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AbstractAlthough the gut microbial metabolites exhibit potential effects on coronary heart disease (CHD), the underlying mechanism remains unclear. In this study, the active gut microbial metabolites acting on CHD and their potential mechanisms of action were explored through a network pharmacological approach. We collected a total of 208 metabolites from the gutMgene database and 726 overlapping targets from the similarity ensemble approach (SEA) and SwissTargetPrediction (STP) database, and ultimately identified 610 targets relevant to CHD. In conjunction with the gutMGene database, we identified 12 key targets. The targets of exogenous substances were removed, and 10 core targets involved in CHD were eventually retained. The microbiota–metabolites–targets–signalling pathways network analysis revealed that C-type lectin receptor signalling pathway, Lachnospiraceae, Escherichia, mitogen-activated protein kinase 1, prostaglandin-endoperoxidase synthase 2, phenylacetylglutamine and alcoholic acid are notable components of CHD and play important roles in the development of CHD. The results of molecular docking experiments demonstrated that AKT1-glycocholic acid and PTGS2-phenylacetylglutamine complexes may act on C-type lectin receptor signalling pathways. In this study, the key substances and potential mechanisms of gut microbial metabolites were analysed via network pharmacological methods, and a scientific basis and comprehensive idea were provided for the effects of gut microbial metabolites on CHD.

Herb compatibility is the soul of traditional Chinese Medicine prescriptions. Coptidis rhizoma (CR) (Coptis chinensis Franch., Coptis deltoidea C.Y.Cheng et Hsiao, or Coptis teeta Wall.; family Ranunculaceae), is a well-known herb. The bitter and cold nature of CR can irritate the spleen and stomach, and certain ingredients in CR may trigger allergic reactions. Herb combinations can help alleviate the side effects caused by CR. Through data analysis and literature research, there are many herbs combined with CR have a high frequency, but only a few are currently used as formulae in clinical practice. The results showed that these six herb pairs are usually widely studied or used as prescriptions in the clinic. This paper describes the six herb pairs from the key traditional uses, changes in bioactive constituents, and compatibility effects, especially with Euodiae fructus (family Rutaceae), Scutellariae radix (family Lamiaceae), Magnoliae Officinalis cortex (family Magnoliaceae), Glycyrrhizae radix et rhizoma (family Fabaceae), Ginseng radix et rhizoma (family Araliaceae), and Aucklandiae radix (family Asteraceae), and found that herbs are more effective when used in combination. Therefore, it is feasible to establish some methods to study herb pairs comprehensively from different perspectives. This paper aims to provide the latest and most comprehensive information on the six herb pairs and summarize the pattern of CR compatibility effects. It aims to attract more attention, and further experimental studies will be conducted to investigate and evaluate the effects of herb pairs containing CR. These data can also provide valuable references for researchers and also provide more possibilities for future applications in clinical practice and new drug development.

As a well-known classical Chinese medicine prescription, Shengxian Decoction (SXD) has been applied for a century to treat cardiovascular diseases, especially coronary heart disease (CHD), but the potentially effective compounds and underlying mechanisms remain unclear. With ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF/MS) and network pharmacology analysis, the potential effective compounds of SXD and their pharmacological mechanisms against CHD were identified and revealed. 57 effective compounds with favorable pharmacokinetic characteristics and biological activities were screened through UPLC-Q-TOF/MS analysis, database and literature mining, interacting with 96 CHD-related targets to support potential synergistic therapeutic actions. Systematic analysis of the PPI network and microarray data further revealed six core targets, including TNF, IL-1β, IL-6, TP53, VEGFA and PTGS2, which were mainly involved in fluid shear stress and atherosclerosis, lipid and atherosclerosis, PI3K-Akt signaling pathway et al. Moreover, the proposed contribution indexes of effective compounds indicated these compounds, including isoferulic acid, quercetin, calycosin, ferulic acid, kaempferol, calycosin 7-O-glycoside, formononetin, astragaloside IV and saikosaponin D, as the core compounds of SXD. The molecular docking results confirmed that those core compound-target pairs exhibited strong binding energy. Furthermore, we validated that SXD significantly alleviated myocardial tissue injury in CHD rats and reversed H/R-induced decreases in H9c2 cell viability by attenuating the production of TNF, IL-6 and IL-1β, and reducing cardiomyocyte apoptosis via down-regulating the TP53, caspase3 and cytochrome C mRNA expression levels as well as caspase3, caspase9 and cytochrome C protein expression levels according to RT-qPCR and Western blot results. Our findings explained the pharmacological mechanisms underlying the effectiveness of SXD in the treatment of CHD, and laid a foundation for future basic and clinical research of SXD.

