Hypoxic-ischemic encephalopathy（HIE） is a disease that occurs when the brain is subjected to hypoxia,resulting in neuronal death and neurological deficits,with a poor prognosis.The mechanisms underlying hypoxic-isch...Hypoxic-ischemic encephalopathy（HIE） is a disease that occurs when the brain is subjected to hypoxia,resulting in neuronal death and neurological deficits,with a poor prognosis.The mechanisms underlying hypoxic-ischemic brain injury include excitatory amino acid release,cellular proteolysis,reactive oxygen species generation,nitric oxide synthesis,and inflammation.The molecular and cellular changes in HIE include protein misfolding,aggregation,and destruction of organelles.The apoptotic pathways activated by ischemia and hypoxia include the mitochondrial pathway,the extrinsic Fas receptor pathway,and the endoplasmic reticulum stress-induced pathway.Numerous treatments for hypoxic-ischemic brain injury caused by HIE have been developed over the last half century.Hypothermia,xenon gas treatment,the use of melatonin and erythropoietin,and hypoxic-ischemic preconditioning have proven effective in HIE patients.Molecular chaperones are proteins ubiquitously present in both prokaryotes and eukaryotes.A large number of molecular chaperones are induced after brain ischemia and hypoxia,among which the heat shock proteins are the most important.Heat shock proteins not only maintain protein homeostasis; they also exert anti-apoptotic effects.Heat shock proteins maintain protein homeostasis by helping to transport proteins to their target destinations,assisting in the proper folding of newly synthesized polypeptides,regulating the degradation of misfolded proteins,inhibiting the aggregation of proteins,and by controlling the refolding of misfolded proteins.In addition,heat shock proteins exert anti-apoptotic effects by interacting with various signaling pathways to block the activation of downstream effectors in numerous apoptotic pathways,including the intrinsic pathway,the endoplasmic reticulum-stress mediated pathway and the extrinsic Fas receptor pathway.Molecular chaperones play a key role in neuroprotection in HIE.In this review,we provide an overview of the mechanisms of HIE and discuss the various treatment strate展开更多
To investigate the relationship between natural killer（NK） cells and traumatic brain injury（TBI）, we tracked an established phenotype of circulating NK cells at several time points in patients with different grade...To investigate the relationship between natural killer（NK） cells and traumatic brain injury（TBI）, we tracked an established phenotype of circulating NK cells at several time points in patients with different grades of TBI. In serial peripheral blood samples, NK cells were prospectively measured by flow cytometry of CD3-CD56＋ lymphocytes. Compared to healthy controls, TBI patients had reductions in both the percentage and the absolute number of NK cells. Furthermore, the magnitude of NK cell reduction correlated with the degree of TBI severity at several time points. That is, NK cell population size was independently associated with lower Glasgow Coma Scale scores. In addition, at some time points, a positive correlation was found between the NK cell counts and Glasgow Outcome Scale scores. Our results indicate that TBI induces a reduction in the number of NK cells, and the magnitude of the reduction appears to parallel the severity of TBI.展开更多
EGb761,a standardized and well-defined product extract of Ginkgo biloba leaves,has beneficial effects on the treatment of multiple diseases,including diabetes and dyslipidemia.However,it is still unclear whether EGb76...EGb761,a standardized and well-defined product extract of Ginkgo biloba leaves,has beneficial effects on the treatment of multiple diseases,including diabetes and dyslipidemia.However,it is still unclear whether EGb761 can increase insulin sensitivity.The objectives of the present study are to evaluate the effects of EGb761 on insulin sensitivity in an obese and insulinresistant mouse model,established through chronic feeding of