Niemann-Pick disease(NPD)is a rare and life-threatening disease caused by the deficiency of acid sphingomyelinase activity which is characterized by intracellular accumulation of sphingomyelin within multiple organs(1...Niemann-Pick disease(NPD)is a rare and life-threatening disease caused by the deficiency of acid sphingomyelinase activity which is characterized by intracellular accumulation of sphingomyelin within multiple organs(1).At present,few non-surgical treatment options are available for NPD apart from enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation.However,neither surgical nor alternative therapies can modify the progression of neurological disorders,which makes the prognosis of NPD except type B bleak(2).NPD type B(NPD-B),known as one visceral form of NPD,is usually clinically manifested as hepatosplenomegaly but without neurological symptoms.Notably,pulmonary parenchymal involvement secondary to the accumulation of sphingomyelin in alveoli is also a feature of NPD-B(3).Scattered reports(4)indicated that liver transplantation(LT)have shown some preliminary results for NPD-B.Owing to the effect of diseased spleen on operation field and pancytopenia associated with hypersplenism,splenectomy is always performed in conjunction with LT.However.展开更多
Induction of osteopontin(OPN),a well-known pro-inflammatory molecule,has been observed in acetaminophen(APAP)-induced hepatotoxicity.However,the precise cell source for OPN induction and its role during APAP-induced h...Induction of osteopontin(OPN),a well-known pro-inflammatory molecule,has been observed in acetaminophen(APAP)-induced hepatotoxicity.However,the precise cell source for OPN induction and its role during APAP-induced hepatotoxicity has not been fully explored.By employing a hepatotoxic mouse model induced by APAP overdose,we demonstrate that both serum and hepatic OPN levels were significantly elevated in response to APAP treatment.Our in vivo and in vitro studies clearly indicated that the induced expression of hepatic OPN was mainly located in necrosis areas and produced by dying or dead hepatocytes.Functional experiments showed that OPN deficiency protected against the APAP-induced liver injury by inhibiting the toxic APAP metabolism via reducing the expression of the cytochrome P450 family 2 subfamily E member 1(CYP2E1).Interestingly,this inhibition of CYP2E1 expression did not occur in unfasted Opn−/−mice,but was significant in fasted Opn−/−mice and maintained for 2hours after APAP challenge in fasted Opn−/−mice.In addition,despite the early protective role of OPN deficiency on APAP-induced hepatotoxicity,OPN deficiency retarded injury resolution by sensitizing hepatocytes to apoptosis and impairing liver regeneration.Finally,we demonstrated that a siRNA-mediated transient hepatic Opn knockdown could sufficiently and significantly protect animals from APAP-induced hepatotoxicity and death.In conclusion,this study clearly defines the cell source of OPN induction in response to APAP treatment,provides a novel insight into the metabolic role of OPN to APAP overdose,and suggests an Opn-targeted therapeutic strategy for the treatment or prevention of APAP-induced hepatotoxicity.展开更多
基金This work was supported by grant from the National Natural Science Foundation of China(Nos.8213000134,82072646 to JG)Clinical Research Plan of SHDC(No.SHDC2020CR3005A to JG)+1 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(No.20191910 to JG)Shanghai Jiao Tong University for SMC-morning Star Youth Scholars Program to JG.
文摘Niemann-Pick disease(NPD)is a rare and life-threatening disease caused by the deficiency of acid sphingomyelinase activity which is characterized by intracellular accumulation of sphingomyelin within multiple organs(1).At present,few non-surgical treatment options are available for NPD apart from enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation.However,neither surgical nor alternative therapies can modify the progression of neurological disorders,which makes the prognosis of NPD except type B bleak(2).NPD type B(NPD-B),known as one visceral form of NPD,is usually clinically manifested as hepatosplenomegaly but without neurological symptoms.Notably,pulmonary parenchymal involvement secondary to the accumulation of sphingomyelin in alveoli is also a feature of NPD-B(3).Scattered reports(4)indicated that liver transplantation(LT)have shown some preliminary results for NPD-B.Owing to the effect of diseased spleen on operation field and pancytopenia associated with hypersplenism,splenectomy is always performed in conjunction with LT.However.
基金supported by the National Natural Science Foundation of China(81670562 and 31300742 to X.K.,81670598 to Q.X.,81372233 to H.W.,and 81673935 to X.S.)a grant from the Shanghai Municipal Education Commission(Gaofeng Clinical Medicine Grant Support(20171911)to X.K.+1 种基金National Science and Technology major grant(2017ZX10203204-006-005)to X.K.the Shanghai Health Bureau Key Joint Efforts Foundation(2013ZYJB001)to Q.X.).
文摘Induction of osteopontin(OPN),a well-known pro-inflammatory molecule,has been observed in acetaminophen(APAP)-induced hepatotoxicity.However,the precise cell source for OPN induction and its role during APAP-induced hepatotoxicity has not been fully explored.By employing a hepatotoxic mouse model induced by APAP overdose,we demonstrate that both serum and hepatic OPN levels were significantly elevated in response to APAP treatment.Our in vivo and in vitro studies clearly indicated that the induced expression of hepatic OPN was mainly located in necrosis areas and produced by dying or dead hepatocytes.Functional experiments showed that OPN deficiency protected against the APAP-induced liver injury by inhibiting the toxic APAP metabolism via reducing the expression of the cytochrome P450 family 2 subfamily E member 1(CYP2E1).Interestingly,this inhibition of CYP2E1 expression did not occur in unfasted Opn−/−mice,but was significant in fasted Opn−/−mice and maintained for 2hours after APAP challenge in fasted Opn−/−mice.In addition,despite the early protective role of OPN deficiency on APAP-induced hepatotoxicity,OPN deficiency retarded injury resolution by sensitizing hepatocytes to apoptosis and impairing liver regeneration.Finally,we demonstrated that a siRNA-mediated transient hepatic Opn knockdown could sufficiently and significantly protect animals from APAP-induced hepatotoxicity and death.In conclusion,this study clearly defines the cell source of OPN induction in response to APAP treatment,provides a novel insight into the metabolic role of OPN to APAP overdose,and suggests an Opn-targeted therapeutic strategy for the treatment or prevention of APAP-induced hepatotoxicity.
