Search Results (11,153)

Background: Dry Eye Disease (DED) is a multifactorial disorder characterized by tear film instability and ocular surface inflammation. Murine models based on environmental stress are widely used to mimic evaporative DED, although many focus on limited disease features. This study aimed to provide an integrated characterization of ocular surface alterations induced by chronic desiccating stress. Methods: Adult mice were housed in a Controlled-Environmental Chamber (CEC) with low humidity and increased airflow for up to 21 days and sacrificed after 14 or 21 days. Corneal damage was assessed by fluorescein staining. Conjunctival histology was evaluated for epithelial morphology, goblet cell (GC) size, and mucin composition. Complement fractions C3 and C5a were assessed by immunohistochemistry. Expression of inflammatory markers (Major Histocompatibility Complex, Class II, DR, HLA-DR; interleukin-1β, IL-1β; tumor necrosis factor-α, TNF-α) was quantified by Real-Time PCR (RT-PCR) in corneal and conjunctival epithelium. Results: Fluorescein staining revealed progressive corneal epithelial damage over time. Histological analysis demonstrated conjunctival epithelial alterations characterized by a significant reduction in GC size and in neutral mucin-positive GCs, consistent with mucin remodeling of the ocular surface epithelium. Increased epithelial deposition of complement fractions C3 and C5a was observed, while molecular analysis confirmed upregulation of inflammatory markers, including HLA-DR, IL-1β, and TNF-α. Collectively, these findings indicate that the model captures key pathophysiological components of DED. Conclusions: The CEC model reproduces major features of evaporative DED, including epithelial damage, GC remodeling, immune activation, and inflammation. As a non-invasive desiccating stress model, it represents a relevant experimental platform for studying ocular surface inflammation and for preclinical evaluation of therapeutic strategies. Full article

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease characterized by progressive cartilage degeneration and subchondral bone remodeling, resulting in chronic pain and functional impairment. Although conservative treatments such as physical therapy and non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used, their effectiveness is limited due to the poorly understood pathophysiology of TMJOA. Identifying reliable molecular biomarkers is essential to improving early diagnosis and guiding therapeutic development. This proof-of-concept study aims to identify candidate salivary biomarkers for TMJOA using an integrative approach combining clinical validation with in silico analysis. RNA sequencing was performed on saliva samples from TMJOA patients and healthy controls. In parallel, publicly available transcriptomic dataset GSE205389 was analyzed to identify differentially expressed genes (DEGs). DEGs were validated using qRT-PCR. Gene set enrichment analysis (GSEA) and Metascape were used to explore biological pathways associated with TMJOA. Integration of clinical and in silico RNA sequencing datasets identified 2758 and 3548 DEGs, respectively, with 743 overlapping genes. Pathway enrichment analyses highlighted immune-related, metabolic and osteoclast-related pathways. Four genes, CRIP1, PPA1 and TARS1 (statistically significant) and GCLC (non-significant trend), were validated by qRT-PCR in the clinical saliva samples, confirming elevated expression in TMJOA patients. Validation of the in silico dataset showed an upregulation of PTK2B, ABL1, TNF and IL-1B, supporting their relevance as salivary biomarkers in TMJOA. This exploratory study identifies four candidate salivary genes, CRIP1, PPA1, TARS1 and GCLC, as candidate salivary biomarkers for TMJOA, offering insights into disease mechanisms. Larger studies are needed to validate these findings and assess their clinical utility. Full article

