Search Results (288)

Baijiu distillers’ grains (BDG), a major fermented cereal by-product of baijiu production, represent an underutilized source of structurally modified dietary fiber with potential value for functional food development. Here, we found that BDG-derived dietary fiber (BDG-DF), mainly composed of mannose (34.83 ± 0.38%) and xylose (35.14 ± 0.25%), promoted short-chain fatty acid production during in vitro fermentation, and its fermentation supernatants reduced IL-1β and TNF-α levels and modestly decreased IL-6 production in a Caco-2/HepG2 co-culture model. In T2D mice, BDG-DF improved glucose tolerance, with high-dose BDG-DF reducing the OGTT area under the curve by 12.4% compared with the T2D group, and alleviated hepatic steatosis. These effects were accompanied by enrichment of Akkermansia and Bifidobacterium and remodeling of bile acid profiles. High-dose BDG-DF was also associated with elevated CA and CDCA levels, altered TGR5/GLP-1 signaling, increased hepatic FXR expression, and reduced CYP7A1 expression. Integrated hepatic proteomics and metabolomics further indicated that BDG-DF was associated with changes in unsaturated fatty acid biosynthesis and PPAR-γ-related metabolic signaling. Overall, these findings suggest that BDG-DF may improve glucose–lipid homeostasis in association with gut microbiota and bile acid remodeling and hepatic PPAR-γ-related metabolic signaling. Full article

Background: GDF15 (growth/differentiation factor-15) is part of the transforming growth factor-beta family and represents a cellular stress-induced gene. It might have a role in metaflammation and adipoflammation. We aimed to investigate the effects of Toll-like receptor (TLR) activation and hypoxia-related pathways together with metabolic factors on GDF15 regulation in adipocytes and adipose tissue (AT). Methods: GDF15 mRNA quantities in the human adipocyte cell line SGBS, in visceral (VAT) and subcutaneous adipose tissue (SAT) (resected from n = 96 obese and characterized patients), and in murine 3T3-L1 adipocytes were measured by real-time RT-PCR. GDF15 protein concentrations in cell supernatants and serum were quantified by ELISA. The following stimuli/pathways were investigated: insulin, glucose, TLR ligands (TLR2/6, TLR3, TLR4, TLR7, TLR9), bile acids, synthetic FXR/TGR5 activators, and HIF1α activators. Results: Basal GDF15 expression is low and only marginally induced in SGBS cells. In contrast, GDF15 is expressed in human SAT and VAT and correlates positively with the corresponding GDF15 protein concentration in peripheral blood serum of obese patients. Among metabolic factors, insulin and bile acids such as ursodeoxycholic acid upregulate GDF15 expression in 3T3-L1 adipocytes, the latter via FXR but not via TGR5. Among innate immune regulators, only TLR7 activation and hypoxic mediators upregulate whereas STAT3 signaling downregulates GDF15. Conclusion: GDF15 expression in human SAT and VAT is correlated to peripheral blood GDF15 concentrations and is regulated by metabolic and innate immune response pathways involved in AT inflammation and metaflammation. Full article

The gut microbiota regulates host physiology and drives extraintestinal diseases through the gut–X axis. Bile acids (BAs) function as key mediators of this interorgan crosstalk by activating nuclear and membrane receptors (FXR, TGR5, PXR, VDR). Traditional Chinese Medicine (TCM) demonstrates efficacy across multiple organ systems through multi-component formulations. This narrative review synthesizes evidence from preclinical and clinical studies supporting that TCM exerts systemic protection via strategic modulation of the microbiota–BA–host receptor axis, which functions as a core regulatory circuit within a larger network of microbial metabolites. Mechanistically, representative TCM formulas remodel gut microbial ecology and reinforce intestinal barrier integrity, leading to optimized BA profiles. These favorable BA signatures engage tissue-specific receptor signaling to resolve inflammation, mitigate fibrosis, and restore metabolic homeostasis across the gut–heart, gut–kidney, gut–liver, gut–bone, and gut–endocrine axes. Support for this causal relationship is provided by microbiota depletion, fecal transplantation, and multi-omics studies, collectively suggesting that TCM’s benefits are microbiota-dependent and at least partially BA-mediated. Moreover, context-dependent modulation of BA receptors, such as differential regulation of FXR, enables TCM to achieve pathology-specific outcomes. Current evidence is derived predominantly from preclinical models, and clinical data remain lacking. Nonetheless, the microbiota–BA–organ axis thus provides a potential framework for understanding TCM’s systemic actions and establishes a molecular basis for developing microbiome-informed precision therapeutics. Future directions include patient stratification and precision intervention design inspired by TCM’s ecological modulation strategies. Full article

