Search Results (808)

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain, altered motility, and visceral hypersensitivity. Emerging evidence implicates G protein-coupled receptors (GPCRs) as key integrators of microbial, immune, endocrine, and neural signals in IBS pathophysiology. This review summarizes recent advances in understanding how GPCRs mediate gut immune regulation, microbiota–host crosstalk, metabolic signaling, and pain processing in IBS. Recent studies show that microbial metabolites (e.g., short-chain fatty acids, biogenic amines, and lipid mediators) signal through GPCRs on immune cells, epithelia, and neurons to influence intestinal homeostasis. On immune cells and neurons, GPCRs also mediate signals from external substances (such as fats, sugars, histamine, etc.) to regulate immune and neural functions. And there are challenges and future directions in targeting GPCRs for IBS, including patient heterogeneity and the complexity of host–microbiome interactions. This review provides a mechanistic framework for GPCR-based therapies in IBS. Full article

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

Over the past decade, research on urolithins has expanded significantly due to their role as mediators between polyphenol-rich diets and human health. Understanding the relationships between ellagitannin intake, gut microbiota composition, and urolithin production is essential for evaluating their biological effects and nutraceutical potential. The primary objective of this review is to critically summarise current knowledge on urolithins, bioactive metabolites derived from ellagitannins in plant-based foods, with a focus on their biosynthesis, bioavailability, protein interactions, and potential therapeutic applications. A comprehensive literature search was conducted using PubMed, Scopus, and Google Scholar to identify studies on urolithin biosynthesis, absorption, transport mechanisms, protein binding, and incorporation into extracellular vesicles. Relevant articles were critically analysed to synthesise current evidence and highlight emerging concepts. Key findings indicate that after absorption, urolithins bind to serum albumin, which facilitates their transport to target tissues, exerting anti-inflammatory and antioxidant actions. Recent evidence also shows that urolithins can be packaged into extracellular vesicles, suggesting novel mechanisms for intracellular transport and potential therapeutic applications. This review highlights gaps in current knowledge and proposes directions for future research to optimise their therapeutic potential. Full article

Marine flora is a significant source of bioactive metabolites. These compounds have been demonstrated to have outstanding bioactivity and biocompatibility, enabling their use in various therapeutic applications. Therefore, examining the biological potential of marine natural compounds remains important, with particular emphasis on their interaction profiles to identify the macromolecular partners they can modulate. This study focused on the interactome profiling of the marine alkaloid caulerpin (CAU), isolated from the alga Caulerpa cylindracea. Along with the discovery of its antitumor properties, this metabolite has garnered attention for its potential therapeutic applications, including modulation of MAO-B and PPARs involved in inflammatory responses, as well as the discovery of its antitumor properties. Two complementary MS-based proteomic approaches were used to identify CAU target proteins in cancer cells: DARTS, which enabled proteome-wide screening to identify proteins interacting with the compound, and t-LIP-MRM-MS, which pinpointed the target protein regions involved in ligand binding. RUVB-like 1 (RUVBL1), a protein that regulates the essential mechanism of carcinogenesis, including chromatin remodeling, DNA repair, and transcriptional control, was discovered as an intriguing CAU target. These results were corroborated via in silico and biological investigations that elucidated CAU role in the regulation of RUVBL1 activity, highlighting its promising therapeutic relevance. Full article

