INTRODUCTION:Sub-health is an intermediate state between health and disease. Early diagnosis in clinical practice is difficult, which delays timely intervention. Traditional Chinese Medicine (TCM) constitution theory divides sub-health into eight categories; however, existing diagnostic tools mainly focus on psychological assessment and lack objective phenotypic indicators. Multimodal technology provides a new direction for the objective diagnosis of sub-health by integrating objective human phenotypic images with expert experience. METHODS:Tongue images, facial images, and infrared thermal images were collected from 1389 participants. In the pre-experiment, Model-1 consisted of a ResNet-18 network, an extended binary classification strategy, and a cross-attention fusion mechanism. Model-2 was developed based on Model-1 by integrating expert experience via Qwen2.5 using structural prompting. Accuracy, recall, precision, specificity, and AUC were used to evaluate model performance. RESULTS:The overall performance of Model-1 was good, with most core indicators of body constitution exceeding 0.7. However, PDC (accuracy 0.722, AUC 0.682) and QDC (accuracy 0.732, AUC 0.705) showed relatively poor performance, characterized by high recall but low specificity. The core indicators of Model-2 improved further. Notably, PDC (accuracy 0.772, AUC 0.732) and QDC (accuracy 0.778, AUC 0.756) were significantly improved, and the imbalance between recall and specificity was also alleviated. DISCUSSION:Multimodal fusion is critical for improving classification performance in TCM constitution recognition. The reasonable integration of clinical expert experience effectively optimizes feature fusion efficacy, highlighting the indispensable value of empirical expertise. Rooted in the empirical characteristics of TCM, embedding expert knowledge into the data-driven framework further enhances the robustness and credibility of the screening model. CONCLUSION:This study established an expert experience-enhanced multimodal model for subhealth and TCM constitution identification. The model achieves objective quantification and accurate classification of sub-health states, providing a valuable technical reference for population health management and early sub-health risk screening.

Sphingolipids, a class of lipids, are widely present in the cell membranes of all eukaryotic and some prokaryotic organisms. These lipids play crucial roles in the formation of the lipid bilayer and are categorised into several groups, including sphingomyelins, ceramides, sphingosine-1-phosphate, and glycosphingolipids. In addition to their structural significance, sphingolipids also show bioactivity, regulating various signalling pathways involved in cell growth, differentiation, ageing, and apoptosis, and are closely associated with several chronic diseases, including obesity and type 2 diabetes mellitus. Notably, dysregulated sphingolipid metabolism contributes to obesity-related metabolic dysfunction through altered lipid accumulation, insulin signalling, organelle stress, and inflammation. This review summarises the various mechanisms and recent research advances related to sphingolipids and their association with obesity. It further examines how the metabolic effects of ceramides vary according to their acyl-chain length, enzyme of origin, tissue distribution, and metabolic context, as well as how adipose depot, sex, age, and metabolic phenotype influence the sphingolipid response to obesity. It further considers plant-derived sphingolipids as a compositionally distinct exogenous input to host sphingolipid pools, comparing their structural and enzymatic features with those of mammalian sphingolipids. Pharmacological, dietary, and lifestyle approaches that modify sphingolipid metabolism are also considered. Accordingly, the review summarises our current knowledge regarding the dietary occurrence, intestinal handling, and metabolic effects of sphingolipids and identifies the evidence gaps that currently limit conclusions regarding their relevance to obesity.