C57BL/6J mice with a high-fat diet(HFD),and to explore potential mechanisms.Mice fed with HFD for 18 weeks(starting from 4 weeks of age)developed obesity,dyslipidemia(as indicated by biochemical measurements of blood glucose,triglyceride(TG),total cholesterol(TC),and free fatty acids(FFA)),and insulin resistance(as determined by the oral glucose tolerance test(OGTT)and the homeostasis model assessment of insulin resistance(HOMA-IR)index),compared to control mice fed with a standard laboratory chow.Oral treatment of the HFD-fed mice with EGb761,at low(100 mg/kg),medium(200 mg/kg),or high(400 mg/kg)doses,via oral gavage(once daily)for 8 weeks(starting from 26 weeks of age)dose-dependently enhanced glucose tolerance in OGTT,and decreased both the insulin levels(by 29%,55%,and 70%,respectively),and the HOMA-IR index values(by 50%,69%,and 80%,respectively).EGb761 treatment also ameliorated HFD-induced obesity,dyslipidemia,and liver injury,as indicated by decreases in body weight(by 4%,11%,and 16%,respectively),blood TC levels(by 23%,32%,and 37%,respectively),blood TG levels(by 17%,23%,and 33%,respectively),blood FAA levels(by 35%,38%,and 46%,respectively),and liver index(liver weight/body weight)values(by 12.8%,25%,and 28%,respectively)in the low,medium,and high EGb761 dose groups,respectively.In further mechanism studies,EGb761 was found to protect hepatic insulin receptor b and insulin receptor substrate 1 from HFD-induced degradation,and to keep the AMP-activated protein kinase,which plays a crucial role in reducing lipotoxicity,from HFD-induced inactivation.We conclude that EGb761 can effe展开更多
The alkenylzincation of internal alkynes is an effective method for the synthesis of multi-substituted conjugated dienes;however,the current catalytic systems for this reaction are limited in terms of substrate scope ...The alkenylzincation of internal alkynes is an effective method for the synthesis of multi-substituted conjugated dienes;however,the current catalytic systems for this reaction are limited in terms of substrate scope and selectivity control,which restricts its practical applications.Herein,we report the first iron-catalyzed alkenylzincation of internal alkynes,which features mild conditions,simple operation,broad substrate scope (including aryl/alkyl,diaryl,and dialkyl acetylenes),excellent functional group tolerance (tolerating highly active functional groups such as ester,methylthio,amide,sulfonyl,cyano,etc.),and high activity (with a turnover number of up to 11500,the highest record for carbometallation reactions).Notably,the catalytic system described in this article also realized the highly selective vinylzincation of unfunctionalized internal alkynes as well as the alkenylzincation of unsymmetrical diarylacetylenes and dialkyl acetylenes,which have not been achieved with other catalytic systems reported in the literatures.The current study provides a highly selective access to synthetically important multi-substituted conjugated dienes.展开更多
Background Acute brain ischaemia elicits pronounced inflammation,which aggravates neural injury.However,the mechanisms governing the resolution of acute neuroinflammation remain poorly understood.In contrast to regula...Background Acute brain ischaemia elicits pronounced inflammation,which aggravates neural injury.However,the mechanisms governing the resolution of acute neuroinflammation remain poorly understood.In contrast to regulatory T and B cells,group 2 innate lymphoid cells(ILC2s)are immunoregulatory cells that can be swiftly mobilised without antigen presentation;whether and how these ILC2s participate in central nervous system inflammation following brain ischaemia is still unknown.Methods Leveraging brain tissues from patients who had an ischaemic stroke and a mouse model of focal ischaemia,we characterised the presence and cytokine release of brain-infiltrating ILC2s.The impact of ILC2s on neural injury was evaluated through antibody depletion and ILC2 adoptive transfer experiments.Using Rag2−/−γc−/−mice receiving passive transfer of IL-4−/−ILC2s,we further