Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we id...Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.展开更多
BACKGROUND The intestinal microcirculation functions in food absorption and metabolic substance exchanges.Accumulating evidence indicates that intestinal microcirculatory dysfunction is a significant source of multipl...BACKGROUND The intestinal microcirculation functions in food absorption and metabolic substance exchanges.Accumulating evidence indicates that intestinal microcirculatory dysfunction is a significant source of multiple gastrointestinal diseases.To date,there has not been a scientometric analysis of intestinal microcirculatory research.AIM To investigate the current status,development trends,and frontiers of intestinal microcirculatory research based on bibliometric analysis.METHODS VOSviewer and CiteSpace 6.1.R2 were used to identify the overall characteristics and knowledge map of intestinal microcirculatory research based on the core literature published from 2000 to 2021 in the Web of Science database.The characteristics of each article,country of origin,institution,journal,cocitations,and other information were analyzed and visualized.RESULTS There were 1364 publications enrolled in the bibliometric analysis,exhibiting an upward trend from 2000 to 2021 with increased participation worldwide.The United States and Dalhousie University took the lead among countries and institutions,respectively.Shock was the most prolific journal,and Nature Reviews Microbiology Clinical had the most citations.The topical hotspots and frontiers in intestinal microcirculatory research were centered on the pathological processes of functional impairment of intestinal microvessels,diverse intestinal illnesses,and clinical treatment.CONCLUSION Our study highlights insights into trends of the published research on the intestinal microcirculation and offers serviceable guidance to researchers by summarizing the prolific areas in intestinal disease research to date.展开更多
BACKGROUND The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery.In diabetes,the balance between oxygen delivery and consumption is impaired.Insulin...BACKGROUND The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery.In diabetes,the balance between oxygen delivery and consumption is impaired.Insulin has been proven to exert complex actions promoting the maintenance of homeostasis of the pancreas under glucotoxicity.AIM To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics.METHODS The pancreatic microcirculatory partial oxygen pressure(PO_(2)),relative hemoglobin(rHb)and hemoglobin oxygen saturation(SO_(2))were evaluated in nondiabetic,type 1 diabetes mellitus(T1DM),and insulin-treated mice.A threedimensional framework was generated to visualize the microcirculatory oxygen profile.Ultrastructural changes in the microvasculature were examined using transmission electron microscopy.An Extracellular Flux Analyzer was used to detect the real-time changes in bioenergetics by measuring the oxygen consumption rate and extracellular acidification rate in islet microvascular endothelial cells(IMECs).RESULTS Significantly lower PO_(2),rHb,and SO_(2) values were observed in T1DM mice than in nondiabetic controls.Insulin administration ameliorated the streptozotocin-induced decreases in these microcirculatory oxygen parameters and improved the mitochondrial ultrastructural abnormalities in IMECs.Bioenergetic profiling revealed that the IMECs did not have spare respiratory capacity.Insulin-treated IMECs exhibited significantly greater basal respiration than glucotoxicity-exposed IMECs(P<0.05).An energy map revealed increased energetic metabolism in insulin-treated IMECs,with significantly increased ATP production,non-mitochondrial respiration,and oxidative metabolism(all P<0.05).Significant negative correlations were revealed between microcirculatory SO_(2) and bioenergetic parameters.CONCLUSION Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics,but this deterioration can be reversed by insulin administration.展开更多