The vaginal microbiome plays a crucial role in maintaining host health by preserving a balanced microenvironment. Nevertheless, the definition of a “normal” vaginal microbiome remains controversial, as its composition varies depending on factors such as ethnicity and geographical origin. In most cases, members of the genus Lactobacillus predominate in healthy vaginal microbiomes, protecting against potential pathogens through specific mechanisms such as the secretion of lactic acid and bacteriocins, among others. A reduction in Lactobacillus abundance, accompanied by an increase in anaerobic organisms, predisposes the host to the development of various pathologies. Among these pathologies is infection with human papillomavirus (HPV) and the subsequent development of cervical cancer. A progressive decline in Lactobacillus has been observed as the lesion advances in different populations worldwide. In the case of the Mexican population, several Lactobacillus have been reported in healthy microbiomes: L. gasseri, L. fermentum, L. rhamnosus, L. jensenii, L. crispatus, L. delbrueckii, L. acidophilus, and L. brevis. In contrast, genera reported in dysbiosis include Sneathia, while Brevibacterium aureum and Brachybacterium conglomeratum have been associated with HPV16 infection and/or SIL. The mere presence of some bacteria is not sufficient to modulate the cellular activity of host cells; therefore, the expression, production and activity of different proteins could be affected by the vaginal microbiome. The impact of the microbiome on host cell function is the result of different metabolites produced by the bacteria, which suppress or activate different signaling and metabolic pathways. The molecular interactions between the host and microbiome, as well as their role in cervical carcinogenesis, are still unknown. In this review, we focus on the vaginal microbiome, HPV, and the impact that the interaction of the microbiome with HPV has in cervical cancer development. Full article

Bacillus-derived lipopeptides are known to possess diverse biological activities, including antimicrobial and anticancer properties, though the mechanisms of such effects at the molecular level remain incompletely understood. We investigated whether non-ribosomal peptide metabolites from Bacillus can directly interact with transmembrane receptors implicated in oxidative stress regulation and cancer progression (NOX4, EGFR, PDGFR, and OCTN2) using molecular docking and 200 ns molecular dynamics simulations of 11 lipopeptide metabolites. Molecular docking revealed several strong ligand–protein interactions, with plipastatin and fengycin emerging as lead compounds demonstrating the highest binding affinities to multiple receptors. For NOX4, iturin D showed the strongest docking score of −7.85 kcal/mol. Fengycin demonstrated a high docking score of −7.38 kcal/mol for PDGFR and −8.1 kcal/mol for EGFR. Plipastatin showed the strongest docking scores of −11.12 kcal/mol for EGFR and −8.7 kcal/mol for OCTN2. Molecular dynamics simulations confirmed complex stability for these lead compounds, with protein RMSD remaining stable at ~1.5 Å and ligand RMSD between 1.9 and 6 Å over 200 ns. Our findings suggest that plipastatin and fengycin may act as modulators of key receptors involved in oxidative stress and cancer-related signaling. However, those in silico predictions require experimental validation. This work provides the first computational evidence of potential lipopeptide–receptor interactions and establishes a foundation for future experimental investigation of probiotic-derived therapeutics. Full article

Alcoholic liver injury (ALI) is a major global public health issue, with oxidative stress imbalance as its core pathological mechanism. The Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2–heme oxygenase-1/glutathione peroxidase 4 signaling pathway (Keap1–Nrf2–HO-1/GPX4) signaling pathway is a key target for regulating hepatic antioxidant defense. This study integrated Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS), Global Natural Products Social Molecular Networking (GNPS) molecular networking, network pharmacology, and animal experiments to systematically explore the hepatoprotective effect and mechanism of Cornus officinalis yeast-fermentation (COF). Component characterization identified 25 bioactive components, including flavonoids, triterpenic acids, and other fermentation-derived metabolites. Network pharmacology identified 441 common targets and 36 core targets of COF and ALI, which were enriched in oxidative stress regulation, inflammatory response, and the Keap1–Nrf2 pathway via Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Molecular docking showed that icariin and other components had stable interactions with Keap1 and Nrf2 (binding energy < −5 kcal/mol). Animal experiments confirmed that COF reduced the liver index of ALI mice, downregulated serum Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) activities, and ameliorated liver pathological damage. Western blot verified that COF inhibited Keap1 expression, promoted Nrf2 nuclear translocation, and upregulated HO-1/GPX4 expression. In conclusion, COF alleviates hepatic oxidative stress by regulating the Keap1–Nrf2–HO-1/GPX4 pathway, providing a scientific basis for its development as a functional food or candidate drug against ALI and a technical paradigm for fermentation-enhanced medicinal plant research. Full article

