Search Results (21,177)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with metabolic abnormalities, shares pathophysiological pathways with metabolic syndrome, and has become a leading cause of chronic liver disease in industrialized nations. In the absence of approved pharmacological treatments and due to its high risk of progression to advanced fibrosis, MASLD represents a significant clinical challenge. Incretin-based therapies, originally developed for the treatment of type 2 diabetes mellitus and obesity, have recently gained attention as promising therapeutic strategies in hepatology. Among them, GLP-1 receptor agonists have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, primarily through weight loss and enhanced insulin sensitivity. Dual agonists targeting both GLP-1 and GIP receptors, such as tirzepatide, have demonstrated superior outcomes in improving hepatic and metabolic parameters. Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited. Full article

Endometriosis (EMT) is characterized by a chronic inflammatory disorder in the female reproductive system, posing significant challenges to global women’s health. Necrosis by Sodium Overload (NESCO) is a novel immunogenic programmed cell death (PCD) pattern that may potentially inhibit natural killer (NK) cell activation by increasing cytotoxicity and the inflammatory response in the EMT microenvironment. By integrating three bulk datasets to compare endometrium tissues between endometriosis patients and normal controls and the NESCO gene list from a public database, we identified NK- and NESCO (NN)-associated hub genes via integrative bioinformatic analyses utilizing Limma, WGCNA, CIBERSORT and machine learning frameworks. The diagnostic performance of NN-associated hub genes was evaluated across the three aforementioned datasets and two independent validation sets. Furthermore, their molecular and immune features were estimated at the bulk and single-cell transcriptomic levels. In addition, endometriosis patients were classified into two novel molecular subgroups based on consensus clustering of NN. Finally, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and molecular docking were used to identify compounds in Chinese traditional medicine (CTM) that can target NN-associated hub genes for endometriosis treatment. FABP4 and SLC2A1 can be considered NN-associated hub genes that are involved in EMT pathogenesis, and natural compounds including the CTM GuiZhiFuLingWan (GZFLW) can be considered therapeutic agents for EMT treatment as they target FABP4 and SLC2A1. Our study is the first to reveal the diagnostic and druggable roles of NESCO and NK cells, the corresponding molecular and immune features of NN-associated hub genes, and the therapeutic potential of GZFLW. Full article

Inflammatory bowel diseases, particularly ulcerative colitis (UC), are chronic relapsing inflammatory disorders with limited therapeutic options. The zinc-finger transcription factor ZBTB4 has been implicated in the initiation and progression of cancer, but its role in UC remains unknown. Here, we found that ZBTB4 deficiency exacerbates dextran sulfate sodium (DSS)-induced colitis in C57BL/6J male mice. Compared with the wild type, ZBTB4 deficiency increases weight loss, colon shortening and proinflammatory cytokine production. RNA-seq analysis revealed that ZBTB4 deficiency enhances Serpine1 expression and activates the NF-κB pathway. NF-κB inhibition by JSH-23 alleviated the effect of ZBTB4 deficiency on DSS-induced colitis. These results imply the protective role of ZBTB4 in UC. Through an integrated drug screening, we identified a natural sesquiterpene lactone, handelin, as a potential compound to enhance ZBTB4 expression in NCM460 cells. Handelin administration relieved colitis in wild-type mice but produced no effect in ZBTB4 knockout mice, demonstrating that its anti-colitic effect depends on ZBTB4 expression. Collectively, our results indicate the key role of ZBTB4 in UC and ZBTB4 agonists may serve as a novel approach for UC treatments. Full article

