Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a ...Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.展开更多
Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and af...Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.展开更多
Inflammation plays an important role in atherosclerosis.Inflammasomes play a crucial role in innate immunity,which mediates the body’s response to various pathogens.Of the different types of inflammasomes,NLRP3 has b...Inflammation plays an important role in atherosclerosis.Inflammasomes play a crucial role in innate immunity,which mediates the body’s response to various pathogens.Of the different types of inflammasomes,NLRP3 has been implicated in atherosclerosis through the production of proinfl ammatory cytokines,IL-1β and IL-18.This review describes the role of the NLRP3 infl ammasome in atherosclerosis and discusses potential therapeutic targets in the infl ammasome pathway.展开更多
Objective:To explore the mechanism and active components of Radix et Rhizoma Rhei in the treatment of Alzheimer's disease(AD)based on molecular docking.Methods:22 major components of Radix et Rhizoma Rhei were scr...Objective:To explore the mechanism and active components of Radix et Rhizoma Rhei in the treatment of Alzheimer's disease(AD)based on molecular docking.Methods:22 major components of Radix et Rhizoma Rhei were screened from TCMSP and related literatures,which docked with the key targets of NLRP3/Caspase-1/GSDMD signaling pathway.NLRP3,Caspase-1,GSDMD inhibitors MCC950,ML132 and LDC7559 were used as positive control to analyze the docking results.Results:The docking results showed that the main components of Radix et Rhizoma Rhei had different degrees of binding with NLRP3,Caspase-1 and GSDMD targets,and the potential active components were mutanochrome and physciondiglucoside.Conclusion:Molecular docking predicts that the main components of Radix et Rhizoma Rhei may act on NLRP3/Caspase-1/GSDMD signaling pathway,and the active components may be mutanochrome and physciondiglucoside,which provides theoretical basis for revealing the anti-inflammatory mechanism and active components of Radix et Rhizoma Rhei in the treatment of AD.展开更多
Objective To investigate the relationship between the expression of NOD-like receptor protein 3(NLRP3)inflammasome in colonic mucosal tissues of ulcerative colitis(UC)patients and UC mice model and the activity of UC....Objective To investigate the relationship between the expression of NOD-like receptor protein 3(NLRP3)inflammasome in colonic mucosal tissues of ulcerative colitis(UC)patients and UC mice model and the activity of UC.Methods From December 2016 to January 2018,at Department of Gastroenterology,the First Affiliated Hospital of Zhejiang Traditional Chinese Medicine University,60 patients with UC were recruited,of which 15 cases at remission phase,15 cases at mild activity phase,and 15 cases at moderate activity phase,and 15 cases at severe activity phase;and 15 healthy subjects were selected as healthy control group.UC mice models were established by dextran sulfate sodium(DSS).Forty-eight BALB/c mice were divided into 2.5%DSS group,5.0%DSS group and 7.5%DSS group and control group.The colon tissues of UC patients and UC mice models were pathologically scored.The expression of NLRP3,cysteinyl aspartate specific proteinase 1(caspase1)and apoptosis-associated speck-like protein containing CARD(ASC)at mRNA level in colon tissues of UC patients and UC mice models were determined by real time fluorescence quantitative polymerase chain reaction(PCR).The expression of NLRP3,caspase-1 and ASC at protein level in colon tissues of UC patients and UC mice models were detected by Western blotting.One-way analysis of variance and SNK-t test were performed for statistical analysis.Results The histopathological scores of colon tissues of UC patients at remission phase,at mild activity phase,at moderate activity phase,at severe activity phase and healthy controls were 2.37±0.46,4.84±1.29,6.82±0.96,9.42±1.13 and 1.23±0.55,respectively;the differences were statistically significant(F=67.68,P<0.01).The higher the degree of inflammation,the higher the pathological score,and the differences were statistically significant(all P<0.05).The pathological scores of colon tissues of mice in the 2.5%DSS group,5.0%DSS group and 7.5%DSS