Ulcerative colitis is a chronic inflammatory bowel disease with unclear pathogenesis, and its incidence is increasing gradually. Recently, with the popularization of the concept of healthy diet, reducing the risk of ulcerative colitis through dietary intervention has become increasingly popular. In this paper, we report on the protective effect of Gallus gallus domesticlus Brisson peptides on dextran sodium sulfate (DSS)-induced ulcerative colitis in mice. For this purpose, we measured changes in body mass, disease activity index (DAI), colon length, hematoxylin-eosin (HE) stained colon sections, the levels of pro-inflammatory cytokines such as interleulin-6 (IL-6), IL-10, IL-1β and tumor necrosis factor-α (TNF-α), intestinal microbial community composition and the levels of short-chain fatty acids in cecal contents. The results indicated that G. gallus domesticlus Brisson peptides significantly alleviated the symptoms of ulcerative colitis such as body mass loss, hematochezia, diarrhea, and the shortening of colon length and colon tissue injury in mice, and significantly decreased the levels of TNF-α, IL-1β and IL-6. In addition, G. gallus domesticlus Brisson peptides alleviated intestinal microflora disturbance induced by DSS, down-regulated the relative abundance of Shigella and Clostridiaceae_Clostridium, increased the relative abundance of Akkermansia, Ruminococcus and Oscillospira, and significantly increased the contents of acetic acid, propionic acid and butyric acid in cecal contents, thereby alleviating colon inflammation induced by DSS in mice.

Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.

Tannin is the major active ingredient of the dried unripe fruits of Chinese raspberry (Rubus chingii Hu), Fupenzi in Chinese, and has the functions of lowering blood sugar, reducing blood lipid, resisting inflammation, delaying aging and preventing cardiovascular and cerebrovascular diseases. In this study, a tannin-enriched fraction was prepared from Fupenzi, and the changes in its tannin content, antioxidant activity and α-glucosidase inhibitory activity before and after in vitro simulated digestion were investigated. Its regulatory effect on the intestinal microflora was analyzed by in vitro anaerobic fermentation. Finally, ultra-high performance liquid chromatography-quadrupole time of flight-tandem mass spectrometry (UPLC-ESI-QTOF-MS/MS) was used to compare the changes in the contents of tannin and its metabolite after in vitro digestion and fermentation. The results showed that the content of hydrolyzed tannin increased first and then decreased during both gastric and intestinal digestion. Gastrointestinal digestion increased 1,1-dipheny1-2-picryl-hydrazyl (DPPH) radical scavenging capacity of the tannin-enriched fraction, with half-maximal inhibitory concentration (IC50) values ranging from 29.15 to 39.65 µg/mL, but had no significant effect on 2,2’-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) cation radical scavenging capacity (P > 0.05). In addition, after simulated intestinal digestion, the α-glucosidase inhibitory activity increased by 7.16–7.86 times. In vitro colonic fermentation experiments showed that tannin-enriched fraction significantly increased the relative abundance of beneficial bacteria such as Coprococcus, Anaerostipes, Ruminococcus and Faecalibaterium. Simulated gastrointestinal digestion reduced its effect in improving beneficial bacteria such as bifidobacteria. UPLC-ESI-QTOF-MS/MS analysis showed that the content of tannin metabolites decreased first and then increased during gastrointestinal digestion; the contents of urolithin A and urolithin B decreased significantly after colon fermentation, and neither urolithin C nor urolithin D was detected. Therefore, this study provides a theoretical basis for the establishment of stable tannin delivery system to improve its bioavailability.

Abstract Background Traditional Chinese medicine (TCM) has been used to treat various diseases for thousands of years. However, the uncertainty of dosage as well as the lack of systemic evaluation of pharmacology and toxicology is one major reason why TCM remains mysterious and is not accepted worldwide. Hence, we aimed to propose an integrated dose–response metabolomics strategy based on both therapeutic effects and adverse reactions to guide the TCM dosage in treatment. Methods The proposed methodology of integrated dose–response metabolomics includes four steps: dose design, multiple comparison of metabolic features, response calculation and dose–response curve fitting. By comparing the changes of all metabolites under different doses and calculating these changes through superposition, it is possible to characterize the global disturbance and thus describe the overall effect and toxicity of TCM induced by different doses. Rhubarb, commonly used for constipation treatment, was selected as a representative TCM. Results This developed strategy was successfully applied to rhubarb. The dose–response curves clearly showed the efficacy and adverse reactions of rhubarb at different doses. The rhubarb dose of 0.69 g/kg (corresponding to 7.66 g in clinic) was selected as the optimal dose because it was 90% of the effective dose and three adverse reactions were acceptable in this case. Conclusion An integrated dose–response metabolomics strategy reflecting both therapeutic effects and adverse reactions was established for the first time, which we believe is helpful to uncover the mysterious veil of TCM dosage. In addition, this strategy benefits the modernization and internationalization of TCM, and broadens the application of metabolomics.

