AIM: To evaluate the effect of artesunate(AS) supplementation on bacterial translocation(BT) and gut microbiota in a rat model of liver cirrhosis. METHODS: Fifty-four male Sprague-Dawley rats were randomly divided int...AIM: To evaluate the effect of artesunate(AS) supplementation on bacterial translocation(BT) and gut microbiota in a rat model of liver cirrhosis. METHODS: Fifty-four male Sprague-Dawley rats were randomly divided into a normal control group(N), a liver cirrhosis group(M) and a liver cirrhosis group intervened with AS(MA). Each group was sampled at 4, 6 and 8 wk. Liver cirrhosis was induced by injection of carbon tetrachloride(CCl4), intragastric administration of 10% ethanol, and feeding a high fat diet. Rats in the MA group were intragastrically administered with AS(25 mg/kg body weight, once daily). Injuries of the liver and intestinal mucosa were assessed by hematoxylineosin or Masson's trichrome staining. Liver index was calculated as a ratio of the organ weight(g) to body weight(g). The gut microbiota was examined by automated ribosomal intergenic-spacer analysis of fecal DNA. BT was assessed by standard microbiological techniques in the blood, mesenteric lymph nodes(MLNs), liver, spleen, and kidney. RESULTS: Compared to group N, the body weight was reduced significantly in groups M and MA due to the development of liver cirrhosis over the period of 8 wk. The body weight was higher in group MA than in group M. The liver indices were significantly elevated at 4, 6 and 8 wk in groups M and MA compared to group N. AS supplementation partially decreased the liver indices in group MA. Marked histopathologic changes in the liver and small intestinal mucosa in group M were observed, which were alleviated in group MA. Levels of pro-inflammatory interleukin-6 and tumor necrosis factor-α were significantly elevated at 8 wk in ileal homogenates in group M compared to group N, which were decreased after AS supplementation in group MA. The dysbiosis of gut microbiota indicated by the mean diversity(Shannon index) and mean similarity(Sorenson index) was severe as the liver cirrhosis developed, and AS supplementation had an apparent intervention effect on the dysbiosis of gut microbiota at 4 wk. The occurrence of BT was increased in the liver of group M compared to that of group N. AS supplementation reduced BT in group MA at 8 wk. BT also occurred in the MLNs, spleen, and kidney, which was reduced by AS supplementation. BT was not detected in the blood in any group.CONCLUSION: Dysbiosis of gut microbiota, injury of intestinal mucosal barrier and BT occurred as liver cirrhosis progressed, which might enhance inflammation and aggravate liver injury. AS may have other nonantimalarial effects that modulate gut microbiota,inhibit BT and alleviate inflammation, resulting in a reduction in CCl4, alcohol and high fat-caused damages to the liver and intestine.展开更多
MicroRNAs (miRNAs), which are a class of highly evolutionarily conserved non-coding RNAs, modulate gene expression and are regulated by specific genes. Several studies have shown that the expression of miRNAs is dereg...MicroRNAs (miRNAs), which are a class of highly evolutionarily conserved non-coding RNAs, modulate gene expression and are regulated by specific genes. Several studies have shown that the expression of miRNAs is deregulated in Hepatitis C virus (HCV) & Hepatitis B virus (HBV) infection, liver cancer progression, tumor invasion and metastasis. There are a number of high-quality review articles relative to the general role of miRNA alterations in carcinogenesis and specific reviews dealing with the miRNA changes in hepatocellular carcinoma (HCC) and cholangio-carcinoma (CCA). Since primary liver cancer is predominantly comprised of HCC and intrahepatic cholangiocarcinoma (ICC), in the present review we specifically focus on recent advances of miRNAs related to tumorigenesis, invasion and metastasis of primary liver cancer, with special emphasis on their relationships to their target genes. HCV & HBV are major causes of liver disease, including acute and chronic hepatitis, liver cirrhosis, and HCC, while HCV infection is a risk factor for ICC. We also discuss the mi-RNA alterations involved in HCV & HBV infection. We briefly describe advances in molecular signaling of miRNAs in liver cancers and present insights into new therapeutic clues that target liver cancer.展开更多
Chinese medicine and herb medicine though used to treat liver diseases are an important cause of liver injury. Many phytochemicals have the potential to injure the liver, some in a dose-related fashion and more often ...Chinese medicine and herb medicine though used to treat liver diseases are an important cause of liver injury. Many phytochemicals have the potential to injure the liver, some in a dose-related fashion and more often in an idiosyncratic fashion, meaning occurrence is uncommon to rare in the population using these treatments. As is the case with pharmaceuticals, the phytochemicals are usually tolerated despite either no or mild transient subclinical injury but rarely in some susceptible patients cause moderate to severe liver injury which is likely mediated by the adaptive immune system.展开更多
