Atrial fibrillation (AF) is the most common sustained arrhythmia globally. Despite certain progress in drug and interventional treatments, AF still presents high morbidity, high mortality, and unsatisfactory clinical outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), initially used to treat type 2 diabetes mellitus (T2DM), have demonstrated cardiorenal protective effects beyond glycemic control and have drawn broad attention for their potential in AF management. This narrative review comprehensively synthesizes clinical evidence and underlying mechanisms regarding the effects of SGLT2i and GLP-1 RA on new-onset AF and post-ablation AF recurrence across common comorbidities, including T2DM, heart failure (HF), chronic kidney disease (CKD) and obesity. Available evidence shows that SGLT2i may be associated with reduced new-onset AF risk in patients with T2DM, HF and CKD, and lower post-ablation AF recurrence in high-risk groups. GLP-1 RA show beneficial effects on AF in individuals with obesity or heart failure with preserved ejection fraction. Their protective effects are mainly mediated by upstream metabolic regulation and direct effects on atrial electrophysiology, as evidenced by cellular, animal, and clinical studies. Notably, most clinical evidence comes from post hoc analyses and observational studies, with AF rarely as a primary endpoint and without systematic measurement, leaving the evidence at a hypothesis-generating stage with limited clinical applicability. Overall, SGLT2i and GLP-1 RA serve as potential adjunctive therapies for AF patients with concomitant cardiometabolic comorbidities. Their AF-related outcomes represent exploratory secondary benefits instead of established therapeutic indications. Further specific randomized controlled trials with prespecified AF endpoint and standardized AF monitoring are needed to verify their clinical efficacy and application prospects.
Ovarian cancer (OC) comprises multiple histotypes with distinct mechanisms, molecular features, and clinical behavior. We used Mendelian randomization (MR) to map histotype-stratified metabolic pathways and connect them to drug targets, establishing a translatable target-metabolic node-histotype risk chain. We built a multi-stage MR framework using Integrative Epidemiology Unit (IEU) OpenGWAS summary statistics. After screening 1400 plasma metabolites against overall ovarian cancer in UK Biobank and Ovarian Cancer Association Consortium (OCAC) with KEGG enrichment, we traced a prespecified amino acid/energy-nitrogen axis using histotype-stratified univariable MR and pathway-restricted multivariable MR. We then performed cis drug-target MR for PPARG, DPP4, ABCC8/KCNJ11, and SLC5A2, integrated triangulation, colocalization, and mediation analyses, and experimentally interrogated the prioritized PPARG/ABCC8-KCNJ11-lactate-invasive mucinous ovarian cancer (IMOC) triangle. Screening nominated 55 and 72 metabolites in UK Biobank and OCAC, respectively (IVW p < 0.05), highlighting amino-acid nitrogen and central-carbon metabolism. Univariable Mendelian randomization (UVMR) showed marked heterogeneity: alanine increased low-grade serous ovarian cancer (LGSOC) risk, glutamate was protective for endometrioid OC, and lactate-related traits most consistently implicated the low-grade/borderline serous lineage. In multivariable Mendelian randomization (MVMR), tryptophan and lactate levels emerged as independent risk nodes for serous low-grade plus low malignant potential (LG + LMP). Drug-target MR prioritized PPARG as protective (OR = 0.18) and ABCC8/KCNJ11 as risk-increasing (OR = 7.50) for IMOC, with opposite target → lactate effects supporting a directionally symmetric target-lactate-IMOC triangle. Experimental perturbation in mucinous ovarian cancer models produced concordant reciprocal changes in lactate and malignant phenotypes, extending this triangle biologically. This integrative MR framework delineates histotype-specific metabolic drivers and links them to actionable targets, providing a roadmap from genetic prioritization to mechanistic and translational validation.
