Search Results (4,813)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease worldwide, and effective pharmacological therapies remain limited. Pemafibrate (Pema), a selective peroxisome proliferator-activated receptor alpha (PPARα) modulator (SPPARMα), has shown promising therapeutic potential in patients with MASLD and hypertriglyceridemia; however, its underlying mechanisms remain incompletely understood. Here, we investigated the therapeutic effects and molecular mechanisms of Pema using in vitro and in vivo MASLD models and evaluated its clinical relevance in patients with MASLD. In a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASLD mouse model, Pema dose-dependently ameliorated hepatic steatosis and fibrosis and significantly suppressed the hepatic expression of inflammatory and fibrogenic genes, including TLR4, TNFα, αSMA, and Col1A1. Pema also favorably altered the gut microbiota by increasing the abundance of the phylum Verrucomicrobia, suggesting modulation of the gut–liver axis. In differentiated 3T3-L1 adipocyte-like cells, Pema induced PPARα expression, inhibited insulin-mediated EGR-1 induction, and significantly reduced leptin secretion. Consistent with these findings, serum insulin and leptin levels, as well as the hepatic accumulation of both molecules, were markedly decreased in Pema-treated MASLD mice. Furthermore, in a clinical cohort of 192 patients with MASLD and hypertriglyceridemia, long-term Pema treatment significantly improved liver-related biochemical parameters, insulin resistance, surrogate markers of liver fibrosis, and serum leptin levels. Collectively, these findings demonstrate that Pema attenuates MASLD progression by suppressing leptin-mediated metabolic and inflammatory signaling while improving the gut microenvironment. These results highlight SPPARMα as a promising therapeutic strategy for MASLD and support further clinical investigation of Pema as a disease-modifying treatment targeting the gut–liver axis. Full article

Background and Clinical Significance: People with HIV (PWH) experience an elevated risk of atherosclerotic cardiovascular disease (ASCVD), driven by chronic immune activation, metabolic toxicities of antiretroviral therapy (ART), and traditional risk factors. Achieving target low-density lipoprotein cholesterol (LDL-C) levels is frequently impeded by adherence barriers, pharmacokinetic drug interactions, or muscle-related symptoms. Inclisiran is a hepatocyte-targeted small interfering RNA that halts proprotein convertase subtilisin/kexin type 9 synthesis, providing a long-acting therapeutic alternative. Case Presentation: We present two PWH with severe hypercholesterolemia and elevated cardiovascular risk on stable ART. Case 1 describes a 54-year-old male with a history of myocardial infarction presenting with persistent, refractory hypercholesterolemia on rosuvastatin and ezetimibe (baseline LDL-C 142 mg/dL). Case 2 describes a 58-year-old male with verified statin intolerance and inadequate response to ezetimibe (baseline LDL-C 194 mg/dL). Following subcutaneous inclisiran administration at Day 1 and Day 90, Case 1 achieved an 80.2% LDL-C reduction to 28 mg/dL at Month 6, and Case 2 achieved a 54.6% reduction to 88 mg/dL at Month 6 as monotherapy. Both patients tolerated therapy well, with stable CD4+ counts and sustained virological suppression. Conclusions: These cases illustrate that inclisiran can effectively lower LDL-C levels across primary and secondary prevention settings in PWH facing oral therapy limitations or statin intolerance. Provider-administered dosing every 6 months overcomes adherence challenges, supporting the inclusion of PWH in broader clinical pathways pending ongoing cardiovascular outcome trials. Full article

Chronic kidney disease (CKD) is sustained by a network of sterile inflammation, oxidative and metabolic stress, uremic toxin retention, gut barrier dysfunction, and maladaptive immune activation. These processes contribute to kidney fibrosis, cardiovascular injury, wasting, and excess mortality, but inflammatory biomarkers do not by themselves establish therapeutic causality. This narrative review integrates mechanistic and therapeutic evidence using an explicit three-layer translational hierarchy. Renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, finerenone, and glucagon-like peptide-1 receptor agonists improve cardiorenal outcomes and have plausible anti-inflammatory actions, although inflammatory mediation remains unproven. Interleukin-1 blockade provides cardiovascular proof of principle and small dialysis feasibility data. Interleukin-6 ligand inhibition produces marked human target engagement; however, headline results from the completed phase 3 ZEUS trial showed no reduction in three-point major adverse cardiovascular events with ziltivekimab despite biomarker suppression, while serious infections were more frequent. POSIBIL6ESKD continues to test clazakizumab in inflamed dialysis patients. Direct NLRP3 inhibition has entered early human CKD development, whereas senescence-directed and microbiota-based approaches remain less mature. Future progress requires inflammatory endotyping, repeated biomarker assessment, mechanistically aligned outcomes, and rigorous infection surveillance. ZEUS underscores that pathway suppression must deliver clinical benefit beyond contemporary standard therapy. Full article

