BACKGROUND Ferroptosis is involved in developing inflammatory diseases;yet,its role in acute hypertriglyceridemic pancreatitis(HTGP)remains unclear.AIM To explore whether ferroptosis is involved in the process of HTGP...BACKGROUND Ferroptosis is involved in developing inflammatory diseases;yet,its role in acute hypertriglyceridemic pancreatitis(HTGP)remains unclear.AIM To explore whether ferroptosis is involved in the process of HTGP and elucidate its potential mechanisms.METHODS An HTGP mouse model was induced using intraperitoneal injection of P-407 and caerulein(CAE).Then,pancreatic tissues from the model animals were subjected to proteome sequencing analysis.The pathological changes and scores of the pancreas,lung,and kidney were determined using hematoxylin-eosin staining.The levels of serum amylase(AMY),triglyceride,and total cholesterol were measured with an automatic blood cell analyzer.Additionally,the serum levels of tumor necrosis factor(TNF)-α,interleukin(IL)-6,and IL-1βwere determined by enzyme linked immunosorbent assay.Malonaldehyde(MDA),glutathione(GSH),and Fe^(2+)were detected in the pancreas.Finally,immunohistochemistry was performed to assess the expression of ferroptosis-related proteins.RESULTS Proteome sequencing revealed that ferroptosis was involved in the process of HTGP and that NADPH oxidase(NOX)2 may participate in ferroptosis regulation.Moreover,the levels of serum AMY,TNF-α,IL-6,and IL-1βwere significantly increased,MDA and Fe^(2+)were upregulated,GSH and ferroptosis-related proteins were reduced,and the injury of the pancreas,lung,and kidney were aggravated in the P407+CAE group compared to CAE and wild type groups(all P<0.05).Notably,the inhibition of ferroptosis and NOX2 attenuated the pathological damage and the release of TNF-α,IL-6,and IL-1βin the serum of the mice.CONCLUSION Ferroptosis was found to have an important role in HTGP and may be considered a potential target for clinical treatment.展开更多
Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component ...Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.展开更多
基金Supported by the National Natural Science Foundation of Shandong Province,No.ZR2021MH032.
文摘BACKGROUND Ferroptosis is involved in developing inflammatory diseases;yet,its role in acute hypertriglyceridemic pancreatitis(HTGP)remains unclear.AIM To explore whether ferroptosis is involved in the process of HTGP and elucidate its potential mechanisms.METHODS An HTGP mouse model was induced using intraperitoneal injection of P-407 and caerulein(CAE).Then,pancreatic tissues from the model animals were subjected to proteome sequencing analysis.The pathological changes and scores of the pancreas,lung,and kidney were determined using hematoxylin-eosin staining.The levels of serum amylase(AMY),triglyceride,and total cholesterol were measured with an automatic blood cell analyzer.Additionally,the serum levels of tumor necrosis factor(TNF)-α,interleukin(IL)-6,and IL-1βwere determined by enzyme linked immunosorbent assay.Malonaldehyde(MDA),glutathione(GSH),and Fe^(2+)were detected in the pancreas.Finally,immunohistochemistry was performed to assess the expression of ferroptosis-related proteins.RESULTS Proteome sequencing revealed that ferroptosis was involved in the process of HTGP and that NADPH oxidase(NOX)2 may participate in ferroptosis regulation.Moreover,the levels of serum AMY,TNF-α,IL-6,and IL-1βwere significantly increased,MDA and Fe^(2+)were upregulated,GSH and ferroptosis-related proteins were reduced,and the injury of the pancreas,lung,and kidney were aggravated in the P407+CAE group compared to CAE and wild type groups(all P<0.05).Notably,the inhibition of ferroptosis and NOX2 attenuated the pathological damage and the release of TNF-α,IL-6,and IL-1βin the serum of the mice.CONCLUSION Ferroptosis was found to have an important role in HTGP and may be considered a potential target for clinical treatment.
基金financially supported by grants from the National Natural Science Foundation of China(8217087381871095)+1 种基金the National Key R&D Program of China(2018YFC2000304)the Tsinghua University Spring Breeze Fund(20211080005).
文摘Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.