Jiuwei Xiaozhi Decoction (JWXZ) is a nine-herb traditional Chinese medicine formula clinically used for hepatic steatosis and dyslipidemia, but its chemical basis and pharmacological mechanisms in metabolic dysfunction-associated steatotic liver disease (MASLD) remain incompletely defined. The chemical profile of JWXZ was characterized by UHPLC-HRMS/MS. Its therapeutic effects were evaluated in a high-fat diet (HFD)-induced mouse model of MASLD, followed by hepatic transcriptomic analysis, network pharmacology, molecular docking, Western blotting, and immunofluorescence validation. UHPLC-HRMS/MS identified 178 chemical constituents in JWXZ, including phenolic acids, flavonoids, flavonoid glycosides, alkaloids, isoflavones, and coumarins. In HFD-fed mice, JWXZ attenuated body weight gain, white adipose accumulation, dyslipidemia, hepatic triglyceride and cholesterol accumulation, serum transaminase elevation, and hepatic steatosis, while improving glucose tolerance and partially restoring whole-body metabolic flexibility. Hepatic transcriptomics identified 124 HFD-dysregulated genes reversed by high-dose JWXZ, with prominent enrichment in cholesterol and sterol biosynthesis, endoplasmic reticulum proteostasis, oxidative stress response, and PPARα-related lipid handling. Integrated transcriptomic and network pharmacology analyses further identified 157 shared targets and 18 overlapping pathways, converging mainly on cholesterol metabolism and PPAR signaling. Protein-level validation showed that JWXZ suppressed SREBP2 proteolytic activation, reduced nuclear SREBP2 abundance, and downregulated HMGCR, SQLE, and PCSK9, indicating inhibition of the hepatic cholesterogenic program. In parallel, JWXZ restored nuclear PPARα abundance and CPT1A expression, consistent with reactivation of fatty acid oxidation. JWXZ also reduced hepatic EGFR phosphorylation and lowered hepatic and circulating TNF-α, IL-6, IL-1β, and MCP-1 levels. Molecular docking provided supportive evidence for potential interactions between representative JWXZ constituents and key regulators, including naringin-HMGCR, chlorogenic acid-SQLE, rhoifolin-PPARα, and rhoifolin-SREBP2. These findings suggest that JWXZ ameliorates HFD-induced MASLD mainly by rebalancing hepatic lipid metabolism through coordinated suppression of SREBP2-mediated cholesterogenesis and restoration of PPARα-mediated fatty acid oxidation, with associated attenuation of EGFR-linked inflammatory responses.

Background Oligoasthenozoospermia is a leading cause of male infertility and has been increasingly associated with the global surge in obesity and exposure to reproductive toxicants. Despite extensive research on each factor individually, their combined pathological effects remain poorly understood.Objectives This study aimed to investigate how obesity and reproductive toxicants independently and synergistically impair male reproductive function by establishing and comparing rat models of oligoasthenozoospermia induced by each factor and their combination.Materials and Methods We constructed three etiologically distinct oligoasthenozoospermia male Sprague-Dawley rat models: a reproductive toxicity model induced by glycosides of Tripterygium wilfordii Hook. f. (GTW), a metabolic dysfunction model induced by a high-fat diet (HFD), and a combined model (HFD + GTW). Animals were randomly assigned and subjected to 12 weeks of treatment. Body weight, metabolic indices, serum sex hormone levels, sperm quality parameters, and histopathological analysis of the testes and epididymis, as well as gut microbiota composition and testicular transcriptome profiles, were systematically evaluated. We also performed quantitative real-time polymerase chain reaction.Results Both GTW and HFD independently impaired reproductive function, leading to decreased sperm count and motility, hormonal disturbances, and moderate testicular damage. The combined model exhibited significantly exacerbated reproductive impairment, including extensive spermatogenic cell loss, disrupted testicular architecture, and the lowest sperm quality indices. Multiomics analysis revealed coordinated alterations in gut microbiota composition and testicular transcriptomes, suggesting crosstalk between metabolic and inflammatory signaling pathways. Quantitative real-time polymerase chain reaction confirmed these transcriptomic patterns, showing upregulation of Ahnak, C1r, S1pr1, and Steap4, alongside downregulation of Alkbh7, Tbpl1, Tent5b, and Ldhal6b in the models.Conclusion This study successfully establishes reliable rat models that mimic both individual and combined etiologies of oligoasthenozoospermia. The interaction between obesity and GTW-induced reproductive toxicity aggravates testicular injury through metabolic disruption and inflammatory pathways, offering an integrative platform for mechanistic and therapeutic research.

