Objective:A complex relationship exists between obstructive sleep apnea syndrome and diabetes mellitus(DM).Chronic intermittent hypoxia(CIH),which is a core pathological feature of obstructive sleep apnea syndrome,may...Objective:A complex relationship exists between obstructive sleep apnea syndrome and diabetes mellitus(DM).Chronic intermittent hypoxia(CIH),which is a core pathological feature of obstructive sleep apnea syndrome,may play an important role in the onset and development of DM-related atherosclerosis(DM-AS).This study aimed to investigate the mechanism of action of tetramethylpyrazine(TMP)in CIH-associated DM-AS.Methods:In vivo,a DM-AS mouse model was established by intraperitoneal injection of streptozotocin combined with a high-fat diet.They were exposed to CIH or normoxic conditions for 8 weeks and received different doses of TMP,rosuvastatin,toyocamycin,and purified water.Glycolipid metabolism,inflammation levels,degree of aortic AS,and expression levels of endoplasmic reticulum stress(ERS)and autophagy proteins were examined in mice.In vitro,human umbilical vein endothelial cells(HUVECs)were treated with high glucose and fat in combination with insulin to establish an insulin-resistant cell model(HUVEC-IR).After pretreatment with 4μ8C(IRE1 inhibitor)and different doses of TMP,intermittent hypoxic intervention was performed.Changes in cell morphology,proliferative activity,glucose consumption,and ability to migrate were observed,and the expression levels of ERS and autophagy proteins were detected.Results:In vivo experiments showed that CIH significantly increased blood glucose levels and Homeostasis Model Assessment of Insulin Resistance(HOMA-IR)(P<0.001 or P<0.05),low-density lipoprotein cholesterol(LDL-C)content(P<0.001),and the levels of three inflammatory factors[interleukin-1 beta(IL-1β),IL-6,and tumor necrosis factor-alpha(TNF-α)]in the mice(P<0.001)compared with those of the mice with DM alone;moreover,the aortic atherosclerotic(AS)plaque area in CIH mice was significantly enlarged(P<0.001).Western blotting results showed that the expressions of aortic IRE1α,XBP1s,Beclin1,and LC3A proteins were significantly increased in CIH mice compared with DM mice(P<0.05).After treatment with different doses of TMP,rosuvastatin calcium,and toyocamycin,serum inflammation and lipid levels and plaque area were significantly reduced in mice(P<0.001 and P<0.001,respectively).The expression levels of aortic XBP1s,Beclin1,and LC3A were reduced in TMP-and toyocamycin-treated mice(P<0.05).In the in vitro experiments,compared with normoxic cells,the cells treated with intermittent hypoxia(IH)showed a significant decrease in cell migration distance(P<0.05),a significant increase in apoptosis rate(P<0.001),a substantial increase in proliferation inhibition rate(P<0.001),a significant increase in the levels of XBP1s and LC3A proteins(P<0.05),and an increase in the number of autophagic vesicles/lysosomes,as observed under transmission electron microscopy.After treatment with different doses of TMP and 4μ8C,cell morphology was significantly restored,apoptosis rate significantly reduced(P<0.001),and XBP1s,Beclin1,and LC3A expressions significantly inhibited(P<0.05).Conclusion:CIH promoted the onset of DM-AS,whereas TMP attenuated ERS and excessive autophagy by modulating the IRE1α-XBP1 signaling pathway and inhibiting XBP1 splicing,thereby ameliorating DM-AS exacerbated by CIH.展开更多