Streptococcus salivarius-derived extracellular vesicles (SsEVs) have emerged as important mediators of host–microbe communication, but their role in oral squamous cell carcinoma (OSCC) remains unclear. In this study, SsEVs were isolated and characterized by transmission electron microscopy and nanoparticle tracking analysis, and their uptake by CAL-27 cells was confirmed by fluorescence imaging. Functional assays demonstrated that SsEVs inhibited the proliferation, migration, and invasion of CAL-27 cells in a concentration-dependent manner. RNA sequencing revealed substantial transcriptional reprogramming following SsEV treatment, with enrichment analyses indicating the suppression of pathways associated with cell adhesion, extracellular matrix remodeling, lipid metabolism, and particularly Notch signaling. Gene set enrichment analysis (GSEA) and gene set nariant analysis (GSVA) consistently identified Notch signaling as significantly downregulated. Further validation showed that SsEVs markedly decreased the expression of JAG1, NOTCH1, and HEYL at both the mRNA and protein levels. In a CAL-27 xenograft model, SsEV treatment significantly inhibited tumor growth and reduced JAGGED1, NOTCH1, and HEYL expression in tumor tissues, as confirmed by immunohistochemistry. Collectively, these findings demonstrate that SsEVs suppress OSCC progression both in vitro and in vivo by inhibiting the JAG1–NOTCH1–HEYL signaling axis, suggesting that microbiota-derived extracellular vesicles may represent a promising therapeutic approach for OSCC. Full article

TDP-43 proteinopathies, encompassing amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE), represent a heterogeneous spectrum of devastating neurodegenerative disorders. For decades, the diverse clinical presentations of these diseases have complicated antemortem diagnosis and hindered the development of disease-modifying therapies. However, recent breakthroughs in basic science are beginning to address these clinical barriers, although substantial hurdles to practical clinical application remain. Structural elucidation via cryo-electron microscopy (Cryo-EM) has shattered the single-protein amyloid dogma by revealing that TDP-43 can form hetero-amyloid filaments with ANXA11, thereby providing a molecular basis for pathological strain diversity. Concurrently, the pathogenic focus has shifted toward nuclear loss of function, which triggers a systemic “RNA crisis” characterized by aberrant alternative polyadenylation (APA) and cryptic exon inclusion (e.g., STMN2, UNC13A). Crucially, this metabolic collapse is profoundly exacerbated by patient-specific genetic risk factors, acting synergistically in a “two-hit” model of neurodegeneration. To translate these findings to the clinic, next-generation diagnostic tools are emerging. Integrating neuron-derived extracellular vesicle (EV) isolation with Seed Amplification Assays (SAAs) holds promise to help overcome the structural camouflage that limits current PET imaging, potentially offering ultra-sensitive, functional strain identification in biofluids. While these structural and diagnostic milestones provide a strong foundation for precision medicine, major challenges in assay standardization and clinical validation must be addressed. Advanced therapeutic strategies—namely, splice-switching antisense oligonucleotides (ASOs) that directly restore RNA metabolism, combined with the targeted suppression of neuronal hyperexcitability—are now entering clinical trials. This review synthesizes how decoding the structural and RNA-metabolic complexities of TDP-43 is paving a promising pathway from bench to bedside, while critically discussing current translational limitations. Full article

Cardiovascular diseases are increasingly recognized as immune-inflammatory disorders in which adaptive immunity shapes tissue injury, repair, and long-term remodeling. T cells are central to these processes because they integrate antigen recognition, lineage-defining transcriptional programs, tissue trafficking, cytokine production, and immunological memory. In this Review, we synthesize current evidence on the Krüppel-like factor (KLF) family as a transcriptional framework linking T-cell biology to cardiovascular disease. KLF2 primarily regulates T-cell quiescence and trafficking, KLF10 supports regulatory T-cell suppressive function and immune-metabolic fitness, KLF4 contributes to inflammatory effector differentiation, and KLF13 regulates delayed inflammatory chemokine expression and, in thymocyte models, exerts a survival-restraining effect through apoptosis-related pathways. Across atherosclerosis, myocardial infarction, myocarditis, hypertension, and heart failure, these KLF-dependent programs may influence the balance between pathogenic effector responses and protective regulatory mechanisms. The strongest direct disease-specific evidence currently supports a role for KLF10 within the CD4⁺ T-cell lineage in experimental atherosclerosis, with complementary functional evidence implicating Treg–macrophage interactions, whereas the roles of KLF-dependent T-cell programs in other cardiovascular settings remain mechanistically compelling but less fully validated. Future progress will require disease-specific T-cell-restricted models, spatially resolved immune analyses, and cell-selective translational strategies to define the therapeutic relevance of the KLF–T-cell axis. Full article

