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
An integral part of the effort to reduce greenhouse gas emissions is carbon footprint accounting.EPA categorizes facility carbon footprints in three scopes.Scope-2 emissions include electricity,heat or steam purchased...An integral part of the effort to reduce greenhouse gas emissions is carbon footprint accounting.EPA categorizes facility carbon footprints in three scopes.Scope-2 emissions include electricity,heat or steam purchased from a utility provider.This paper evaluates the existing calculation methods for scope-2 CO2 emissions for purchased electricity.The electricity grid in US is complex and is divided spatially into states,eGRID regions,balancing authorities(BAs),and utilities.Up to hourly temporal granularity can be obtained from available datasets.A matrix is developed that categorizes different datasets based on the complexity to calculate the carbon emission factors.Spatial and temporal variations are evaluated.There are significant spatial overlap between regions in different categories and emission factors within a region show sub-regional variation.An area analysis is done using zip-code polygons to determine whether a state or balancing authority is smaller for all the overlapping cases.Temporal variations in emission factors are significant depending on the balancing authority considered.A single method to calculate scope-2 emission factors may not be accurate and efficient in every case and a nuanced assessment of emission factors is warranted.An implementation pathway for a“smart carbon calculator”—one that gives accurate carbon footprint that is the spatially and temporally most granular is suggested.展开更多
Background:Prostate adenocarcinoma(PRAD)is one of the most commonly diagnosed cancers in men.Expanding evidence suggests a significant association between cancer progression and RNA modifications.However,our knowledge...Background:Prostate adenocarcinoma(PRAD)is one of the most commonly diagnosed cancers in men.Expanding evidence suggests a significant association between cancer progression and RNA modifications.However,our knowledge of the link between m^(5)C and hm^(5)C pathways with PRAD is limited.Therefore,we aimed to explore the diagnostic and prognostic values of m^(5)C and hm^(5)C regulators in PRAD.Methods:In this study,genetic alterations in m^(5)C and hm^(5)C regulators were identified using publicly available databases.Expression levels of regulators in PRAD samples were retrieved via the RTCGA package in the R environment.Differentially expressed genes in these pathways between tumor and non-tumor samples were identified using the R‘limma’package.Correlation among m^(5)C and hm^(5)C pathway members was examined employing the‘Hmisc’package in R.We utilized the‘survminer’package in R for applying the Kaplan-Meier method to estimate the overall survival rate of m^(5)C and hm^(5)C regulators.The discrimination power of selected regulators between tumor and non-tumor samples was analyzed by the receiver operating characteristic curve.Furthermore,gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses were carried out to enrich the affected biological processes and pathways.Results:Differentially expressed genes in these pathways between tumor and non-tumor samples,correlation among m^(5)C and hm^(5)C pathway members,and prognostic value of the regulators were evaluated.Obtained results unveiled the mRNA level differences as the key genetic alterations for m^(5)C and hm^(5)C regulators between tumor and non-tumor samples.UHRF1,TET3,and NEIL1 were significantly upregulated in tumor samples,whereas MECP2 and EGR1 were significantly downregulated for m^(5)C and hm^(5)C regulators.UHRF1,DNMT1,NSUN2,NSUN4,C1orf77,C3orf37,WDR77,NEIL1,and TDG genes were identified as candidate prognostic markers of overall survival.The upregulated genes in patient samples with genetic alterations in m^(5)C and hm^(5)C pathways enriched cell cycle-related processes.Conclusion:In summary,our findings suggest that the m^(5)C and hm^(5)C regulators might play a role in PRAD development by activation of proliferation,and the UHRF1,NSUN2,and NEIL1 genes have the potential to be utilized as clinical biomarkers.Established correlative relationships require experimental validation through functional studies in prostate cancer cell lines.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
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.
文摘An integral part of the effort to reduce greenhouse gas emissions is carbon footprint accounting.EPA categorizes facility carbon footprints in three scopes.Scope-2 emissions include electricity,heat or steam purchased from a utility provider.This paper evaluates the existing calculation methods for scope-2 CO2 emissions for purchased electricity.The electricity grid in US is complex and is divided spatially into states,eGRID regions,balancing authorities(BAs),and utilities.Up to hourly temporal granularity can be obtained from available datasets.A matrix is developed that categorizes different datasets based on the complexity to calculate the carbon emission factors.Spatial and temporal variations are evaluated.There are significant spatial overlap between regions in different categories and emission factors within a region show sub-regional variation.An area analysis is done using zip-code polygons to determine whether a state or balancing authority is smaller for all the overlapping cases.Temporal variations in emission factors are significant depending on the balancing authority considered.A single method to calculate scope-2 emission factors may not be accurate and efficient in every case and a nuanced assessment of emission factors is warranted.An implementation pathway for a“smart carbon calculator”—one that gives accurate carbon footprint that is the spatially and temporally most granular is suggested.
基金Health Institutes of Turkey(TUSEBProject No.TA01-4213)for the financial support of the present study.
文摘Background:Prostate adenocarcinoma(PRAD)is one of the most commonly diagnosed cancers in men.Expanding evidence suggests a significant association between cancer progression and RNA modifications.However,our knowledge of the link between m^(5)C and hm^(5)C pathways with PRAD is limited.Therefore,we aimed to explore the diagnostic and prognostic values of m^(5)C and hm^(5)C regulators in PRAD.Methods:In this study,genetic alterations in m^(5)C and hm^(5)C regulators were identified using publicly available databases.Expression levels of regulators in PRAD samples were retrieved via the RTCGA package in the R environment.Differentially expressed genes in these pathways between tumor and non-tumor samples were identified using the R‘limma’package.Correlation among m^(5)C and hm^(5)C pathway members was examined employing the‘Hmisc’package in R.We utilized the‘survminer’package in R for applying the Kaplan-Meier method to estimate the overall survival rate of m^(5)C and hm^(5)C regulators.The discrimination power of selected regulators between tumor and non-tumor samples was analyzed by the receiver operating characteristic curve.Furthermore,gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses were carried out to enrich the affected biological processes and pathways.Results:Differentially expressed genes in these pathways between tumor and non-tumor samples,correlation among m^(5)C and hm^(5)C pathway members,and prognostic value of the regulators were evaluated.Obtained results unveiled the mRNA level differences as the key genetic alterations for m^(5)C and hm^(5)C regulators between tumor and non-tumor samples.UHRF1,TET3,and NEIL1 were significantly upregulated in tumor samples,whereas MECP2 and EGR1 were significantly downregulated for m^(5)C and hm^(5)C regulators.UHRF1,DNMT1,NSUN2,NSUN4,C1orf77,C3orf37,WDR77,NEIL1,and TDG genes were identified as candidate prognostic markers of overall survival.The upregulated genes in patient samples with genetic alterations in m^(5)C and hm^(5)C pathways enriched cell cycle-related processes.Conclusion:In summary,our findings suggest that the m^(5)C and hm^(5)C regulators might play a role in PRAD development by activation of proliferation,and the UHRF1,NSUN2,and NEIL1 genes have the potential to be utilized as clinical biomarkers.Established correlative relationships require experimental validation through functional studies in prostate cancer cell lines.
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。
