Hepatic ischemia-reperfusion injury(IRI)is an intricate and inevitable physiological event occurred in the liver transplantation(LT)and it is of paramount importance to devise novel and efficient methods to ameliorate...Hepatic ischemia-reperfusion injury(IRI)is an intricate and inevitable physiological event occurred in the liver transplantation(LT)and it is of paramount importance to devise novel and efficient methods to ameliorate IRl.Herein,we report a"one stone for two birds"strategy for IRI therapy.In this study,we engineered carvacrol-artesunate(CAR-ART)nanoparticles(CANPs)utilizing CAR and ART as precursor monomers and simulated IRl in an in vivo mouse model.Our research results indicate that CANPs proficiently surmount the constraints linked with the solitary components utilized in preceding studies such as water solubility,stability,and biocompatibility.Furthermore,they exhibit a distinctive accumulation in the liver.From an immunological standpoint,CANPs have been observed to significantly impede the accumulation and activation of various immune cells such as macrophages,neutrophils,and Kupffer cells.This results in the restoration of the hepatic immune cell distribution to a state akin to that of a normal liver.Furthermore,CANPs markedly inhibit the accumulation of a multitude of pro-inflammatory cytokines.Cellularly,it has been observed that CANPs significantly hinder the onset of ferroptosis in hepatocytes.This is accomplished by inhibiting the accumulation of crucial enzymes such as long-chain-fatty-acid-CoA ligase 4(ACSL4),as well as associated lipid oxidation intermediates like malondialdehyde(MDA),which are relevant to the process of ferroptosis.Consequently,a solitary intravenous administration of CANPs has the potential to simultaneously inhibit ferroptosis of hepatocytes and normalize proinflammatory immune cells,one stone for two birds.In conclusion,CANPs may serve as a promising multi-bioactive nanotherapeutic agent and a bioresponsive targeting delivery nanocarrier,offering a potentially effective treatment strategy for hepatic IRI.展开更多
Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissec...Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment strategies.We established an HCC model of acquired LR.Cell counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells.Molecular and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms.Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance.We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1943,p-MYH9(Ser1943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1αin lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro.Therefore,the p-MYH9(Ser1943)/USP22/HIF-1αaxis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1943),USP22,and HIF-1αmight be valuable as novel biomarkers and targets.展开更多
基金This research gained support from the National Key Research and Development Program of China(No.2021YFA1100500)the Major Research Plan of the National Natural Science Foundation of China(No.92159202)+3 种基金the National Natural Science Foundation of China(Nos.32171368 and 81930016)State Key Laboratory for Diagnosis and Treatment of Infectious Diseases(No.zz202310)the Non profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2023-PT320-02)the International Science and Technology Cooperation Project of Zhejiang province.
文摘Hepatic ischemia-reperfusion injury(IRI)is an intricate and inevitable physiological event occurred in the liver transplantation(LT)and it is of paramount importance to devise novel and efficient methods to ameliorate IRl.Herein,we report a"one stone for two birds"strategy for IRI therapy.In this study,we engineered carvacrol-artesunate(CAR-ART)nanoparticles(CANPs)utilizing CAR and ART as precursor monomers and simulated IRl in an in vivo mouse model.Our research results indicate that CANPs proficiently surmount the constraints linked with the solitary components utilized in preceding studies such as water solubility,stability,and biocompatibility.Furthermore,they exhibit a distinctive accumulation in the liver.From an immunological standpoint,CANPs have been observed to significantly impede the accumulation and activation of various immune cells such as macrophages,neutrophils,and Kupffer cells.This results in the restoration of the hepatic immune cell distribution to a state akin to that of a normal liver.Furthermore,CANPs markedly inhibit the accumulation of a multitude of pro-inflammatory cytokines.Cellularly,it has been observed that CANPs significantly hinder the onset of ferroptosis in hepatocytes.This is accomplished by inhibiting the accumulation of crucial enzymes such as long-chain-fatty-acid-CoA ligase 4(ACSL4),as well as associated lipid oxidation intermediates like malondialdehyde(MDA),which are relevant to the process of ferroptosis.Consequently,a solitary intravenous administration of CANPs has the potential to simultaneously inhibit ferroptosis of hepatocytes and normalize proinflammatory immune cells,one stone for two birds.In conclusion,CANPs may serve as a promising multi-bioactive nanotherapeutic agent and a bioresponsive targeting delivery nanocarrier,offering a potentially effective treatment strategy for hepatic IRI.
基金National Key Research and Development Program of China(2022YFA1106800),National Natural Science Foundation of China(82203070,82200726,82200727,92159202 and 82273270)Project of Medical and Health Technology Program in Zhejiang Province(2024KY853).
文摘Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment strategies.We established an HCC model of acquired LR.Cell counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells.Molecular and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms.Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance.We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1943,p-MYH9(Ser1943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1αin lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro.Therefore,the p-MYH9(Ser1943)/USP22/HIF-1αaxis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1943),USP22,and HIF-1αmight be valuable as novel biomarkers and targets.