Biomarkers play a pivotal role in contemporary medical research, particularly in the early diagnosis of diseases and personalized treatment. Although previous studies have systematically reviewed markers across various disease domains, an integrated framework that connects major physiological systems, encompasses multiple organs, and spans a broad spectrum of diseases is still lacking. In the context of modern health challenges, marked by the high prevalence of chronic diseases and widespread comorbidities, establishing a panoramic biomarker navigation system is imperative. This review offers the initial comprehensive elucidation of the biomarker interaction networks across diverse systems, organs, and diseases, and delineates the operational framework for establishing a "biomarker navigation system". The core contribution of this work is a transition from 'knowledge enumeration' to a more integrated, systems-level approach. This provides new perspectives in systems biology for understanding the shared pathological foundations of comorbidities. Furthermore, it provides a theoretical basis for a reorientation in medicine, from a focus on 'treating existing diseases' to 'preventive interventions' and from 'single-disease management' to a comprehensive, systems-based approach. To facilitate the exploration and application of this system-organ-disease-biomarker network, we developed the "Human Biomarker Navigator" web platform (http://www.hbiomarker.com), which allows researchers and clinicians to efficiently retrieve the functional characteristics and clinical significance of diverse biomarkers across different disease contexts.

Metabolic diseases pose a major global health challenge, the pathogenesis of which centers on “metabolic reprogramming”; that is, the adaptive or pathological rewiring of metabolic pathways. Emerging evidence indicates that gut microbiota dysbiosis triggers its metabolic reprogramming prior to host disease onset and plays a pivotal role in the development of metabolic disorders. However, unlike host metabolic reprogramming, which has been well characterized, the pathogenic mechanisms resulting from gut microbiota metabolic reprogramming remain poorly understood, creating a critical knowledge gap regarding its role in systemic metabolic diseases. To address this gap, this review introduces the concept of gut microbiota metabolic reprogramming and establishes its foundational role in systemic metabolic disease. We propose that gut microbiota metabolic reprogramming constitutes an early pathogenic event, preceding and potentially driving subsequent metabolic alterations in the host. Within this framework, we systematically reveal that an imbalance in the gut microbiota leads to its significant metabolic reprogramming, including lipid, glucose, amino acid, and uric acid metabolism, which in turn regulates host-wide metabolic and immune homeostasis and contributes to the development of metabolic diseases. By integrating these mechanisms into a coherent model, our work provides a novel paradigm for understanding metabolic regulation. This model refines the fundamental pathophysiology of metabolic disorders and highlights new possibilities for targeting the microbiome for the prevention and treatment of metabolic disorders.

Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF's effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA)- induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. In vivo, QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF's mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated-Adenosine 5'-monophosphate (AMP)- activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. In vitro, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagyfacilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.

The increasing incidence and associated metabolic complications pose major challenges in the treatment of hyperlipidaemia. Cinnamon is a food and medicinal resource associated with lipid metabolism, but the mechanism by which its active components, cinnamic acid (CA) and cinnamaldehyde (CM), alleviate hyperlipidaemia remains unclear. Biochemical, pathological, gut microbiota, and metabolomic analyses were performed to investigate the effects of CA and CM on HFD-fed mice and the underlying mechanisms involved. Supplementation with CA and CM reduced body weight, liver, and adipose tissue accumulation in HFD-induced mice; improved glucose and lipid metabolism; and decreased inflammation and oxidative stress levels, with CM showing superior efficacy. Faecal microbiota transplantation confirmed that the therapeutic effect was closely related to core gut bacteria and metabolites. Specifically, CA and CM inhibited the growth of lipid metabolism-related genera (e.g., Turicibacter and Romboutsia) and metabolites (e.g., PC, LysoPCs, prostaglandin E2, and arachidonic acid) while promoting the growth of beneficial genera (e.g., Oscillospiraceae and Colidextribacter) and metabolites (e.g., linoleic acid, phytosphingosine, and stercobilin). Additionally, Spearman's correlation analysis revealed that serum and hepatic lipids, as well as inflammatory factors, were positively correlated with Erysipelatoclostridium, Turicibacter, Eubacterium fissicatena, Enterorhabdus, cervonoyl ethanolamide, and acetoxystachybotrydial acetate, whereas they were negatively correlated with Lachnospiraceae NK4A136, stercobilin, LysoPE (15:0/0:0), and phytosphingosine. In contrast, hepatic oxidative stress markers exhibited the opposite correlation pattern. In conclusion, CA and CM have the potential to regulate the core gut microbiota and metabolites to improve lipid metabolism and decrease related inflammation and oxidative stress levels.

