AIM:To investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo.METHODS:C57BL/6J mice were randomly assigned to five groups and intraperitoneally ad...AIM:To investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo.METHODS:C57BL/6J mice were randomly assigned to five groups and intraperitoneally administered 0.9% saline,Salvia miltiorrhiza and Carthamus tinctorius extract [Danhong injection(DHI),0.75 and 3 g/kg mixed extract] or reduced glutathione for injection(RGI,300 mg/kg) for 30 min before exposure to lipopolysaccharide(LPS,16 mg/kg). After intraperitoneal LPS stimulation for 90 min or 6 h,the mice were sacrificed by ether anaesthesia,and serum and liver samples were collected. Histological analysis(H&E) and terminal deoxynucleotidyl transferase-mediated d UTP nick end-labelling(TUNEL) staining were performed. Alanine transferase(ALT),aspartate transaminase(AST),total bilirubin(TBil),glutathione-S-transferase(GST),malondialdehyde(MDA),tumour necrosis factor(TNF)-α,interleukin(IL)-6,and caspase-3 levels were measured. Bax,Bcl-2,P-IκBα,IκBα,P-NF-κB p65,and NF-κB p65 protein levels were determined by Western blot. TNF-α,IL-6,caspase-3,Bax and Bcl-2 m RNA expression was measured by real-time reverse transcription-polymerase chain reaction(RT-PCR).RESULTS:Hematoxylin-eosin staining and TUNEL results suggested that DHI(3 g/kg) treatment alleviated inflammatory and apoptotic(P < 0.01) injury in the liver of mice. DHI treatment dose-dependently blunted the abnormal changes in biochemical parameters such as ALT(72.53 ± 2.83 for 3 g/kg,P < 0.01),AST(76.97 ± 5.00 for 3 g/kg,P < 0.01),TBil(1.17 ± 0.10 for 3 g/kg,P < 0.01),MDA(0.81 ± 0.36 for 3 g/kg,P < 0.01),and GST(358.86 ± 12.09 for 3 g/kg,P < 0.01). Moreover,DHI(3 g/kg) remarkably decreased LPS-induced protein expression of TNF-α(340.55 ± 10.18 for 3 g/kg,P < 0.01),IL-6(261.34 ± 10.18 for 3 g/kg,P < 0.01),and enzyme activity of caspase-3(0.93 ± 0.029 for 3 g/kg,P < 0.01). The LPS-induced m RNA expression of TNF-α,IL-6 and caspase-3 was also decreased by DHI. Western blot analysis revealed that DHI antagonised LPS-stimulated decrease of Bcl-2 and increase of Bax protein expression. Furthermore,DHI inhibited LPS-induced IκBα and NF-κB p65 phosphorylation.CONCLUSION:DHI may be a multi-function protectant against acute hepatic injury in mice through its antiinflammatory,anti-oxidative and anti-apoptotic activities.展开更多
This article describes cases of anti-tumor necrosis factor(TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of ...This article describes cases of anti-tumor necrosis factor(TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis(AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.展开更多
The asialoglycoprotein (ASGP) receptor is a wellcharacterized hepatic receptor that is recycled via the common cellular process of receptor-mediated endocytosis (RME). The RME process plays an integral part in the pro...The asialoglycoprotein (ASGP) receptor is a wellcharacterized hepatic receptor that is recycled via the common cellular process of receptor-mediated endocytosis (RME). The RME process plays an integral part in the proper traff icking and routing of receptors and ligands in the healthy cell. Thus, the missorting or altered transport of proteins during RME is thought to play a role in several diseases associated with hepatocyte and liver dysfunction. Previously, we examined in detail alterations that occur in hepatocellular RME and associated receptor functions as a result of one particular liver injury, alcoholic liver disease (ALD). The studies revealed profound ethanolmediated impairments to the ASGP receptor and the RME process, indicating the importance of this receptor and the maintenance of proper endocytic events in normal tissue. To further clarify these observations, studies were performed utilizing knockout mice (lacking a functional ASGP receptor) to which were administered several liver toxicants. In addition to alcohol, we examined the effects following administration of antiFas (CD95) antibody, carbon tetrachloride (CCl4) and lipopolysaccharide (LPS)/galactosamine. The results of these studies demonstrated that the knockout mice sustained enhanced liver injury in response to all of the treatments, as shown by increased indices of liver damage, such as enhancement of serum enzyme levels, histopathological scores, as well as hepatocellular death. Overall, the work completed to date suggests a possible link between hepatic receptors and liver injury. In particular, adequate function and content of the ASGP receptor may provide protection against various toxinmediated liver diseases.展开更多