group were 4.54±0.74,6.02±1.00 and 8.43±1.46,respectively;the higher the dose of DSS,the higher the pathological score,and the differences were statistically significant(all P<0.05).The expression of NLRP3 at mRNA level of UC at remission phase,mild activity phase,moderate activity phase,severe activity phase and healthy controls were 1.15±0.10,1.49±0.13,2.00±0.25,2.05±0.33 and 0.61±0.09,respectively;the expression of caspase-1 at mRNA level were 1.13±0.08,1.51±0.19,2.10±0.23,2.88±0.33 and 0.61±0.11,respectively;the expression of ASC at mRNA level were 1.12±0.08,1.88±0.33,2.53±0.22,3.20±0.24 and 0.59±0.12,respectively;the differences between groups were statistically significant(F=108.43,63.25 and 105.25,all P<0.01).The higher the degree of inflammation,the higher the mRNA expression levels of NLRP3,caspase-1 and ASC,and the differences were statistically significant(all P<0.01).The higher the dose of DSS,the higher the protein expression levels of NLRP3,caspase-1 and ASC at mRNA level.The higher the degree of inflammation,the higher expression of NLRP3,caspase-1 and ASC in colon tissues of UC patients.The higher dose of DSS,the higher the protein expression levels of NLRP3,caspase-1 and ASC in colon tissues of mice.Conclusion The expression level of NLRP3 inflammasome is different in different stages of UC,the higher degree of inflammatory activity,the higher the expressie level.It is helpful to evaluate the activity of UC by detecting the expression level of NLRP3 inflammasome.展开更多
基金supported by grants from the National Natural Science Foundation of China, Nos. 81930031 (to JNZ), 81720108015 (to JNZ), 81901525 (to SZ), 82101440 (to DDS), 81801234 (to YZ) and 82071389 (to GLY)the Natural Science Foundation of Tianjin, Nos. 20JCQNJC01270 (to JWW), 20JCQNJC00460 (to GLY), 18JCQNJC81000 (to HTR)+4 种基金Scientific Research Project of Tianjin Education Commission (Natural Science), No. 2018KJ052 (to ZWZ)Tianjin Health and Health Committee Science and Technology Project, No. QN20015 (to JWW)the Science & Technology Development Fund of Tianjin Education Commission for Higher Education, No. 2016YD02 (to YW)Tianjin Key Science and Technology Projects of Innovative Drugs and Medical Devices, No. 19ZXYXSY00070 (to YW)the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW)
文摘Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.
基金supported by American Diabetes Association,American Heart Association,NIH NIEHS,NIH NIA,NIH NINDS,and NIH ARRA
文摘Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
文摘Inflammation plays an important role in atherosclerosis.Inflammasomes play a crucial role in innate immunity,which mediates the body’s response to various pathogens.Of the different types of inflammasomes,NLRP3 has been implicated in atherosclerosis through the production of proinfl ammatory cytokines,IL-1β and IL-18.This review describes the role of the NLRP3 infl ammasome in atherosclerosis and discusses potential therapeutic targets in the infl ammasome pathway.
基金Overseas Visiting and Study Program for Excellent Young Backbone Talents in Anhui Universities(No.gxgwfx2020041)The National Natural Science Foundation of China(No.81873351)Graduate Science and Technology Innovation Fund project of Anhui University of Traditional Chinese Medicine(No.2020YB07)。
文摘Objective:To explore the mechanism and active components of Radix et Rhizoma Rhei in the treatment of Alzheimer's disease(AD)based on molecular docking.Methods:22 major components of Radix et Rhizoma Rhei were screened from TCMSP and related literatures,which docked with the key targets of NLRP3/Caspase-1/GSDMD signaling pathway.NLRP3,Caspase-1,GSDMD inhibitors MCC950,ML132 and LDC7559 were used as positive control to analyze the docking results.Results:The docking results showed that the main components of Radix et Rhizoma Rhei had different degrees of binding with NLRP3,Caspase-1 and GSDMD targets,and the potential active components were mutanochrome and physciondiglucoside.Conclusion:Molecular docking predicts that the main components of Radix et Rhizoma Rhei may act on NLRP3/Caspase-1/GSDMD signaling pathway,and the active components may be mutanochrome and physciondiglucoside,which provides theoretical basis for revealing the anti-inflammatory mechanism and active components of Radix et Rhizoma Rhei in the treatment of AD.