Perinatal depression (PND) is a severe mood disorder affecting mothers during pregnancy and postpartum, with implications for both maternal and neonatal health. Emerging evidence suggests that gut microbiota-derived metabolites play a critical role in neuroinflammation and neurotransmission. In this study, we employed an in silico approach to evaluate the pharmacokinetic and therapeutic potential of metabolites produced by Lactobacillus helveticus and Bifidobacterium longum in targeting key proteins implicated in PND, including BDNF, CCL2, TNF, IL17A, IL1B, CXCL8, IL6, IL10. The ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles of selected microbial metabolites, including acetate, lactate, formate, folic acid, riboflavin, kynurenic acid, γ-aminobutyric acid, and vitamin B12 were assessed using computational tools to predict their bioavailability and safety. Enrichment analysis was performed to identify biological pathways and molecular mechanisms modulated by these metabolites, with a focus on neuroinflammation, stress response, and neurogenesis. Additionally, molecular docking studies were conducted to evaluate the binding affinities of these metabolites toward the selected PND-associated targets, providing insights into their potential as neuroactive agents. Our findings suggest that specific microbial metabolites exhibit favorable ADMET properties and strong binding interactions with key proteins implicated in PND pathophysiology. These results highlight the therapeutic potential of gut microbiota-derived metabolites in modulating neuroinflammatory and neuroendocrine pathways, paving the way for novel microbiome-based interventions for perinatal depression. Further experimental validation is warranted to confirm these computational predictions and explore the clinical relevance of these findings. Full article

Zanthoxylum piperitum is a food and culinary plant commonly used in East Asia. In traditional medicine, its fruits, seeds, and bark have been utilized to treat digestive disorders, pain, and stomachache. Prior research has demonstrated its health benefits, particularly its significant antioxidant properties. However, limited research has investigated the specific metabolites responsible for these pharmacological effects. In this study, the antioxidant activities (EC₅₀: 9.1–1084.5 μg/mL) and metabolite profiles of different organs (fruits, pericarps, and seeds) of Z. piperitum collected from different regions were comparatively analyzed. Chemical structures of 91 metabolites from different organs were identified using UHPLC-Orbitrap-MS/MS based on untargeted metabolomics. The LC-DPPH method was employed to screen antioxidants from the extracts of the most active organ (the pericarps). The potential effects of the active compounds on oxidation-related diseases were evaluated by integrating compound–target interaction network analysis. Protein–protein interaction (PPI) networks revealed EGFR, STAT3, AKT1, TNF, BCL2, CASP3, ESR1, PPARA, CYP19A1, and CDK2 as central hub genes. The significance of compound and target interactions was further supported by molecular docking studies, which demonstrated favorable binding affinities, with most proteins exhibiting docked scores below −4.27 kcal/mol. The extracts of Z. piperitum fruits and pericarps also exhibited antioxidative activity against ROS production in LPS-stimulated RAW264.7 cells. Our findings demonstrate the application of an optimized extraction process and underscore the medicinal value of this food-plant by characterizing its bioactive constituents. The results indicate that Z. piperitum may serve not only as a health-promoting food but also has the potential for prevention or treatment of oxidative-stress-related diseases. Future research should focus on in vivo studies by exploring the therapeutic mechanisms of actions of the active extracts. Full article