The emerging threat of antibiotic-resistant pathogens and the limitations that conventional cancer chemotherapies display have created an urgent need for the development of innovative therapeutic strategies. Combining the pleiotropic biological roles of antimicrobial peptides (AMPs) and nanomaterials through their conjugation presents a promising possibility of targeting both microbial membranes and malignant cells. In the present study, we engineered a novel bioactive material by immobilizing the insect-derived AMP Papiliocin onto multi-walled—decorated with polyethylene–glycol—carbon nanotubes (PEG-MWCNTs) to prevent proteolytic degradation of the peptide and enhance its cellular delivery. Recombinant Papiliocin was cloned, heterologously expressed, purified and conjugated onto the PEG-MWCNT carrier. Successful expression and conjugation were validated via immunoblotting and Fourier transform infrared (FT-IR) spectroscopy, respectively. Further physicochemical characterization of the bionanocomposites was conducted using Dynamic Light Scattering (DLS) and Zeta potential measurements. Biologically, the biofunctionalized material exhibited potent, broad-spectrum antimicrobial activity both on Staphylococcus aureus and Escherichia coli, inhibiting almost 90% of the latter’s growth, highlighting the bioconjugate’s specific interactions with the Gram-negative pathogens’ membranes. Furthermore, it significantly reduced biofilm formation in Candida albicans, as indicated by the TCP assay. In parallel with its antimicrobial effects, CNTs-PEG–Papiliocin significantly reduced cancer cell viability and induced apoptosis via the extrinsic apoptosis pathway in HeLa cells, a response assisted by efficient intracellular delivery. Notably, cytotoxicity assays demonstrated lesser cytotoxic effect against non-tumorigenic HaCaT cells relative to the cancerous cell line. Collectively, these findings indicate the Papiliocin–biofunctionalized CNTs as a versatile, dual-action therapeutic agent with potential for antimicrobial activity and anticancer mode of action. Full article

Breast cancer has emerged as the preeminent global health crisis in oncology, currently standing as the most frequently diagnosed malignancy among women worldwide. Establishing novel predictive biomarkers is paramount to truly personalize treatment approaches, minimize unnecessary toxicity, and significantly improve long-term outcomes for patients with breast cancer. Breast cancer transcriptomic datasets were retrieved from the Gene Expression Omnibus and processed through standardized normalization procedures. Mutation-driven regulation of SYTL4 expression, treatment response to trastuzumab, cancer hallmark enrichment, and survival associations were evaluated using established bioinformatic tools and enrichment analysis based on integrated cancer hallmark gene sets. Additionally, DNA methylation profiles were analyzed. Herein, it is shown that SYTL4 mRNA expression is significantly (p = 2.01 × 10⁻⁴) diminished in breast cancer bearing BRCA1 mutations, suggesting a mechanistic interplay between BRCA1-driven genomic instability and SYTL4-regulated signaling cascades. Kaplan–Meier survival analysis demonstrated that elevated SYTL4 mRNA expression is significantly associated with improved overall survival in HER2-positive breast cancer patients (HR = 0.72; p = 0.034). Consistently, SYTL4 expression was significantly higher in patients who responded to trastuzumab therapy, supporting its potential as a biomarker of therapeutic response. Epigenetic analysis further revealed significant differential DNA methylation of SYTL4 between tumor and unaffected control tissues (p < 2.2 × 10⁻¹⁶), with region-specific hypomethylation in tumor regulatory regions. KEGG pathway and cancer hallmark enrichment analyses indicated that genes with prominent methylation changes are involved in cytokine signaling, growth factor pathways, and extracellular matrix remodeling, with the strongest associations observed for hallmarks related to genome instability, replicative immortality, resisting cell death, and metabolic reprogramming. In summary, we present that the gene SYTL4 is a prospective biomarker for survival and trastuzumab treatment responsiveness. Our observations posit that SYTL4 expression may signify a biological milieu conducive to sustained HER2 reliance and amplified therapeutic vulnerability. Full article

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies. Full article

Neurochemical imbalances in the striatum are thought to contribute to the pathophysiology of DYT1 dystonia (TOR1A), a severe movement disorder. Parvalbumin-positive GABAergic fast-spiking interneurons (PV+ FSI) exert a powerful inhibition within the striatal microcircuitry. To elucidate the impact of PV+ FSI on striatal neurotransmitter dynamics in a DYT1 knock-in (KI) mouse model, we combined optogenetic inhibition of PV+ FSI with in vivo microdialysis (optodialysis) and LC-MS/MS analysis. Dialysates were collected across baseline (light off), stimulation (light on, 595 nm), and post-stimulation (light off) periods. Basal extracellular concentrations of several analytes, including GABA, dopamine, and adenosine, showed no significant differences between wild-type (WT) and DYT1 KI mice. In WT mice, PV+ FSI inhibition decreased GABA and adenosine levels. In contrast, DYT1 KI mice showed no change in GABA and only a delayed reduction in adenosine post-stimulation. Dopamine, choline, or 5-HIAA were largely unaffected by optogenetic inhibition, with the exception of a genotype-specific reduction of 5-HIAA in the post-stimulation period. These findings suggest impaired inhibitory and neuromodulatory control in the DYT1 KI mice, potentially reflecting compensatory circuit adaptations. The results provide novel insights into striatal microcircuit function in DYT1 dystonia, establish a basis for exploring circuit-level alterations in other movement disorders, and may inform future therapeutic strategies. Full article

