Search Results (2,155)

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive stage of metabolic dysfunction-associated steatotic liver disease characterized by lipid dysregulation, oxidative stress, inflammation, and fibrosis. Because these processes occur simultaneously, compounds targeting multiple pathways may offer therapeutic benefit. Naringin, a citrus-derived flavonoid, has reported antioxidant and anti-inflammatory properties, but its integrated effects in MASH remain unclear. In this study, the effects of naringin were evaluated using combined in silico analysis and in vivo experiments. Network pharmacology and molecular docking predicted targets related to lipid metabolism, oxidative stress, inflammation, and fibrosis, which were validated in a methionine- and choline-deficient diet-induced mouse model. Naringin reduced hepatic lipid accumulation and improved serum AST and ALT levels. It modulated oxidative stress-related genes, attenuated inflammatory responses, and reduced fibrogenic markers. Naringin also decreased Ly6Chigh inflammatory monocytes and Kupffer cell activation, and reduced hypothalamic microglial activation. These findings suggest that naringin exerts multi-target effects across hepatic, systemic, and central pathways, supporting its potential as a therapeutic candidate for MASH. Full article

Fungal endophytes are symbiotic microorganisms that establish strong relationships inside plant tissues, providing potential advantages, especially in grasses, by enhancing tolerance to both abiotic and biotic stresses. This review investigates the molecular mechanisms through which fungal endophytes mediate stress tolerance, targeting host–pathogen interactions. By modulating pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and effector proteins, fungal endophytes may contribute to priming the plant’s immune system, enhancing its resistance to pathogen invasion. Moreover, endophyte colonization regulates core processes such as osmotic regulation, reactive oxygen species (ROS) detoxification, and secondary metabolite biosynthesis that enable plants to tolerate environmental stresses like drought, heat, and salinity. The review highlights the impact of endophytes on immune priming, systemic acquired resistance (SAR), and the regulation of non-coding RNAs that regulate host gene networks associated with stress tolerance. Furthermore, the integration of advanced multi-omics techniques genomics, transcriptomics, proteomics, metabolomics, and fluxomics has revealed emerging insights into the genetic and metabolic pathways driving these symbiotic associations. However, grass-specific molecular datasets remain limited, and the consistency of endophyte-mediated tolerance across host species and environmental conditions is not yet fully resolved. Fungal endophytes increase grass stress resilience through coordinated pathogen recognition, RNA regulation, and metabolic reprogramming while AI-assisted multi-omics approaches are emerging as tools for identifying candidate regulatory networks, although empirical validation in grass–endophyte systems remains limited. Together, these advances highlight the potential for climate-smart and sustainable crop improvement. Future research integrating functional genomics, field validation, and biosafety assessment will be essential for translating endophyte-based strategies into reliable agricultural applications. Full article

Diarrhea is a common gastrointestinal disorder in animals, often worsened by antibiotic use. Pulsatilla chinensis (PC) is traditionally used for gastrointestinal issues, but its bioactive constituents and mechanisms remain unclear. This study investigated the preventive effects of PC in a canine model of antibiotic-associated diarrhea using an integrated multi-omics approach. LC–MS identified key constituents of PC, including anemoside B4, berberine, stigmasterol, and quercetin. In silico analyses predicted that stigmasterol and quercetin target EGFR and AKT1, modulating inflammation and epithelial repair via PI3K–Akt and IL-17 signaling pathways. In vivo, treatment with PC significantly reduced serum pro-inflammatory cytokines such as TNF-α and IL-6 and elevated immune markers including IgG and IgA compared to the control group. Furthermore, 16S rRNA analysis revealed that PC restored gut microbial diversity, reflected by increased Sobs and Chao1 indices, enriched beneficial Lactobacillus, and decreased the abundance of inflammation-associated taxa such as Proteobacteria, Desulfobacterota, and Escherichia-Shigella. These findings suggest that PC suppresses inflammation and remodels the gut microbiome, providing a mechanistic basis for its use as an herbal alternative to antibiotics. Future studies should include fecal microbiota transplantation and targeted metabolomics to establish causality and optimize therapeutic strategies. Full article