Drug-induced liver injury (DILI) remains one of the most challenging adverse drug reactions in clinical practice, particularly in its idiosyncratic form, which is not dose-dependent and is largely driven by host-specific immune and genetic factors. Recent genomic studies have revealed strong associations between certain human leukocyte antigen (HLA) alleles and susceptibility to DILI, supporting an immunogenetic mechanism in which drug or metabolite–protein adducts act as neoantigens, triggering aberrant T-cell activation and hepatocellular injury. This review summarizes current evidence on the contribution of HLA polymorphisms to the pathogenesis of idiosyncratic DILI, highlighting allele-specific risk patterns, such as HLA-B*57:01 associated with flucloxacillin, HLA-DRB1*15:01–DQB1*06:02 in amoxicillin–clavulanate, and HLA-B*35:02 in minocycline-induced liver injury. Furthermore, ethnic variability and allele-haplotype interactions are discussed as potential modulators of susceptibility and clinical phenotype. By integrating genetic and immunological insights, the identification of HLA signatures offers promising tools for precision medicine, enabling earlier identification of at-risk individuals and improved prevention of severe hepatotoxic reactions. Full article

Short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are microbial metabolites with recognised roles in gut and immune homeostasis, but their therapeutic relevance in gastric cancer, particularly in combination with chemotherapeutics, remains unclear. This study investigated the antiproliferative synergy between a combined SCFA mixture (APB) and doxorubicin (Dox) in AGS gastric adenocarcinoma cells using integrated cellular, molecular, and proteomic approaches. APB and Dox each inhibited cell proliferation, with IC₅₀ values of 568.33 ± 82.56 μg/mL and 0.22 ± 0.04 μg/mL, respectively, and their combination (3000 + 0.27 μg/mL) enhanced cytotoxicity, achieving 103.46% inhibition and reducing the APB IC₅₀ to 512.80 ± 18.37 μg/mL. Combination index values confirmed synergistic interactions (CI₅₀ = 0.61; CI₉₅ = 0.13). APB+Dox significantly increased apoptosis (94.83%) with minimal necrosis (4.64%) and induced strong ROS generation comparable to APB alone, while Dox showed limited oxidative effects. Proteomic profiling revealed downregulation of ribosomal proteins and cell cycle regulators in Dox and APB+Dox groups, with the combination further enhancing apoptosis-related pathways and stress responses. Overall, these findings indicate that SCFA-based interventions, exemplified by APB+Dox, may offer a low-toxicity strategy to potentiate chemotherapy efficacy in gastric cancer through apoptosis induction, redox disruption, and attenuation of drug resistance. Full article

Background: The in vivo accumulation of Advanced Glycation End products (AGEs) is associated with the development of several chronic aging-related and degenerative diseases, as they alter protein structures and activate oxidative and inflammatory processes through interactions with the receptor for AGEs (RAGE). Plant secondary metabolites play a key role in counteracting the glycation process through various mechanisms of action. Therefore, Aloysia citrodora leaf polyphenolic extract could represent a source of anti-glycative compounds. Methods: The methanolic extract was characterized by RP-HPLC-DAD-MSⁿ, and its anti-glycative properties were investigated using several in vitro assays mimicking the different steps of the glycation reaction. In parallel, molecular docking studies were carried out to evaluate potential interactions between the identified metabolites and RAGE. Furthermore, A. citrodora metabolites’ stability under simulated in vitro digestion was assessed, and the anti-glycative activity of the bioaccessible fraction was investigated. Results:A. citrodora extract, rich in iridoid glycosides, phenylethanoid glycosides, and flavones, strongly inhibited AGE formation (from 10% to 100%) in both the middle and end step of the reaction and had high methylglyoxal and glyoxal trapping capacity. However, the digestion process affected extract stability, particularly under intestinal conditions, yielding an overall bioaccessibility of about 40% and leading to a subsequent reduction in anti-glycative properties. Finally, molecular modeling analysis highlighted the ability of the studied metabolites to bind RAGE. Conclusions:A. citrodora represents a promising source of natural anti-glycative agents with potential applications as food ingredients. However, it is essential to improve the extract bioaccessibility and to preserve its anti-glycative properties by developing a suitable formulation. Full article

