was utilized to evaluate the therapeutic efficacy and underlying mechanisms. Hepatosomatic indices, histological architecture and fibrosis severity were examined. Lactate concentrations within the systemic circulation and hepatic parenchyma, alongside comprehensive lipid profiles, were measured. The expressions of genes and proteins involved in hepatic lactate metabolism were delineated via qPCR and Western blotting. Results: The 8-week HIIT intervention effectively improved liver lipid accumulation, hepatocellular injury, and oxidative stress caused by a high-fat diet. Fibrotic expansion and suppressed hepatic stellate cell activation were restricted markedly, as evidenced by the downregulation of collagen type I alpha 1 chain and alpha-smooth muscle actin(α-SMA). HIIT reversed the HFD-induced accumulation of lactate in both systemic circulation and liver tissues, which was found to positively correlate with hepatic α-SMA. Mechanistically, HIIT regulated the expression of the lactate metabolism-related proteins lactate dehydrogenase A and monocarboxylate transporter 1, while selectively enhancing the expression of the gluconeogenic enzymes. Conclusions: Our findings indicate that HIIT effectively ameliorated MASLD and associated hepatic fibrosis by remodeling the hepatic lactate metabolic axis, specifically through the suppression of lactate production and the enhancement of its clearance. These results indicate that targeting lactate homeostasis might be a promising therapeutic strategy for MASLD. Full article

L-citrulline is a non-protein amino acid with critical roles in perinatal and neonatal physiology through the intestinal–renal arginine–citrulline axis and nitric oxide (NO) production. During pregnancy, L-citrulline supports placental angiogenesis, vascular adaptation, and fetal growth through augmentation of arginine availability and endothelial NO production. In neonates, particularly preterm infants, developmental immaturity of citrulline and arginine synthesis contributes to hypoargininemia and may increase susceptibility to necrotizing enterocolitis, bronchopulmonary dysplasia with pulmonary hypertension, sepsis, and impaired intestinal function. Although L-citrulline has emerged as a promising modulator of NO bioavailability, prior reviews have largely focused on either adult cardiovascular disease or isolated neonatal applications, with limited integration of its mechanistic and translational relevance across the perinatal and neonatal continuum. Collectively, current evidence supports L-citrulline as a promising translational target in maternal–fetal and neonatal medicine because of its central role in vascular, inflammatory, and metabolic regulation. However, adequately powered clinical trials are needed to define optimal dosing, timing, patient selection, and long-term outcomes before routine clinical implementation can be recommended. This review provides a comprehensive evaluation of L-citrulline metabolism and its therapeutic potential from pregnancy through neonatal life, with emphasis on the intestinal–renal arginine–citrulline axis, endothelial function, and NO-mediated vascular regulation. We specifically examine the role of citrulline in key pathophysiologic mechanisms underlying maternal and neonatal disease, including endothelial dysfunction, impaired NO bioavailability, inflammation, oxidative stress, and abnormal placental vascular remodeling. Full article

