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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature non-alcoholic fatty liver disease (NAFLD) is an important part of the metabolic syndrome, ranging from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and has now become global cirrhosis and hepatocellular carcinoma The main reason
.
However, due to the complex and unclear pathophysiological mechanism, there are currently no drugs specifically approved for the treatment of NASH
.
Breviscapine is a natural flavonoid prescription drug isolated from the traditional Chinese herbal medicine Breviscapine.
It has a wide range of pharmacological properties, including its effects on metabolism
.
However, the anti-NASH efficacy and mechanism of breviscapine have not been characterized yet
.
On October 30, 2021, the Guo Jiao team of Guangdong Pharmaceutical University published an online research paper titled "Breviscapine Alleviates Nonalcoholic Steatohepatitis by Inhibiting TGF-β-activated Kinase 1-dependent Signaling".
The study evaluated Dengzhan in vivo and in vitro The effect of flower element on the development of liver steatosis, inflammation and fibrosis under metabolic stress
.
Breviscapine treatment significantly reduced lipid accumulation, inflammatory cell infiltration, liver damage, and fibrosis in mice fed a high-fat diet (HFD), high-fat/high-cholesterol (HFHC) diet, or methionine and choline deficiency (MCD)
.
In addition, breviscapine can reduce lipid accumulation, inflammation and lipotoxicity in liver cells undergoing metabolic stress
.
RNA sequencing and multi-omics analysis further showed that the key mechanism of breviscapine's anti-NASH effect is the inhibition of TAK1 phosphorylation and the subsequent MAPK signal cascade
.
Treatment with the TAK1 inhibitor 5Z-7-oxozeaenol eliminated the liver protection under breviscapine-mediated metabolic stress
.
Molecular docking indicates that breviscapine directly binds to TAK1
.
In conclusion, breviscapine prevents the progression of NASH induced by metabolic stress by directly inhibiting TAK1 signaling
.
Breviscapine may be a new drug candidate for the treatment of NASH
.
On October 14, 2021, the Guo Jiao team of Guangdong Pharmaceutical University published an online research paper entitled "Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling" in the Journal of Hepatology (IF=25.
08).
Studies have found that glutathione S-transferase Mu 2 (GSTM2) is a sensitive responder and effective inhibitor of the progress of NASH
.
GSTM2 was significantly down-regulated during the progression of NASH
.
Hepatocyte GSTM2 deficiency significantly aggravated insulin resistance, liver steatosis, inflammation and fibrosis caused by high-fat diet and high-fat/high-cholesterol diet
.
In terms of mechanism, GSTM2 maintains the MAPK pathway by directly interacting with apoptosis signal-regulated kinase 1 (ASK1)
.
In addition, GSTM2 directly binds to the amino terminal (N-terminal) region of ASK1 and inhibits ASK1 N-terminal dimerization, and subsequently inhibits ASK1 phosphorylation and the activation of the downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction
.
In summary, this study shows that GSTM2 in hepatocytes is an endogenous inhibitory factor that prevents the progression of NASH by blocking the N-terminal dimerization and phosphorylation of ASK1
.
The study paved the way for the development of NASH treatment strategies by activating GSTM2
.
Non-alcoholic fatty liver disease (NAFLD) is a widespread liver dysfunction and is becoming the main cause of liver dysfunction worldwide
.
Non-alcoholic steatohepatitis (NASH) is the inflammatory subtype of NAFLD, which is accompanied by steatosis and insulin resistance, as well as evidence of liver cell damage (ballooning) and inflammation with or without fibrosis
.
Patients with NASH are at increased risk of advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC)
.
Although many clinical and experimental studies have been conducted, the detailed molecular mechanism involved in the pathogenesis of NASH remains to be elucidated
.
Since the pathophysiology of NASH is complex, several targets and approaches must be addressed to improve the therapeutic effect of NASH treatment
.
The development of NASH involves multiple mechanisms, so its treatment may require a single drug or combination therapy with different cellular/molecular targets
.
Glutathione S transferase (GST) is a type II detoxification enzyme family that catalyzes the binding of glutathione (GSH) to a variety of xenobiotics and metabolites
.