Atherosclerosis, with its complex pathogenesis, is a leading underlying cause of many cardiovascular diseases, which are increasingly prevalent in the population. Sphingolipids play an important role in the development of atherosclerosis. Key metabolites and enzymes in sphingolipid metabolism influence the pathogenesis of atherosclerosis in a variety of ways, including inflammatory responses and oxidative stress. Thus, an investigation of sphingolipid metabolism-related metabolites and key enzymes may provide novel insights and treatment targets for atherosclerosis. This review discusses various mechanisms and research progress on the relationship between various sphingolipid metabolites, related enzymes, and atherosclerosis. Finally, we look into the future research direction of phytosphingolipids.

Metabolic-associated fatty liver disease (MAFLD) is a common chronic metabolic disease worldwide that seriously threatens human health. The Xiaoji-chenpi formula (XCF), derived from QingGanSan (QGS), has previously been proven to be clinically effective in MAFLD. However, its pharmacological activity and mechanism have not been studied in depth. In this study, we explored and determined the optimal amounts of cholesterol and fat additives (4% and 20%, respectively) for the modeling of zebrafish MAFLD via orthogonal tests. The zebrafish MAFLD model was used for preliminary screening and determination of the pharmacological activity of XCF on MAFLD. XCF significantly reduced the body mass index (BMI), improved the morphology of liver cells and reduced the number of lipid vacuoles, which were better than the corresponding pharmacological activity of silymarin and resveratrol in zebrafish with MAFLD. The four main active compounds in XCF were identified by HPLC analysis as chlorogenic acid, naringin, hesperidin and quercetin. MAFLD in the mouse model was induced by a high-fat diet (HFD), and the pharmacological activity and mechanism of XCF were investigated by measuring plasma and hepatic physiological indices. XCF reduced the plasma TC and TG levels, reduced the liver TC and TG levels, and relieved liver lipid accumulation and inflammation in the mice. Key differentially expressed genes were identified through transcriptomics and detected via western blotting. XCF regulated the levels of INSIG1, SREBP1, FASN, ACC, SPP1, LGALS3, TNF-α and IL-1β in the livers of the MAFLD mice and improved the disease status. Our research provides a basis for developing an effective functional product for treating the occurrence and progression of MAFLD.

Metabolic-associated fatty liver disease (MAFLD) has become the most common liver disease, affecting more than 25% of the adult population worldwide. Functional foods, dietary supplements, and dietary patterns are considered effective measures for treating MAFLD; however, their mechanisms remain unclear. Recent investigations have proven that the gut microbiota is a pivotal regulatory node in MAFLD pathogenesis, with dietary interventions targeting the gut-liver axis showing promising therapeutic potential. This review summarizes the relationships among the gut microbiota, its metabolites, and MAFLD, as well as the effects of functional foods, dietary supplements, and dietary patterns that target the gut microbiota on MAFLD. These interventions maintain gut microbiota homeostasis, modulate the levels of gut metabolites, and regulate physiological pathways such as hepatic lipid accumulation and inflammation, thereby affecting the development of MAFLD. This review provides new insights into the mechanisms of dietary interventions and a novel therapeutic strategy for patients with MAFLD.