Background/Objectives: L-carnitine and Coenzyme Q10 (CoQ10) are widely used in health and sports supplementation settings to improve energy metabolism, reduce fatigue, and support recovery. Although generally perceived as safe, their safety profiles are mainly based on pre-marketing studies and selected clinical populations, while real-world pharmacovigilance evidence remains limited. This study aimed to evaluate and compare the adverse drug reaction (ADR) reporting patterns associated with L-carnitine and CoQ10 using the EudraVigilance database. Methods: A retrospective pharmacovigilance analysis was conducted using spontaneous individual case safety reports (ICSRs) retrieved from the EudraVigilance database. ADRs associated with L-carnitine and CoQ10 were analyzed and compared at the System Organ Class (SOC) level. Disproportionality analyses were performed using the reporting odds ratio (ROR) and proportional reporting ratio (PRR). Results: A total of 257 ICSRs for L-carnitine and 271 for CoQ10 were identified. Serious cases accounted for 34.2% of L-carnitine reports and 74.5% of CoQ10 reports. For L-carnitine, the most frequently reported SOC categories were gastrointestinal disorders, skin and subcutaneous tissue disorders, general disorders and administration site conditions, and nervous system disorders. For CoQ10, the most commonly reported SOC categories were general disorders and administration site conditions, nervous system disorders, investigations, and gastrointestinal disorders. Comparative disproportionality analysis showed higher reporting frequencies for CoQ10 in blood and lymphatic system disorders (ROR 3.04; PRR 2.99), musculoskeletal and connective tissue disorders (ROR 2.63; PRR 2.52). Conclusions: Real-world pharmacovigilance data suggest partially different ADR reporting patterns for L-carnitine and CoQ10 compared with those described in pre-marketing studies. CoQ10 was associated with a higher proportion of serious reports and greater disproportionality signals for selected SOC categories; however, these findings should be interpreted cautiously, as reporting patterns may be influenced by reporting bias, comorbidities, concomitant therapies, and differences in the populations using these compounds. Continuous pharmacovigilance monitoring and periodic reassessment of their benefit-risk profile remain essential given their widespread use in health and sports supplementation settings.
Diabetic retinopathy (DR) and retinal aging, though arising from distinct causes, share converging mechanisms-including oxidative stress, chronic inflammation, mitochondrial dysfunction, and AGE accumulation-that compromise retinal integrity. These overlaps suggest common gene expression patterns, and highlight the contribution of disease-associated or accelerated aging processes to diabetes-induced retinal injury. We systematically retrieved DR- and aging-related human genes from public genetic databases, identified their overlap, and focused on those involved in key metabolic pathways (AGEs, oxidative stress, lipid metabolism, and autophagy). Genes were then cross-validated across multiple databases and filtered by ocular expression to ensure relevance to retinal pathology. Our findings show that although DR and retinal aging arise from distinct etiologies, they converge on four principal metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and impaired autophagy-that collectively drive similar vascular, neuronal, and inflammatory injury within the retina. Shared genes with high ocular expression reinforce the biological relevance of these pathways, while multi-pathway hub genes appear to function as central regulators that integrate redox imbalance, metabolic disruption, and proteostatic failure. These results provide a unified molecular perspective of retinal degeneration and support the potential development of therapeutic approaches designed to simultaneously target age- and diabetes-associated retinal pathology. This review suggests that DR and retinal aging, although initiated by distinct triggers, converge on shared metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and autophagy impairment-mediated by genes expressed in ocular tissues. Within these intersecting pathways, shared hub genes emerge as central control nodes that may amplify molecular dysfunction and represent potential therapeutic entry points. By mapping these molecular intersections, this study may provide a unified mechanistic perspective of retinal degeneration and support the development of dual-purpose strategies aimed at preventing or mitigating both DR and aging-related retinal decline. These findings highlight potential translational opportunities for targeting shared metabolic networks; however, they should be interpreted as hypothesis-generating and require further experimental and clinical validation to establish causal relationships and therapeutic relevance.
Patients with head and neck squamous cell carcinoma (HNSCC) continue to face poor prognosis, highlighting an urgent need for new diagnostic markers and therapeutic targets. While metabolic reprogramming and immune microenvironment dysregulation are crucial drivers of HNSCC progression, the key causal molecular mechanisms linking these processes remain elusive. Post-translational modifications, especially protein lactylation, may serve as a vital interface for this metabolic-immune "crosstalk". We developed an integrative analytical framework merging lactylation proteomics, transcriptomics, and Mendelian randomization (MR). Differential expression analysis was conducted on three public transcriptomic cohorts (53 HNSCC vs. 53 controls), and the resulting genes were overlapped with a systematically compiled set of 2, 124 lactylation-related genes. Causal risk genes were then identified using MR analysis with large-scale genetic instruments (from expression quantitative trait locus data) and HNSCC genome-wide association study summary statistics. The functional roles of candidate genes were explored through enrichment analysis, Gene Set Variation Analysis, and immune deconvolution (CIBERSORT). Experimental validation was performed using quantitative real-time PCR and Western blotting in an independent The Cancer Genome Atlas dataset and in HNSCC cell lines. We identified 212 lactylation-associated differentially expressed genes. MR analysis established CD44 and APP as genetic causal risk factors for HNSCC, with both genes significantly overexpressed in patient tissues. Functional profiling indicated that high CD44 expression correlated with activation of mTOR signaling and ECM-receptor interaction pathways, and was positively associated with M0 macrophage infiltration. Conversely, high APP expression was linked to activated protein secretion and ECM pathways, and showed a positive correlation with M2 macrophage abundance. The marked upregulation of CD44 and APP in HNSCC was consistently confirmed in the independent validation cohort and in cellular models. By pioneering a multi-omics causal inference approach in HNSCC, this study identifies CD44 and APP as genetic causal risk factors for disease susceptibility and progression. These genes connect distinct metabolic pathways with specific immune cell subsets, functioning as central hubs within the HNSCC metabolic-immune crosstalk network. Our work provides a critical theoretical basis for future development of lactylation pathway-based biomarkers and targeted interventions.