The structure of GST superfamily members is highly conserved, including the amino-terminal (N-terminal) domain with characteristic thioredoxin (Trx) folds and the strong helical carboxy-terminal (C-terminal) domain
.
The active site and GSH binding site (G-site) are located in the N-terminal domain, and the residues involved in the binding of hydrophobic substrates are generally located in the C-terminal domain
.
GST can be divided into 4 human families (isoenzymes) with different but sometimes overlapping substrate specificities
.
These families are called alpha (A), mu (M), pi (P) and theta (T)
.
The article pattern diagram (picture from Journal of Hepatology) has identified five isoforms of GSTM (denoted as M1-M5)
.
Glutathione S-transferase Mu2 (Gstm2) is a mu isoenzyme of GST, which has unique characteristics compared with other isoenzymes of its kind
.
In particular, there are regional differences in the expression of several GSTs in the liver lobules, and the expression of GSTM2 in the hepatocyte population around the vein is higher than that in the hepatocyte population around the portal vein
.
In addition, it was found that the expression of GSTM2 in the liver of obese rats was reduced
.
However, the role of GSTM2 in hepatocyte lipid accumulation and inflammation in the pathogenesis of NASH remains unknown
.
In order to clarify the potential protective role of GSTM2 in the pathogenesis of NASH, this study aimed to investigate the role of GSTM2 in NASH and determine whether hepatocyte-specific GSTM2 overexpression can reduce insulin resistance, liver steatosis and inflammation
.
The results of this study indicate that GSTM2 is down-regulated in liver cells during the progression of NASH
.
Comprehensive RNA sequencing and functional analysis showed that hepatocyte-specific GSTM2 deficiency enhances lipid deposition, inflammation, and fibrosis in NASH
.
In terms of mechanism, GSTM2 of hepatocytes directly binds to the N-terminal of apoptosis signal-regulated kinase 1 (ASK1) and inhibits its dimerization and phosphorylation, as well as subsequent c-Jun N-terminal kinase (JNK) and p38 signal transduction.
Activate
.
These data strongly support GSTM2 as a functional candidate gene for regulating liver cell injury and inflammation, and as a valuable therapeutic target in human NASH
.
Reference message: https://#%20https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32221
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature non-alcoholic fatty liver disease (NAFLD) is an important part of the metabolic syndrome, ranging from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and has now become global cirrhosis and hepatocellular carcinoma The main reason
.
However, due to the complex and unclear pathophysiological mechanism, there are currently no drugs specifically approved for the treatment of NASH
.
Breviscapine is a natural flavonoid prescription drug isolated from the traditional Chinese herbal medicine Breviscapine.
It has a wide range of pharmacological properties, including its effects on metabolism
.
However, the anti-NASH efficacy and mechanism of breviscapine have not been characterized yet
.
On October 30, 2021, the Guo Jiao team of Guangdong Pharmaceutical University published an online research paper titled "Breviscapine Alleviates Nonalcoholic Steatohepatitis by Inhibiting TGF-β-activated Kinase 1-dependent Signaling".
The study evaluated Dengzhan in vivo and in vitro The effect of flower element on the development of liver steatosis, inflammation and fibrosis under metabolic stress
.
Breviscapine treatment significantly reduced lipid accumulation, inflammatory cell infiltration, liver damage, and fibrosis in mice fed a high-fat diet (HFD), high-fat/high-cholesterol (HFHC) diet, or methionine and choline deficiency (MCD)
.
In addition, breviscapine can reduce lipid accumulation, inflammation and lipotoxicity in liver cells undergoing metabolic stress
.
RNA sequencing and multi-omics analysis further showed that the key mechanism of breviscapine's anti-NASH effect is the inhibition of TAK1 phosphorylation and the subsequent MAPK signal cascade
.
Treatment with the TAK1 inhibitor 5Z-7-oxozeaenol eliminated the liver protection under breviscapine-mediated metabolic stress
.
Molecular docking indicates that breviscapine directly binds to TAK1
.
In conclusion, breviscapine prevents the progression of NASH induced by metabolic stress by directly inhibiting TAK1 signaling
.
Breviscapine may be a new drug candidate for the treatment of NASH
.
On October 14, 2021, the Guo Jiao team of Guangdong Pharmaceutical University published an online research paper entitled "Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling" in the Journal of Hepatology (IF=25.