In the search for new antischistosomal 3-benzylmenadiones (benzylMDs), the screening of a library developed in our laboratory led to the identification of two regioisomeric analogues, the 2′,5′- and 3′,5′-dimethoxy-benzylMD—designated schistodiones A_2′,5′ and A_3′,5′—which were investigated for their activity against the platyhelminth Schistosoma mansoni and various protozoan parasites, bacteria, and fungi. Reported work has shown that benzylMDs act as prodrugs: their bioactivation undergoes a cascade of redox reactions within the parasite, generating multiple drug metabolites, e.g., the main benzoylmenadione (benzoylMD) intermediates, and reactive oxygen species that interfere with key metabolic pathways. Among the secondary metabolites, benzoxanthones have been identified as potential products generated along this oxidative pathway. The aim of the study was to synthetize methoxylated benzoxanthones, as putative metabolites generated from these antischistosomal benzylMDs. During the synthetic work, several difficulties arose, including the absence of starting reagents, the incompatibility of certain reactions with methoxy groups, the possible formation of several isomers, and the easy re-oxidation of sensitive intermediates. To overcome these obstacles, we developed a new retrosynthetic strategy using modified precursors: replacing methoxy groups with O-methylenemethoxy (OMOM) groups that are more stable in basic media, using aldehydes or aromatic esters as precursors, and replacing certain substituents with groups that are easier and less costly to introduce (chlorine or nitro). Selected metabolites (benzoylMDs, benzoxanthones) were then tested in parasite and cellular assays. Furthermore, benzoylMDs were tested as subversive substrates of S. mansoni thioredoxin-glutathione reductase (SmTGR) and selected drug metabolites were investigated in SmTGR modeling experiments. From a One Health perspective, these benzylMD derivatives pose limited environmental risk because their metabolites lack toxicity when encountered externally, as toxicity requires intracellular metabolic activation and localized formation of reactive intermediates in close proximity to their cellular targets inside parasites. Full article

The occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related to intestinal flora imbalance, intestinal barrier damage, and gut-liver axis dysfunction. Due to their multi-target regulatory effects and advantages in intestinal microecological intervention, Chinese herbal monomers have shown promising application prospects in the prevention and treatment of MASLD. However, basic research on their toxicity still lags behind, and issues related to safety and clinical translation urgently need attention. This article systematically reviews the research progress on how flavonoids, triterpenoids, alkaloids, and polysaccharides improve hepatic steatosis, inflammatory responses, and metabolic disorders from a toxicological perspective by reshaping the intestinal microbiota, repairing the intestinal mucosal barrier, regulating short-chain fatty acid and bile acid metabolism, and synergistically acting on signaling pathways such as TLR4/NF-kB, FXR, TGR5, SIRT1, and the NLRP3 inflammasome. Furthermore, by combining methods such as 16S rRNA sequencing, metagenomics, metabolomics, and multi-omics integration, the article analyzes their application value and limitations in toxicological mechanism research, and discusses the translational bottlenecks faced by Chinese herbal monomers in pharmacokinetics, bioavailability, quality standardization, targeted delivery, and toxicological safety. Existing evidence indicates that Chinese herbal monomers have a three-in-one intervention advantage of microecological remodeling-metabolic regulation-inflammation inhibition, but their long-term medication safety, toxic target organs, dose-effect/toxicity relationships, and potential drug interactions still need further clarification. This article aims to provide a systematic reference for the safety evaluation and clinical translational research of Chinese herbal monomers in the prevention and treatment of MASLD. Full article

Pork production is closely linked to skeletal muscle growth and anabolic processes. This study investigated the effects of dietary supplementation with a multi-strain probiotic (Lactiplantibacillus plantarum, Streptococcus thermophilus, and Bacillus subtilis) on the growth performance, carcass traits, gut microbiota, and potential signaling pathways in growing pigs. A total of 144 weaning piglets (28 days old) were randomly allocated to two groups and fed diets with or without probiotics (0.1%) for 18 weeks. Pigs fed with probiotics showed significantly improved feed efficiency (p < 0.05) and greater muscle mass in the loin eye, arm shoulder, and blade shoulder regions. Microbiome analysis revealed significant enrichment of short-chain fatty acid (SCFA)-producing taxa, including Acidaminococcus, Allisonella, Dialister, and Megasphaera, alongside an increased cecal butyrate level in pigs fed probiotics. Integrated fecal microbiome and serum metabolomics analysis demonstrated that the metabolite profile was substantially altered by the supplementation of probiotics. Additionally, serum insulin levels, expression of the bile acid receptor tgr5, and upstream genes in the PI3K/Akt/mTOR pathway (igf1r, insr, and pi3k) were significantly upregulated (p < 0.05). Collectively, these results suggest that a multi-strain probiotic supplementation may be a promising strategy for improving muscle deposition and feed efficiency in commercial pig production. Full article