The microstructural responses of In_(0.32)Ga_(0.68)N and In_(0.9)Ga_(0.1)N films to 2.25 GeV Xe ion irradiation have been investigated using x-ray diffraction,Raman scattering,ion channeling and transmission electron ...The microstructural responses of In_(0.32)Ga_(0.68)N and In_(0.9)Ga_(0.1)N films to 2.25 GeV Xe ion irradiation have been investigated using x-ray diffraction,Raman scattering,ion channeling and transmission electron microscopy.It was found that the In-rich In_(0.9)Ga_(0.1)N is more susceptible to irradiation than the Ga-rich In_(0.32)Ga_(0.68)N.Xe ion irradiation with a fluence of 7×10^(11)ions·cm^(-2)leads to little damage in In_(0.32)Ga_(0.68)N but an obvious lattice expansion in In_(0.9)Ga_(0.1)N.The level of lattice disorder in In_(0.9)Ga_(0.1)N increases after irradiation,due to the huge electronic energy deposition of the incident Xe ions.However,no Xe ion tracks were observed to be formed,which is attributed to the very high velocity of 2.25 Ge V Xe ions.Point defects and/or small defect clusters are probably the dominant defect type in Xe-irradiated In_(0.9)Ga_(0.1)N.展开更多
Camalexin （3-thiazol-2＇-yl-indole） is the major phytoalexin found in Arabidopsis thaliana. Several key intermediates and corresponding enzymes have been identified in camalexin biosynthesis through mutant screening...Camalexin （3-thiazol-2＇-yl-indole） is the major phytoalexin found in Arabidopsis thaliana. Several key intermediates and corresponding enzymes have been identified in camalexin biosynthesis through mutant screening and biochemical experiments. Camalexin is formed when indole-3-acetonitrile （IAN） is catalyzed by the cytochrome P450 monooxygenase CYP71A13. Here, we demonstrate that the Ara- bidopsis GH3.5 protein, a multifunctional acetyl-amido synthetase, is involved in camalexin biosynthesis via conjugating indole-3-carboxylic acid （ICA） and cysteine （Cys） and regulating camalexin biosynthesis genes. Camalexin levels were increased in the activation-tagged mutant gh3.5-1D in both Col-0 and cyp71A13-2 mutant backgrounds after pathogen infection. The recombinant GH3.5 protein catalyzed the conjugation of ICA and Cys to form a possible intermediate indole-3-acyl-cysteinate （ICA（Cys）） in vitro. In support of the in vitro reaction, feeding with ICA and Cys increased camalexin levels in Col-0 and gh3.5-1D. Dihydrocamalexic acid （DHCA）, the precursor of camalexin and the substrate for PAD3, was accumulated in gh3.5-1DIpad3-1, suggesting that ICA（Cys） could be an additional precursor of DHCA for camalexin biosynthesis. Furthermore, expression of the major camalexin biosynthesis genes CYP79B2, CYP71A12, CYP71A13 and PAD3 was strongly induced in gh3.5-1D. Our study suggests that GH3.5 is involved in camalexin biosynthesis through direct catalyzation of the formation of ICA（Cys）, and upregulation of the major biosynthetic pathway genes.展开更多
基金National Natural Science Foundation of China(81870850)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX23_0322)。
文摘Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.
基金Supported by the Beijing Municipal Natural Science Foundation,No.7212068the National Natural Science Foundation of China,No.81900747.
文摘BACKGROUND The intestinal microcirculation functions in food absorption and metabolic substance exchanges.Accumulating evidence indicates that intestinal microcirculatory dysfunction is a significant source of multiple gastrointestinal diseases.To date,there has not been a scientometric analysis of intestinal microcirculatory research.AIM To investigate the current status,development trends,and frontiers of intestinal microcirculatory research based on bibliometric analysis.METHODS VOSviewer and CiteSpace 6.1.R2 were used to identify the overall characteristics and knowledge map of intestinal microcirculatory research based on the core literature published from 2000 to 2021 in the Web of Science database.The characteristics of each article,country of origin,institution,journal,cocitations,and other information were analyzed and visualized.RESULTS There were 1364 publications enrolled in the bibliometric analysis,exhibiting an upward trend from 2000 to 2021 with increased participation worldwide.The United States and Dalhousie University took the lead among countries and institutions,respectively.Shock was the most prolific journal,and Nature Reviews Microbiology Clinical had the most citations.The topical hotspots and frontiers in intestinal microcirculatory research were centered on the pathological processes of functional impairment of intestinal microvessels,diverse intestinal illnesses,and clinical treatment.CONCLUSION Our study highlights insights into trends of the published research on the intestinal microcirculation and offers serviceable guidance to researchers by summarizing the prolific areas in intestinal disease research to date.
基金Supported by the Beijing Municipal Natural Science Foundation,No.7212068the National Natural Science Foundation of China,No.81900747.