Gouty arthritis (GA) is an inflammatory joint disease caused by the deposition of monosodium urate (MSU) crystals within the joint space and surrounding tissues. In traditional Chinese medicine, Rhizoma Drynariae (Gusuibu) has long been widely used in the clinical treatment of GA, and flavonoids are considered its key bioactive constituents. This research employed network pharmacology to construct a component-target network of total flavonoids of Rhizoma Drynariae (TFRD) against GA, thereby identifying key components, core targets, and related pathways. Rat models were established by intra-articular injection of a monosodium urate crystal suspension and treated with TFRD or the positive control, colchicine, by oral gavage. After sample collection, network pharmacology-based prediction results were subsequently validated using rat serum metabolomics, enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. Network pharmacology analysis indicated that the anti-GA effects of TFRD are mediated through key targets, including IL6, AKT1, TNF, EGFR, JUN, and PTGS2, and are mainly associated with inflammation, immune, and apoptosis-related pathways, such as the IL-17, TNF, NF-κB, MAPK, PI3K-AKT, JAK-STAT, and T-cell receptor signaling pathways. Similarly, metabolomics also uncovered the pivotal roles of the inflammatory response. Hematoxylin and eosin (H&E) staining confirmed that TFRD reduced infiltration of inflammatory cells. ELISA assay confirmed that the TFRD group significantly inhibited the expression of inflammatory factors TNF-α, IL-6, and IL-17A in synovial tissue. Western blot analysis revealed that TFRD inhibited the GA-induced hyperphosphorylation of AKT, MAPK p38, and NF-κB p65 in rat synovial tissue. TFRD can effectively ameliorate the inflammation-triggered changes in the GA rats by directly modulating related inflammatory factors and pathways.
Antibiotic-associated diarrhea (AAD) remains a common complication of antibiotic therapy. While probiotics show therapeutic potential, the novel strain Bacillus subtilis THC1I has not been previously evaluated for AAD treatment. This study aimed to assess the effects of B. subtilis THC1I on intestinal barrier integrity and gut microbiota dysbiosis in an AAD mouse model. Fifty mice were randomized into five groups (n = 10): control, model, positive control (Enterogermina®, B. clausii), and a B. subtilis THC1I spore suspension at 0.82 × 10⁹ and 1.64 × 10⁹ CFU/kg/day. AAD was induced with gentamycin sulfate and cefradine for five consecutive days. Outcomes included clinical symptoms, hematological and biochemical parameters, colonic macroscopic and histopathological indices, inflammatory cytokines, and gut microbiota analyzed by 16S rRNA sequencing. B. subtilis THC1I significantly improved body weight, water intake, fecal scores, and fecal water content. Treatment restored electrolyte balance (sodium and potassium), reduced white blood cell counts, and decreased relative colon weight and inflammation scores. Histopathological analysis revealed restored epithelial architecture and increased goblet cell density. Pro-inflammatory cytokines (TNF-α, IL-1β) were significantly reduced. B. subtilis THC1I partially improved microbial diversity (Shannon index) and modulated microbiota composition at both phylum and genus levels, decreasing pathogenic bacteria (Proteobacteria phylum: Escherichia-Shigella, Klebsiella, Salmonella; Firmicutes phylum: Clostridioides), and modulating the dysbiotic overgrowth of the beneficial commensal Blautia, while promoting beneficial bacteria (Bacteroidota phylum: Bacteroides, Muribaculaceae; Firmicutes phylum: Lachnospiraceae, Lactobacillus). B. subtilis THC1I demonstrates restorative effects on intestinal barrier damage and gut microbiota dysbiosis in AAD mice, supporting its potential as a therapeutic candidate for clinical application.