Emerging evidence highlights the gut microbiota as a critical modulator in the pathogenesis of heart failure (HF), particularly among patients with type 2 diabetes mellitus (T2DM). Dysbiosis contributes to systemic inflammation, endothelial dysfunction, and adverse cardiac remodeling via microbial metabolites such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs). However, the therapeutic intersection between the gut microbiota and pharmacological interventions remains insufficiently integrated. Sodium-glucose cotransporter-2 inhibitors (SGLT2is), a cornerstone of T2DM management, confer cardioprotective effects that may involve microbiota-mediated pathways. This review provides a novel synthesis of how SGLT2is influence gut ecology, specifically through altered glucose excretion and osmotic shifts, to potentially restore SCFA-producing taxa. By delineating the structural transitions from gut physiology to SGLT2i-modulated cardiac outcomes, we emphasize the gut–heart axis as a pivotal therapeutic target. This focused framework offers new insights into the triadic interplay between microbiome stability and cardiometabolic health, moving beyond traditional glucose-centric paradigms. Full article

Environmental DNA (eDNA) metabarcoding has emerged as a powerful tool for biodiversity monitoring, yet its accuracy is fundamentally constrained by the completeness and taxonomic reliability of reference sequence databases. For the Three Gorges Reservoir (TGR), no integrated multi-marker eDNA reference library exists, hampering standardized fish conservation monitoring under the Yangtze River Ten-Year Fishing Ban. Here, we constructed a comprehensive, multi-marker eDNA reference database for the fish fauna of the TGR, encompassing mitochondrial 12S rRNA, 16S rRNA, and cytochrome c oxidase subunit I (COI) gene sequences from 173 specimens (120 species) collected between 2021 and 2024. After integrating publicly available sequences, the final database comprised 161 species. Then, we quantitatively compared species annotation performance between this local database and public repositories. Results showed that while public databases achieved higher nominal species coverage (94.67%), they exhibited critical deficiencies in annotation accuracy, correctly annotating only 77.97% (12S rRNA), 75.00% (16S rRNA), and 38.14% (COI) of sequences from shared species under controlled conditions. In contrast, the local database exhibited 92.37%, 93.10% and 100% annotation accuracy for the respective markers. Optimal interspecific Kimura 2-parameter (K2P) thresholds for species delimitation were 0.00448 (12S rRNA), 0.00531 (16S rRNA), and 0.00734 (COI). In addition, 15, 0, and 4 species pairs exhibited zero interspecific distance for 12S rRNA, 16S rRNA, and COI, respectively. These limitations reinforce the need for cautious interpretation of eDNA metabarcoding results and the integration of multiple markers or complementary nuclear loci. This study provides preliminary evidence that regionally curated, multi-marker reference libraries could improve taxonomic assignment reliability in eDNA metabarcoding compared to uncurated public repositories, providing a foundational resource for biodiversity conservation. Full article

Obesity, a heterogeneous metabolic disease, is linked with severe comorbidities, prominently increasing morbidity and mortality. A weight loss between 5% and 10% is already sufficient to induce clinically relevant improvements in human health. Activation of energy expenditure through an impact on the brown and beige adipose tissues has recently become an interesting new target in obesity treatment. Obeticholic acid (OCA) is a semisynthetic derivative of the primary human bile acid, chenodeoxycholic acid. The compound is an agonist of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor (TGR5), activating the cellular pathways such as fibroblast growth factor-19, tissue-specific uncoupling protein 1, or type 2 iodothyronine deiodinase associated with energy expenditure and brown adipose tissue activity. So far, OCA has been approved to treat primary biliary cholangitis. Interestingly, the drug demonstrated therapeutic effects in animal models of obesity. Preliminary results from the human studies show that OCA administration holds potential as a treatment option in obesity, although some adverse effects may occur. Long-term administration of OCA might constitute an attractive therapeutic add-on approach, complementary to the currently approved treatments. The design of OCA derivatives targeting similar mechanisms, yet with a better pharmacological profile, seems to be an exciting pathway in the search of novel anti-obesity drugs. Further clinical trials involving larger cohorts of patients, with and without comorbidities, are warranted to confirm the benefits and safety of OCA administration. Full article