Background: Polysaccharide-based dynamic hydrogels are promising for wound management due to their biocompatibility, injectability, and tunable biofunctionality. The integration of therapeutic gasotransmitter donors offers a strategy to modulate the wound microenvironment. Objectives: This study aimed to develop an injectable, self-healing carbohydrate hydrogel capable of sustained hydrogen sulfide (H₂S) release for burn wound therapy, and to evaluate its physicochemical properties, in vivo efficacy, and mechanism of action. Methods: A dynamic hydrogel (ACMOD) was fabricated via Schiff-base crosslinking between oxidized dextran (OD) and carboxymethyl chitosan (CMCS), incorporating the H₂S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH). Rheological and recovery tests characterized its mechanical and self-healing properties. Efficacy and mechanisms were assessed in a rat full-thickness burn model, analyzing wound closure, histology, oxidative stress, macrophage polarization, angiogenesis, and collagen deposition. Results: ACMOD exhibited shear-thinning, rapid self-healing, and strong tissue adherence. Sustained H₂S release from ACMOD significantly accelerated wound closure and improved tissue regeneration compared to controls. Mechanistically, H₂S attenuated oxidative stress, promoted a pro-regenerative M2 macrophage phenotype, enhanced angiogenesis via VEGF upregulation, and fostered organized collagen deposition and extracellular matrix remodeling. Conclusions: This work demonstrates a versatile, carbohydrate-based dynamic hydrogel platform that synergizes polymer network dynamics with bioactive H₂S delivery to effectively promote burn wound healing. The findings underscore the potential of polysaccharide hydrogels with integrated gasotransmitter release for regenerative therapy and biomaterials applications. Full article

The loss of estrogen following menopause is associated with a marked increase in cardiometabolic risk, accompanied by adverse changes in lipid metabolism, insulin sensitivity, vascular function, and systemic inflammatory tone. Emerging evidence suggests that estrogen signaling interacts with chromatin regulatory mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, across multiple metabolic tissues. In this review, we examine current evidence linking estrogen receptor signaling to epigenetic modulation in cardiovascular, hepatic, adipose, vascular, and immune systems. We propose that epigenetic remodeling represents a plausible and testable mechanistic framework connecting estrogen depletion to cardiometabolic disease progression, while acknowledging that much of the mechanistic evidence derives from preclinical and in vitro systems and that direct longitudinal validation in human cardiovascular tissues remains limited. We further explore how this framework may contribute to understanding the “estrogen paradox” and the heterogeneous outcomes of hormone replacement therapy (HRT), particularly within the context of the timing hypothesis. Finally, we evaluate pharmacologic and lifestyle interventions, including structured exercise, dietary modulation, and cardiometabolic therapeutics, through the lens of potential epigenetic influence. Clarifying tissue-specific and immune-integrated chromatin responses to estrogen loss will be essential for advancing precision strategies aimed at improving cardiometabolic health in postmenopausal women. Full article

Gut microbiota dysbiosis is implicated in metabolic disorders, yet taxonomic and functional alterations in canine diabetes remain incompletely defined. Here, we performed shotgun metagenomic sequencing of fecal samples from 38 diabetic dogs and 37 healthy controls under controlled conditions (no recent antibiotic/probiotic exposure and stable commercial diets). Alpha-diversity indices did not differ between groups, whereas beta-diversity revealed significant separation of community structure at both genus and species levels (p < 0.05). Linear discriminant analysis effect size (LEfSe) identified enrichment of opportunistic-associated taxa in diabetic dogs, including Enterobacterales/Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae, Salmonella enterica) and Enterococcus faecalis. In contrast, healthy dogs were enriched for putatively beneficial taxa linked to bile acid and short-chain fatty acid (SCFA) metabolism, including Turicibacter spp. and Romboutsia spp. Functional profiling showed higher abundances of pathways related to carbohydrate/energy metabolism, membrane transport, and virulence/colonization in diabetic dogs; 17 KEGG level-3 pathways and 320 KOs differed at FDR < 0.05, with enriched modules including bacterial secretion systems, lipopolysaccharide biosynthesis, chemotaxis/flagellar assembly, and biofilm formation. Collectively, canine diabetes is associated with a remodeled gut microbiome characterized by expansion of opportunistic pathogens and elevated virulence and metabolic potential, supporting exploration of microbiota-targeted strategies as a complement to conventional management. Full article