Spinal cord regeneration after injury remains a major clinical challenge due to the persistent inflammatory microenvironment associated with immune cell infiltration. Withaferin A (WA), a natural anti-inflammatory steroidal lactone with potential NF-κB-modulating activity, was identified by network-based screening as a candidate for spinal cord injury (SCI) and selected for further study. This study aimed to identify and evaluate potential anti-inflammatory small-molecule therapeutics for SCI using a network-based drug screening strategy. Experimental study combining computational drug screening, in vitro macrophage assays and in vivo SCI mouse models. Network pharmacology identified 296 candidate drugs targeting 113 SCI-related genes. Five top candidates, selected for chemical diversity and accessibility, were tested in LPS-stimulated in vitro models for effects on macrophage polarization and cytokine release. Molecular docking was used to predict drug-target interactions. The lead compound, WA, was then evaluated in SCI mice for inflammation, angiogenesis, neuroregeneration and motor recovery. WA showed the strongest anti-inflammatory activity, dose-dependently inhibiting LPS-induced M1 polarization and TNF-α/IL-6 secretion while promoting M2 polarization and IL-4/IL-10 secretion. Integrated computational and experimental analyses identified Cys160 in a hydrophobic pocket of NF-κB p65 as the covalent binding site of WA. In vivo, WA modulated macrophage polarization, reduced inflammatory mediator secretion, increased VEGF immunoreactivity and promoted neuroregeneration and motor recovery. WA exerts significant anti-inflammatory and neuroregenerative effects in SCI models. It also increases VEGF immunoreactivity, suggesting a potential pro-angiogenic effect after injury. These findings support WA as a promising therapeutic candidate for SCI.
Pulmonary arterial hypertension (PAH) is increasingly recognized as a metabolically dysregulated and inflammatory vascular disease rather than a purely haemodynamic disorder. Among emerging metabolic pathways, the bile acid-oxysterol axis has gained attention as a potential link between sterol imbalance, endothelial dysfunction, and pulmonary vascular remodeling. This narrative review examines current evidence linking selected bile acid and oxysterol species to PAH phenotypes and discusses their potential mechanistic and translational implications. Human lung tissue studies, circulating metabolomics, and experimental models suggest that selected bile acid intermediates and oxysterol species may carry biological information beyond nonspecific disease severity, although their effects are molecule-specific, receptor-specific, and context-dependent rather than uniform across the entire metabolite class. In particular, recent work implicates disturbed lysosomal sterol trafficking and impaired endothelial lysosomal acidification, including NCOA7-related mechanisms, in generating pro-inflammatory sterol signatures that promote endothelial immunoactivation and worsen experimental PAH. At the same time, the biological origin and interpretation of these metabolites are likely heterogeneous, involving lung-intrinsic sterol remodeling, systemic gut-liver signals, and potential confounding from right-heart failure or congestive hepatopathy. We argue that the bile acid-oxysterol axis should not be viewed as uniformly causal or purely biomarker-like across all patients, but rather as a compartment- and endotype-dependent framework whose interpretation depends on the level of evidence considered. This framework has important implications for biomarker development, therapeutic targeting, and precision trial design, and identifies sterol trafficking and lysosomal homeostasis as promising areas for future investigation.
Cisplatin is a key treatment for head and neck squamous cell carcinoma (HNSCC), but the development of resistance severely limits its effectiveness. The molecular determinants underlying cisplatin resistance in HNSCC remain unclear. Multiple databases were used to screen the core genes related to cisplatin resistance in HNSCC patients. Tumor tissue samples from HNSCC patients were collected and the expression of FOXA2 was verified through various pathological tests to establish the correlation between FOXA2 expression and the clinical characteristics of the patients. The in vitro and patient-derived organoids (PDOs) models were used to verify the regulatory effect of FOXA2 on the cisplatin resistance of HNSCC. Transcriptome sequencing combined with multi-omics analysis demonstrated that LAMC2 is a downstream target of FOXA2 in regulating cisplatin resistance. Bioinformatic screening of cisplatin-resistant cohorts revealed that FOXA2 was the only gene significantly associated with poor survival outcomes in TCGA-HNSCC patients. Transcriptomic profiling and pathway enrichment analyses revealed the activation of the PI3K/AKT signaling cascade. We identified LAMC2 as a direct transcriptional target of FOXA2. Chromatin immunoprecipitation and luciferase reporter assays confirmed FOXA2 binding to the LAMC2 promoter, resulting in transcriptional activation. FOXA2-mediated upregulation of LAMC2 increased PI3K and AKT phosphorylation, and LAMC2 overexpression reversed the impaired malignant phenotypes caused by FOXA2 silencing. In xenograft models and PDO systems, FOXA2 overexpression reduced responsiveness to cisplatin, whereas FOXA2 inhibition significantly increased therapeutic sensitivity. Our research has identified a previously unrecognized regulatory axis involving FOXA2, LAMC2, and PI3K/AKT, which plays a crucial role in the progression and resistance to cisplatin in HNSCC. Therefore, targeting the FOXA2-LAMC2 axis may represent a novel therapeutic strategy to overcome cisplatin resistance in HNSCC.