According to traditional Chinese medicine (TCM) constitutional theory, individuals with phlegm-dampness constitution (PDC) are at increased risk for metabolic disorders. Previous studies have indicated that PDC individuals exhibit gene expression changes associated with metabolic disorders, even individuals with normal metabolic indices. However, the biological mechanisms underlying these changes remain unclear. The gut microbiota has recently emerged as a promising avenue for elucidating TCM principles. Here, we revealed that individuals with PDC have distinct gut microbiota and serum metabolite profiles. A decrease in phytosphingosine was associated with increased PDC scores and metabolic disorder severity. Subsequent experiments demonstrated that Flavonifractor plautii can biosynthesize phytosphingosine, which was also negatively correlated with the PDC score. Interestingly, both F. plautii and phytosphingosine levels decreased in PDC subjects with normal metabolic indices. Fecal transplantation from these individuals accelerated the development of metabolic disorders in mice. However, supplementation with F. plautii and phytosphingosine ameliorated metabolic disorders by increasing phytosphingosine levels in the gut‒hepatic axis. Mechanistic investigations confirmed that phytosphingosine can directly bind to hepatic peroxisome proliferator-activated receptor α (PPARα) and activate its nuclear transcription activity, thereby regulating downstream gene expression related to glucose‒lipid metabolism. Our research indicates that the decrease in F. plautii and its product, phytosphingosine, contributes to gene expression changes related to metabolic disorders in PDC individuals and increases their susceptibility to metabolic disorders. These findings suggest that diagnosing PDC may be beneficial for identifying at-risk populations among apparently healthy individuals, thereby advancing the broader field of metabolic disorder prevention and TCM integration.

BACKGROUND:Hyperuricemia, a prevalent chronic metabolic disorder caused by purine metabolism disturbances, is characterized by elevated serum uric acid (UA) levels. Prolonged hyperuricemia can cause severe complications such as gout or kidney damage. However, the toxic side effects of and adverse reactions to UA-lowering drugs are becoming increasingly prominent. Therefore, new targets and drugs for hyperuricemia are needed. PURPOSE:This review aims to summarize recent research progress on the prevention and treatment mechanisms for gut microbiota-hyperuricemia from the perspective of plant-derived natural products. METHODS:Data from PubMed, Web of Science, ScienceDirect, and the CNKI databases spanning from January 2020 to December 2024 were reviewed. The aim of this study is to categorize and summarize the relevant mechanisms through which natural products improve hyperuricemia via the gut microbiota. The retrieved data followed PRISMA criteria (Preferred Reporting Items for Systematic reviews and Meta-Analyses). RESULTS:Regulating gut microbiota as a treatment for hyperuricemia. Targeting the gut microbiota could reduce host UA levels by promoting purine degradation, reducing UA production, and increasing UA excretion. Moreover, the gut microbiota also exerts anti-inflammatory and antioxidant effects that alleviate complications such as renal damage caused by hyperuricemia. Due to their diverse sources, multicomponent synergy, multitarget effects, and minimal side effects, plant-derived natural products have been extensively utilized in the management of hyperuricemia. Especially, utilizing natural products from plants to regulate the gut microbiota has become a new strategy for reducing UA levels. CONCLUSION:This review comprehensively summarizes recent advances in understanding the preventive and therapeutic mechanisms of plant-derived natural products in ameliorating hyperuricemia and its comorbidities through gut microbiota modulation. This review contributes a novel perspective for the development of safer and more efficacious UA-lowering products.