08).
Studies have found that glutathione S-transferase Mu 2 (GSTM2) is a sensitive responder and effective inhibitor of the progress of NASH
.
GSTM2 was significantly down-regulated during the progression of NASH
.
Hepatocyte GSTM2 deficiency significantly aggravated insulin resistance, liver steatosis, inflammation and fibrosis caused by high-fat diet and high-fat/high-cholesterol diet
.
In terms of mechanism, GSTM2 maintains the MAPK pathway by directly interacting with apoptosis signal-regulated kinase 1 (ASK1)
.
In addition, GSTM2 directly binds to the amino terminal (N-terminal) region of ASK1 and inhibits ASK1 N-terminal dimerization, and subsequently inhibits ASK1 phosphorylation and the activation of the downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction
.
In summary, this study shows that GSTM2 in hepatocytes is an endogenous inhibitory factor that prevents the progression of NASH by blocking the N-terminal dimerization and phosphorylation of ASK1
.
The study paved the way for the development of NASH treatment strategies by activating GSTM2
.
Non-alcoholic fatty liver disease (NAFLD) is a widespread liver dysfunction and is becoming the main cause of liver dysfunction worldwide
.
Non-alcoholic steatohepatitis (NASH) is the inflammatory subtype of NAFLD, which is accompanied by steatosis and insulin resistance, as well as evidence of liver cell damage (ballooning) and inflammation with or without fibrosis
.
Patients with NASH are at increased risk of advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC)
.
Although many clinical and experimental studies have been conducted, the detailed molecular mechanism involved in the pathogenesis of NASH remains to be elucidated
.
Since the pathophysiology of NASH is complex, several targets and approaches must be addressed to improve the therapeutic effect of NASH treatment
.
The development of NASH involves multiple mechanisms, so its treatment may require a single drug or combination therapy with different cellular/molecular targets
.
Glutathione S transferase (GST) is a type II detoxification enzyme family that catalyzes the binding of glutathione (GSH) to a variety of xenobiotics and metabolites
.
The structure of GST superfamily members is highly conserved, including the amino-terminal (N-terminal) domain with characteristic thioredoxin (Trx) folds and the strong helical carboxy-terminal (C-terminal) domain
.
The active site and GSH binding site (G-site) are located in the N-terminal domain, and the residues involved in the binding of hydrophobic substrates are generally located in the C-terminal domain
.
GST can be divided into 4 human families (isoenzymes) with different but sometimes overlapping substrate specificities
.
These families are called alpha (A), mu (M), pi (P) and theta (T)
.
The article pattern diagram (picture from Journal of Hepatology) has identified five isoforms of GSTM (denoted as M1-M5)
.
Glutathione S-transferase Mu2 (Gstm2) is a mu isoenzyme of GST, which has unique characteristics compared with other isoenzymes of its kind
.
In particular, there are regional differences in the expression of several GSTs in the liver lobules, and the expression of GSTM2 in the hepatocyte population around the vein is higher than that in the hepatocyte population around the portal vein
.
In addition, it was found that the expression of GSTM2 in the liver of obese rats was reduced
.
However, the role of GSTM2 in hepatocyte lipid accumulation and inflammation in the pathogenesis of NASH remains unknown
.
In order to clarify the potential protective role of GSTM2 in the pathogenesis of NASH, this study aimed to investigate the role of GSTM2 in NASH and determine whether hepatocyte-specific GSTM2 overexpression can reduce insulin resistance, liver steatosis and inflammation
.
The results of this study indicate that GSTM2 is down-regulated in liver cells during the progression of NASH
.
Comprehensive RNA sequencing and functional analysis showed that hepatocyte-specific GSTM2 deficiency enhances lipid deposition, inflammation, and fibrosis in NASH
.
In terms of mechanism, GSTM2 of hepatocytes directly binds to the N-terminal of apoptosis signal-regulated kinase 1 (ASK1) and inhibits its dimerization and phosphorylation, as well as subsequent c-Jun N-terminal kinase (JNK) and p38 signal transduction.
Activate
.
These data strongly support GSTM2 as a functional candidate gene for regulating liver cell injury and inflammation, and as a valuable therapeutic target in human NASH
.
Reference message: https://#%20https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32221
