Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.

The microbiota-gut-brain axis plays a pivotal role in neuropsychiatric disorders, particularly in depression. Escitalopram (ESC) is a first-line antidepressant, however, its regulatory mechanisms on the microbiota-gut-brain axis in the treatment of depression remain unclear. The antidepressant effects of ESC were evaluated using the forced swim test in Wistar-Kyoto (WKY) rats, while damage in the gut and brain regions was assessed through H&E staining and immunohistochemistry. The therapeutic mechanisms in WKY rats with depression-like behavior were investigated through 16S rRNA sequencing of the gut microbiota, serum untargeted metabolomics, and hippocampal proteomics. Results indicated that ESC intervention improved depressive-like behaviors, as evidenced by increased swimming times in WKY rats, and also restored intestinal permeability and brain tissue integrity. Significant changes in the gut microbiota composition, particularly an increase in Bacteroides barnesiae, as well as increases in serum sphingolipid metabolites (Sphinganine 1-phosphate, Sphingosine, and Sphingosine-1-phosphate) and hippocampal proteins (Sptlc1, Enpp5, Enpp2), were strongly correlated. These robust correlations suggest that ESC may exert its antidepressant effects by modulating sphingolipid metabolism through the influence of gut microbiota. Accordingly, this research elucidates novel mechanisms underlying the antidepressant efficacy of ESC and highlights the pivotal importance of the microbiota-gut-brain axis in mediating these effects.

Background: Sepsis-induced acute kidney injury (S-AKI) is a form of acute renal failure resulting from a systemic inflammatory response triggered by infection, and has emerged as a significant public health challenge. Prior studies have demonstrated that artesunate (ART) exerts therapeutic effects on S-AKI by mitigating inflammation and oxidative stress. However, the precise regulatory mechanisms remain to be fully elucidated. Methods: This study investigates the impact of ART on renal function in a sepsis mouse model and its effect on LPS-induced cytotoxicity in HK-2 cells, aiming to clarify the potential therapeutic mechanisms underlying ART’s efficacy in S-AKI. We evaluated changes in body weight, kidney index, biochemical markers, and histopathological alterations in mice, as well as proliferation and apoptosis in HK-2 cells. Additionally, metabolomics and transcriptomics were employed to identify key pathways involved in ART’s therapeutic actions. Results: Our findings indicate that ART significantly improves renal function in sepsis mice, evidenced by increased body weight, reduced kidney index, and diminished pathological damage. Furthermore, ART alleviates LPS-induced cytotoxicity in HK-2 cells, reduce the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, and increase the levels of antioxidant GSH. Integrative analysis of metabolomics and transcriptomics reveals that ART intervention markedly decreases lactate levels, inhibits excessive AMPK activation, relieves mTOR pathway suppression, and suppresses excessive autophagy, thereby attenuating inflammation and oxidative stress, and mitigating renal cell injury. Conclusion: The findings suggest that ART may mitigate inflammation and oxidative stress while improving renal function in S-AKI by modulating the lactate/AMPK/mTOR pathway and inhibiting excessive autophagy.

Background: Toxicity concerns persist in the fields of public health, environmental science, and pharmacology. The intricate and vital role of the gastrointestinal microbiome in influencing toxicity and overall human health has gained increasing recognition in recent years. This study presents a comprehensive bibliometric analysis to evaluate the global scientific output, emerging trends, and research focal points in the area of gastrointestinal microbiome and toxicity.Methods: The Web of Science Core Collection database was retrieved for publications on the gastrointestinal microbiome and toxicity from 1980 to 2022. Our analysis included scholarly research papers written in English and excluded duplicate publications. We used Biblioshiny and R to summarize the count and citation metrics of included articles, and visualized research trends and keywords. CiteSpace was used to identify reference literature, keywords, and citation bursts. VOSviewer was used to visualize the network of related countries, institutions, authors, co-cited authors, and keywords.Results: A total of 2,140 articles were included, allowing us to identify significant countries, institutions, authors, and research focal points. Our results indicate a growing trend in the field, with China and the United States leading the research. The most productive journal in this area is Science of the Total Environment. Key findings revealed that research hotspots have shifted from drugs to environmental pollutants, emphasizing microplastics. Important mechanisms studied include oxidative stress, metabolism, inflammation, and apoptosis, with target organs being the gastrointestinal tract, liver, and brain. Furthermore, we highlight the rising significance of the gut-brain axis and the usage of zebrafish as a model organism.Conclusion: Despite certain limitations, such as focusing solely on English-language publications and excluding unpublished literature, our findings provide valuable insights into the current state of research on toxicity and the gastrointestinal microbiome. In the future, modifications to the gastrointestinal microbiome could offer new directions for treating and mitigating toxicity. These discoveries provide a comprehensive perspective on the broader scope of this research field.