Colorectal cancer (CRC) develops gradually from precancerous adenomas and is highly curable when detected early. In Malaysia, however, most cases are diagnosed at advanced stages, leading to poorer outcomes despite the availability of screening programmes such as the immunological Faecal Occult Blood Test (iFOBT). Limited screening uptake and poor adherence contribute to delayed diagnosis. Therefore, effective non-invasive and patient-friendly screening tools are essential. Background/Objectives: This study aims to validate the diagnostic performance of the multi-target stool DNA (mt-sDNA) test. Methods: This cross-sectional validation study was conducted at the Endoscopic Center, Hospital Canselor Tuanku Muhriz (HCTM), from January 2024 to September 2025. Adults aged 18–75 years undergoing elective or emergency colonoscopy were included. Results: Among 246 patients, most were male (56.5%), Malay (65.2%), and aged 55–75 years (91.3%). CRC prevalence was 8.5%. A significant association was observed between age group and colonoscopy findings (p = 0.005), with older individuals more likely to have CRC or adenomatous lesions. Most CRC (90.4%) and advanced adenoma (84.6%) cases occurred in symptomatic patients; however, this difference did not demonstrate a significant association with colonoscopy outcomes (p = 0.069). Per rectal bleeding, constitutional symptoms, altered bowel habit, abdominal pain and constipation were significantly associated with CRC and adenomatous lesions. The mt-sDNA test showed a sensitivity of 63.2%, specificity of 85.0%, positive predictive value of 36.4%, and negative predictive value of 94.4%. Conclusions: Preliminary findings indicate that mt-sDNA demonstrates good specificity and high negative predictive value, but moderate sensitivity and low positive predictive value. Full article

Background/Objectives: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway are effective drugs for migraine prevention. The worsening of symptoms after treatment discontinuation has raised the question of whether these agents are associated with sustained central neurophysiological adaptation. This study investigated treatment-associated changes in sensory processing and cortical network efficiency during preventive treatment with CGRP monoclonal antibodies (mAbs). Methods: Twenty-two patients with episodic migraine (21 female, 46.2 ± 13.8 years) and 22 age- and sex-matched healthy controls underwent visual and somatosensory evoked-potential (VEP, SSEP) assessments and quantitative electroencephalography (qEEG). Patients were investigated before treatment initiation (V0) and after 3 months of CGRP mAb treatment (V3). Healthy controls were assessed once. Results: The lack of habituation of VEPs at V0 shifted toward habituation at V3 following treatment with CGRP mAbs (Δslope: −0.37 ± 0.83, p = 0.03). VEP habituation at V3 no longer differed significantly from controls. SSEP amplitudes remained stable and did not differ significantly between groups across the study interval. Exploratory qEEG parameters indicated a less efficient cortical network organization at V0 that was no longer significantly different from controls at V3. Conclusions: Three months of CGRP mAb treatment was associated with a partial normalization of selected neurophysiological parameters, particularly VEP habituation and exploratory qEEG network measures. Given the study design and small sample size, these findings indicate adaptive changes in multi-domain processing, yet these should not be overinterpreted as proof of disease modification. Full article

Acute lymphoblastic leukemia (ALL) is a clinically diverse cancer in which microRNA (miRNA)-mediated post-transcriptional regulation contributes to leukemogenesis and subtype heterogeneity. In this study, miRNA expression profiling by microarray was performed on ALL cases (B-ALL and T-ALL) and healthy controls. Data were normalized and analyzed for differential expression using false discovery rate (FDR)-adjusted p-values. Differentially expressed miRNAs were further examined using unsupervised visualization to assess overall disease-related expression patterns. To explore their biological significance, experimentally validated miRNA–target interactions were obtained using multiMiR, limited to validated databases (miRTarBase, TarBase, and miRecords) and summarized via target-burden ranking, miRNA–target network analysis, and Circos–style interaction mapping. A unique miRNA expression signature was identified in ALL. Upregulated miRNAs included miR-106a-5p, miR-106b-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-181b-5p, and miR-128-3p, while miR-127-3p, miR-139-5p, miR-433-3p, and miR-584-5p were downregulated. Validated targets concentrated on key leukemia-related genes like PTEN, BCL2L11, CDKN1A, CCND1, RB1, E2F1, and TGFBR2. KEGG pathway analysis highlighted pathways associated with leukemic cell survival and growth, including MAPK, cell cycle, autophagy, Hippo, ubiquitin-mediated proteolysis, and mTOR signaling pathways. These findings reveal a concise ALL-associated miRNA panel predominantly comprising the miR-17/20/106 family and provide a prioritized set of candidate regulatory networks for subtype-specific validation and functional follow-up studies. Full article