This paper presents a comparative analysis of unconventional roundabouts, commonly referred to as third-generation roundabouts, based on case studies from the United States and Europe, specifically Croatia and Italy. These intersection designs deviate from traditional circular geometries to overcome limitations in safety, capacity, and spatial integration, especially in constrained or high-demand environments. The study focuses on three major typologies: raindrop, turbo, and two-geometry roundabouts (TGRs), examining their geometric characteristics, operational principles, and context-specific implementations. Based on real-world examples and qualitative assessments, each national section investigates design rationale and performance considerations in relation to local traffic dynamics. The paper contributes to the understanding of adaptive and context-sensitive intersection design, offering a conceptual framework for comparing unconventional roundabout typologies across different regulatory environments. The comparative analysis reveals that each typology responds to specific operational and spatial constraints rather than representing a universally optimal solution. In particular, raindrop and dog-bone roundabouts are most effective in interchange contexts, turbo roundabouts enhance safety and capacity in regulated multilane environments, while TGRs provide greater adaptability in constrained and irregular urban settings. These findings highlight the importance of context-dependent design strategies and support the need for flexible and context-sensitive evaluation frameworks. Full article

Deep reinforcement learning (DRL) has been increasingly used in reservoir operation, but several key challenges and limitations need further study. This paper developed a novel and optimal reservoir operation model incorporating inflow forecasts based on DRL and the deterministic policy gradient algorithm. A multi-dimensional reward function was derived from the objective functions and constraints, and an optimal scheduling scheme was established with dynamically weighted reward functions. The observed daily flow data and 5-day inflow forecasts of the Three Gorges Reservoir (TGR) during flood seasons (from 10 June to 31 October) from 2010 to 2025 were used to evaluate the model performance and compared with the actual operation results. The results show that, compared with the actual operation, Scheme-1 with dynamic weights increases annual average flood prevention storage capacity by approximately 36.8%, enhances power generation by about 2.86 billion kW·h (≈5.49%), and reduces spillway waste water volume by around 3.33 billion m³. This study demonstrates that the optimal scheduling model can substantially improve the overall efficiency of reservoir operation, and the improvement is even more pronounced when the reward function weights are set dynamically. Full article

The presence of an unbalanced gut microbiome and the dysregulation of bile acid signalling are considered pivotal causes of various inflammation-based diseases. The Takeda G protein-coupled receptor (TGR5), TGR5 is a bile acid-responsive receptor that modulates inflammatory signalling pathways, making it an enticing molecular target for the discovery of novel anti-inflammatory agents. Herein, a comprehensive in silico approach was employed to identify potential TGR5 agonists from sterol-rich phytocompounds present in Triphala, a traditional polyherbal formulation. Using in silico computational methods, such as molecular docking and molecular dynamics simulations (MDS), we screened the putative agonistic potential of 10 phytocompounds obtained from Terminalia chebula, Terminalia bellirica, and Phyllanthus emblica against the crystal structure of human TGR5 (PDB ID: 7XTQ). Based on binding energy and molecular interactions, ergosterol (−12.34 ± 0.17 kcal/mol) and stigmasterol (−10.35 ± 0.04 kcal/mol) were predicted to be the top and best compounds. Furthermore, the stability of these two compounds in the docked complex was analysed using MDS for 200 ns. The mean Cα RMSD values were 0.22 ± 0.02 nm for both ergosterol- and stigmasterol-bound complexes, compared to 0.21 ± 0.02 nm for the unbound apo protein. Further, the molecular mechanics/Poisson–Boltzmann surface area (MMPBSA) analysis revealed that ergosterol exhibited binding free energy (−139.868 ± 12.318 kJ/mol) comparable to that of the co-crystallised ligand R399 −93.424 ± 8.919 kJ/mol. In silico ADMET predictions indicated acceptable drug-like properties and low toxicity for both compounds. Collectively, these computational findings suggest that ergosterol is a promising putative TGR5 agonist, warranting further experimental validation of its potential role in modulating inflammation-related pathways. Full article