assessed the contribution of interleukin(IL)-4,produced by ILC2s,in ischaemic brain injury.Results We demonstrate that ILC2s accumulate in the areas surrounding the infarct in brain tissues of patients with cerebral ischaemia,as well as in mice subjected to focal cerebral ischaemia.Oligodendrocytes were a major source of IL-33,which contributed to ILC2s mobilisation.Adoptive transfer and expansion of ILC2s reduced brain infarction.Importantly,brain-infiltrating ILC2s reduced the magnitude of stroke injury severity through the production of IL-4.Conclusions Our findings revealed that brain ischaemia mobilises ILC2s to curb neuroinflammation and brain injury,expanding the current understanding of inflammatory networks following stroke.展开更多
文摘Hypoxic-ischemic encephalopathy（HIE） is a disease that occurs when the brain is subjected to hypoxia,resulting in neuronal death and neurological deficits,with a poor prognosis.The mechanisms underlying hypoxic-ischemic brain injury include excitatory amino acid release,cellular proteolysis,reactive oxygen species generation,nitric oxide synthesis,and inflammation.The molecular and cellular changes in HIE include protein misfolding,aggregation,and destruction of organelles.The apoptotic pathways activated by ischemia and hypoxia include the mitochondrial pathway,the extrinsic Fas receptor pathway,and the endoplasmic reticulum stress-induced pathway.Numerous treatments for hypoxic-ischemic brain injury caused by HIE have been developed over the last half century.Hypothermia,xenon gas treatment,the use of melatonin and erythropoietin,and hypoxic-ischemic preconditioning have proven effective in HIE patients.Molecular chaperones are proteins ubiquitously present in both prokaryotes and eukaryotes.A large number of molecular chaperones are induced after brain ischemia and hypoxia,among which the heat shock proteins are the most important.Heat shock proteins not only maintain protein homeostasis; they also exert anti-apoptotic effects.Heat shock proteins maintain protein homeostasis by helping to transport proteins to their target destinations,assisting in the proper folding of newly synthesized polypeptides,regulating the degradation of misfolded proteins,inhibiting the aggregation of proteins,and by controlling the refolding of misfolded proteins.In addition,heat shock proteins exert anti-apoptotic effects by interacting with various signaling pathways to block the activation of downstream effectors in numerous apoptotic pathways,including the intrinsic pathway,the endoplasmic reticulum-stress mediated pathway and the extrinsic Fas receptor pathway.Molecular chaperones play a key role in neuroprotection in HIE.In this review,we provide an overview of the mechanisms of HIE and discuss the various treatment strate
基金supported in part by the National Natural Science Foundation of China (81370029 and 81200907)the Tianjin Research Program of Application Foundation and Advanced Technology (12JCQNJC6800)+1 种基金a National Key Clinical Specialty Construction Project of China (12ZCDZSY17400)a National Clinical Key subject Construction Project of the NHFPC Fund
文摘To investigate the relationship between natural killer（NK） cells and traumatic brain injury（TBI）, we tracked an established phenotype of circulating NK cells at several time points in patients with different grades of TBI. In serial peripheral blood samples, NK cells were prospectively measured by flow cytometry of CD3-CD56＋ lymphocytes. Compared to healthy controls, TBI patients had reductions in both the percentage and the absolute number of NK cells. Furthermore, the magnitude of NK cell reduction correlated with the degree of TBI severity at several time points. That is, NK cell population size was independently associated with lower Glasgow Coma Scale scores. In addition, at some time points, a positive correlation was found between the NK cell counts and Glasgow Outcome Scale scores. Our results indicate that TBI induces a reduction in the number of NK cells, and the magnitude of the reduction appears to parallel the severity of TBI.