Active sonar tracking of multiple underwater targets is frequently challenged by intense reverberation, which leads to sonar returns that are both non-stationary and non-Gaussian. In such scenarios, the generalized labeled multi-Bernoulli (GLMB) filter, which relies on a Gaussian assumption, often experiences a rise in an Optimal Subpattern Assignment (OSPA) distance, along with recurrent label switching. To mitigate this problem, a robust delta-generalized labeled multi-Bernoulli technique (ST-δ-GLMB) is introduced; it characterizes noise using a Student’s t-distribution and employs variational Bayes to estimate the corresponding parameters. More precisely, the Student’s t-distribution is utilized to represent measurement non-stationarity, and an online variational Bayesian estimation of the noise parameters is conducted within a multi-target framework based on the Student’s t-model. Moreover, without altering the GLMB data-association and label-management machinery, we derive closed-form updates and propagation for the Student’s t-parameters, thereby keeping the recursive computational burden and practical implementability under control. Finally, Monte Carlo simulations and lake-trial data demonstrate that, under non-stationary and heavy-clutter conditions, ST-δ-GLMB maintains stable track continuity and accurate target-number (cardinality) estimates in the presence of non-stationary measurements. Full article

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals notable for their high persistence and extensive applications. With the advancement of detection technologies in recent years, PFAS have been frequently identified in environmental media and human biological samples, raising significant global concerns about their potential health risks. PFAS exhibit distinctive toxicokinetic behaviors, including efficient absorption, strong protein binding, limited metabolism, and slow excretion, which lead to prolonged biological half-lives and considerable bioaccumulation in humans. These properties contribute to a range of adverse health outcomes, such as endocrine disruption, immune suppression, liver damage, reproductive toxicity, carcinogenic potential, and cardiovascular disease. This review synthesizes evidence on PFAS-associated health risks from a multisystem, multitarget perspective, elucidating the key molecular pathways involved, thereby providing a scientific basis for understanding their complex toxicological effects and for developing targeted prevention and control strategies. Future research should prioritize characterizing the toxicological profiles of individual PFAS compounds, evaluating the health impacts of combined (mixture) exposures, and assessing risks associated with chronic, low-dose exposure to support the development of public health strategies and regulatory decisions. Full article

Oxidative stress is a key contributor to the pathogenesis of immune-mediated diseases through its effects on cellular metabolism, mitochondrial function, immune signaling pathways, and inflammatory tissue injury. Disruption of redox homeostasis promotes metabolic reprogramming and persistent activation of innate and adaptive immune responses, contributing to disease progression across multiple inflammatory and autoimmune disorders. Recent advances in high throughput molecular technologies have generated large scale multi-omics datasets that enable comprehensive investigation of redox-associated mechanisms at a systems level. Integration of these datasets with computational analytical approaches has facilitated the identification of multidimensional molecular signatures associated with disease development and progression. This systematic review evaluates studies applying computational frameworks to analyze redox-related molecular data in immune-mediated diseases including multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, Sjögren’s syndrome, and inflammatory bowel disease. Across the reviewed studies, oxidative stress associated with molecular signatures were consistently linked to immune activation, mitochondrial metabolism, and inflammatory signaling pathways. Computational analyses also identified regulatory genes involved in antioxidant defense and metabolic regulation, as well as pathways associated with regulated cell death. These findings highlight the translational potential of computational redox analysis for biomarker discovery, disease stratification, and development of targeted therapeutic strategies aimed at restoring redox balance and improving clinical management of immune-mediated diseases. Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent mucosal inflammation and dysregulated immune–metabolic responses. Koumiss, a traditional fermented mare’s milk, has long been used in ethnomedicine for gastrointestinal disorders; however, its molecular mechanisms in UC remain unclear. In this study, an integrated multi-omics approach combining network pharmacology, quantitative proteomics, and molecular docking was employed to elucidate the therapeutic mechanism of koumiss powder (KP) in a dextran sulfate sodium (DSS)-induced murine colitis model. Network pharmacology identified twelve bioactive compounds targeting fourteen UC-associated proteins, predominantly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In vivo experiments demonstrated that high-dose KP significantly alleviated disease activity, improved colon shortening and histopathological injury, reduced serum TNF-α and IL-6 levels, and restored anti-inflammatory cytokines IL-4 and IL-10. Proteomic analysis further revealed activation of the PPAR signaling pathway, with significant upregulation of Plin4 and Sorbs1. Immunofluorescence staining further confirmed that KP restored the expression of PPARA and increased the levels of Plin4 and Sorbs1 in colonic tissues. Molecular docking confirmed strong binding affinities between key koumiss-derived lipid metabolites, including 13(S)-HOTrE and stearoyl ethanolamide, and PPAR-related target proteins. Collectively, these findings demonstrate that koumiss exerts protective effects against experimental UC primarily through activation of PPAR-mediated lipid metabolic and anti-inflammatory pathways. This study provides mechanistic insight into the biological activity of koumiss and highlights the value of multi-omics integration in natural product research. Full article

