Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations.

The liver possesses a distinctive capacity for regeneration within the human body. Under normal circumstances, liver cells replicate themselves to maintain liver function. Compensatory replication of healthy hepatocytes is sufficient for the regeneration after acute liver injuries. In the late stage of chronic liver damage, a large number of hepatocytes die and hepatocyte replication is blocked. Liver regeneration has more complex mechanisms, such as the transdifferentiation between cell types or hepatic progenitor cells mediated. Dysregulation of liver regeneration causes severe chronic liver disease. Gaining a more comprehensive understanding of liver regeneration mechanisms would facilitate the advancement of efficient therapeutic approaches. This review provides an overview of the signalling pathways linked to different aspects of liver regeneration in various liver diseases. Moreover, new knowledge on cellular interactions during the regenerative process is also presented. Finally, this paper explores the potential applications of new technologies, such as nanotechnology, stem cell transplantation and organoids, in liver regeneration after injury, offering fresh perspectives on treating liver disease.

Xiaoyaosan against depression through suppressing LPS mediated TLR4/NLRP3 signaling pathway in "microbiota-gut-brain" axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression impairs not only central nervous system, but also peripheral systems of the host. Gut microbiota have been proved to be involved in the pathogenesis of depression. Xiaoyaosan (XYS) has a history of over a thousand years in China for treating depression, dramatically alleviating anxiety, cognitive disorders, and especially gastrointestinal dysfunctions. Yet, it still just scratches the surface of the anti-depression mechanisms of XYS. AIM OF THE STUDY: This study aims to elucidate the mechanism of actions of XYS from the perspective of "microbiota-gut-brain" axis. MATERIALS AND METHODS: We firstly evaluated the effects of XYS on the macroscopic behaviors of depressed rats that induced by chronic unpredictable mild stress (CUMS). Secondly, the effects of XYS on intestinal homeostasis of depressed rats were revealed by using dysbacteriosis model. Subsequently, the underlying mechanisms were demonstrated by 16S rRNA gene sequencing technology and molecular biology methods. Finally, correlation analysis and visualization of the anti-depression effects of XYS were performed from the "microbiota - gut - brain" perspective. RESULTS: Our data indicated that XYS ameliorated the depression-like symptoms of CUMS rats, partly depending on the presence of gut microbiota. Furthermore, we illustrated that XYS reversed CUMS-induced gut dysbiosis of depressed rats in terms of decreasing the Bacteroidetes/Firmicutes ratio and the abundances of Bacteroides, and Corynebacterium, while increasing the abundances of Lactobacillus and Adlercreutzia. The significant enrichment of Bacteroides and the level of lipopolysaccharides (LPS) suggested that depression damaged the immune responses and gut barrier. Mechanistically, XYS significantly down-regulated the expression levels of factors that involved in TLR4/NLRP3 signaling pathway in the colon and brain tissues of depressed rats. In addition, XYS significantly increased the levels of claudin 1 and ZO-1, showing that XYS positively maintained the integrity of gut and blood-brain barriers (BBB). CONCLUSION: Our study offers insights into the anti-depression effects of XYS through a lens of "microbiota-TLR4/NLRP3 signaling pathway-barriers", providing a foundation for enhancing clinical efficiency and enriching drug selection, and contributing to our understanding of the mechanisms of traditional Chinese medicines (TCMs) in treating depression.

Gastrointestinal Characteristics of Constipation from the Perspectives of Microbiome and Metabolome.

BACKGROUND: Constipation is one of the most common gastrointestinal complaints. Yet, the underlying mechanisms of constipation remain to be explored deeply. Integration of microbiome and metabolome is powerful and promising to demonstrate characteristics of constipation. AIM OF STUDY: This study aimed to characterize intestinal microbiome and metabolome of constipation. In addition, this study revealed the correlations among behaviors, intestinal microbiota, and metabolites interrupted by constipation. METHODS: Firstly, the constipation model was successfully applied. At the macro level, the ability of learning, memory, locomotor activity, and the defecation index of rats with constipation-like phenotype were characterized. At the micro-level, 16S rRNA sequencing was applied to analyze the intestinal microbiota in rats with constipation-like phenotype. 1H nuclear magnetic resonance (NMR)-based metabolomics was employed to investigate the metabolic phenotype of constipation. In addition, we constructed a correlation network, intuitively showing the correlations among behaviors, intestinal microbiota, and metabolites. RESULTS: Constipation significantly attenuated the locomotor activity, memory recognition, and frequency of defecation of rats, while increased the time of defecation. Constipation significantly changed the diversity of intestinal microbial communities, which correspondingly involved in 5 functional pathways. Besides, 28 fecal metabolites were found to be associated with constipation, among which 14 metabolites were further screened that can be used to diagnose constipation. On top of this, associated networks intuitively showed the correlations among behaviors, intestinal microbiota, and metabolites. CONCLUSIONS: The current findings are significant in terms of not only laying a foundation for understanding characteristics of constipation, but also providing accurate diagnosis and treatments of constipation clinically.

Astragaloside IV Alleviates Depression in Rats by Modulating Intestinal Microbiota, T-Immune Balance, and Metabolome.