Podophyllotoxin (PPT), a lignan extracted from the roots and stems of Podophyllum species, exhibits significant enterotoxicity that limits its clinical application. However, its underlying mechanisms remain unclear. This study aimed to elucidate the mechanisms underlying PPT-induced enterotoxicity. Changes in body weight, fecal morphology, toxic phenotypes, and histopathological features were evaluated. 3D reconstruction, 16S rRNA sequencing, targeted short-chain fatty acids (SCFAs) analysis, and inflammatory cytokine assays were performed. The findings demonstrated that PPT induced pathological changes in rats, including weight loss, diarrhea, and colonic damage. PPT administration significantly reduced beneficial bacteria such as Lactobacillus, while increasing harmful bacteria such as Escherichia-Shigella. The predicted pathways of bacterial invasion of epithelial cells and lipopolysaccharide biosynthesis were significantly upregulated. Levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were also increased. Additionally, the expression of undecaprenyl-diphosphate synthase (UPPS) and SCFAs production was reduced. These findings indicate that PPT may alter gut microbial composition, increase Escherichia-Shigella invasion in the intestinal epithelial cells, promote lipopolysaccharide production, enhance the release of pro-inflammatory cytokines, including TNF-α and IL-6, and inhibit UPPS expression and SCFAs generation, collectively contributing to enterotoxicity. This study provides novel insights into the mechanisms behind PPT-induced enterotoxicity, which is essential for preventing and treating PPT toxicity.

Introduction: Quercetin (QUE), a plant-derived flavonoid abundant in many vegetables, has been implicated in glycaemic regulation; however, its application in functional foods is limited by poor stability during upper-gastrointestinal transit and low oral bioavailability. This study aimed to develop a porous-starch-based delivery system to improve the bioavailability and metabolic benefits of QUE. Methods: Porous-starch-encapsulated quercetin microspheres (PSQ) were engineered using corn-derived porous starch as a carrier. The in vitro release behavior of PSQ was evaluated under simulated gastric and intestinal conditions. The metabolic effects of PSQ were further investigated in a type 2 diabetes mellitus (T2DM) mouse model by comparing PSQ with free QUE. Glucose metabolism, lipid metabolism, gut microbiota composition, and caecal short-chain fatty acids (SCFAs) were systematically analyzed. Results: In vitro, PSQ showed restrained release under gastric-like conditions but enhanced release under intestinal-like conditions, indicating reduced premature release and improved intestinal-phase availability. In T2DM mice, PSQ administration improved body weight, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), serum glycated protein (GSP), and HOMA-derived indices of islet function, while partially alleviating serum and hepatic lipid abnormalities. The higher PSQ dose exhibited stronger effects than the lower dose and free QUE. Microbiota analysis revealed PSQ-associated enrichment of beneficial metabolic-related genera, including Lactobacillus, Adlercreutzia , and Limosilactobacillus , together with depletion of taxa such as Lawsonibacter and Bilophila . These microbial alterations were accompanied by increased caecal SCFA levels, which were significantly correlated with glycaemic and biochemical parameters. Correlation-network analysis identified Turicimonas and Muribaculum as potential microbial signatures associated with metabolic regulation. Discussion: Porous-starch encapsulation provides partial gastric protection and enhances intestinal availability of quercetin, thereby potentiating its metabolic benefits in T2DM mice. The improved metabolic outcomes were accompanied by coordinated modulation of gut microbiota and SCFA production, supporting PSQ as a promising strategy for developing QUE-based functional food interventions.