Peripheral nerve injuries pose a significant clinical challenge due to the limited self-repair capacity and the complexity of neural tissue architecture. Tissue engineering strategies applied to the peripheral nerve system aim to restore functional nerve constructs by combining scaffolds, cells, and biochemical cues to recreate the native microenvironment. This work aimed to propose the electrical conductivity as a functional readout of structural and biological remodeling in engineered peripheral nerve scaffolds, along with functional and molecular evaluations. To this end, bioimpedance measurements were combined with equivalent circuit modeling to track state-dependent changes across different levels of tissue organization. Murine sciatic nerves were decellularized and recellularized with neural populations to generate engineered constructs, and their electrical properties were assessed using broadband bioimpedance spectroscopy. Distinct impedance profiles were observed across control, decellularized, and recellularized samples, reflecting structural and functional changes associated with cell removal and repopulation. Furthermore, a multilayer series RC circuit model was implemented to accurately reproduce the measured spectra, enabling the extraction of layer-specific electrical parameters. Analysis of these parameters revealed that decellularization reduces compartmental resistances and increases inter-layer coupling, whereas recellularization restores outer-layer resistances and reduces coupling, consistent with functional tissue organization. Overall, the results demonstrate that bioimpedance provides a readout of the scaffold biological state and cellular integration, and that equivalent circuit modeling offers a quantitative framework to link structural remodeling to electrical function in engineered peripheral nerve tissues. Full article

Background/Objectives: Lung cancer remains a major global health burden, largely driven by cigarette use. Although electronic cigarettes (e-cigarettes) are viewed as safer alternatives due to their reduced chemical load, growing evidence shows their vapor can disrupt cellular transcriptomes, including long noncoding RNAs (lncRNAs). In this study, we examined the regulation and function of vape-associated lncRNA transcript 1 (VALT1), a novel transcript upregulated in the oral transcriptomes of e-cigarette users and similarly elevated in non-small-cell lung cancer (NSCLC) tumors. Methods: Publicly available RNA-seq datasets were analyzed, and VALT1 was identified as an e-cigarette-responsive lncRNA. Its dose-dependent induction by e-cigarette smoke extract (eCSE) and cytoplasmic localization were confirmed via RT-qPCR. Its effects on cancer-associated phenotypes including proliferation, ROS detoxification, resistance to apoptosis, migration, cytoskeletal disorganization, and nuclear remodeling were assessed through overexpression and siRNA-mediated knockdown in A549 and BEAS-2B cells. Results: Acute eCSE exposure induced a biphasic, dose-dependent increase in VALT1 expression, accompanied by enhanced proliferation, ROS detoxification, apoptosis resistance, migration, cytoskeletal disorganization, and nuclear remodeling in A549 cells. VALT1 overexpression reproduced these phenotypes in both cell lines without eCSE treatment, whereas knockdown attenuated them. VALT1 promoted survival under cytotoxic stress in A549 but not BEAS-2B cells. Conclusions: These findings support an active role for VALT1 as an e-cigarette vapor-upregulated transcript that contributes to its phenotypic readout and enhances cellular survival under extracellular chemical stress—thereby aggravating tumorigenic phenotypes even in the absence of mutations that contribute to malignant transformation. Full article