This study aims to explore the effects of Astragaloside IV (AS-IV) on abnormal behaviors, intestinal microbiota, intestinal T-immune balance, and fecal metabolism of a model of depression in rats. Herein, we integrally applied 16S rRNA sequencing, molecular biological techniques, and 1H NMR-based fecal metabolomics to demonstrate the antidepression activity of AS-IV. The results suggested that AS-IV regulated the depression-like behaviors of rats, which are presented by an increase of body weight, upregulation of sucrose preference rates, and a decrease of immobility time. Additionally, AS-IV increased the abundances of beneficial bacteria (Lactobacillus and Oscillospira) in a model of depression in rats. Moreover, AS-IV regulated significantly the imbalance of Th17/Treg cells, and the abnormal contents of both anti-inflammatory factors and pro-inflammatory factors. Besides, fecal metabolomics showed that AS-IV improved the abnormal levels of short-chain fatty acids and amino acids. Collectively, our research supplemented new data, supporting the potential of AS-IV as an effective diet or diet composition to improve depression-like behaviors, dysfunctions of microbiota, imbalance of T immune, and the abnormality of fecal metabolome. However, the causality of the other actions was not proven because of the experimental design and the methodology used. The current findings suggest that AS-IV could function as a promising diet or diet composition to alleviate depressed symptoms.

Microbiome and metabolome integrally reveal the anti-depression effects of Cistanche deserticola polysaccharides from the perspective of gut homeostasis.

Polysaccharides are one of the active components of Cistanche deserticola (CD). Cistanche deserticola polysaccharides (CDPs) significantly regulate gut microbiota, immune activity, and neuroprotective functions. However, it merely scratches the surface that the anti-depression effects of CDPs. We aimed to demonstrate the anti-depression effects of CDPs and the underlying mechanisms from the perspectives of gut homeostasis by behavioral evaluations and applying integrally microbiome, metabolome, and molecular biology. CDPs showed significant effects on improving abnormal behaviors of depressed rats. Additionally, CDPs maintained Th17/Treg balance and modulated gut immunity of depressed rats. Comprehensive microbiome and metabolome analysis showed that CDPs significantly ameliorated abundances of beneficial bacteria, and increased the contents of SCFAs, consequently maintaining gut homeostasis. Besides, the anti-depression effects of CDPs involved in amino acid metabolism including BCAAs, glutamine, etc., maintaining metabolic balance. The current findings provide not only deep understanding of depression focusing on gut, but also evidence about the anti-depression effects of CDPs, broadening clinic applications of CDPs. Of note, the present study is of significance in a long run, in terms of providing novel strategies and protocols for revealing mechanisms of anti-depression drugs, and for the discovery of new antidepressants and functional foods from natural products.

Gut microbiome and tissue metabolomics reveal the compatibility effects of Xiaoyaosan on depression based on "gut-liver-kidney" axis.

BACKGROUND: Depression affects not only the central nervous system, but also the peripheral system. Xiaoyaosan (XYS), a classical traditional Chinese medicine (TCM) prescription, exhibits definite anti-depression effects demonstrated both clinically and experimentally. However, its compatibility has not been entirely revealed due partly to the complex compositions of herbs contained. AIM: Based on the strategy of "Efficacy Group", this study aimed to reveal the compatibility of XYS from the perspective of "gut-liver-kidney" axis. METHODS: Firstly, XYS was divided into two efficacy groups, i.e. Shugan (SG) and Jianpi (JP) groups. Classic behaviors of rats were measured to confirm the anti-depression effects of XYS and its two efficacy groups. On top of this, gut microbiota analysis and kidney metabolomics were performed by 16S rRNA sequencing and 1H NMR, respectively. RESULTS: We found that XYS and its efficacy groups significantly regulated the abnormalities of behaviors and kidney metabolism of depressed rats, as well as intestinal disorders, but to different degrees. The regulatory effects of XYS and its efficacy groups on behaviors and kidney metabolomics of depressed rats had the same order, i.e. XYS > SG > JP, while the order of regulating gut microbiota was XYS > JP > SG. Both XYS and its efficacy groups significantly ameliorated gut microbiota disturbed, especially significant modulation of Peptostreptococcaceae. XYS significantly regulated nine kidney metabolites, while SG and JP regulated four and five differential metabolites, respectively, indicating that the two efficacy groups synergistically exhibited anti-depression effects, consequently contributing to the overall anti-depression effects of XYS. CONCLUSION: The current findings not only innovatively demonstrate the anti-depression effects and compatibility of XYS from the perspective of "gut-liver-kidney" axis, comprehensively using "Efficacy Group" strategy, macro behavioristics, metabolome and microbiome, and also provide a new perspective, strategy, and methodology for studying complex diseases and the compatibility of TCMs.

A Review of Aberrant DNA Methylation and Epigenetic Agents Targeting DNA Methyltransferases in Endometriosis.

BACKGROUND: Endometriosis (EMS) is a gynecological disease defined by the translocation and growth of endometrial tissue in other tissues or organs outside the uterus. Its clinical manifestations are dysmenorrhea, irregular menstruation, and even infertility. Although EMS is a benign disease, it has the characteristics of malignant tumor and the potential of malignant transformation. Recent studies have found that EMS may involve epigenetic changes and that various epigenetic aberrations, especially aberrant DNA methylation may play an essential role in the pathogenesis of EMS. Previous studies have elucidated the epigenetic regulators of EMS and reported variations in epigenetic patterns of genes known to be associated with abnormal hormonal, immune, and inflammatory states of EMS. With the development of high-throughput sequencing and other biomolecular technologies, we have a better understanding of genome-wide methylation in EMS. OBJECTIVE: This article will discuss the potentiality of targeting DNA methylation as the therapeutic approach for EMS. RESULTS: This article reviews the role of DNA methylation in the pathophysiology of EMS and provides insight into a novel therapeutic approach for EMS by targeting DNA methylation modifiers. We also review the current progress in using DNA methylation inhibitors in EMS therapy and the potential promise and challenges ahead. CONCLUSION: Aberrant DNA methylation plays an essential role in the pathogenesis of EMS and epigenetic agents targeting DNA methyltransferases are expected to be the theoretical basis for the new treatment of EMS.