Contribution of gut microbiota to drug-induced liver injury.

Drug-induced liver injury (DILI) is caused by various drugs with complex pathogenesis, and diverse clinical and pathological phenotypes. Drugs damage the liver directly through drug hepatotoxicity, or indirectly through drug-mediated oxidative stress, immune injury and inflammatory insult, which eventually lead to hepatocyte necrosis. Recent studies have found that the composition, relative content and distribution of gut microbiota in patients and animal models of DILI have changed significantly. It has been confirmed that gut microbial dysbiosis brings about intestinal barrier destruction and microorganisms translocation, and the alteration of microbial metabolites may cause or aggravate DILI. In addition, antibiotics, probiotics, and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut microbiota. In this review, we discussed how the altered gut microbiota participates in DILI.

Acute effect of ambient fine particulate matter on heart rate variability: an updated systematic review and meta-analysis of panel studies.

BACKGROUND: Decreased heart rate variability (HRV) is a predictor of autonomic system dysfunction, and is considered as a potential mechanism of increased risk of cardiovascular disease (CVD) induced by exposure to particulate matter less than 2.5 µm in diameter (PM2.5). Previous studies have suggested that exposure to PM2.5 may lead to decreased HRV levels, but the results remain inconsistent. METHODS: An updated systematic review and meta-analysis of panel studies till November 1, 2019 was conducted to evaluate the acute effect of exposure to ambient PM2.5 on HRV. We searched electronic databases (PubMed, Web of Science, and Embase) to identify panel studies reporting the associations between exposure to PM2.5 and the four indicators of HRV (standard deviation of all normal-to-normal intervals (SDNN), root mean square of successive differences in adjacent normal-to-normal intervals (rMSSD), high frequency power (HF), and low frequency power (LF)). Random-effects model was used to calculate the pooled effect estimates. RESULTS: A total of 33 panel studies were included in our meta-analysis, with 16 studies conducted in North America, 12 studies in Asia, and 5 studies in Europe. The pooled results showed a 10 µg/m3 increase in PM2.5 exposure which was significantly associated with a - 0.92% change in SDNN (95% confidence intervals (95%CI) - 1.26%, - 0.59%), - 1.47% change in rMSSD (95%CI - 2.17%, - 0.77%), - 2.17% change in HF (95%CI - 3.24%, - 1.10%), and - 1.52% change in LF (95%CI - 2.50%, - 0.54%), respectively. Overall, subgroup analysis suggested that short-term exposure to PM2.5 was associated with lower HRV levels in Asians, healthy population, and those aged ≥ 40 years. CONCLUSION: Short-term exposure to PM2.5 was associated with decreased HRV levels. Future studies are warranted to clarity the exact mechanism of exposure to PM2.5 on the cardiovascular system through disturbance of autonomic nervous function.

The role of gut microbiota, exosomes, and their interaction in the pathogenesis of ALD.

BACKGROUND: The liver disorders caused by alcohol abuse are termed alcoholic-related liver disease (ALD), including alcoholic steatosis, alcoholic steatohepatitis alcoholic hepatitis, and alcoholic cirrhosis, posing a significant threat to human health. Currently, ALD pathogenesis has not been completely clarified, which is likely to be related to the direct damage caused by alcohol and its metabolic products, oxidative stress, gut dysbiosis, and exosomes. AIMS: The existing studies suggest that both the gut microbiota and exosomes contribute to the development of ALD. Moreover, there exists an interaction between the gut microbiota and exosomes. We discuss whether this interaction plays a role in the pathogenesis of ALD and whether it can be a potential therapeutic target for ALD treatment. KEY SCIENTIFIC CONCEPTS OF REVIEW: Chronic alcohol intake alters the diversity and composition of gut microbiota, which greatly contributes to ALD's progression. Some approaches targeting the gut microbiota, including probiotics, fecal microbiota transplantation, and phage therapy, have been confirmed to effectively ameliorate ALD in many animal experiments and/or several clinical trials. In ALD, the levels of exosomes and the expression profile of microRNA have also changed, which affects the pathogenesis of ALD. Moreover, there is an interplay between exosomes and the gut microbiota, which also putatively acts as a pathogenic factor of ALD.

Hepatocyte programmed cell death: the trigger for inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis.