Background/Objectives: Drug resistance is a major challenge in cancer therapy, and mitochondria contribute to this process by controlling both metabolic adaptability and cell survival signaling. Mitophagy, the selective lysosomal removal of dysfunctional mitochondria, has been implicated in therapy resistance, yet its role in sunitinib-resistant renal cancer remains poorly defined. Methods: In this study, acquired sunitinib resistance was established in ACHN renal cancer cells through eight months of stepwise dose escalation. Initial selection conditions were determined using CCK-8 viability and crystal violet colony assays in parental ACHN cells, whereas sustained proliferation under continuous sunitinib exposure was used as the operational criterion for the resistant phenotype. Resistant and parental sensitive cells were treated with 25 µM and 50 µM succinic acid, alone or in combination with sunitinib. Gene expression of BNIP3, NIX, FUNDC1, LC3, PINK1, Parkin, PGAM5, SRC, LONP1, and ATP5F1A was measured by RT-qPCR, and BNIP3 and NIX protein levels were assessed by ELISA. Results: Resistant cells showed significant upregulation of receptor-mediated mitophagy components BNIP3, NIX and FUNDC1 (p < 0.05), with no significant change in LC3, alongside suppression of PINK1, Parkin, and mitochondrial homeostasis-associated genes LONP1, PGAM5, and ATP5F1A (p < 0.05). Succinic acid predominantly reduced BNIP3 and NIX protein levels in both cell lines and suppressed BNIP3, NIX, and LC3 mRNA expression in resistant cells. In contrast, the sunitinib + 50 µM succinic acid combination selectively increased PARKIN, PGAM5, LONP1, and ATP5F1A expression in resistant cells (2.49- to 5.98-fold; p < 0.005), a pattern not observed in parental cells. Conclusions: These findings indicate that sunitinib resistance in ACHN cells is associated with upregulated transcription of receptor-mediated mitophagy components and downregulated transcription of PINK1/Parkin pathway genes, and that exogenous succinic acid selectively upregulates PARKIN and other mitochondrial homeostasis-related gene expression in resistant, but not parental, cells. Full article

High carbonate alkalinity (CA) is a major constraint on shrimp culture in saline–alkaline waters. The hepatopancreas is central to shrimp immunity and metabolic regulation. Litopenaeus vannamei underwent a 7-day exposure period to 5 mmol/L CA, followed by a subsequent 7-day recovery phase after removal of the stressor. The physiological regulatory mechanism of the hepatopancreas during CA stress and recovery was investigated by integrating multiple biological levels including histomorphology, antioxidant and immune indices, energy metabolism, and metabolite profiles. Results showed that CA stress induced structural changes in the hepatopancreas and triggered stress responses. Specifically, a significant upregulation was observed in genes involved in antioxidation (romo1, nrf2, gpx, hsp70), apoptosis (casp-9, casp-3), endoplasmic reticulum (ER) stress (ire1, xbp1), immune defense (alf, crus, pen-3, lys, propo), and detoxification (cyp450). CA stress also increased osmoregulatory genes (ccp, nhe, ca, aqp, vatp, nka-β, nka-α), whereas clc and tip4 were suppressed. CA stress reduced the levels of energy-metabolism-related biochemical indicators, including glucose (GLU), pyruvic acid (PYR), lactic acid (LAC) and triglycerides (TG), while markedly inducing the expression of genes involved in carbohydrate metabolism (ldh, pdh, hk, pk), lipid metabolism (ampk, srebp, fas), the tricarboxylic acid (TCA) cycle (mdh, cs, idh, odh, sdh, fh), and the electron transport chain (ETC) (ndh, cytc, coi, cco, atph). Moreover, the hepatopancreatic metabolic profile was remodeled, especially “phenylalanine, tyrosine and tryptophan biosynthesis” and the metabolism of β-alanine, arachidonic acid, linoleic acid, and sphingolipids being substantially altered during both the stress and recovery phases. Several functional metabolites linked to stress responses were further pinpointed. Following stress relief, some physiological parameters partially recovered, yet overall function failed to return to normal. Collectively, CA stress compromised hepatopancreatic homeostasis by damaging morphological integrity, eliciting stress and immune responses, and perturbing energy metabolism and metabolite homeostasis; these adverse effects were not readily reversible in the short term. Full article