Abstract Large‐scale artificial intelligence (AI) models such as ChatGPT have the potential to improve performance on many benchmarks and real‐world tasks. However, it is difficult to develop and maintain these models because of their complexity and resource requirements. As a result, they are still inaccessible to healthcare industries and clinicians. This situation might soon be changed because of advancements in graphics processing unit (GPU) programming and parallel computing. More importantly, leveraging existing large‐scale AIs such as GPT‐4 and Med‐PaLM and integrating them into multiagent models (e.g., Visual‐ChatGPT) will facilitate real‐world implementations. This review aims to raise awareness of the potential applications of these models in healthcare. We provide a general overview of several advanced large‐scale AI models, including language models, vision‐language models, graph learning models, language‐conditioned multiagent models, and multimodal embodied models. We discuss their potential medical applications in addition to the challenges and future directions. Importantly, we stress the need to align these models with human values and goals, such as using reinforcement learning from human feedback, to ensure that they provide accurate and personalized insights that support human decision‐making and improve healthcare outcomes.

IntroductionIn China and other Asian nations, Geum japonicum (GJ) is used as functional vegetables or as a type of folk medicine. Ellagic acid (EA) is one of the main active ingredients in GJ and has been utilized in food, cosmetics, and medicinal goods worldwide. Natural deep eutectic solvents (NADESs) have gradually replaced organic solvents for efficient extraction of plant-derived active compounds due to its environmental protection, low toxicity, low solubility, reusability, etc.MethodsNADES with the highest EA yield was selected and the extraction conditions were optimized by response surface methodology (RSM), the antioxidant activity of NADES extract was determined, and finally Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) were used to explain the mechanism for the increase of EA yield in GJ.ResultsIn this work, several NADESs were tailored for the ultrasound assisted extraction (UAE) of EA from GJ, among which choline chloride-oxalic acid (ChCl:Oa) was the most effective. In optimal conditions, ChCl:Oa extract produced higher EA yields than common organic solvents including methanol, ethanol, and acetone. In vitro antioxidant experiments showed that ChCl:Oa extract had stronger DPPH radical scavenging ability than other solvent extracts. Mechanically, FT-IR results indicated that ChCl:Oa could form a hydrogen bonding with EA, which enhanced the stability of EA. Meanwhile, ChCl:Oa-UAE treatment could destroy the tissue structure of GJ, thereby improving EA yield.DiscussionIn conclusion, these results imply that the ChCl:Oa-UAE method might be an environmentally friendly approach for extracting EA from GJ.

Social entrepreneurship, as a way for enterprises to fulfill social responsibility, is becoming one of the key means to reconcile social contradictions in China. In the field of social entrepreneurship as entrepreneurship research focus in the emerging background, such as type business start-ups face “vulnerable” new defects, social entrepreneurship, how to deal with scarce resources, social entrepreneurship resources come from and how to create such basic problems as what kind of results is still not well explain, related research is still in a state of “cumulative pieces”. Therefore, this paper focuses on the social opportunity identification of commercial new ventures, and empirically analyzes the mechanism of social entrepreneurial opportunity identification and resource patchwork on their growth. The results demonstrate that finding social entrepreneurial opportunities is an important part of how resource collages can help social enterprises grow, and the entrepreneur’s social network allows for the mediating effect of resource collage. The more sources of “strong relationships” in entrepreneurs’ social networks, the stronger the impact of social entrepreneurial opportunity identification on the growth performance of commercial startups. Focusing on the field of corporate social entrepreneurship, our findings establish a complete chain of social entrepreneurship processes, from motivation to behavior to corporate sustainability. The findings confirm the mechanism by which social entrepreneurial opportunity identification and resource patchwork help to improve the growth performance of commercial new ventures, and also suggest that entrepreneurs’ social networks can relieve entrepreneurs’ dependence on external network construction to a certain extent.

GRAPHICAL ABSTRACT

Neuropathic pain (NP) affects 7%–10% of the general population and is still hard to cure. Here, we validated the therapeutic effect and demonstrated the mechanism of paeoniflorin and liquiritin combination (PL) on NP from the perspective of integrated lipidomics and transcriptomics for the first time. SwissTargetPrediction indicated that PL mainly targets lipid metabolism. Notably, lipidomics revealed that imbalanced lipid levels in the NP model could be reprogrammed to normal levels by PL treatment. RNA-sequencing showed that PL treatment could also rebalance the lipid metabolism in an indirect manner. Pathway analysis highly enriched the calcium signaling pathway among the most significant categories. Altogether, these findings suggested that PL can not only balance the lipid metabolism in direct and indirect manners but also reverse the dysfunctional activation of the calcium signaling pathway, thereby alleviating NP. This helps to better understand the mechanisms of NP and provides a new important potential therapeutic option for NP.