Pathologic pregnancies including recurrent pregnancy loss, stillbirth, early-onset pre-eclampsia and early-onset fetal growth restriction form a continuous spectrum throughout gestation and have attracted wide attention. Autoimmune disorders and associated acquired thrombophilia are key etiological factors. However, because of the complicated associations between various clinical manifestations, laboratory examinations and treatments, the management of pathologic pregnancies with autoimmune disorders and associated acquired thrombophilia are difficult. This viewpoint article presents a comprehensive full gestation management strategy emphasizing early identification and multidisciplinary management to improve pregnancy outcomes in these patients. Future research should focus on novel biomarkers, therapeutic methods and crosstalk mechanisms between autoimmune disorders and thrombophilia to optimize clinical strategies. Full article

Aronia melanocarpa (black chokeberry) is a polyphenol-rich fruit recognized as a novel food ingredient; however, its efficacy against constipation and its underlying mechanisms remains poorly understood. In this study, we evaluated the therapeutic effects of the ethanol extract of A. melanocarpa fruit (AMFE) on loperamide-induced constipation in mice and investigated its mechanisms using serum pharmaco-chemistry, network pharmacology, and molecular docking analyses. AMFE treatment increased the intestinal transit rate and fecal water content in a dose-dependent manner, alleviated colonic histopathological damage, and restored the serum levels of gastrointestinal neurotransmitters (5-HT, MTL, SP, GAS, and VIP), inflammatory cytokines (IL-1β, IL-6, and TNF-α), and colonic oxidative stress markers (GSH and MDA). Using UHPLC-Q-TOF-MS, 31 compounds were identified in AMFE, of which 22 were detected in serum, including 14 prototype compounds and eight metabolites. Network pharmacology analysis revealed 472 common targets shared between AMFE and constipation, with AKT1, STAT3, JUN, GAPDH, IL-6, and TP53 as core targets. KEGG enrichment analysis highlighted the PI3K/AKT signaling pathway as a key regulatory axis. Molecular docking confirmed strong binding affinities between key active compounds (catechin, kaempferol, caffeic acid, naringenin, and isorhamnetin). Please see the core end of the document for further details on the references and targets, particularly isorhamnetin with GAPDH. Collectively, AMFE alleviated constipation through multi-component, multi-target, and multi-pathway mechanisms, providing a scientific basis for the development of A. melanocarpa as a functional food and therapeutic candidate for constipation. Full article

Crohn’s disease (CD) is a chronic immune-mediated inflammatory disorder characterized by transmural inflammation and a progressive course that frequently leads to structural complications such as intestinal fibrosis. Fibrostenosing disease represents a major clinical challenge, affecting up to 50% of patients over time and often requiring surgical intervention. Despite advances in anti-inflammatory therapies, no effective treatments currently exist to prevent or reverse established fibrosis. Intestinal fibrosis arises from a dysregulated tissue remodeling process driven by excessive extracellular matrix deposition and persistent activation of mesenchymal cells, particularly fibroblasts and myofibroblasts. This process is orchestrated through complex interactions between immune and non-immune cells and mediated by key signaling pathways, including transforming growth factor beta (TGF-β1) and the TL1A/DR3 axis. Genetic susceptibility, notably variants in NOD2 and other fibrosis-related genes, contributes not only to disease risk but also to phenotype progression. Epigenetic mechanisms, particularly microRNAs such as the miR-29 and miR-200 families, further modulate fibrogenesis and represent promising non-invasive biomarkers. Additionally, intestinal dysbiosis and specific microbial signatures, including reduced short-chain fatty acid-producing bacteria and the presence of adherent-invasive Escherichia coli, play a critical role in promoting fibrotic pathways. Mesenteric adipose tissue, especially creeping fat, also contributes to fibrosis through immune and metabolic signaling. Emerging biomarkers related to collagen metabolism and advances in molecular profiling are improving early detection strategies. Novel therapeutic approaches targeting fibrogenic pathways, including anti-TL1A agents, show promising preliminary results. A deeper understanding of these mechanisms is essential to develop effective antifibrotic therapies and improve long-term outcomes in CD. Full article