This study investigated the effects of dietary sodium butyrate supplementation on Nile tilapia, with emphasis on growth performance, biochemical alterations, histological characteristics, and gene expression patterns under both normal conditions and glyphosate exposure. A total of 90 Nile tilapia with an initial mean body weight of 7.93 ± 0.026 g were randomly allocated into two experimental groups, with each group comprising three replicate units. The control group was fed a basal diet, while the second group received 1.5 g/kg of sodium butyrate mixed into their food for 8 weeks. Afterward, each group was further divided into two: one without any challenge and the other exposed to 0.6 mg/L GLY. The findings indicated that fish fed with SB exhibited a significant improvement (p < 0.05) in final body weight (FBW), weight gain percentage (WG %), specific growth rate (SGR), protein efficiency ratio (PER), and survival rate, along with a reduction in feed conversion ratio (FCR) compared to the control group. Additionally, there was an enhancement in hepatic antioxidant capacity, along with a downregulation of hepatic ilgf1bp and myostatin. Fish subjected to GLY displayed the highest activities of ALT and AST, elevated levels of BUN and creatinine, and a decrease in lysozyme activity. Sodium butyrate supplementation mitigated glyphosate-induced hepatic and renal impairment and regulated the mRNA expression of intestinal tight junction-associated and apoptosis-related genes. These findings suggest that dietary sodium butyrate may be used as a promising alternative feed additive in sustainable Nile tilapia aquaculture. Its inclusion could help protect fish against glyphosate-associated stress, improve growth performance, enhance antioxidant and immune-related biochemical responses, and provide anti-inflammatory and anti-apoptotic benefits under both basal conditions and following glyphosate exposure.
Osteoporosis is increasingly recognized as a disorder of impaired skeletal adaptation in which endocrine stress, metabolic injury, altered mechanotransduction, remodeling imbalance, and redox vulnerability converge. Bone is also a circadian tissue, and ferroptosis is now directly implicated in skeletal cell dysfunction across several osteoporosis-related settings. This review examines whether proteostatic instability of brain and muscle ARNT-like 1 (BMAL1) could represent a mechanistically relevant link between these processes. To keep interpretation proportionate to the available data, bone-established evidence is distinguished from extra-skeletal bridge mechanisms and disease-contextual extrapolations that remain unproven in bone. Current evidence supports three conclusions. First, circadian regulation in bone extends beyond BMAL1 transcript abundance and must be interpreted within the broader clock network. Second, ferroptosis is directly established in osteoblasts and osteocytes across postmenopausal, glucocorticoid-related, diabetic, iron-overload, and unloading-related contexts. Third, BMAL1 is functionally important for skeletal differentiation and stress adaptation, but selective BMAL1 degradation and clockophagy have not yet been demonstrated in skeletal cells. Taken together, the literature does not justify describing clockophagy as an established skeletal pathway, but it does support a testable framework for defining when BMAL1 proteostasis may become pathogenic in osteoporosis and which experiments could most decisively validate or refute that possibility.