By replacing and removing defective or infected cells, programmed cell death (PCD) contributes to homeostasis maintenance and body development, which is ubiquitously present in mammals and can occur at any time. Besides apoptosis, more novel modalities of PCD have been described recently, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. PCD not only regulates multiple physiological processes, but also participates in the pathogenesis of diverse disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is mainly classified into metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), and the latter putatively progresses to cirrhosis and hepatocellular carcinoma. Owing to increased incidence and obscure etiology of MASH, its management still remains a tremendous challenge. Recently, hepatocyte PCD has been attracted much attention as a potent driver of the pathological progression from MASL to MASH, and some pharmacological agents have been proved to exert their salutary effects on MASH partly via the regulation of the activity of hepatocyte PCD. The current review recapitulates the pathogenesis of different modalities of PCD, clarifies the mechanisms underlying how metabolic disorders in MASLD induce hepatocyte PCD and how hepatocyte PCD contributes to inflammatory and fibrotic progression of MASH, discusses several signaling pathways in hepatocytes governing the execution of PCD, and summarizes some potential pharmacological agents for MASH treatment which exert their therapeutic effects partly via the regulation of hepatocyte PCD. These findings indicate that hepatocyte PCD putatively represents a new therapeutic point of intervention for MASH.

TRIF-dependent signaling and its role in liver diseases.

TIR domain-containing adaptor inducing IFN-ß (TRIF) is a crucial adaptor molecule downstream of toll-like receptors 3 (TLR3) and 4 (TLR4). TRIF directly binds to TLR3 through its TIR domain, while it associates with TLR4 indirectly through the bridge adaptor molecule TRIF-related adaptor molecule (TRAM). TRIF plays a pivotal role in regulating interferon beta 1 (IFN-ß) response, nuclear factor kappa B (NF-κB) signaling, apoptosis, and necroptosis signaling mediated by TLR3 and TLR4. It accomplishes these by recruiting and activating various kinases or transcription factors via its distinct domains. In this review, we comprehensively summarize the TRIF-dependent signaling pathways mediated by TLR3 and TLR4, elucidating key target molecules and downstream pathways. Furthermore, we provide an overview of TRIF's impact on several liver disorders, including drug-induced liver injury, ischemia-reperfusion liver injury, autoimmune hepatitis, viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We also explore its effects on liver steatosis, inflammation, fibrosis, and carcinogenesis. A comprehensive understanding of the TRIF-dependent signaling pathways, as well as the intricate relationship between TRIF and liver diseases, can facilitate the identification of potential drug targets and the development of novel and effective therapeutics against hepatic disorders.

A universal plasma metabolites-derived signature predicts cardiovascular disease risk in MAFLD.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is a novel concept proposed in 2020, which is more practical for identifying patients with fatty liver disease with high risk of disease progression. Fatty liver is a driver for extrahepatic complications, particularly cardiovascular diseases (CVD). Although the risk of CVD in MAFLD could be predicted by carotid ultrasound test, a very early stage prediction method before the formation of pathological damage is still lacking. METHODS: Stool microbiomes and plasma metabolites were compared across 196 well-characterized participants encompassing normal controls, simple MAFLD patients, MAFLD patients with carotid artery pathological changes, and MAFLD patients with diagnosed coronary artery disease (CAD). 16S rDNA sequencing data and untargeted metabolomic profiles were interrogatively analyzed using differential abundance analysis and random forest (RF) machine learning algorithm to identify discriminatory gut microbiomes and metabolomic. RESULTS: Characteristic microbial changes in MAFLD patients with CVD risk were represented by the increase of Clostridia and Firmicutes-to-Bacteroidetes ratios. Faecalibacterium was negatively correlated with mean-intima-media thickness (IMT), TC, and TG. Megamonas, Bacteroides, Parabacteroides, and Escherichia were positively correlated with the exacerbation of pathological indexes. MAFLD patients with CVD risk were characterized by the decrease of lithocholic acid taurine conjugate, and the increase of ethylvanillin propylene glycol acetal, both of which had close relationship with Ruminococcus and Gemmiger. Biotin l-sulfoxide had positive correlation with mean-IMT, TG, and weight. The general auxin pesticide beta-naphthoxyacetic acid and the food additive glucosyl steviol were both positively correlated with the increase of mean-IMT. The model combining the metabolite signatures with 9 clinical parameters accurately distinguished MAFLD with CVD risk in the proband and validation cohort. It was found that citral was the most important discriminative metabolite marker, which was validated by both in vitro and in vivo experiments. CONCLUSIONS: Simple MAFLD patients and MAFLD patients with CVD risk had divergent gut microbes and plasma metabolites. The predictive model based on metabolites and 9 clinical parameters could effectively discriminate MAFLD patients with CVD risk at a very early stage.

Ferroptosis in non-alcoholic liver disease: Molecular mechanisms and therapeutic implications.