Melittin, the principal active peptide of bee venom, exhibits potent cytotoxicity against cancer cells. However, its lipid-level mechanisms remain unclear. Here, we present the first untargeted lipidomic dataset that reveals melittin-induced lipid remodeling in triple-negative breast cancer (TNBC) cells (MDA-MB-231). Cells were exposed to 4 μg/mL of melittin for 15 min, and lipid extracts were analyzed by employing high-resolution LC–MS/MS in both ion modes. Data were processed with XCMS and metaX for peak extraction, normalization, and metabolite annotation, followed by multivariate and KEGG pathway analyses. The results highlight significant alterations in phospholipids, sphingolipids, and acylglycerols, indicative of melittin-mediated disruption of membrane integrity and lipid metabolism. All raw and processed data are publicly accessible at NGDC (accession number PRJCA048975). This dataset not only serves as a comprehensive resource for investigating lipid-based mechanisms underlying melittin’s anticancer effects but also supports its potential in lipid-targeted therapeutic strategies for TNBC. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder traditionally defined by dopaminergic neuronal loss and Lewy body pathology; however, increasing evidence indicates that metabolic dysfunction contributes to both motor and non-motor manifestations of disease. While metabolomics studies in PD have largely focused on peripheral biofluids or subcortical brain regions, metabolic remodeling within cortical regions critical for cognition remains poorly characterized. Here, we applied LC-MS/MS-based untargeted metabolomics to post-mortem frontal cortex tissue from PD and neurologically normal control donors, with statistical models adjusted for age, sex, and post-mortem interval. A total of 893 metabolites were quantified, of which 234 exhibited significant differential abundance following false discovery rate correction. Pathway enrichment and network-based integration revealed coordinated metabolic remodeling characterized by predicted inhibition of β-alanine metabolism and pantothenate-dependent coenzyme A biosynthesis alongside activation of amino acid, vitamin B-dependent, cofactor-related, redox-associated, oxidative stress, and inflammatory pathways. Recurrent alterations in pantothenic acid, β-alanine-related intermediates, arginine- and histidine-derived metabolites, lumichrome, and vitamin B₆-associated species may reflect cortical metabolic perturbations associated with mitochondrial bioenergetic vulnerability and oxidative stress. Together, these findings indicate selective metabolic vulnerability in the PD frontal cortex rather than diffuse metabolic collapse. Full article

Background/Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with epithelial remodeling, impaired mucociliary clearance, and altered nitric oxide (NO) metabolism. However, cell type-specific mechanisms underlying epithelial NO signaling remain poorly understood. This study investigated NO-related signaling in differentiated human sinonasal epithelial cells. Methods: Human sinonasal tissues were obtained from patients with CRSwNP (n = 20) and control subjects (n = 20). Air–liquid interface (ALI) cultures were established from donor-derived epithelial cells. Ciliated and non-ciliated cells were identified by immunostaining for acetylated α-tubulin and BCAM. Expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) was analyzed by quantitative RT-PCR. Intracellular NO-related fluorescence signals were evaluated using DAF-FM fluorescence imaging. Results: CRSwNP tissues exhibited significantly increased iNOS expression and elevated iNOS/eNOS ratios, whereas eNOS expression did not differ significantly from that in controls. ALI cultures reproduced differentiated sinonasal epithelium containing both ciliated and non-ciliated cell populations. DAF-FM fluorescence signals were significantly higher in ciliated cells than in non-ciliated cells (80.3 ± 25.3 vs. 49.3 ± 21.1). Non-selective NOS inhibition markedly reduced fluorescence signals in both cell types, whereas selective iNOS inhibition reduced but did not abolish signals in ciliated cells. Conclusions: NO-related signaling appears to differ among epithelial cell subtypes. Persistence of fluorescence signals after selective iNOS inhibition suggests a contribution of constitutive NOS activity in ciliated cells, whereas non-ciliated cells appear to rely more heavily on iNOS-dependent pathways. These findings support the hypothesis that altered epithelial NO signaling contributes to epithelial dysfunction and impaired mucociliary homeostasis in CRSwNP. Full article