基金Supported by National Natural Science Foundation of China,No.81173469 and No.81273891the Key New Drug Creation and Manufacturing Program,No.2012ZX09304007
文摘AIM:To investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo.METHODS:C57BL/6J mice were randomly assigned to five groups and intraperitoneally administered 0.9% saline,Salvia miltiorrhiza and Carthamus tinctorius extract [Danhong injection(DHI),0.75 and 3 g/kg mixed extract] or reduced glutathione for injection(RGI,300 mg/kg) for 30 min before exposure to lipopolysaccharide(LPS,16 mg/kg). After intraperitoneal LPS stimulation for 90 min or 6 h,the mice were sacrificed by ether anaesthesia,and serum and liver samples were collected. Histological analysis(H&E) and terminal deoxynucleotidyl transferase-mediated d UTP nick end-labelling(TUNEL) staining were performed. Alanine transferase(ALT),aspartate transaminase(AST),total bilirubin(TBil),glutathione-S-transferase(GST),malondialdehyde(MDA),tumour necrosis factor(TNF)-α,interleukin(IL)-6,and caspase-3 levels were measured. Bax,Bcl-2,P-IκBα,IκBα,P-NF-κB p65,and NF-κB p65 protein levels were determined by Western blot. TNF-α,IL-6,caspase-3,Bax and Bcl-2 m RNA expression was measured by real-time reverse transcription-polymerase chain reaction(RT-PCR).RESULTS:Hematoxylin-eosin staining and TUNEL results suggested that DHI(3 g/kg) treatment alleviated inflammatory and apoptotic(P < 0.01) injury in the liver of mice. DHI treatment dose-dependently blunted the abnormal changes in biochemical parameters such as ALT(72.53 ± 2.83 for 3 g/kg,P < 0.01),AST(76.97 ± 5.00 for 3 g/kg,P < 0.01),TBil(1.17 ± 0.10 for 3 g/kg,P < 0.01),MDA(0.81 ± 0.36 for 3 g/kg,P < 0.01),and GST(358.86 ± 12.09 for 3 g/kg,P < 0.01). Moreover,DHI(3 g/kg) remarkably decreased LPS-induced protein expression of TNF-α(340.55 ± 10.18 for 3 g/kg,P < 0.01),IL-6(261.34 ± 10.18 for 3 g/kg,P < 0.01),and enzyme activity of caspase-3(0.93 ± 0.029 for 3 g/kg,P < 0.01). The LPS-induced m RNA expression of TNF-α,IL-6 and caspase-3 was also decreased by DHI. Western blot analysis revealed that DHI antagonised LPS-stimulated decrease of Bcl-2 and increase of Bax protein expression. Furthermore,DHI inhibited LPS-induced IκBα and NF-κB p65 phosphorylation.CONCLUSION:DHI may be a multi-function protectant against acute hepatic injury in mice through its antiinflammatory,anti-oxidative and anti-apoptotic activities.
文摘This article describes cases of anti-tumor necrosis factor(TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis(AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.
基金Supported by The National Institute on Alcohol Abuse and Alcoholismthe Department of Veterans Affairs
文摘The asialoglycoprotein (ASGP) receptor is a wellcharacterized hepatic receptor that is recycled via the common cellular process of receptor-mediated endocytosis (RME). The RME process plays an integral part in the proper traff icking and routing of receptors and ligands in the healthy cell. Thus, the missorting or altered transport of proteins during RME is thought to play a role in several diseases associated with hepatocyte and liver dysfunction. Previously, we examined in detail alterations that occur in hepatocellular RME and associated receptor functions as a result of one particular liver injury, alcoholic liver disease (ALD). The studies revealed profound ethanolmediated impairments to the ASGP receptor and the RME process, indicating the importance of this receptor and the maintenance of proper endocytic events in normal tissue. To further clarify these observations, studies were performed utilizing knockout mice (lacking a functional ASGP receptor) to which were administered several liver toxicants. In addition to alcohol, we examined the effects following administration of antiFas (CD95) antibody, carbon tetrachloride (CCl4) and lipopolysaccharide (LPS)/galactosamine. The results of these studies demonstrated that the knockout mice sustained enhanced liver injury in response to all of the treatments, as shown by increased indices of liver damage, such as enhancement of serum enzyme levels, histopathological scores, as well as hepatocellular death. Overall, the work completed to date suggests a possible link between hepatic receptors and liver injury. In particular, adequate function and content of the ASGP receptor may provide protection against various toxinmediated liver diseases.