本文讨论了内质网应激在心脏和血管疾病中的角色,特别是聚焦于三个主要途径:PERK、IRE1和ATF6,以及它们如何影响心脏的健康状况。研究显示,内质网应激通过这些路径可以调控心肌细胞的生存、血管内皮的工作方式以及血管平滑肌细胞的行为...本文讨论了内质网应激在心脏和血管疾病中的角色,特别是聚焦于三个主要途径:PERK、IRE1和ATF6,以及它们如何影响心脏的健康状况。研究显示,内质网应激通过这些路径可以调控心肌细胞的生存、血管内皮的工作方式以及血管平滑肌细胞的行为,这些都对心血管系统的健康至关重要。一定程度的内质网应激可以帮助细胞适应不利条件,但如果应激过度,可能会损害心血管功能,加重疾病的发展。This article discusses the role of endoplasmic reticulum stress in heart and vascular disease, focusing specifically on three major pathways: PERK, IRE1, and ATF6, and how they affect the health of the heart. The study shows that endoplasmic reticulum stress, through these pathways, can regulate the survival of cardiomyocytes, the way the vascular endothelium works, and the behavior of vascular smooth muscle cells, all of which are critical to the health of the cardiovascular system. A certain level of endoplasmic reticulum stress can help cells adapt to unfavorable conditions, but if the stress is excessive, it may impair cardiovascular function and exacerbate disease progression.展开更多
Long-term intake of high-fat diet(HFD)leads to systemic hypo-inflammation,which is involved in the pathogenesis of many liver diseases.The aim of this study was to evaluate the interventional effect of inulin addition...Long-term intake of high-fat diet(HFD)leads to systemic hypo-inflammation,which is involved in the pathogenesis of many liver diseases.The aim of this study was to evaluate the interventional effect of inulin addition on HFD-induced non-alcoholic fatty liver disease(NAFLD).Here,we assessed liver inflammation and lipid metabolism by enzyme linked immunosorbent assay(ELISA)kits and real-time quantitative polymerase chain reaction(q PCR),and explored its relationship with intestinal flora and metabolites by 16S r DNA gene sequencing and untargeted metabolomics.In addition,we determined the effect of the inositol-requiring enzyme-1α-X-box binding protein 1(IRE1α-XBP1)pathway on liver macrophage polarization by flow cytometry.In conclusion,our study has demonstrated that inulin ameliorates high levels of bile acids and colonic immune disorders induced by HFD,and improves hepatic macrophage polarization and hepatic lipid metabolism via the intestine-hepatic axis,thus providing a mechanistic basis for therapeutic approaches to modulate bile acids to improve colonic inflammation and NAFLD.展开更多
基金the National Natural Science Foundation of China(82074264)。
文摘Objective:A complex relationship exists between obstructive sleep apnea syndrome and diabetes mellitus(DM).Chronic intermittent hypoxia(CIH),which is a core pathological feature of obstructive sleep apnea syndrome,may play an important role in the onset and development of DM-related atherosclerosis(DM-AS).This study aimed to investigate the mechanism of action of tetramethylpyrazine(TMP)in CIH-associated DM-AS.Methods:In vivo,a DM-AS mouse model was established by intraperitoneal injection of streptozotocin combined with a high-fat diet.They were exposed to CIH or normoxic conditions for 8 weeks and received different doses of TMP,rosuvastatin,toyocamycin,and purified water.Glycolipid metabolism,inflammation levels,degree of aortic AS,and expression levels of endoplasmic reticulum stress(ERS)and autophagy proteins were examined in mice.In vitro,human umbilical vein endothelial cells(HUVECs)were treated with high glucose and fat in combination with insulin to establish an insulin-resistant cell model(HUVEC-IR).After pretreatment with 4μ8C(IRE1 inhibitor)and different doses of TMP,intermittent hypoxic intervention was performed.Changes in cell morphology,proliferative activity,glucose consumption,and ability to migrate were observed,and the expression levels of ERS and autophagy proteins were detected.Results:In vivo experiments showed that CIH significantly increased blood glucose levels and Homeostasis Model Assessment of Insulin Resistance(HOMA-IR)(P<0.001 or P<0.05),low-density lipoprotein cholesterol(LDL-C)content(P<0.001),and the levels of three inflammatory factors[interleukin-1 beta(IL-1β),IL-6,and tumor necrosis factor-alpha(TNF-α)]in the mice(P<0.001)compared with those of the mice