Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is cha...Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.展开更多
Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like be...Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors,and potential therapeutical strategies,remain scarce.In the present study,after long-term exposure to real-world PM2.5 for 15 weeks,male mice displayed depression-like behaviors,which were revealed using the open field and sucrose preference tests.Mechanistically,chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction-oxidation balance in the mouse hippocampus.Furthermore,PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling.Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication;this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown.Importantly,the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication.Together,our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication,and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors.展开更多
BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
目的探讨利拉鲁肽联合卡格列净治疗2型糖尿病(T2DM)的效果及对血清脂肪因子和炎症因子水平的影响。方法前瞻性选取2023年1月至2024年12月就诊于北京市垂杨柳医院的104例T2DM患者作为研究对象。按照随机数字表法将患者分为对照组与联合组...目的探讨利拉鲁肽联合卡格列净治疗2型糖尿病(T2DM)的效果及对血清脂肪因子和炎症因子水平的影响。方法前瞻性选取2023年1月至2024年12月就诊于北京市垂杨柳医院的104例T2DM患者作为研究对象。按照随机数字表法将患者分为对照组与联合组,每组各52例。对照组予以卡格列净治疗,联合组予以利拉鲁肽联合卡格列净治疗,两组均治疗3个月。治疗前、治疗3个月后,检测患者血糖指标[空腹血糖、餐后2 h血糖(2 h PPG)、糖化血红蛋白(GHb)]、胰岛功能[空腹C肽、餐后2 h C肽(2 h CP)、稳态模型评估胰岛素抵抗指数(HOMA-IR)]、脂肪因子(鸢尾素、降脂素、瘦素)和炎症因子[白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)]水平,并对比组间差异。结果治疗3个月后,两组患者的空腹血糖、2 h PPG和GHb均较治疗前显著降低,且联合治疗组的空腹血糖、2 h PPG和GHb均低于对照组,差异均有统计学意义(P<0.05)。治疗3个月后,两组患者的HOMA-IR均较治疗前显著降低,FCP和2 h CP水平均较治疗前上升,且联合治疗组的HOMA-IR低于对照组,CP和2 h CP水平均高于对照组,差异均有统计学意义(P<0.05)。治疗3个月后,两组患者的血清鸢尾素、降脂素水平均较治疗前显著提升,瘦素均较治疗前显著降低,且联合治疗组的血清鸢尾素、降脂素水平均高于对照组,瘦素低于对照组,差异均有统计学意义(P<0.05)。治疗3个月后,两组患者的血清IL-6、TNF-α水平均较治疗前显著降低,且联合治疗组的血清IL-6、TNF-α水平均低于对照组,差异均有统计学意义(P<0.05)。结论利拉鲁肽联合卡格列净用于血糖控制不佳的T2DM患者降糖治疗,可提升血糖控制效果,改善胰岛功能,其机制可能与调节脂肪因子和减轻炎症有关。展开更多
A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoho...A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoholic liver injury,viral hepatitis,hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.The underlying pathogenic mechanisms are multifactorial,encompassing oxidative stress,inflammatory cascades,mitochondrial impairment,and disturbances in immune homeostasis.Hepatic encephalopathy patients experience cognitive impairment,mood disturbances,and psychomotor dysfunction,significantly reducing quality of life through mechanisms including oxidative stress,neuroinflammation,and neurotransmitter imbalances.The nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway serves as a critical antioxidative defense mechanism in these conditions.Nrf2 regulates the expression of protective enzymes,while HO-1 exerts anti-inflammatory,anti-apoptotic,and antifibrotic effects through heme degradation products.Natural herbal monomers as Nrf2 activators offer advantages of low toxicity,multi-target actions,and extensive traditional use.Various herbal monomers demonstrate specific effects against different liver diseases:In fatty liver,baicalin alleviates lipid accumulation and inflammation;In alcoholic liver disease,curcumin enhances Nrf2 activity reducing oxidative damage;In drug-induced liver injury,dihydromyricetin mitigates oxidative stress;In viral hepatitis,andrographolide inhibits hepatitis C virus replication;In liver fibrosis,multiple compounds inhibit stellate cell activation.These natural compounds simultaneously alleviate hepatic dysfunction and neuropsychiatric symptoms by modulating the Nrf2/HO-1 pathway,though clinical application still faces challenges such as low bioavailability,requiring further research.展开更多
基金supported by grants from the Zhejiang Provincial TCM Science and Technology Plan Project,No.2023ZL156(to YH)Ningbo Top Medical and Health Research Program,No.2022020304(to XG)+1 种基金the Natural Science Foundation of Ningbo,No.2023J019(to YH)Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province,No.2022E10026(to YH)。
文摘Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.
基金National Basic Research Plan Project of China,No.2023YFC3708303the National Natural Science Foundation of China,No.82241084the High-level Talent in Public Health of Beijing,No.Discipline Leaders-03-29(all to XL).
文摘Long-term exposure to ambient fine particulate matter(PM2.5)may increase the risk of neurotoxicity in human populations.However,research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors,and potential therapeutical strategies,remain scarce.In the present study,after long-term exposure to real-world PM2.5 for 15 weeks,male mice displayed depression-like behaviors,which were revealed using the open field and sucrose preference tests.Mechanistically,chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction-oxidation balance in the mouse hippocampus.Furthermore,PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling.Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication;this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown.Importantly,the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication.Together,our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication,and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors.
基金Supported by the Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
文摘目的探讨利拉鲁肽联合卡格列净治疗2型糖尿病(T2DM)的效果及对血清脂肪因子和炎症因子水平的影响。方法前瞻性选取2023年1月至2024年12月就诊于北京市垂杨柳医院的104例T2DM患者作为研究对象。按照随机数字表法将患者分为对照组与联合组,每组各52例。对照组予以卡格列净治疗,联合组予以利拉鲁肽联合卡格列净治疗,两组均治疗3个月。治疗前、治疗3个月后,检测患者血糖指标[空腹血糖、餐后2 h血糖(2 h PPG)、糖化血红蛋白(GHb)]、胰岛功能[空腹C肽、餐后2 h C肽(2 h CP)、稳态模型评估胰岛素抵抗指数(HOMA-IR)]、脂肪因子(鸢尾素、降脂素、瘦素)和炎症因子[白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)]水平,并对比组间差异。结果治疗3个月后,两组患者的空腹血糖、2 h PPG和GHb均较治疗前显著降低,且联合治疗组的空腹血糖、2 h PPG和GHb均低于对照组,差异均有统计学意义(P<0.05)。治疗3个月后,两组患者的HOMA-IR均较治疗前显著降低,FCP和2 h CP水平均较治疗前上升,且联合治疗组的HOMA-IR低于对照组,CP和2 h CP水平均高于对照组,差异均有统计学意义(P<0.05)。治疗3个月后,两组患者的血清鸢尾素、降脂素水平均较治疗前显著提升,瘦素均较治疗前显著降低,且联合治疗组的血清鸢尾素、降脂素水平均高于对照组,瘦素低于对照组,差异均有统计学意义(P<0.05)。治疗3个月后,两组患者的血清IL-6、TNF-α水平均较治疗前显著降低,且联合治疗组的血清IL-6、TNF-α水平均低于对照组,差异均有统计学意义(P<0.05)。结论利拉鲁肽联合卡格列净用于血糖控制不佳的T2DM患者降糖治疗,可提升血糖控制效果,改善胰岛功能,其机制可能与调节脂肪因子和减轻炎症有关。