Obesity is a major risk factor for colorectal cancer (CRC) and is increasingly recognized as a contributor to cancer-related cognitive impairment; however, the mechanistic pathways linking metabolic dysfunction, tumor progression, and brain dysfunction remain incompletely defined. Emerging evidence indicates that obesity-induced gut microbial dysbiosis and intestinal barrier disruption may serve as a biologically plausible mechanism connecting these processes via the gut–brain axis although direct clinical causality remains to be firmly established. In obesity, alterations in gut microbiota composition characterized by depletion of barrier-protective taxa and enrichment of pro-inflammatory and genotoxic pathobionts compromise epithelial tight-junction integrity and promote metabolic endotoxemia. The translocation of microbial products, including lipopolysaccharide, sustains chronic systemic inflammation, accelerates CRC progression, and remodels the tumor microenvironment. Notably, these peripheral inflammatory signals extend beyond the intestine and tumor, disrupting blood–brain barrier integrity, activating microglia and astrocytes, and impairing synaptic plasticity within hippocampal and frontal networks. Clinically, these processes manifest as cancer-related cognitive impairment (CRCI), with predominant deficits in attention, processing speed, and working memory, which are often detectable around the time of diagnosis and independent of chemotherapy exposure. This review synthesizes in vivo, in vitro, and human evidence into a proposed theoretical “two-barrier failure” model of obesity-associated CRC and cognitive dysfunction. In addition to mechanistic synthesis, we discuss barrier-centered therapeutic strategies, including targeted probiotics, postbiotics, SCFA supplementation, obesity management through dietary and weight-loss interventions, and potential pharmacological approaches to epithelial and neurovascular barrier protection. We also outline testable clinical trial designs for evaluating these interventions in obesity-associated CRC. Full article

Background/Objectives: Whether anesthetic maintenance influences tumor biology in cervical cancer remains unsettled. We examined whether plasma extracellular vesicles (EVs) collected during sevoflurane or propofol anesthesia differentially affect HeLa cell behavior and explored lipidomic alterations associated with the biologically active EV condition. Methods: In a single-center prospective observational cohort, paired plasma samples were collected before anesthesia induction and before wound closure from 53 patients with stage II cervical cancer undergoing radical surgery under sevoflurane (n = 28) or propofol (n = 25) anesthesia. EV preparations were characterized by transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting for EV markers. Their effects on HeLa cell proliferation, invasion, and wound closure, as well as HUVEC tube formation, were examined in vitro. EV miRNA profiles were analyzed by small-RNA sequencing. Lipidomic profiling by LC-MS and immunoblot analysis of EGFR/PKCα/NF-κB signaling were performed in recipient HeLa cells exposed to sevoflurane-associated EVs. Results: EVs collected after sevoflurane anesthesia increased HeLa cell proliferation, invasion, and wound closure and enhanced endothelial branching in HUVEC tube-formation assays, whereas post-propofol EVs showed no comparable phenotype. Small-RNA sequencing identified distinct anesthesia-associated EV miRNA changes, with the sevoflurane-related signature enriched in glycerolipid metabolism, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, phosphatidylinositol signaling, and inositol phosphate metabolism. In HeLa cells treated with post-sevoflurane EVs, lipidomic analysis showed clear separation from pre-sevoflurane EV-treated cells and identified increased diacylglycerol (DG) species, including DG (16:1/18:2), DG (16:0/16:1), DG (18:2/18:2), DG (18:2/20:4), and DG (16:0/18:2). These changes were accompanied by higher p-EGFR, PKCα, and p-NF-κB p65 levels. Several DG species correlated positively with proliferation and invasion readouts and inversely with residual wound area. Conclusions: Plasma EVs collected after sevoflurane anesthesia were associated with a more aggressive phenotype in recipient cervical cancer cells and with lipid remodeling characterized by DG accumulation and altered EGFR/PKCα/NF-κB signaling. The data support an exploratory mechanistic model linking sevoflurane-associated EV cargo to metabolic reprogramming in cervical cancer cells. Full article

Tumor metastasis constitutes a frequent contributor to high mortality rates, with EMT intimately implicated in this disseminative process. Accumulating evidence in recent years indicates that neoplastic cells undergoing EMT frequently exhibit concurrent metabolic reprogramming. Multiple modalities—including glycolysis, mitochondrial oxidative phosphorylation, lipid metabolism, as well as amino acid metabolism—cooperatively supply energy, facilitate membrane remodeling, and sustain redox homeostasis. Specifically, glycolytic flux, oxidative phosphorylation, lipid turnover, and amino acid catabolism/anabolism function in a concerted manner to meet the bioenergetic demands, support biogenesis of cellular membranes, and preserve the intracellular redox equilibrium during phenotypic conversion. Notably, intermediate metabolites can in turn modulate the trajectory of EMT through signal transduction cascades or epigenetic modifications. This review systematically delineates the bidirectional regulatory circuitry interconnecting EMT and metabolic reprogramming; furthermore, it examines the implications of this crosstalk for neoplastic disease progression. Finally, therapeutic strategies targeting the nexus of metabolic reprogramming and EMT are summarized. Full article