Ferroptosis refers to a novel modality of regulated cell death characterized by excessive iron accumulation and overwhelming lipid peroxidation, which takes an important part in multiple pathological processes associated with cell death. Considering the crucial roles of the liver in iron and lipid metabolism and its predisposition to oxidative insults, more and more studies have been conducted to explore the relationship between ferroptosis and various liver disorders, including non-alcoholic fatty liver disease (NAFLD). With increased morbidity and high mortality rates, NAFLD has currently emerged as a global public health issue. However, the etiology of NAFLD is not fully understood. In recent years, an accumulating body of evidence have suggested that ferroptosis plays a pivotal role in the pathogenesis of NAFLD, but the precise mechanisms underlying how ferroptosis affects NAFLD still remain obscure. Here, we summarize the molecular mechanisms of ferroptosis and its complicated regulation systems, delineate the different effects that ferroptosis exerts in different stages of NAFLD, and discuss some potential effective therapies targeting ferroptosis for NAFLD treatment, which putatively points out a novel direction for NAFLD treatment.

Bile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) has been the second most common cause of liver transplantation in the United States. To date, NASH pathogenesis has not been fully elucidated but is multifactorial, involving insulin resistance, obesity, metabolic disorders, diet, dysbiosis, and gene polymorphism. An effective and approved therapy for NASH has also not been established. Bile acid is long known to have physiological detergent function in emulsifying and absorbing lipids and lipid-soluble molecules within the intestinal lumen. With more and more in-depth understandings of bile acid, it has been deemed to be a pivotal signaling molecule, which is capable of regulating lipid and glucose metabolism, liver inflammation, and fibrosis. In recent years, a plethora of studies have delineated that disrupted bile acid homeostasis is intimately correlated with NASH disease severity. AIMS: The review aims to clarify the role of bile acid in hepatic lipid and glucose metabolism, liver inflammation, as well as liver fibrosis, and discusses the safety and efficacy of some pharmacological agents targeting bile acid and its associated pathways for NASH. KEY SCIENTIFIC CONCEPTS OF REVIEW: Bile acid has a salutary effect on hepatic metabolic disorders, which can ameliorate liver fat accumulation and insulin resistance mainly through activating Takeda G-protein coupled receptor 5 and farnesoid X receptor. Moreover, bile acid also exerts anti-inflammation and anti-fibrosis properties. Furthermore, bile acid has great potential in nonalcoholic liver disease stratification and treatment of NASH.

The critical role of gut microbiota in obesity.

Obesity is a global epidemic characterized by energy disequilibrium, metabolic disorder, fat mass development, and chronic low-grade inflammation, which significantly affects the health state of individuals of all ages and strains the socioeconomic system. The prevalence of obesity is rising at alarming rates and its etiology involves complicated interplay of diet, genetic, and environmental factors. The gut microbiota, as an important constituent of environmental factors, has been confirmed to correlate with the onset and progression of obesity. However, the specific relationship between obesity and the gut microbiota, and its associated mechanisms, have not been fully elucidated. In this review, we have summarized that the microbial diversity was significantly decreased and the Firmicutes/Bacteroidetes ratio was significantly increased in obesity. The altered gut microbiota and associated metabolites contributed to the progression of the disease by disrupting energy homeostasis, promoting lipid synthesis and storage, modulating central appetite and feeding behavior, as well as triggering chronic inflammation, and that the intentional manipulation of gut microbiota held promise as novel therapies for obesity, including probiotics, prebiotics, and fecal microbiota transplantation.

The Gut Microbiota: A Novel Player in Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease distributed globally in all ethnicities with increasing prevalence. If left untreated, the disease will lead to cirrhosis, liver failure, or death. The intestinal microbiota is a complex ecosystem located in the human intestine, which extensively affects the human physiological and pathological processes. With more and more in-depth understandings of intestinal microbiota, a substantial body of studies have verified that the intestinal microbiota plays a crucial role in a variety of digestive system diseases, including alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). However, only a few studies have paid attention to evaluate the relationship between AIH and the intestinal microbiota. While AIH pathogenesis is not fully elucidated yet, some studies have indicated that intestinal microbiota putatively made significant contributions to the occurrence and the development of AIH by triggering several specific signaling pathways, altering the metabolism of intestinal microbiota, as well as modulating the immune response in the intestine and liver. By collecting the latest related literatures, this review summarized the increasing trend of the aerobic bacteria abundance in both AIH patients and AIH mice models. Moreover, the combination of specific bacteria species was found distinct to AIH patients, which could be a promising tool for diagnosing AIH. In addition, there were alterations of luminal metabolites and immune responses, including decreased short-chain fatty acids (SCFAs), increased pathogen associated molecular patterns (PAMPs), imbalanced regulatory T (Treg)/Th17 cells, follicular regulatory T (TFR)/follicular helper T (TFH) cells, and activated natural killer T (NKT) cells. These alterations participate in the onset and the progression of AIH via multiple mechanisms. Therefore, some therapeutic methods based on restoration of intestinal microbiota composition, including probiotics and fecal microbiota transplantation (FMT), as well as targeted intestinal microbiota-associated signaling pathways, confer novel insights into the treatment for AIH patients.