To evaluate whether cumin (Cuminum cyminum) oil attenuates nandrolone decanoate (ND)-induced hepatic alterations in rats. Eighty male Sprague-Dawley rats were randomized into six groups: control, cumin oil alone, ND low dose (10 mg/kg/week), ND high dose (20 mg/kg/week), ND low dose + cumin oil, and ND high dose + cumin oil. Cumin oil was administered orally at 400 mg/kg/day for 4 weeks. Outcomes included relative liver weight index, serum ALT/AST, total bilirubin, lipid profile, and blinded histopathology. Both ND doses increased ALT/AST and bilirubin levels and worsened the lipid profile compared with controls, with more pronounced and significant alterations in the high-dose ND group. Co-administration of cumin oil attenuated ND-associated elevations in liver enzymes and bilirubin, improved lipid parameters, and was associated with reduced histological damage compared with ND alone. Interestingly, cumin oil alone increased ALT/AST and lipid parameters compared with controls, although liver architecture remained unremarkable on H&E. In this rat model, cumin oil co-administration partially attenuated ND-induced hepatic biochemical, lipid, and histological alterations. However, cumin oil alone increased ALT/AST and lipid parameters despite unremarkable H&E morphology. Therefore, the present findings should be interpreted as evidence of context-dependent attenuation during ND exposure, not as proof of an independent hepatoprotective or lipid-lowering effect of cumin oil in healthy rats. Dose-ranging, safety evaluation, batch-specific chemical profiling, preparation standardization, and mechanistic studies incorporating antioxidant/oxidative stress markers such as MDA, GSH, SOD, CAT, GPx, and molecular endpoints are needed to clarify pathways and translational relevance.
This meta-analysis evaluated the efficacy and feasibility of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and identified key moderators. Controlled trials were systematically searched (PubMed, Web of Science, CNKI; initially in Feb 2025 and updated Jan 2026). Random-effects meta-analyses used SMDs; risk of bias, methodological quality, and evidence certainty were systematically assessed. Thirty-seven trials (1546 participants, 51% female, moderate quality) showed HIIT significantly improved 12 outcomes vs. controls, including body composition (g - 0.94 to -0.52), cardiometabolic parameters (-1.56 to 1.34), and liver markers (-1.06 to -0.50), while MICT benefited 18 outcomes, including body composition (-0.84 to -0.60), cardiometabolic parameters (-1.42 to 1.79), and liver markers (-0.72 to -0.67). HIIT was superior for total cholesterol reduction (g - 0.44, p < 0.05). Subgroup analyses identified significant moderation by obesity status, training frequency, exercise modality, and progression. Meta-regression revealed MICT effects moderated by age, BMI, and prescription parameters (e.g., session duration, weekly time, program length), with significant associations for body fat, lipids, and glycemic control changes. Exploratory nonlinear meta-regression showed distinct dose-response patterns for liver enzyme biomarker improved emerging beyond baseline, 260-280 MET-min per MICT session. Feasibility was high (adherence 83.4%, completion 83.9%), and safety was relatively high. Both HIIT and MICT effectively improve anthropometric, metabolic parameters, and liver function indicators in patients with MASLD, while demonstrating high feasibility and safety. Moderators' analyses identified key moderators and dose-response, informing evidence-based exercise prescription considerations for MASLD management. PROSPERO (CRD42025646755).
Metabolic dysfunction associated steatotic liver disease (MASLD) and its advanced form, MASH, are closely linked to cardiac dysfunction, particularly heart failure with preserved ejection fraction (HFpEF). However, the mechanisms underlying MASLD-associated HFpEF and its reversibility remain poorly understood, largely due to the lack of robust preclinical models. Here, we established a translational model of MASLD-associated cardiac dysfunction that recapitulates the key features of human HFpEF. We applied functional and transcriptomic analyses of the left ventricle (LV) to define the pathways associated with cardiac dysfunction and its reversibility. Alms1-/- (Foz/Foz) mice and wild-type littermates were fed normal chow (NC) or Western diet (WD) for up to 36 weeks (wk). Reversibility was modeled by switching WD-fed Foz/Foz mice at 12wk back to NC for 12wk. Cardiac assessment included echocardiography, invasive hemodynamics with dobutamine stimulation, histopathology, electron microscopy and isolated cardiomyocyte contractility. LV transcriptomes were profiled by bulk RNA sequencing and analyzed by differential expression and pathway enrichment. Foz/Foz mice on WD for 24wk developed metabolic syndrome and MASH with advanced liver fibrosis. Cardiac phenotyping showed LV hypertrophy, impaired cardiomyocyte contractility, reduced β-adrenergic reserve, elevated plasma BNP, and increased mortality while the ejection fraction was preserved (>50%), consistent with HFpEF. The progression of cardiac dysfunction was closely associated with liver fibrosis that developed during MASH. Switching WD-fed Foz/Foz mice at 12wk to normal chow diet reversed hepatic fibrosis, restored LV function, and reduced mortality, demonstrating plasticity of the liver-heart axis. LV transcriptomic analysis revealed that cardiac impairment in these mice was associated with mitochondrial dysfunction, altered substrate utilization, extracellular matrix remodeling, and metabolic stress; pathways that are similarly dysregulated in human HFpEF. Cardiac electron microscopy revealed swollen mitochondria with disrupted cristae, which improved following dietary intervention. Mitochondrial dysfunction and fibroinflammatory remodeling are prominent features of MASLD-associated cardiac dysfunction. Reversal of hepatic and cardiac phenotypes with dietary intervention, together with elucidation of underlying pathways, establish the Foz/Foz model as a useful translational platform for studying liver-heart axis in MASLD.