Acute and chronic inflammation underlies the pathogenesis of numerous diseases, including autoimmune disorders, atherosclerosis, infections, and cancer. Although non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are widely used to control inflammation, their clinical utility is limited by adverse effects such as gastrointestinal toxicity and immunosuppression. Specialized pro-resolving mediators (SPMs), a family of endogenous lipid mediators derived from omega-3 fatty acids, have emerged as promising therapeutics because they actively promote the resolution of inflammation without suppressing host immunity. However, their clinical translation is hindered by poor chemical stability, rapid metabolic degradation, and short circulation half-lives. To overcome these limitations, a variety of delivery platforms—including liposomes, extracellular vesicles, PLGA nanoparticles, and hydrogels—have been developed to improve SPM stability, pharmacokinetics, and therapeutic efficacy. This review summarizes the cellular targets of SPMs, current delivery challenges, and emerging strategies for cell- and tissue-specific SPM delivery. We also discuss future opportunities for targeted SPM therapies in the treatment of inflammatory diseases and cancer. Full article

High-temperature stress impairs plant growth and alters secondary metabolism. Polymethoxyflavones (PMFs) are citrus-specific flavonoids with important nutritional benefits; however, their transcriptional responses to heat stress remain poorly understood. Here, five-month-old ‘Ponkan’ citrus seedlings were exposed to 40 °C for 6, 11, and 21 days. HPLC analysis showed that the accumulation of four major PMFs (sinensetin, nobiletin, tangeretin, and 5-demethylnobiletin) was significantly reduced in leaves under heat stress. RNA-seq identified 3424 differentially expressed genes shared across all three time points, which were enriched in pathways associated with microtubule cytoskeleton organization, cell cycle regulation, and glyoxylate and dicarboxylate metabolism. Further analysis of the PMF biosynthetic pathway revealed that 14 of 18 key structural genes, including CHS, CHI, FNSII, and OMT family members, were downregulated by heat treatment. In addition, several bHLH, AP2/EREBP, and MYB transcription factors, known regulators of flavonoid biosynthesis, exhibited expression patterns closely associated with PMF accumulation. RT-qPCR analysis validated the transcriptome results. Collectively, these findings suggest that heat stress suppresses PMF accumulation through coordinated repression of PMF biosynthetic genes and their potential regulators. This study provides new insights into the molecular basis of heat-responsive PMF metabolism and offers potential targets for maintaining citrus nutritional quality under elevated temperatures. Full article

Hair follicle stem cells (HFSCs) are critical for hair follicle (HF) morphogenesis and cyclic hair regeneration. Periostin (POSTN), an extracellular matrix protein involved in tissue development and skin cell regulation, remains poorly characterized in HFSCs. In this study, we constructed CRISPR/Cas9 vectors targeting POSTN and validated their editing efficiency in primary HFSCs. POSTN editing significantly suppressed cell proliferation and promoted apoptosis. Transcriptomic analysis identified 988 differentially expressed genes (DEGs) enriched in immune responses and MAPK, PI3K–Akt, and cAMP pathways. Metabolomic analysis revealed 98 differential metabolites (DMs) associated with nucleotide metabolism and FoxO, AMPK, and cAMP pathways. Integrated multi-omics analysis showed extensive correlations between DEGs and DMs, and highlighted the cAMP pathway as the core regulatory axis. Western blot (WB) validation confirmed that POSTN editing reduced PKA and CREB phosphorylation, indicating inhibition of the cAMP/PKA/CREB signaling. These findings demonstrate that POSTN regulates HFSCs’ proliferation and apoptosis partially via the cAMP/PKA/CREB pathway, providing novel insights into the functional regulation of HFSCs. Full article