Background: Intervertebral disc degeneration (IVDD) is driven by the interplay between inflammatory signaling, extracellular matrix (ECM) degradation, and impaired cellular adaptation. Although several nutraceutical compounds have been reported to exert protective effects in IVDD-related models, their multitarget mechanisms within integrated molecular networks remain incompletely characterized. Methods: An in silico framework integrating molecular docking with network-based analyses was employed to evaluate resveratrol, quercetin, melatonin, curcumin, and baicalein against a predefined panel of IVDD-associated targets, within an exploratory in silico framework. Binding affinities and interaction profiles were assessed using molecular docking, followed by protein–protein interaction (PPI) network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and hub gene identification. Results: Docking analyses revealed binding energies ranging from −4.59 to −13.25 kcal/mol, with curcumin and quercetin showing plausible docking poses across a subset of selected targets under the applied protocol. Network analysis showed a highly interconnected structure centered on key inflammatory regulators, including NFKB1, IL6, TNF, IL1B, STAT3, and NLRP3, together with ECM-associated components such as ACAN, COL2A1, SOX9, MMP13, and ADAMTS5. Enrichment analyses further suggested significant associations with inflammatory signaling pathways, cytokine regulation, and ECM organization. Conclusions: These findings are compatible with a distributed, multitarget interaction pattern of nutraceutical compounds within IVDD-associated molecular networks. By integrating molecular docking with network-based analyses, this study offers a system-level framework for interpreting previously reported effects within a disease-specific context. Docking-derived interaction patterns should be interpreted as qualitative and exploratory observations, as docking scores represent model-dependent estimates and do not establish comparable pharmacological effects across heterogeneous targets. The results should be considered hypothesis-generating and require experimental validation. Full article

Prominin-1 (Prom1/CD133) has long been recognized as a structural determinant of photoreceptor outer segment (OS) morphogenesis, yet rapidly accumulating evidence extends its role to retinal pigment epithelium (RPE) homeostasis, encompassing autophagy–lysosomal flux, outer segment phagocytosis, mitochondrial function, and regulation of inflammatory stress. This review synthesizes mechanistic and transcriptomic insights that position PROM1 as a central regulator of photoreceptor and RPE integrity, reframing Prom1 disease as a multi-compartment retinal disorder relevant to both inherited retinal dystrophies (IRDs) and atrophic age-related macular degeneration (aAMD). We develop a dual-axis conceptual model in which Prom1 dysfunction can initiate pathology in either the photoreceptors (OS morphogenesis failure) or the RPE, including impaired autophagic flux, lysosomal activity, defective phagocytosis, and Epithelial-Mesenchymal Transition (EMT)-like de-differentiation, with secondary cross-compartmental degeneration. Clinically, autosomal-dominant missense variants associate with macular or cone-rod dystrophy, whereas biallelic truncating/splice-site mutations drive early-onset rod–cone disease and panretinal/RPE atrophy, illustrating genotype–phenotype diversity. By integrating recent high-resolution transcriptomic data from Prom1-deficient RPE cells with long-standing insights into photoreceptor biology, we highlight converging pathways of degeneration that challenge a photoreceptor-centric view and unify disparate phenotypes within a single molecular framework. These insights broaden the therapeutic landscape, advancing gene augmentation and pathway-targeted strategies to preserve RPE integrity, sustain photoreceptor function, and modify disease course in PROM1-associated IRDs and atrophic AMD. Full article