Pathogenic microbes utilize virulence strategies to subvert host immune responses, highlighting a continuous race between the pathogen and the host. The emergence of multidrug- resistant and hypervirulent strains of Klebsiella pneumoniae (Kp) poses a critical threat to public health. This critical evaluation identifies key gaps in understanding the interplay between Kp and host innate immunity. This review provides a comprehensive overview of the mechanisms by which Kp triggers various forms of cell death. Dysregulated cell death may exacerbate cytokine release, contributing to the hyperinflammatory response characteristic of sepsis. The rise in antimicrobial resistance (AMR) in Kp necessitates the exploration of alternative therapeutic approaches. This review highlights that immunomodulatory approaches targeting cell death regulators or immune checkpoints may offer host-directed strategies against Kp-induced sepsis. Although novel immunotherapies offer potential to restore immune balance, their clinical applicability remains constrained by limited translational evidence. Full article

Epithelial ovarian cancer (EOC) poses a challenge owing to its high rate of recurrence and drug resistance, resulting in a 5-year survival rate of 30% in advanced stages. To elucidate the molecular mechanisms underlying EOC recurrence, we analyzed transcriptome data from patients with EOC and identified elevated USP19, a deubiquitinating enzyme, as being elevated in patients without recurrence in our previous study. Single-cell RNA sequencing analysis revealed that increased USP19 expression in epithelial cells is associated with activation of apoptotic pathways, suggesting that USP19 may inhibit EOC recurrence through deubiquitination of its binding proteins. Using the protein–protein interaction database, we identified DnaJC7 as a binding partner of USP19 and confirmed their interaction experimentally. USP19-mediated deubiquitination of DnaJC7 increases its protein stability. Notably, upregulation of USP19 and DnaJC7 disrupted the interaction between p53 and MDM2, and knockdown of USP19 and DnaJC7 resulted in decreased p53 expression following cisplatin treatment. These findings highlight the therapeutic potential of enhancing the USP19-DnaJC7 axis to stabilize p53 and improve cisplatin efficacy. Promoting USP19-mediated deubiquitination by stabilizing DnaJC7 may offer a novel combination strategy to enhance the efficacy of cisplatin-based cancer therapy. Full article

Leishmaniasis remains a major neglected tropical disease with limited therapeutic options, challenged by drug toxicity and emerging resistance to current treatments like miltefosine. In this study, a virtual library of approximately 150 azole-derived compounds was screened in silico to identify promising thiazole and imidazole scaffolds, leading to the rational design of novel hybrid molecules. Molecular docking against thioredoxin reductase (PDB ID: 4CBQ), a key enzyme in the redox metabolism of Leishmania mexicana, showed improved binding affinity compared to miltefosine, with compound 3f showing the most favourable interaction profile. Among the synthesized series 3a–f, compound 3f (4-NO₂Ph) exhibited the most favourable predicted binding parameters within the series (∆G = −16.08, Ki = 0.0019 nM). Biological evaluation was performed against L. mexicana promastigotes as an early-stage phenotypic screening model to identify active compounds with potential relevance during the initial infective phase, and a markedly improved in vitro inhibitory effect (IC₅₀ = 22.41 µM) compared to miltefosine (IC₅₀ = 132.42 µM), representing a six-fold increase in molar potency. Furthermore, hybrid thiazolyl–imidazole systems (series 3) consistently outperformed single-core analogues, likely due to enhanced molecular planarity and lipophilicity provided by the imine linkage. Cytotoxicity assays in Vero cells revealed a high safety margin for the lead compounds, with compound 3f achieving a Selectivity Index (SI) of around 89, significantly outperforming the reference drug. Acute toxicity studies (LD₅₀) in murine models further confirmed the safety profile, with values exceeding 2000 mg/kg for the most active derivatives. These findings identify thiazolyl–imidazole hybrids as promising early-stage scaffolds for antileishmanial drug discovery, particularly for early infection/prophylactic screening. Full article