Carbonyl stress, chronic inflammation, and progressive tissue injury accompany type 2 diabetes mellitus (T2DM) and obesity. Yet, the molecular systems that connect these processes with cardiac, vascular and neuronal complications are incompletely defined. This review examines the AGE–RAGE–DIAPH1 axis as a mechanistic link between metabolic dysfunction and diabetic myocardial and neuronal injury, with emphasis on vascular and myocardial remodeling and emerging implications for autonomic neuronal vulnerability. We summarize current evidence on the formation and accumulation of advanced glycation end-products and other RAGE ligands in metabolic disease, DIAPH1’s structural and signaling role as an intracellular effector of RAGE, and the cellular consequences of pathway activation in vascular, neural, and cardiac tissues. Across experimental models, this signaling axis promotes oxidative stress and inflammatory activation, leading to endothelial dysfunction and barrier failure. Subsequent fibrotic remodeling provides a biologically plausible route through which metabolic stress may be translated into persistent organ injury. In the heart, these mechanisms are linked to coronary microvascular dysfunction, altered cardiomyocyte phenotype, calcium handling abnormalities, and myocardial fibrosis. In the autonomic nervous system, limited but emerging data connect RAGE activation to oxidative injury and mitochondrial dysfunction, abnormal neuronal excitability, and structural vulnerability. Direct evidence linking DIAPH1 to autonomic neurons is lacking. We also review biomarker candidates related to this pathway, including circulating AGEs and soluble RAGE isoforms, skin AGE measurements, imaging markers of myocardial remodeling, and autonomic functional measures. Finally, we discuss pharmacological and natural compounds that target AGE formation, ligand accumulation, RAGE signaling, or intracellular protein interactions linked to this axis. Overall, the available evidence supports the AGE–RAGE–DIAPH1 axis as a credible mechanistic concept and a potentially informative translational hypothesis in T2DM. However, the AGE–RAGE component is supported more strongly than DIAPH1-specific involvement in human diabetic myocardial disorder or cardiovascular autonomic neuropathy. The value of DIAPH1 as a biomarker or therapeutic target in these neurocardiac complications remains to be established. Full article

Cardiovascular remodeling, encompassing vascular remodeling, myocardial remodeling, and fibrosis-associated tissue remodeling, underlies atherosclerosis, pulmonary hypertension, myocardial infarction, myocardial fibrosis, and other cardiovascular diseases. Its regulation has traditionally been studied through transcriptional, inflammatory, metabolic, mechanical, and intercellular signaling mechanisms. Recent advances in epitranscriptomics have identified N6-methyladenosine (m⁶A) RNA methylation as an additional post-transcriptional layer that interacts with microRNA (miRNA) pathways during cardiovascular disease progression. This review summarizes current evidence for m⁶A-miRNA crosstalk in cardiovascular remodeling, focusing on epitranscriptomic checkpoints that regulate miRNA fate, feedback-like regulatory circuits involving miRNAs and the m⁶A machinery, and cell-type-specific programs across endothelial cells, vascular smooth muscle cells, fibroblasts, and cardiomyocytes. We further discuss emerging analytical technologies and translational implications of this regulatory axis. Future studies should clarify causal mechanisms, cell-type and disease-stage specificity, and translational feasibility. Together, this multilayered framework provides a systems-level perspective on how RNA regulatory networks may shape pathological remodeling in cardiovascular disease. Full article