Fusobacterium nucleatum (F. nucleatum), a key oral pathogen, promotes colorectal cancer (CRC) progression via gut translocation. Although gut probiotics provide colonization resistance against pathogens, antibiotic-induced dysbiosis may facilitate F. nucleatum integration and increase the risk of CRC. The mechanisms underlying probiotic–F. nucleatum antagonism and antibiotic modulation remain unclear. A 33-strain probiotic consortium and F. nucleatum subsp. Polymorphum (F. polymorphum) ATCC 10953 were co-cultured. The inhibitory effects of probiotics on F. nucleatum and the impacts of antibiotics (ABXs) on the microbial community structure in the co-culture system and on the probiotic-mediated inhibition of F. nucleatum were evaluated using spent medium assays, plate confrontation tests, growth curves, qRT-PCR, metagenomic sequencing, and transcriptomics. Hydrogen peroxide/pH/lysine assays and coaggregation models were performed to probe the associated mechanisms. Probiotics strongly inhibited the growth of F. nucleatum in a dose-dependent manner, primarily via organic acids, while F. nucleatum enriched amino acid/vitamin biosynthesis pathways without major growth suppression. Antibiotics weakened probiotic antagonism, shifted species abundance (↓ L. plantarum, ↑ L. paracasei), induced adaptive stress responses in F. nucleatum (↑ nucleotide metabolism, propanediol degradation, pdxS), and reduced lysine biosynthesis. Lysine supplementation restored probiotic abundance and disrupted F. nucleatum coaggregation. Multi-strain probiotics exert potent colonization resistance effects against F. nucleatum, mainly through organic acids and metabolic interference. Antibiotic-induced dysbiosis impairs this protective effect and may promote the persistence of F. nucleatum, which has been implicated in CRC risk. Targeted probiotic strategies may offer novel preventive approaches. Full article

Sarcopenia is an age-related skeletal muscle disorder characterized by reduced muscle mass, strength, and physical performance, as well as increased risk of disability, hospitalization, and mortality. Emerging evidence suggests that gut microbiota alterations may contribute to muscle decline via a microbiota–gut–muscle axis, acting as a context-dependent modulator rather than a primary causal driver. This narrative review synthesizes mechanistic, clinical, and translational evidence linking gut dysbiosis to sarcopenia. Preclinical studies show that microbiota modulation (e.g., antibiotics, probiotics, prebiotics, postbiotics, fecal microbiota transplantation) affects muscle mass, strength, and metabolism through pathways including inflammation, mitochondrial dysfunction, altered short-chain fatty acid production, and impaired anabolic signaling. In humans, observational studies associate lower microbial diversity and reduced short-chain fatty acid-producing taxa with poorer muscle outcomes, but findings are heterogeneous and non-causal. Interventional trials remain limited and characterized by small sample sizes, with effects more consistent for functional outcomes than muscle mass. Overall, the gut microbiota represents a modifiable contributor within the complex biology of sarcopenia. Future studies should integrate microbiome profiling and multi-omics approaches within well-designed clinical trials to identify responder phenotypes and define the role of microbiota-targeted strategies within multimodal interventions. Full article

Increasing evidence suggests pancreatic cancer develops within a host–microbe ecosystem in which microbial communities across anatomical niches interact with tumour biology, immune regulation, metabolism, and therapeutic response. This review examines pancreatic cancer through the lens of humans as holobionts, integrating evidence from the oral, gut, biliary, and intratumoural microbiomes. Epidemiological and sequencing studies demonstrate consistent microbial alterations across these niches in pancreatic cancer, including oral dysbiosis associated with periodontal pathogens, gut microbial shifts toward pro-inflammatory taxa, disease-specific biliary microbial signatures, and the presence of distinct intratumoural microbial communities. Mechanistic studies indicate that intestinal barrier disruption, microbial translocation, immune and metabolite signalling can influence tumour immune architecture, macrophage polarisation, T-cell infiltration, oncogenic signalling pathways, and chemotherapeutic metabolism, particularly inactivation by tumour-associated bacteria. Microbiome-driven shifts in immunometabolism can reprogramme immune-cell metabolic pathways, impairing effective T-cell activation, promoting tumour-supportive macrophage phenotypes. Emerging therapeutic strategies aim to modulate the microbiome–tumour axis, including dietary interventions, probiotics and immunonutrition, faecal microbiota transplantation, engineered microbial therapies, and microbiome-informed antibiotic strategies. While pre-clinical findings are compelling and early-phase clinical studies suggest feasibility, most evidence remains associative and heterogeneous across cohorts and methodologies. Understanding pancreatic cancer as a multi-site ecological system may help explain inter-patient variability in disease progression and treatment response. This could usher in a new era for therapeutic manipulation where future progress will depend on longitudinal, multi-omic, and interventional studies to determine whether microbiome-targeted strategies can produce clinically meaningful improvements in pancreatic cancer outcomes. Full article