with DM alone;moreover,the aortic atherosclerotic(AS)plaque area in CIH mice was significantly enlarged(P<0.001).Western blotting results showed that the expressions of aortic IRE1α,XBP1s,Beclin1,and LC3A proteins were significantly increased in CIH mice compared with DM mice(P<0.05).After treatment with different doses of TMP,rosuvastatin calcium,and toyocamycin,serum inflammation and lipid levels and plaque area were significantly reduced in mice(P<0.001 and P<0.001,respectively).The expression levels of aortic XBP1s,Beclin1,and LC3A were reduced in TMP-and toyocamycin-treated mice(P<0.05).In the in vitro experiments,compared with normoxic cells,the cells treated with intermittent hypoxia(IH)showed a significant decrease in cell migration distance(P<0.05),a significant increase in apoptosis rate(P<0.001),a substantial increase in proliferation inhibition rate(P<0.001),a significant increase in the levels of XBP1s and LC3A proteins(P<0.05),and an increase in the number of autophagic vesicles/lysosomes,as observed under transmission electron microscopy.After treatment with different doses of TMP and 4μ8C,cell morphology was significantly restored,apoptosis rate significantly reduced(P<0.001),and XBP1s,Beclin1,and LC3A expressions significantly inhibited(P<0.05).Conclusion:CIH promoted the onset of DM-AS,whereas TMP attenuated ERS and excessive autophagy by modulating the IRE1α-XBP1 signaling pathway and inhibiting XBP1 splicing,thereby ameliorating DM-AS exacerbated by CIH.
文摘本文讨论了内质网应激在心脏和血管疾病中的角色,特别是聚焦于三个主要途径:PERK、IRE1和ATF6,以及它们如何影响心脏的健康状况。研究显示,内质网应激通过这些路径可以调控心肌细胞的生存、血管内皮的工作方式以及血管平滑肌细胞的行为,这些都对心血管系统的健康至关重要。一定程度的内质网应激可以帮助细胞适应不利条件,但如果应激过度,可能会损害心血管功能,加重疾病的发展。This article discusses the role of endoplasmic reticulum stress in heart and vascular disease, focusing specifically on three major pathways: PERK, IRE1, and ATF6, and how they affect the health of the heart. The study shows that endoplasmic reticulum stress, through these pathways, can regulate the survival of cardiomyocytes, the way the vascular endothelium works, and the behavior of vascular smooth muscle cells, all of which are critical to the health of the cardiovascular system. A certain level of endoplasmic reticulum stress can help cells adapt to unfavorable conditions, but if the stress is excessive, it may impair cardiovascular function and exacerbate disease progression.
基金supported by the projects of the National Natural Science Foundation of China(31901701)the National Key Research and Development Program of China(2019YFC1606704)+1 种基金Key R&D Program Project of Shaanxi Province(2024NC-YBXM-151-4)Science and Technology Plan Project of Xi'an(2014JH-NYYB-0103)。
文摘Long-term intake of high-fat diet(HFD)leads to systemic hypo-inflammation,which is involved in the pathogenesis of many liver diseases.The aim of this study was to evaluate the interventional effect of inulin addition on HFD-induced non-alcoholic fatty liver disease(NAFLD).Here,we assessed liver inflammation and lipid metabolism by enzyme linked immunosorbent assay(ELISA)kits and real-time quantitative polymerase chain reaction(q PCR),and explored its relationship with intestinal flora and metabolites by 16S r DNA gene sequencing and untargeted metabolomics.In addition,we determined the effect of the inositol-requiring enzyme-1α-X-box binding protein 1(IRE1α-XBP1)pathway on liver macrophage polarization by flow cytometry.In conclusion,our study has demonstrated that inulin ameliorates high levels of bile acids and colonic immune disorders induced by HFD,and improves hepatic macrophage polarization and hepatic lipid metabolism via the intestine-hepatic axis,thus providing a mechanistic basis for therapeutic approaches to modulate bile acids to improve colonic inflammation and NAFLD.