The human digestive system is first colonized at birth with many microorganisms that impact on the overall health of the individual via various metabolic, immune, and neuroendocrine pathways. Such microorganisms are referred to as probiotics, according to the FAO and WHO, and they exert effects on host and microbiota interaction primarily through strain-specific bioactive metabolites that act both locally and systemically. The current review will detail the various types of bioactive metabolites and their roles in regulating redox homeostasis via the reduction of reactive oxygen species (ROS) and increases in antioxidant defenses. These include catalase, glutathione peroxidase, and superoxide dismutase, which are believed to be responsible for reducing inflammation and improving epithelial barrier function. In addition to the traditional single-strain approach to probiotics, synbiotics represent an alternative strategy to improve microbial survival, functional stability, and microbiome homeostasis. Synbiotics consist of a combination of probiotic organisms and selective prebiotics that enhance the survivability and functional capacity of the individual strains and thus the overall functional resilience of the gut microbiome. Emerging evidence from mechanistic, experimental, and clinical studies demonstrates the increasing relevance of synbiotics in both therapeutic and translational contexts in the modern healthcare system.
Vasculogenic mimicry (VM) contributes significantly to tumor aggressiveness and resistance to anti-angiogenic therapies. Simultaneous inhibition of both angiogenesis and VM represents a promising strategy to improve therapeutic outcomes in aggressive cancers, such as triple-negative breast cancer (TNBC), which responds poorly to anti-angiogenic therapies. In this study, we identified carvacrol, a natural monoterpenoid phenol widely used as a food additive, as a dual inhibitor of angiogenesis and VM in TNBC. Carvacrol preferentially inhibited angiogenesis in endothelial cells (ECs) and VM in TNBC cells at concentrations that had minimal effects on TNBC cell proliferation. Mechanistically, carvacrol directly bound to the vanilloid-like (VL) site of transient receptor potential melastatin 7 (TRPM7), thereby inhibiting channel activity and attenuating Zn2+ influx. This triggered dephosphorylation of the mammalian target of rapamycin (mTOR) and subsequent proteasomal and lysosomal degradation of key receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR2), Tie2, fibroblast growth factor receptor 1 (FGFR1), and insulin-like growth factor 1 receptor (IGF1R) in ECs, as well as FGFR1 and IGF1R in TNBC cells. Genetic knockdown of TRPM7 recapitulated the anti-vascular effects and signaling alterations induced by carvacrol. In vivo, carvacrol effectively suppressed TNBC vascularization and growth in a mouse dorsal skinfold chamber model and an orthotopic xenograft model. Together, these findings suggest that carvacrol preferentially targets angiogenesis and VM in TNBC by suppressing the TRPM7/Zn2+/mTOR/RTKs axis, highlighting it as a promising therapeutic candidate for TNBC and potentially other tumors resistant to anti-angiogenic therapies, while positioning the TRPM7 channel as a novel anti-vascular target for TNBC treatment.
Hydroxysafflor Yellow A (HSYA), the major bioactive component from Carthamus tinctorius L., exerts significant protective effects against myocardial ischemia-reperfusion injury (MIRI). Mitophagy is pivotal in the pathological process of MIRI, yet the specific molecular mechanism underlying HSYA-mediated mitophagy regulation remains unclear. This study aimed to investigate the association between HSYA treatment and mitochondrial autophagy in murine MIRI and to explore the potential mechanistic role of the SIRT1-FOXO3-BNIP3 signaling pathway using functional loss-of-function and rescue experiments. These findings may provide preliminary evidence supporting the clinical translational potential in MIRI therapy. Mouse myocardial ischemia-reperfusion injury (MIRI) model and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced AC16 cardiomyocyte injury models were established. Metabolomics, molecular docking, and surface plasmon resonance (SPR) techniques were combined to screen the potential targets of HSYA. The SIRT1 inhibitor EX527 and SIRT1 siRNA were used to verify the underlying mechanism. Cardiac function, myocardial infarct size, mitochondrial function, the expression of autophagy-related proteins, and protein-protein interaction were detected and analyzed. Compared with the MIRI group, HSYA significantly improved cardiac function in mice, as evidenced by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (p < 0.01), attenuated ST-segment elevation, and improved myocardial perfusion. HSYA also markedly reduced myocardial infarct size (p < 0.01) and serum levels of CK-MB, LDH, and cTnI (all p < 0.01) and ameliorated myocardial histopathological damage and mitochondrial ultrastructural integrity. Mechanistic studies revealed that HSYA significantly upregulated the expression of SIRT1, FOXO3, BNIP3, Beclin-1, and the LC3II/I ratio while downregulating p62 expression (p < 0.01), consistent with enhanced mitophagy-related activity. Furthermore, these protective effects were markedly attenuated upon SIRT1 inhibition or siRNA-mediated silencing, whereas HSYA intervention partially reversed these alterations. Additionally, co-immunoprecipitation (Co-IP) and pull-down assays demonstrated that HSYA promoted protein-protein interactions between SIRT1-FOXO3, FOXO3-BNIP3, and BNIP3-LC3B. These findings highlight that HSYA is associated with improved cardiac function, enhanced mitophagy-related activity, and upregulated SIRT1-FOXO3-BNIP3 signaling, providing robust experimental evidence for its clinical translational application in MIRI treatment.