Hepatic ischemia/reperfusion injury(HIRI) is a serious complication that occurs following shock and/or liver surgery. Gut microbiota and their metabolites are key upstream modulators of development of liver injury. He...Hepatic ischemia/reperfusion injury(HIRI) is a serious complication that occurs following shock and/or liver surgery. Gut microbiota and their metabolites are key upstream modulators of development of liver injury. Herein, we investigated the potential contribution of gut microbes to HIRI.Ischemia/reperfusion surgery was performed to establish a murine model of HIRI. 16 S r RNA gene sequencing and metabolomics were used for microbial analysis. Transcriptomics and proteomics analysis were employed to study the host cell responses. Our results establish HIRI was significantly increased when surgery occurred in the evening(ZT12, 20:00) when compared with the morning(ZT0, 08:00);however, antibiotic pretreatment reduced this diurnal variation. The abundance of a microbial metabolite3,4-dihydroxyphenylpropionic acid was significantly higher in ZT0 when compared with ZT12 in the gut and this compound significantly protected mice against HIRI. Furthermore, 3,4-dihydroxyphenylpropionic acid suppressed the macrophage pro-inflammatory response in vivo and in vitro. This metabolite inhibits histone deacetylase activity by reducing its phosphorylation. Histone deacetylase inhibition suppressed macrophage pro-inflammatory activation and diminished the diurnal variation of HIRI. Our findings revealed a novel protective microbial metabolite against HIRI in mice. The potential underlying mechanism was at least in part, via 3,4-dihydroxyphenylpropionic acid-dependent immune regulation and histone deacetylase(HDAC) inhibition in macrophages.展开更多
基金Supported by the National Natural Science Foundation of ChinaNo.81070339+13 种基金the International Science and Technology Cooperation Project of ShanxiNo.2010081068the Key Laboratory Foundation of Cellular Physiology Department of Shanxi Medical School and Provincial Ministry of EducationNo.2010-09the Fund for Returned Students of ShanxiNo.211-091the Fund for Returned Medical Doctors of Changzhi Medical CollegeNo.2010-01Science and Technology Innovation Team Project of Changzhi Medical CollegeNo.CX201409College Student Innovation and Entrepreneurship Training Project of Shanxi ProvinceNo.2014308the US NIH(to Cheng Ji)No.R21AA023952 and No.P30DK48522-21
文摘AIM: To evaluate the effect of artesunate(AS) supplementation on bacterial translocation(BT) and gut microbiota in a rat model of liver cirrhosis. METHODS: Fifty-four male Sprague-Dawley rats were randomly divided into a normal control group(N), a liver cirrhosis group(M) and a liver cirrhosis group intervened with AS(MA). Each group was sampled at 4, 6 and 8 wk. Liver cirrhosis was induced by injection of carbon tetrachloride(CCl4), intragastric administration of 10% ethanol, and feeding a high fat diet. Rats in the MA group were intragastrically administered with AS(25 mg/kg body weight, once daily). Injuries of the liver and intestinal mucosa were assessed by hematoxylineosin or Masson's trichrome staining. Liver index was calculated as a ratio of the organ weight(g) to body weight(g). The gut microbiota was examined by automated ribosomal intergenic-spacer analysis of fecal DNA. BT was assessed by standard microbiological techniques in the blood, mesenteric lymph nodes(MLNs), liver, spleen, and kidney. RESULTS: Compared to group N, the body weight was reduced significantly in groups M and MA due to the development of liver cirrhosis over the period of 8 wk. The body weight was higher in group MA than in group M. The liver indices were significantly elevated at 4, 6 and 8 wk in groups M and MA compared to group N. AS supplementation partially decreased the liver indices in group MA. Marked histopathologic changes in the liver and small intestinal mucosa in group M were observed, which were alleviated in group MA. Levels of pro-inflammatory interleukin-6 and tumor necrosis factor-α were significantly elevated at 8 wk in ileal homogenates in group M compared to group N, which were decreased after AS supplementation in group MA. The dysbiosis of gut microbiota indicated by the mean diversity(Shannon index) and mean similarity(Sorenson index) was severe as the liver cirrhosis developed, and AS supplementation had an apparent intervention effect on the dysbiosis of gut microbiota at 4 wk. The occurrence of BT was increased in the liver of group M compared to that of group N. AS supplementation reduced BT in group MA at 8 wk. BT also occurred in the MLNs, spleen, and kidney, which was reduced by AS supplementation. BT was not detected in the blood in any group.CONCLUSION: Dysbiosis of gut microbiota, injury of intestinal mucosal barrier and BT occurred as liver cirrhosis progressed, which might enhance inflammation and aggravate liver injury. AS may have other nonantimalarial effects that modulate gut microbiota,inhibit BT and alleviate inflammation, resulting in a reduction in CCl4, alcohol and high fat-caused damages to the liver and intestine.