The mammalian heart rapidly loses regenerative capacity after birth and responds to myocardial infarction (MI) with scar formation and development of interstitial fibrosis. Cardiac fibroblasts orchestrate extracellular matrix (ECM) remodeling and cell–cell communication during development and injury; however, how fibroblast heterogeneity and fibroblast communication networks differ between regenerative neonatal and non-regenerative adult hearts remains incompletely defined. We performed scRNA-seq analysis on metabolically active CD45⁻/CD31⁻ nonmyocyte cells from the left ventricles of normal neonatal (P3) and adult (P84) mice to probe heterogeneity in a cardiac fibroblast-enriched population. We identified five transcriptionally distinct cardiac fibroblast subclusters (CF0-CF4) demonstrating different distributions across ages, including an adult-enriched immune/complement-associated program (CF0); an ECM structural-associated program present across ages (CF1); and neonatal-enriched contractile/ECM-remodeling (CF2), Wnt-modulating matrix-regulatory (CF3), and proliferative (CF4) programs. Matrisome category scoring revealed age-dependent divergence in ECM programs: neonatal fibroblasts showed higher enrichment of core matrisome components (particularly collagens and proteoglycans), whereas adult fibroblasts were relatively enriched for matrisome-associated categories, including ECM regulators and secreted factors. Ligand–receptor inference using CellChat demonstrated a broad reduction in fibroblast–fibroblast interaction strength and information flow in adult networks, and adult-enriched signaling was dominated by immune/chemotactic pathways. Finally, projection of subcluster marker programs onto an independent bulk RNA-seq dataset of cardiac fibroblasts 3 days after MI revealed that adult injury partially recapitulates neonatal-associated programs, including activation of the contractile/ECM-remodeling program (CF2) and robust induction of a cell-cycle-associated program (CF4), but lacks an additional neonatal-specific injury program associated with the Wnt-modulating subset (CF3), which was weakly induced or absent in adults. This cardiac fibroblast-enriched single-cell study defines age-dependent fibroblast states, ECM specialization, and communication network architecture that distinguish regenerative neonatal from non-regenerative adult hearts. It also provides a framework to interpret divergent stromal responses after MI and to prioritize fibroblast programs for regenerative and anti-fibrotic strategies. Full article

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of heart failure and are now established as disease-modifying therapies across the spectrum of left ventricular ejection fraction. More recently, these agents have been evaluated in the early post-acute myocardial infarction (AMI) setting, raising interest in their potential role beyond heart failure prevention. Evidence from post-AMI randomized trials and contemporary meta-analyses consistently shows neutral effects on ischemic coronary outcomes, despite favorable effects on heart failure-related endpoints, ventricular remodeling, and cardiometabolic parameters. At the same time, data from experimental and translational research provide a biological framework in which SGLT2i exert anti-atherogenic effects through multiple complementary mechanisms, including improvement of cardiometabolic risk factors, attenuation of vascular and systemic inflammation, modulation of endothelial function, regulation of vascular smooth muscle cell behavior, macrophage inflammatory polarization, inhibition of inflammasome signaling, and modulation of the perivascular adipose tissue–vascular interface. Taken together, the available evidence highlights a dissociation between clinical trial outcomes in the early post-AMI phase and the underlying vascular biology associated with SGLT2 inhibition. While the dominant early clinical effects of SGLT2i appear to relate to hemodynamic and heart failure-preventive mechanisms, their potential impact on atherosclerotic disease may be more gradual and context-dependent. This review summarizes current clinical and mechanistic evidence supporting this interpretation and discusses the implications for understanding the role of SGLT2i in patients after AMI. Full article

Lung cancer progression is regulated by multiple factors, including ferroptosis and gut microbiota-mediated butyrate metabolism. This study investigates the anti-tumor effects of ginsenoside Rh4 on lung cancer cells via ferroptosis mechanisms in vitro and in vivo. In vitro, ginsenoside Rh4 inhibited the proliferation of Lewis lung carcinoma (LLC) and A549 cells and triggered ferroptosis, effects that were suppressed by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). In vivo, tumor-bearing mouse models were established and treated with 100 mg/kg ginsenoside Rh4 for 21 days. Tumor growth, ferroptosis markers, gut microbiota, and butyrate were analyzed, with in vitro validation of butyrate’s pathway effects. Ginsenoside Rh4 induced ferroptosis in LLC cells both in vitro and in vivo, inhibiting tumor growth. It promoted ferroptosis by disrupting iron homeostasis through elevated Fe²⁺ and transferrin receptor (TFRC), and impaired antioxidant defense via depletion of glutathione (GSH) and reduction in ferritin heavy chain 1 (FTH1), solute carrier family 40 member 1 (SLC40A1), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). Additionally, ginsenoside Rh4 enhanced lipid peroxidation, indicated by increased lipid peroxides (LPO) and malondialdehyde (MDA). In vivo, it suppressed the KEAP1/NRF2/HO-1 pathway, reducing antioxidant enzyme activity. Gut microbiota modulation and butyrate production further amplified ferroptosis by activating transcription factor 3 (ATF3)-mediated GPX4 suppression. Ginsenoside Rh4 induces ferroptosis by inhibiting the KEAP1/NRF2/HO-1 pathway and remodeling the gut microbiota to increase butyrate levels, which synergistically enhance tumor cell ferroptosis sensitivity through ATF3 activation and suppression of GPX4. Full article