The Current Situation and Future Trend of Leukemia Mortality by Sex and Area in China.

Leukemia is one of the most common cancers. We conducted this study to comprehensively analyze the temporal trends of leukemia mortality during 2003-2017 and project the trends until 2030. We extracted national-level data on annual leukemia mortality from China Health Statistics Yearbooks (2003-2017). We applied the Joinpoint regression model to assess leukemia mortality trends in urban and rural China by sex during 2003-2017. We also produced sex-specific leukemia mortality using the adjusted Global Burden Disease (GBD) 2016 projection model. In urban areas, age-standardized leukemia mortality decreased significantly among females during 2003-2017 (APC = -0.9%; 95% CI: -1.7, -0.1%). In rural areas, significant decreases of age-standardized leukemia mortality were both found among males (APC = -1.7%; 95% CI: -2.9, -0.5%) and females (APC = -1.6%; 95% CI: -2.6, -0.7%) from 2008 to 2017. Rural-urban and sex disparities of leukemia mortality will continue to exist until the year 2030. According to projection, the leukemia mortality rates of males and rural populations are higher than that of females and urban populations. In 2030, leukemia mortality is projected to decrease to 3.03/100,000 and 3.33/100,000 among the males in urban and rural areas, respectively. In females, leukemia mortality will decrease to 1.87/100,000 and 2.26/100,000 among urban and rural areas, respectively. Our study suggests that more precautionary measures to reduce leukemia mortality are need, and more attention should be paid to rural residents and males in primary prevention of leukemia in China.

Anticancer effects of rosmarinic acid in human oral cancer cells is mediated via endoplasmic reticulum stress, apoptosis, G2/M cell cycle arrest and inhibition of cell migration.

PURPOSE: This investigation was undertaken to infer the anticancer effects of rosmarinic acid against human oral cancer cells. METHODS: Normal hTRET-OME oral cell line and oral cancer cell line SCC-15 were used in the present study. CDK-8 was used to determine the proliferation of cancer cells. Apoptosis of cancer cells was assessed by DAPI staining method. Flow cytometric procedure was employed to study the cancer cell cycle phase distribution. The migratory potential of cancer cells was estimated by transwell assay. RESULTS: Rosmarinic acid inhibited the proliferation of oral cancer cells and the level of inhibition was dose-dependent. The antiproliferative role of rosmarinic acid was exerted through apoptotis induction and arrest of cell cycle at G2/M phase in oral cancer cells. Treatment of rosmarinic acid also resulted in endoplasmic reticulum stress and affected negatively the migratory potential of cancer cells in a concentration-dependent manner. CONCLUSION: The results of this study revealed the anticancer potential of rosmarinic acid against the oral cancer cell growth and propagation. The study envisages the importance of natural compounds for their usage against human cancers.

The short- and long-term associations of particulate matter with inflammation and blood coagulation markers: A meta-analysis.

Inflammation and the coagulation cascade are considered to be the potential mechanisms of ambient particulate matter (PM) exposure-induced adverse cardiovascular events. Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and fibrinogen are arguably the four most commonly assayed markers to reflect the relationships of PM with inflammation and blood coagulation. This review summarized and quantitatively analyzed the existing studies reporting short- and long-term associations of PM2.5(PM with an aerodynamic diameter ≤2.5 µm)/PM10 (PM with an aerodynamic diameter≤10 µm) with important inflammation and blood coagulation markers (TNF-α, IL-6, IL-8, fibrinogen). We reviewed relevant studies published up to July 2020, using three English databases (PubMed, Web of Science, Embase) and two Chinese databases (Wang-Fang, China National Knowledge Infrastructure). The OHAT tool, with some modification, was applied to evaluate risk of bias. Meta-analyses were conducted with random-effects models for calculating the pooled estimate of markers. To assess the potential effect modifiers and the source of heterogeneity, we conducted subgroup analyses and meta-regression analyses where appropriate. The assessment and correction of publication bias were based on Begg's and Egger's test and "trim-and-fill" analysis. We identified 44 eligible studies. For short-term PM exposure, the percent change of a 10 µg/m3 PM2.5 increase on TNF-α and fibrinogen was 3.51% (95% confidence interval (CI): 1.21%, 5.81%) and 0.54% (95% confidence interval (CI): 0.21%, 0.86%) respectively. We also found a significant short-term association between PM10 and fibrinogen (percent change = 0.17%, 95% CI: 0.04%, 0.29%). Overall analysis showed that long-term associations of fibrinogen with PM2.5 and PM10 were not significant. Subgroup analysis showed that long-term associations of fibrinogen with PM2.5 and PM10 were significant only found in studies conducted in Asia. Our findings support significant short-term associations of PM with TNF-α and fibrinogen. Future epidemiological studies should address the role long-term PM exposure plays in inflammation and blood coagulation markers level change.