Periodontitis is associated with various systemic diseases,among the most important of which is inflammatory bowel disease(IBD).However,the mechanisms by which IBD exacerbates periodontitis remain unclear.Activation o...Periodontitis is associated with various systemic diseases,among the most important of which is inflammatory bowel disease(IBD).However,the mechanisms by which IBD exacerbates periodontitis remain unclear.Activation of the nicotinamide adenine dinucleotide phosphate(NADPH)oxidase 2(NOX2)/reactive oxygen species(ROS)axis in macrophages can worsen intestinal inflammation and periodontitis.Nonetheless,whether IBD aggravates periodontitis by activating the NOX2/ROS axis,specifically in oral macrophages is unknown.In this study,we established animal models and analyzed single-cell RNA data to investigate these pathogenic pathways.Periodontal inflammation was exacerbated via the NOX2/ROS pathway in tumor necrosis factor M1-like macrophages during colitis.Notably,when a NOX2 inhibitor was administered,resulting in reduced ROS expression in periodontal tissue,both periodontal and intestinal inflammation were significantly alleviated,and disruption of the periodontal and intestinal microbiota was reduced.By uncovering the pathogenic pathways linking these two diseases,this study provides insight into potential treatments for periodontitis and related systemic conditions.展开更多
The incomplete degradation of tumour cells by macrophages(Mϕ)is a contributing factor to tumour progression and metastasis,and the degradation function of Mϕis mediated through phagosomes and lysosomes.In our prelimin...The incomplete degradation of tumour cells by macrophages(Mϕ)is a contributing factor to tumour progression and metastasis,and the degradation function of Mϕis mediated through phagosomes and lysosomes.In our preliminary experiments,we found that overactivation of NADPH oxidase 2(NOX2)reduced the ability of Mϕto degrade engulfed tumour cells.Above this,we screened out liquiritin from Glycyrrhiza uralensis Fisch,which can significantly inhibit NOX2 activity and inhibit tumours,to elucidate that suppressing NOX2 can enhance the ability of Mϕto degrade tumour cells.We found that the tumour environment could activate the NOX2 activity in Mϕphagosomes,causing Mϕto produce excessive reactive oxygen species(ROS),thus prohibiting the formation of phagolysosomes before degradation.Conversely,inhibiting NOX2 in Mϕby liquiritin can reduce ROS and promote phagosome-lysosome fusion,therefore improving the enzymatic degradation of tumour cells after phagocytosis,and subsequently promote T cell activity by presenting antigens.We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox,blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox,thereby inhibiting the activity of NOX2.This study elucidates the specific mechanism by which Mϕcannot degrade tumour cells after phagocytosis,and indicates that liquiritin can promote the ability of Mϕto degrade tumour cells by suppressing NOX2.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
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
基金supported by grants-in-aid from the National Science Foundation China(No.81991501)the National Key R&D Program of China(2022YFA1206100 and 2022YFE0118300)supported by the Research Foundation of Peking University School and Hospital of Stomatology(PKUSS20230109).
文摘Periodontitis is associated with various systemic diseases,among the most important of which is inflammatory bowel disease(IBD).However,the mechanisms by which IBD exacerbates periodontitis remain unclear.Activation of the nicotinamide adenine dinucleotide phosphate(NADPH)oxidase 2(NOX2)/reactive oxygen species(ROS)axis in macrophages can worsen intestinal inflammation and periodontitis.Nonetheless,whether IBD aggravates periodontitis by activating the NOX2/ROS axis,specifically in oral macrophages is unknown.In this study,we established animal models and analyzed single-cell RNA data to investigate these pathogenic pathways.Periodontal inflammation was exacerbated via the NOX2/ROS pathway in tumor necrosis factor M1-like macrophages during colitis.Notably,when a NOX2 inhibitor was administered,resulting in reduced ROS expression in periodontal tissue,both periodontal and intestinal inflammation were significantly alleviated,and disruption of the periodontal and intestinal microbiota was reduced.By uncovering the pathogenic pathways linking these two diseases,this study provides insight into potential treatments for periodontitis and related systemic conditions.
基金supported by National Natural Science Foundation of China(Grant No.:82074092)Natural Science Foundation of Guangdong Province,China(Grant No.:2023A1515011141)+1 种基金Research projects in Key Fields of Universities in Guangdong Province,China(Grant No.:2023ZDZX2020)Guangzhou Municipal Bureau of Science and Technology,China(Grant No.:202201011631).
文摘The incomplete degradation of tumour cells by macrophages(Mϕ)is a contributing factor to tumour progression and metastasis,and the degradation function of Mϕis mediated through phagosomes and lysosomes.In our preliminary experiments,we found that overactivation of NADPH oxidase 2(NOX2)reduced the ability of Mϕto degrade engulfed tumour cells.Above this,we screened out liquiritin from Glycyrrhiza uralensis Fisch,which can significantly inhibit NOX2 activity and inhibit tumours,to elucidate that suppressing NOX2 can enhance the ability of Mϕto degrade tumour cells.We found that the tumour environment could activate the NOX2 activity in Mϕphagosomes,causing Mϕto produce excessive reactive oxygen species(ROS),thus prohibiting the formation of phagolysosomes before degradation.Conversely,inhibiting NOX2 in Mϕby liquiritin can reduce ROS and promote phagosome-lysosome fusion,therefore improving the enzymatic degradation of tumour cells after phagocytosis,and subsequently promote T cell activity by presenting antigens.We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox,blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox,thereby inhibiting the activity of NOX2.This study elucidates the specific mechanism by which Mϕcannot degrade tumour cells after phagocytosis,and indicates that liquiritin can promote the ability of Mϕto degrade tumour cells by suppressing NOX2.
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.
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.