Metabolites, once viewed mainly as energy substrates or structural precursors, are now increasingly recognized as key extracellular signaling mediators that regulate diverse physiological processes. This review synthesizes and systematizes current knowledge on metabolite-mediated signaling through G-protein-coupled receptors (GPCRs) in teleosts and, importantly, highlights new conceptual links between specific metabolite–GPCR axes and key physiological functions relevant to aquaculture. By integrating evidence across metabolite–GPCRs axes, including succinate–SUCNR1, aromatic amino acids (tryptophan and phenylalanine)–GPR142, basic amino acids (L-arginine)–GPRC6A, and lactate–GPR81. We clarify how metabolite–receptor interactions have the potential to modulate glucose homeostasis, immune responses, energy metabolism, and stress coping. A major contribution of this review is illustrating how metabolites act not only as nutrients but also as extracellular signaling molecules governing core physiological processes via GPCRs. Particularly from an evolutionary perspective, compared with peptide-activated GPCRs, metabolite-sensing GPCRs are relatively conserved across different species, suggesting that relevant findings from biomedical research could be translated to aquaculture applications. Therefore, understanding GPCR-mediated metabolite sensing provides a molecular foundation for improving nutrient formulation, developing functional feeds, and designing selective breeding strategies in precision aquaculture. Full article

Background: The ATP-binding cassette (ABC) G subfamily, a key member of the ABC protein family, mediates plant stress responses by transporting metabolites across membranes, but its mechanism of action in tomato (Solanum lycopersicum L.) remains poorly understood. Methods: We systematically analyzed the evolutionary relationships, structural characteristics, stress-responsive expression patterns, and functional roles in response to saline-alkali stress of the SlABCG gene family in tomato, using a combination of approaches including phylogenetic analysis (MEGA), gene structure and motif analysis (GSDS, MEME), cis-acting element prediction, homology analysis, transcriptome analysis, protein-protein interaction prediction, and qRT-PCR validation. Results: We identified a total of 41 SlABCG genes from the tomato genome. These genes, together with 43 ABCG genes from Arabidopsis thaliana, were clustered into five distinct clades. There are 35 collinear gene pairs between the SlABCG gene family in tomato and the ABCG gene family in Arabidopsis, while 39 collinear gene pairs exist among ABCG genes within the tomato genome itself.The promoter regions of SlABCG genes contain cis-acting elements associated with responses to salicylic acid, low temperature, and gibberellin stresses. Transcriptome sequencing revealed that six SlABCG genes responded to saline-alkali stress. Gene regulatory network prediction revealed that multiple genes related to saline-alkali stress were regulated. Expression profile analysis of the 25 upregulated genes revealed that all of them were significantly upregulated during the saline-alkali stress treatment. Conclusions: In summary, our results provide deep insights into the characteristics of the SlABCG subfamily, facilitate the design of effective analysis strategies, and offer data support for exploring the roles of ABCG transporters under different stress conditions. Full article

Lichens are a source of diverse compounds with a wide range of biological activities, making them of significant interest for novel drug development. In this study, metabolites were extracted from Lobariaceae lichens, and their antioxidant and antibacterial properties were experimentally investigated and explained using various computational approaches. Specifically, four lichen metabolites were analyzed using three methods to assess their antioxidant capacity. Antibacterial activity assays were conducted against four pathogens, and the minimum inhibitory concentrations (MICs) of the most promising compounds were determined. Ab initio studies were performed to evaluate radical stability. A pharmacological target responsible for the antibacterial effect was identified, and possible binding sites and modes were studied in silico. Metabolite IX, physciosporin, exhibited the highest antioxidant activity, which was associated with the theoretical stability of the radical. Additionally, IX exhibited an MIC of 0.97 μg/mL against S. pyogenes, surpassing the potency of streptomycin. The RecA protein was identified as a potential target, and a possible binding site and pattern of interactions at that site were described. Finally, IX showed low cytotoxicity in human cancer cell lines and was predicted to have favorable oral absorption properties, supporting its potential as a promising antioxidant and antibacterial agent against S. pyogenes. Full article