Overweight and obesity are chronic diseases that result from complex interactions including genetics, environment, eating behaviors, and limited access to a healthy diet. Amaranth protein (AmProt) has several health benefits, but no studies have examined its effects on the modulation of children's gut microbiota. The work aimed to analyze serum levels and changes in gut microbiota in children aged 8-10 years with different body mass index (BMI) values after supplementation with AmProt. Participating children were allocated into three groups according to their BMI: normal weight (NW), overweight (OW), and with obesity (OB). Children received AmProt for 90 days. Levels of fasting blood glucose, cholesterol, triglycerides, and insulin were analyzed before and after diet supplementation. HOMA-IR and adinopectin/leptin ratio were evaluated. Feces were collected and metagenome analysis was carried out. No changes in glucose levels were observed across groups and treatments; however, cholesterol and triglycerides levels tended to decrease. The HOMA-IR value increased in relation to BMI and no changes were observed after treatment. Firmicutes were highly abundant in all groups. The lower abundance of Ruminococcus was observed in the OW and OB groups. In the OW group, Blautia, Butyricicoccus, and Roseburia were also observed in increased abundance. In all groups, AmProt consumption tended to increase the abundance of Coproccus, Prevotella, and Collinsella. Conclusions: Supplementation of the children's diet with AmProt showed an improvement in serum cholesterol and triglyceride levels, which could be related to changes in the microbiota related to lipid metabolism.
Gastric cancer (GC) is one of the main causes of cancer-related global mortality. The emergence of drug resistance and toxicity in current therapies highlights the need for novel treatment strategies. Quercetin, a natural flavonoid, has demonstrated anticancer activity; however, its molecular mechanism, particularly its effect on key targets in GC, remains underexplored. A comprehensive in silico and in vitro methods were used to elucidate the anticancer potential of Quercetin. Network pharmacology analysis was used to identify potential GC-related targets, followed by molecular docking and 200 ns molecular dynamics (MD) simulations to evaluate the binding affinity and stability of the Quercetin-target complex. In vitro experiments, including gene expression analysis and fluorescence binding assays, were conducted using AGS gastric cancer cells to validate the computational findings.nsulin-like growth factor 1 (IGF1) emerged as a key hub gene associated with GC progression. Molecular docking predicted a favorable interaction between Quercetin and IGF1, with a docking score of - 6.3 kcal/mol and multiple hydrogen-bond interactions. MD simulations confirmed the stability of the Quercetin-IGF1 complex, with reduced RMSD values (0.48 nm vs. 0.63 nm for unbound IGF1), favorable free energy profiles, and stable hydrogen bonding. In vitro studies demonstrated a significant downregulation of IGF1 mRNA expression (p < 0.001) and a dose-dependent inhibition of IGF1 activity by Quercetin. The integration of network pharmacology, computational modeling, and experimental validation suggests that Quercetin may modulate the IGF1 signaling axis and influence IGF1-associated pathways in gastric cancer. The stable binding and significant inhibitory effect observed suggests that Quercetin may interrupt IGF1-mediated signaling pathways involved in tumor growth and survival. This study identifies Quercetin as a potential modulator of IGF1-associated signaling pathways with significant therapeutic promise for gastric cancer. The findings provide mechanistic insights supporting the further development of Quercetin as a targeted therapy for IGF1-driven malignancies.