基金supported by the National S&T Major Project(Nos.2009ZX09103-432 and 2009ZX09301-003-12-1)Natural Sciences Funds of Inner Mongolian Autonomous Region(No.20080404Zd31)。
文摘EGb761,a standardized and well-defined product extract of Ginkgo biloba leaves,has beneficial effects on the treatment of multiple diseases,including diabetes and dyslipidemia.However,it is still unclear whether EGb761 can increase insulin sensitivity.The objectives of the present study are to evaluate the effects of EGb761 on insulin sensitivity in an obese and insulinresistant mouse model,established through chronic feeding of C57BL/6J mice with a high-fat diet(HFD),and to explore potential mechanisms.Mice fed with HFD for 18 weeks(starting from 4 weeks of age)developed obesity,dyslipidemia(as indicated by biochemical measurements of blood glucose,triglyceride(TG),total cholesterol(TC),and free fatty acids(FFA)),and insulin resistance(as determined by the oral glucose tolerance test(OGTT)and the homeostasis model assessment of insulin resistance(HOMA-IR)index),compared to control mice fed with a standard laboratory chow.Oral treatment of the HFD-fed mice with EGb761,at low(100 mg/kg),medium(200 mg/kg),or high(400 mg/kg)doses,via oral gavage(once daily)for 8 weeks(starting from 26 weeks of age)dose-dependently enhanced glucose tolerance in OGTT,and decreased both the insulin levels(by 29%,55%,and 70%,respectively),and the HOMA-IR index values(by 50%,69%,and 80%,respectively).EGb761 treatment also ameliorated HFD-induced obesity,dyslipidemia,and liver injury,as indicated by decreases in body weight(by 4%,11%,and 16%,respectively),blood TC levels(by 23%,32%,and 37%,respectively),blood TG levels(by 17%,23%,and 33%,respectively),blood FAA levels(by 35%,38%,and 46%,respectively),and liver index(liver weight/body weight)values(by 12.8%,25%,and 28%,respectively)in the low,medium,and high EGb761 dose groups,respectively.In further mechanism studies,EGb761 was found to protect hepatic insulin receptor b and insulin receptor substrate 1 from HFD-induced degradation,and to keep the AMP-activated protein kinase,which plays a crucial role in reducing lipotoxicity,from HFD-induced inactivation.We conclude that EGb761 can effe
基金National Key R&D Program of China(2021YFA1500200)National Natural Science Foundation of China(92256301,92156006,22221002)+2 种基金"111"project(B06005)of the Ministry of Education of ChinaHaihe Laboratory of Sustainable Chemical Transformations,Fundamental Research Funds for the Central UniversitiesNew Cornerstone Science Foundation through the XPLORER PRIZE for financial support.
文摘The alkenylzincation of internal alkynes is an effective method for the synthesis of multi-substituted conjugated dienes;however,the current catalytic systems for this reaction are limited in terms of substrate scope and selectivity control,which restricts its practical applications.Herein,we report the first iron-catalyzed alkenylzincation of internal alkynes,which features mild conditions,simple operation,broad substrate scope (including aryl/alkyl,diaryl,and dialkyl acetylenes),excellent functional group tolerance (tolerating highly active functional groups such as ester,methylthio,amide,sulfonyl,cyano,etc.),and high activity (with a turnover number of up to 11500,the highest record for carbometallation reactions).Notably,the catalytic system described in this article also realized the highly selective vinylzincation of unfunctionalized internal alkynes as well as the alkenylzincation of unsymmetrical diarylacetylenes and dialkyl acetylenes,which have not been achieved with other catalytic systems reported in the literatures.The current study provides a highly selective access to synthetically important multi-substituted conjugated dienes.
基金in part,by the National Natural Science Foundation of China(82071327,81971094,81771274).
文摘Background Acute brain ischaemia elicits pronounced inflammation,which aggravates neural injury.However,the mechanisms governing the resolution of acute neuroinflammation remain poorly understood.In contrast to regulatory T and B cells,group 2 innate lymphoid cells(ILC2s)are immunoregulatory cells that can be swiftly mobilised without antigen presentation;whether and how these ILC2s participate in central nervous system inflammation following brain ischaemia is still unknown.Methods Leveraging brain tissues from patients who had an ischaemic stroke and a mouse model of focal ischaemia,we characterised the presence and cytokine release of brain-infiltrating ILC2s.The impact of ILC2s on neural injury was evaluated through antibody depletion and ILC2 adoptive transfer experiments.Using Rag2−/−γc−/−mice receiving passive transfer of IL-4−/−ILC2s,we further assessed the contribution of interleukin(IL)-4,produced by ILC2s,in ischaemic brain injury.Results We demonstrate that ILC2s accumulate in the areas surrounding the infarct in brain tissues of patients with cerebral ischaemia,as well as in mice subjected to focal cerebral ischaemia.Oligodendrocytes were a major source of IL-33,which contributed to ILC2s mobilisation.Adoptive transfer and expansion of ILC2s reduced brain infarction.Importantly,brain-infiltrating ILC2s reduced the magnitude of stroke injury severity through the production of IL-4.Conclusions Our findings revealed that brain ischaemia mobilises ILC2s to curb neuroinflammation and brain injury,expanding the current understanding of inflammatory networks following stroke.