文摘MicroRNAs (miRNAs), which are a class of highly evolutionarily conserved non-coding RNAs, modulate gene expression and are regulated by specific genes. Several studies have shown that the expression of miRNAs is deregulated in Hepatitis C virus (HCV) & Hepatitis B virus (HBV) infection, liver cancer progression, tumor invasion and metastasis. There are a number of high-quality review articles relative to the general role of miRNA alterations in carcinogenesis and specific reviews dealing with the miRNA changes in hepatocellular carcinoma (HCC) and cholangio-carcinoma (CCA). Since primary liver cancer is predominantly comprised of HCC and intrahepatic cholangiocarcinoma (ICC), in the present review we specifically focus on recent advances of miRNAs related to tumorigenesis, invasion and metastasis of primary liver cancer, with special emphasis on their relationships to their target genes. HCV & HBV are major causes of liver disease, including acute and chronic hepatitis, liver cirrhosis, and HCC, while HCV infection is a risk factor for ICC. We also discuss the mi-RNA alterations involved in HCV & HBV infection. We briefly describe advances in molecular signaling of miRNAs in liver cancers and present insights into new therapeutic clues that target liver cancer.
文摘Chinese medicine and herb medicine though used to treat liver diseases are an important cause of liver injury. Many phytochemicals have the potential to injure the liver, some in a dose-related fashion and more often in an idiosyncratic fashion, meaning occurrence is uncommon to rare in the population using these treatments. As is the case with pharmaceuticals, the phytochemicals are usually tolerated despite either no or mild transient subclinical injury but rarely in some susceptible patients cause moderate to severe liver injury which is likely mediated by the adaptive immune system.
基金supported by the National Natural Science Foundation of China(81873926,32071124)Natural Science Funds for Distinguished Young Scholar of Guangdong province grant(2016A030306043,China)to Peng Chen+2 种基金Grants from the NSFCGuangdong Joint Foundation of China(U1601225)Natural Science Foundation of China(81971895)Special Support Plan for Outstanding Talents of Guangdong Province(2019JC05Y340,China)to Yong Jiang。
文摘Hepatic ischemia/reperfusion injury(HIRI) is a serious complication that occurs following shock and/or liver surgery. Gut microbiota and their metabolites are key upstream modulators of development of liver injury. Herein, we investigated the potential contribution of gut microbes to HIRI.Ischemia/reperfusion surgery was performed to establish a murine model of HIRI. 16 S r RNA gene sequencing and metabolomics were used for microbial analysis. Transcriptomics and proteomics analysis were employed to study the host cell responses. Our results establish HIRI was significantly increased when surgery occurred in the evening(ZT12, 20:00) when compared with the morning(ZT0, 08:00);however, antibiotic pretreatment reduced this diurnal variation. The abundance of a microbial metabolite3,4-dihydroxyphenylpropionic acid was significantly higher in ZT0 when compared with ZT12 in the gut and this compound significantly protected mice against HIRI. Furthermore, 3,4-dihydroxyphenylpropionic acid suppressed the macrophage pro-inflammatory response in vivo and in vitro. This metabolite inhibits histone deacetylase activity by reducing its phosphorylation. Histone deacetylase inhibition suppressed macrophage pro-inflammatory activation and diminished the diurnal variation of HIRI. Our findings revealed a novel protective microbial metabolite against HIRI in mice. The potential underlying mechanism was at least in part, via 3,4-dihydroxyphenylpropionic acid-dependent immune regulation and histone deacetylase(HDAC) inhibition in macrophages.