Females with iron overload suffer from follicular dysplasia, and effective therapeutic strategies for preserving fertility remain lacking. As a natural aliphatic polyamine, spermidine exerts antioxidant activity and plays an anti-ferroptosis role in the pathogenesis of various diseases. However, the role and underlying mechanism of spermidine in iron overload-induced ovarian ferroptosis remain largely elusive. This study aimed to investigate the therapeutic potential of spermidine against iron overload-induced ferroptosis in ovarian granulosa cells and elucidate its molecular mechanism. As a result, iron overload models were established in female mice (in vivo, ferrous sulfate) and porcine ovarian granulosa cells (in vitro, ferric ammonium citrate), with spermidine administered at 3 mM (in vivo) or 150 μM (in vitro). Ferritin heavy chain (FHC) and solute carrier family 7 member 11 (SLC7A11) silencing were performed via siRNA transfection, and relevant controls were set. In vivo studies showed that spermidine elevated serum estradiol and progesterone levels, enhanced ovarian catalase (CAT) and superoxide dismutase (SOD) activities, improved granulosa cell mitochondrial morphology, and increased estrous cycle regularity from 35.6% (high-iron group) to 63.1%. In vitro, spermidine improved ferric ammonium citrate (FAC)-impaired cell viability; attenuated reactive oxygen species (ROS) accumulation; upregulated FHC, Nrf2/p-Nrf2/GPX4, SLC7A11 and anti-müllerian hormone (AMH) expression; and inhibited excessive autophagy (decreased LC3BII/I ratio). Mechanistically, spermidine activated AKT-mediated autophagy, modulated iron homeostasis and glutathione (GSH) synthesis via FHC, alleviated ferroptosis-related Nrf2/p-Nrf2/HO-1 pathway overactivation, reduced lipid peroxidation and DNA damage, and restored mitochondrial function. SLC7A11 silencing disrupted glutathione metabolism, induced mitochondrial ROS accumulation, and inhibited autophagy. Proteomic analysis identified microsomal glutathione S-transferase 3 (MGST3) as a potential key downstream target of spermidine in suppressing SLC7A11-mediated ferroptosis. This study reveals a novel therapeutic strategy wherein spermidine protects against ovarian ferroptosis and preserves ovarian function by regulating iron homeostasis through the FHC/SLC7A11 axis. Full article

Objectives: The dependence of non-small cell lung cancer (NSCLC) on glutamine has made targeting glutamine metabolism an attractive therapeutic approach. Dietary interventions are increasingly considered as adjuvant cancer therapies. This study aims to explore the relationship between glutamine starvation and ferroptosis in NSCLC and to elucidate the underlying molecular mechanisms. Methods: The effects of glutamine starvation were evaluated both in A549 and H460 NSCLC cell lines and in vivo using xenograft models in SCID mice. Assessments included cell viability, migration, clonogenic capacity, and the expression of key proteins. To gain mechanistic insight, AMPK was either overexpressed or inhibited, and key markers of ferritinophagy (including ULK1, BECN1, NCOA4, and LC3-II/I) and ferroptosis (such as ACSL4, GPX4, and xCT) were analyzed. Results: Glutamine starvation markedly suppressed tumor growth in both in vitro and in vivo settings, while also reducing cell migration and clonogenicity in cultured cells. This intervention activated AMPK, as indicated by increases in both total and phosphorylated forms, and upregulated PDZD8 expression. Mechanistically, AMPK activation played a critical role in driving ferritinophagy and ferroptosis—manipulation of AMPK consistently altered key markers of these processes. Furthermore, AMPK levels influenced PDZD8 protein expression. Notably, overexpressing PDZD8 alone was sufficient in promoting both ferritinophagy and ferroptosis, indicating that PDZD8 acts as a critical downstream mediator of AMPK in this pathway. Conclusions: Our findings reveal that glutamine starvation triggers ferroptosis in NSCLC via activation of ferritinophagy, mediated by the AMPK/PDZD8 signaling pathway. These results support the potential of dietary glutamine restriction as a novel therapeutic approach for NSCLC. Full article