Background Erectile dysfunction (ED) is a common male sexual disorder, with the vasculogenic subtype primarily driven by endothelial injury and metabolic dysfunction. Current research often lacks a systematic, time-course analysis of its progressive pathology. We aimed to delineate the temporal dynamics of functional impairment, structural remodeling, and molecular alterations using two rat models: high-fat diet (HFD) and HFD combined with iliac artery cuff placement (HFD + Surgery), evaluating them at weeks 4, 8, 12, and 16. Results The HFD + Surgery group exhibited earlier onset and more severe pathological changes than the HFD group. By week 4, early functional impairment was evident, marked by downregulation of endothelial nitric oxide synthase (eNOS) and calponin. From week 8, we observed reduced erectile function (maximal ICP/MAP ratios) and nitric oxide (NO) levels, smooth muscle phenotypic transition, metabolic disturbances, and sustained inflammatory and oxidative stress activation. Fibrosis-driven structural remodeling commenced after week 12, characterized by significant increases in TGF-β1 expression and collagen deposition. Conclusions Our findings delineate a clear, three-stage pathological progression of vasculogenic ED: early dysfunction (weeks 4–8), phenotypic transition and metabolic disturbance (weeks 8–12), and structural remodeling (after week 12). This comprehensive analysis highlights the synergistic role of ischemia in disease progression and provides critical temporal data for identifying key mechanistic targets and optimal intervention windows.

BackgroundLipid metabolism disorders have become a major global public health issue. Due to the complexity of these diseases, additional research and drugs are needed. Oroxin A, the major component of Oroxylum indicum (L.) Kurz (Bignoniaceae), can improve the lipid profiles of diabetic and insulin-resistant (IR) rats. Because insulin resistance is strongly correlated with lipid metabolism, improving insulin resistance may also constitute an effective strategy for improving lipid metabolism. Thus, additional research on the efficacy and mechanism of oroxin An under non-IR conditions is needed.MethodsIn this study, we established lipid metabolism disorder model rats by high-fat diet feeding and fatty HepG2 cell lines by treatment with oleic acid and evaluated the therapeutic effect and mechanism of oroxin A in vitro and in vivo through biochemical indicator analysis, pathological staining, immunoblotting, and immunofluorescence staining.ResultsOroxin A improved disordered lipid metabolism under non-IR conditions, improved the plasma and hepatic lipid profiles, and enhanced the lipid-lowering action of atorvastatin. Additionally, oroxin A reduced the total triglyceride (TG) levels by inhibiting sterol regulatory element-binding protein 1 (SREBP1) expression and reducing the expression of acetyl coenzyme A carboxylase (ACC) and fatty acid synthase (FASN) in vivo and in vitro. Oroxin A also reduced the total cholesterol (TC) levels by inhibiting SREBP2 expression and reducing HMGCR expression in vivo and in vitro. In addition, oroxin A bound to low-density lipoprotein receptor (LDLR) and increased AMPK phosphorylation.ConclusionsOur results suggested that oroxin A may modulate the nuclear transcriptional activity of SREBPs by binding to LDLR proteins and increasing AMPK phosphorylation. Oroxin A may thus reduce lipid synthesis and could be used for the treatment and prevention of lipid metabolism disorders.

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by the excessive accumulation of fat in hepatocytes. However, due to the complex pathogenesis of MAFLD, there are no officially approved drugs for treatment. Therefore, there is an urgent need to find safe and effective anti-MAFLD drugs. Recently, the relationship between the gut microbiota and MAFLD has been widely recognized, and treating MAFLD by regulating the gut microbiota may be a new therapeutic strategy. Natural products, especially plant natural products, have attracted much attention in the treatment of MAFLD due to their multiple targets and pathways and few side effects. Moreover, the structure and function of the gut microbiota can be influenced by exposure to plant natural products. However, the effects of plant natural products on MAFLD through targeting of the gut microbiota and the underlying mechanisms are poorly understood. Based on the above information and to address the potential therapeutic role of plant natural products in MAFLD, we systematically summarize the effects and mechanisms of action of plant natural products in the prevention and treatment of MAFLD through targeting of the gut microbiota. This narrative review provides feasible ideas for further exploration of safer and more effective natural drugs for the prevention and treatment of MAFLD.