Background/Objectives: Dietary intake of fruits and vegetables (FVs) has been inversely associated with a lower risk of ulcerative colitis. Using a pig model, we evaluated the effect of FV supplementation on dextran sulfate sodium (DSS)-induced colitis. Methods: Six-week-old pigs were fed a grower diet (negative control), grower diet + 4% DSS (positive control), half-FV diet + DSS, or full-FV diet + DSS. FV levels matched half or full daily recommendations from the Dietary Guidelines for Americans (DGA). Clinical signs were monitored; proximal colon contents (PCs) and mucosa (PCM) were analyzed for metagenome, transcriptome and histopathology. Results: Full-FV pigs showed no diarrhea, less fecal occult blood (FOB), crypt hyperplasia, but no changes in gene expression or microbiome diversity (p < 0.05). Half-FV pigs had increased FOB, differentially expressed genes (DEGs) linked to tissue remodeling, crypt/goblet cell hyperplasia and two cases of diarrhea (p < 0.05). DSS controls showed reduced immune-related DEGs, altered microbiome, PCM erosion, FOB, and persistent diarrhea in one pig (p < 0.05). Conclusions: A three-week full-FV diet conferred protection against DSS-induced colitis, with a dose-dependent protection of intestinal tissue and gut metagenome under inflammatory challenge. Full article

Background: Non-surgical procedures utilizing microcurrent radiofrequency (RF) represent a non-invasive option for patients experiencing skin laxity and loss of firmness due to aging, hormonal changes, or weight fluctuations. Such treatments benefit individuals seeking both preventive measures to delay visible aging and corrective approaches to improve existing skin laxity without invasive surgery. The Plasma IQ medical device generates microcurrent RF energy that produces controlled heating, leading to targeted tissue ablation and subsequent remodelling. This study aimed to evaluate the clinical efficacy of Plasma IQ in the treatment of skin laxity. Materials and Methods: Thirty patients presenting with facial skin laxity and photodamage underwent treatment with the Plasma IQ device. Clinical outcomes were assessed prior to the procedure and at 7, 21 and 90 days post-treatment. Results: RF treatment produced a measurable improvement in skin elasticity (+22.51%). The distance between the upper eyelid margin and the beginning of the eyelid fold increased by 2.01 mm (+46.94%) at day 21 and by 2.11 mm (+49.11%) at day 90. Conclusions: Microcurrent RF delivered by the Plasma IQ device is an effective non-invasive method for periocular skin rejuvenation. The treatment improves skin elasticity, reduces wrinkles around the eyes, and increases the visible distance between the upper eyelid margin and fold, thereby enhancing upper eyelid definition. Full article