文摘BACKGROUND The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery.In diabetes,the balance between oxygen delivery and consumption is impaired.Insulin has been proven to exert complex actions promoting the maintenance of homeostasis of the pancreas under glucotoxicity.AIM To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics.METHODS The pancreatic microcirculatory partial oxygen pressure(PO_(2)),relative hemoglobin(rHb)and hemoglobin oxygen saturation(SO_(2))were evaluated in nondiabetic,type 1 diabetes mellitus(T1DM),and insulin-treated mice.A threedimensional framework was generated to visualize the microcirculatory oxygen profile.Ultrastructural changes in the microvasculature were examined using transmission electron microscopy.An Extracellular Flux Analyzer was used to detect the real-time changes in bioenergetics by measuring the oxygen consumption rate and extracellular acidification rate in islet microvascular endothelial cells(IMECs).RESULTS Significantly lower PO_(2),rHb,and SO_(2) values were observed in T1DM mice than in nondiabetic controls.Insulin administration ameliorated the streptozotocin-induced decreases in these microcirculatory oxygen parameters and improved the mitochondrial ultrastructural abnormalities in IMECs.Bioenergetic profiling revealed that the IMECs did not have spare respiratory capacity.Insulin-treated IMECs exhibited significantly greater basal respiration than glucotoxicity-exposed IMECs(P<0.05).An energy map revealed increased energetic metabolism in insulin-treated IMECs,with significantly increased ATP production,non-mitochondrial respiration,and oxidative metabolism(all P<0.05).Significant negative correlations were revealed between microcirculatory SO_(2) and bioenergetic parameters.CONCLUSION Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics,but this deterioration can be reversed by insulin administration.
基金Project supported by the National Natural Science Foundation of China(Grant No.11875154)State Key Laboratory of Intense Pulsed Radiation Simulation and Effect(Grant No.SKLIPR2014)。
文摘The microstructural responses of In_(0.32)Ga_(0.68)N and In_(0.9)Ga_(0.1)N films to 2.25 GeV Xe ion irradiation have been investigated using x-ray diffraction,Raman scattering,ion channeling and transmission electron microscopy.It was found that the In-rich In_(0.9)Ga_(0.1)N is more susceptible to irradiation than the Ga-rich In_(0.32)Ga_(0.68)N.Xe ion irradiation with a fluence of 7×10^(11)ions·cm^(-2)leads to little damage in In_(0.32)Ga_(0.68)N but an obvious lattice expansion in In_(0.9)Ga_(0.1)N.The level of lattice disorder in In_(0.9)Ga_(0.1)N increases after irradiation,due to the huge electronic energy deposition of the incident Xe ions.However,no Xe ion tracks were observed to be formed,which is attributed to the very high velocity of 2.25 Ge V Xe ions.Point defects and/or small defect clusters are probably the dominant defect type in Xe-irradiated In_(0.9)Ga_(0.1)N.
基金supported by grants from the Ministry of Science and Technology of China (2011CB100700 and 2007AA10Z107)from the CAS International Partnership Program for Creative Research Teams
文摘Camalexin （3-thiazol-2＇-yl-indole） is the major phytoalexin found in Arabidopsis thaliana. Several key intermediates and corresponding enzymes have been identified in camalexin biosynthesis through mutant screening and biochemical experiments. Camalexin is formed when indole-3-acetonitrile （IAN） is catalyzed by the cytochrome P450 monooxygenase CYP71A13. Here, we demonstrate that the Ara- bidopsis GH3.5 protein, a multifunctional acetyl-amido synthetase, is involved in camalexin biosynthesis via conjugating indole-3-carboxylic acid （ICA） and cysteine （Cys） and regulating camalexin biosynthesis genes. Camalexin levels were increased in the activation-tagged mutant gh3.5-1D in both Col-0 and cyp71A13-2 mutant backgrounds after pathogen infection. The recombinant GH3.5 protein catalyzed the conjugation of ICA and Cys to form a possible intermediate indole-3-acyl-cysteinate （ICA（Cys）） in vitro. In support of the in vitro reaction, feeding with ICA and Cys increased camalexin levels in Col-0 and gh3.5-1D. Dihydrocamalexic acid （DHCA）, the precursor of camalexin and the substrate for PAD3, was accumulated in gh3.5-1DIpad3-1, suggesting that ICA（Cys） could be an additional precursor of DHCA for camalexin biosynthesis. Furthermore, expression of the major camalexin biosynthesis genes CYP79B2, CYP71A12, CYP71A13 and PAD3 was strongly induced in gh3.5-1D. Our study suggests that GH3.5 is involved in camalexin biosynthesis through direct catalyzation of the formation of ICA（Cys）, and upregulation of the major biosynthetic pathway genes.