Chronic inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, are systemic immune-mediated disorders driven by dysregulated immune responses. The gut–skin axis is a bidirectional network linking intestinal microorganisms, their metabolites, and host immunity. It connects microbiome composition and function with systemic inflammation and cutaneous pathology, shaping disease-specific mechanisms such as Th2/IL-4/IL-13-mediated barrier dysfunction in AD and Th17/IL-23/IL-17-driven hyperproliferation in psoriasis. Microbiota-derived metabolites, including short-chain fatty acids, tryptophan-derived aryl hydrocarbon receptor ligands, and bile acid-dependent FXR/TGR5 signaling, modulate immune homeostasis and epithelial integrity. Gut dysbiosis, impaired metabolite production, and barrier dysfunction disrupt regulatory networks, amplifying inflammation. Microbiota-targeted interventions, including probiotics, synbiotics, postbiotics, and precision nutrition, may serve as adjunctive therapies, although further well-controlled clinical studies are needed. Integrating multi-omics, metabolomics, and functional microbial profiling, alongside investigations of the gut mycobiome and virome, will be critical to identify predictive biomarkers and optimize therapeutic strategies. These concepts remain mechanistically compelling but largely theoretical, requiring validation in longitudinal and interventional studies. Full article

Agonists of the G protein-coupled receptor TGR5 have long been sought-after for their metabolic benefits. Intestinal TGR5 activation induces secretion of the antidiabetic hormone GLP-1, which can systemically improve diabetes phenotypes in multiple organs. However, no TGR5 agonist drug candidate has succeeded in clinical trials due to their low potency and unwanted side effects. A challenge in the field has been the development of TGR5 agonists that are non-toxic, long-acting, and have functional selectivity for G protein-biased agonism. In this study, we propose a systematic pipeline for engineering optimal TGR5 agonists with antidiabetic properties. This pipeline is interdisciplinary, combining in silico, in vitro, and in vivo assays to design and validate drug candidates. We identify 2 lead compounds that outline the necessary beneficial properties for a successful TGR5 agonist against diabetes. We uncover the molecular mechanisms that allow TGR5 agonists to induce the transcription of their target, TGR5, in intestinal enteroendocrine cells. Lastly, we investigate the molecular interactions of our lead candidates in the TGR5 binding pocket to identify optimal parameters for stability and biological activity. Our strategy for TGR5 agonist design and evaluation has the potential to guide the discovery process for targeted TGR5 therapeutics for metabolic diseases. Full article

Objective: Based on previous findings on the Lingguizhugan (LGZG)-mediated gut–liver axis, this study clarifies the therapeutic mechanisms of LGZG in metabolic dysfunction-associated steatotic liver disease (MASLD), with a focus on the gut microbiota–bile acid–TGR5 (GPBAR1) axis. Methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce MASLD, followed by 4-week LGZG intervention (21.57 g/kg/day, oral gavage). Metabolic phenotypes, gut microbiota (16S rRNA sequencing), serum/hepatic bile acids (targeted metabolomics), and molecular targets (qPCR/Western blot) were analyzed. Results: LGZG significantly alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis, while enhancing whole-body energy expenditure (increased oxygen consumption (VO₂), and heat production (p < 0.05). It also reduced serum ALT (p < 0.001) and AST levels (p < 0.01). Mechanistically, LGZG remodeled the gut microbiota, specifically increasing Akkermansia, Bifidobacterium and Lachnospiraceae_NK4A236_group while decreasing Lactobacillus. This shift inhibited the intestinal FXR-Fgf15 axis, concurrently activating the hepatic alternative bile acid synthesis pathway (upregulating CYP27A1 and CYP7B1 protein expression; p < 0.001 and p < 0.01, respectively). Consequently, systemic accumulation of non-12α-hydroxylated bile acids (non-12-OH BAs) such as hyocholic acid (HCA) and 7-ketolithocholic acid (7-ketoLCA) occurred—known TGR5 agonists and intestinal FXR antagonists. These changes elevated serum GLP-1 levels (p < 0.05) and activated adipose TGR5-cAMP/PKA/CREB signaling. The metabolic benefits primarily originated from non-12-OH BAs enrichment and TGR5-mediated adipose browning, not hepatic FXR activation. Conclusions: Our findings show that LGZG ameliorates MASLD by remodeling bile acid profiles via intestinal FXR-Fgf15 axis inhibition and hepatic alternative synthesis pathway activation. This study highlights the TGR5-targeting properties of LGZG, providing a mechanistic basis for its therapeutic use in metabolic disorders. Full article