Background: Myocardial infarction (MI) is the leading cause of morbidity and mortality globally. A major pathological progression of MI is the excess generation of reactive oxygen species (ROS), which results in oxidative stress and damage to the ischemic heart. Because damage to the myocardium is irreversible, the development of new therapeutic agents that can decrease the degree of ischemic damage following MI is crucial. The traditional Chinese medicine formulation, Qishen Yiqi dropping pills (QSYQ), has been clinically used in the treatment of various cardiovascular diseases; however, the precise mechanisms underlying its therapeutic effects remain unelucidated. Methods: In this study, we established murine models of MI via coronary artery ligation to investigate the protective effects and mechanisms of QSYQ following MI. Results: The administration of QSYQ significantly improved cardiac function, reduced infarct size, and attenuated ventricular remodeling in mice that underwent MI. Moreover, MI-induced oxidative stress and downregulated levels of antioxidant enzymes were prevented in mice administered QSYQ via upregulating the SIRT3/FOXO3a signaling pathway. Importantly, pretreatment with a selective SIRT3 inhibitor 3-TYP abolished the cardioprotective effects of QSYQ. Conclusions: Our findings elucidate the role and mechanism of QSYQ in protecting against oxidative damage and restoring redox homeostasis following myocardial infarction. This study provides support for the therapeutic potential of QSYQ in the clinical treatment of myocardial ischemic diseases. Full article

Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi (O. tsutsugamushi), remains a major public-health concern in the Asia–Pacific region. Genome-wide inference is complicated by extensive repetitive DNA and frequent genome rearrangement. We isolated O. tsutsugamushi HMU_001 from a scrub typhus patient on Hainan Island, China. Intracellular morphology was examined and replication was quantified in endothelial cells. Using long-read sequencing with short-read polishing, we generated a closed circular genome and performed standardized comparative analyses across all available complete O. tsutsugamushi genomes. HMU_001 assembled as a 1,895,724 bp genome and, among the 17 complete genomes analyzed in this study, represented the most compact genome. Repeats comprised 873,550 bp (46.08%) and included 72 RAGE loci (4 relatively complete) and 283 insertion sequences (54 intact). Repeat content varied widely and largely explained genome size differences. A core-gene phylogeny resolved four clades with partial geographic structure, while tsa56 genotypes were only partly congruent with it. Genome synteny was generally limited across strains but markedly higher among the closest relatives, consistent with ongoing rearrangement. HMU_001 expands representation of complete O. tsutsugamushi genomes by adding a TA763_A lineage strain from a high-incidence island setting. Comparative analyses support a model in which repeat proliferation and decay drive genome evolution and structural remodeling. Full article

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a wide range of neurological complications, among which persistent cognitive impairment and memory deficits are increasingly recognized as key symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID). Although clinical and epidemiological studies have documented these symptoms across diverse patient populations, the underlying neurobiological mechanisms remain incompletely understood. Growing evidence from human studies, neuropathological analyses, and experimental models indicates that neuroimmune and inflammatory processes plays a central role in COVID-19-associated cognitive dysfunction. As the brain’s resident immune cells, microglia are vital for synaptic health, neuroplasticity, and memory, yet these processes may be compromised after SARS-CoV-2 infection. Systemic inflammation, blood–brain barrier (BBB) disruption, endothelial injury, and cytokine signaling can induce sustained microglial activation and priming, leading to inflammasome activation, complement-mediated synaptic remodeling, oxidative stress, and impaired hippocampal neurogenesis. These processes collectively disrupt neural circuits involved in learning and memory and may underlie the persistent “brain fog” reported by COVID-19 survivors. This review synthesizes clinical, biomarker, neuroimaging, and mechanistic evidence linking SARS-CoV-2 infection to microglia-mediated neuroinflammation and memory impairment. In contrast to prior reviews that broadly describe neuroinflammation in COVID-19, we integrate multidimensional evidence into a microglia-centric immunovascular framework that highlights converging pathogenic pathways underlying cognitive symptoms. We further discuss emerging biomarkers of glial activation and evaluate current and prospective therapeutic strategies targeting microglial and neuroimmune pathways. Understanding the role of microglial dysregulation in post-COVID cognitive impairment may facilitate the development of targeted interventions to mitigate long-term neurological consequences of COVID-19. Full article