Background: Drug repurposing represents an accelerated and cost-effective approach to discovering novel oncologic therapeutics. Here, we investigated the anticancer potential and underlying mechanisms of marbofloxacin (MBF), a veterinary fluoroquinolone (FQ), against breast cancer (BC) cells. Methods: The cellular impacts of MBF on cell viability, anchorage-dependent growth, tumorigenicity, migration, apoptosis, proliferation, senescence, and mitochondrial function were thoroughly characterized. To further elucidate its mechanistic activity, real-time qRT-PCR, untargeted LC-MS/MS-based metabolomics, network pharmacology, and molecular docking analysis were integrated. Results: MBF suppressed BC cell growth by inhibiting cellular proliferation and migration, disrupting mitochondrial membrane potential, and inducing ROS-mediated apoptosis and irreversible cellular senescence. These phenotypic impacts were accompanied by upregulation of tumor suppressors such as CDKN1A and PUMA and downregulation of oncogenes including MKI67, BIRC5, and BCL-2. Metabolomic analysis revealed broad suppression of biosynthesis-related metabolic pathways, characterized by the depletion of critical polyamines and nucleotide pathways. Network pharmacology and molecular docking analyses identified EGFR and HSP90AA1 as putative hub proteins potentially associated with the observed anticancer phenotype. Conclusions: These results provide initial evidence that MBF induces metabolic and molecular rewiring in BC, highlighting its promise as a repositionable therapeutic candidate. Full article

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article

Background/Objectives: Obesity is a chronic, progressive, and relapsing disease that requires long-term, multidisciplinary management rather than episodic weight-loss treatment. Although novel incretin-based anti-obesity pharmacotherapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists, have markedly improved the clinical management of obesity, weight reduction alone does not fully capture treatment success. Body composition, lean mass preservation, physical function, nutritional adequacy, psychological well-being, adherence, and long-term weight-loss maintenance are increasingly recognized as essential therapeutic outcomes. This narrative review critically examines the role of lifestyle medicine as a co-therapeutic strategy during modern anti-obesity pharmacotherapy, with particular attention to physical activity, nutrition, behavioral support, and individualized monitoring. Methods: A narrative literature search was conducted in PubMed up to June 2026. The review included studies addressing adults with overweight or obesity and evidence related to anti-obesity pharmacotherapy, physical activity, nutrition, body composition, functional outcomes, eating behavior, quality of life, treatment tolerability, adherence, weight regain, and long-term maintenance. Results: Current evidence indicates that incretin-based therapies produce substantial and clinically meaningful weight loss, but pharmacological efficacy may be limited by reductions in lean mass, gastrointestinal adverse events, inadequate nutritional intake, treatment discontinuation, and weight regain after drug withdrawal. Physical activity should be considered a therapeutic component rather than only a tool for increasing energy expenditure, as aerobic exercise supports cardiometabolic health and cardiorespiratory fitness, while resistance training helps preserve muscle strength, bone health, and functional capacity. Nutritional strategies are equally important, particularly during appetite suppression, to maintain adequate protein, fiber, fluids, micronutrients, and diet quality. Behavioral factors, including sleep, stress, mood, stigma, self-regulation, and the food environment, may influence adherence and long-term outcomes. Conclusions: Novel anti-obesity drugs should not be viewed as replacements for lifestyle medicine but as powerful tools within an integrated chronic-care model. The goal of treatment should move beyond maximal body-weight reduction to durable improvements in body composition, metabolic health, physical function, nutritional status, quality of life, and weight-loss maintenance. Full article

Dysregulation of the kynurenine pathway (KYNP) is increasingly recognized as a hallmark of cancer-associated metabolic reprogramming, contributing to immune evasion, oxidative stress, and tumor progression through the activity of enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO2). This systematic review aimed to evaluate the current evidence on the ability of phytochemicals to modulate the KYNP and their potential implications for cancer prevention and therapy. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included English-language articles and book chapters published between 2016 and 2026 that were retrieved from the Scopus and PubMed databases. A keyword co-occurrence network was generated using VOSviewer (v1.6.20) based on the complete Scopus and PubMed exports of the included studies to identify major research themes. The available evidence indicates that phytochemicals restore anticancer immunity by targeting multiple components of the KYNP, including inhibition of IDO1-mediated kynurenine production and suppression of downstream aryl hydrocarbon receptor signalling, thereby enhancing cytotoxic T-cell responses, reducing immunosuppressive cell populations, and improving antitumor immune activity. Collectively, these findings support the KYNP as a promising immunometabolic target and highlight phytochemicals as potential complementary agents for cancer immunotherapy while emphasizing the need for further investigation of the biological and immunological roles of IDO2. Full article