文摘Objective To investigate the relationship between the expression of NOD-like receptor protein 3(NLRP3)inflammasome in colonic mucosal tissues of ulcerative colitis(UC)patients and UC mice model and the activity of UC.Methods From December 2016 to January 2018,at Department of Gastroenterology,the First Affiliated Hospital of Zhejiang Traditional Chinese Medicine University,60 patients with UC were recruited,of which 15 cases at remission phase,15 cases at mild activity phase,and 15 cases at moderate activity phase,and 15 cases at severe activity phase;and 15 healthy subjects were selected as healthy control group.UC mice models were established by dextran sulfate sodium(DSS).Forty-eight BALB/c mice were divided into 2.5%DSS group,5.0%DSS group and 7.5%DSS group and control group.The colon tissues of UC patients and UC mice models were pathologically scored.The expression of NLRP3,cysteinyl aspartate specific proteinase 1(caspase1)and apoptosis-associated speck-like protein containing CARD(ASC)at mRNA level in colon tissues of UC patients and UC mice models were determined by real time fluorescence quantitative polymerase chain reaction(PCR).The expression of NLRP3,caspase-1 and ASC at protein level in colon tissues of UC patients and UC mice models were detected by Western blotting.One-way analysis of variance and SNK-t test were performed for statistical analysis.Results The histopathological scores of colon tissues of UC patients at remission phase,at mild activity phase,at moderate activity phase,at severe activity phase and healthy controls were 2.37±0.46,4.84±1.29,6.82±0.96,9.42±1.13 and 1.23±0.55,respectively;the differences were statistically significant(F=67.68,P<0.01).The higher the degree of inflammation,the higher the pathological score,and the differences were statistically significant(all P<0.05).The pathological scores of colon tissues of mice in the 2.5%DSS group,5.0%DSS group and 7.5%DSS group were 4.54±0.74,6.02±1.00 and 8.43±1.46,respectively;the higher the dose of DSS,the higher the pathological score,and the differences were statistically significant(all P<0.05).The expression of NLRP3 at mRNA level of UC at remission phase,mild activity phase,moderate activity phase,severe activity phase and healthy controls were 1.15±0.10,1.49±0.13,2.00±0.25,2.05±0.33 and 0.61±0.09,respectively;the expression of caspase-1 at mRNA level were 1.13±0.08,1.51±0.19,2.10±0.23,2.88±0.33 and 0.61±0.11,respectively;the expression of ASC at mRNA level were 1.12±0.08,1.88±0.33,2.53±0.22,3.20±0.24 and 0.59±0.12,respectively;the differences between groups were statistically significant(F=108.43,63.25 and 105.25,all P<0.01).The higher the degree of inflammation,the higher the mRNA expression levels of NLRP3,caspase-1 and ASC,and the differences were statistically significant(all P<0.01).The higher the dose of DSS,the higher the protein expression levels of NLRP3,caspase-1 and ASC at mRNA level.The higher the degree of inflammation,the higher expression of NLRP3,caspase-1 and ASC in colon tissues of UC patients.The higher dose of DSS,the higher the protein expression levels of NLRP3,caspase-1 and ASC in colon tissues of mice.Conclusion The expression level of NLRP3 inflammasome is different in different stages of UC,the higher degree of inflammatory activity,the higher the expressie level.It is helpful to evaluate the activity of UC by detecting the expression level of NLRP3 inflammasome.
