BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibito...BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.展开更多
Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we...Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.展开更多
BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its me...BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.展开更多
The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors' histological features an...The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors' histological features and angiogenesis were investigated by means of immunohistochemical technique. The expression of bFGF and FGFR-1 was detected by antibody of bFGF or FGFR-1. The tumors' angiogenesis was evaluated by microvascular density (MVD) and, which was observed by use of CD34-antibody immunohistochemically. The results showed that there were varied degrees of the expression of bFGF and FGFR-1 proteins in meningiomas. The expression was correlated with the tumors' histological characters and angiogenesis. It was concluded that bFGF and FGFR-1 might play important roles in meningiomas' angiogenesis and proliferation. The expression positive rate of bFGF and FGFR-1 may provide an indication of evaluating the histological and malignant degree of the tumor.展开更多
BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and...BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.展开更多
Glia-derived axonal growth inhibitory proteins limit functional repair following damage to the adult cen- tral nervous system （CNS）. Nogo proteins, myelin-as- sociated glycoprotein （MAG）, oligodendrocyte myelin gl...Glia-derived axonal growth inhibitory proteins limit functional repair following damage to the adult cen- tral nervous system （CNS）. Nogo proteins, myelin-as- sociated glycoprotein （MAG）, oligodendrocyte myelin glycoprotein （OMgp） and B lymphocyte stimulator （BLyS）, are 4 inhibitors that commonly interact with the neuronal receptor, Nogo receptor-1 （NgR1）, lead- ing to inhibition of axonal growth. Here, we demon- strate that lateral olfactory tract usher substance （LOTUS） binds to NgR1 and blocks the binding of all four ligands to NgR1, resulting in the suppression of axonal growth inhibition induced by these NgR1 li- gands. LOTUS allows neurons to overcome NgRl-me- diated axonal growth inhibition, raising the possibility that LOTUS may be useful in future therapeutic ap- proaches as an endogenous potent inhibitor of NgR1 for promoting neuronal regeneration.展开更多
Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by...Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.展开更多
There is evidence that the expression of members of the fibroblast growth factor （FGF） protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined w...There is evidence that the expression of members of the fibroblast growth factor （FGF） protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined whether the expression of fibroblast growth factor-2 （FGF2） and fibroblast growth factor receptor-1 （FGFR1） protein is altered following chronic stress in an animal model. Rats were exposed to 35 days of chronic unpredictable mild stress, and then tested using open-field and sucrose consumption tests. Compared with the control group, rats in the chronic stress group exhibited obvious depressive-like behaviors, including anhedonia, anxiety and decreased mobility. The results of western blot analysis and immunohistochemical analysis revealed a downregulation of the expression of FGF2 and FGFR1 in the hippocampus of rats, particularly in the CA1, CA3 and dentate gyrus. This decreased expression is in accord with the results of post-mortem studies in humans with major depressive disorder. These findings suggest that FGF2 and FGFR1 proteins participate in the pathophysiology of depressive-like behavior, and may play an important role in the mechanism of chronic stress-induced depression.展开更多
[Objectives]To investigate the spasticity of rat tail and the expression of dopamine receptor-1(DRD1)mRNA in the spinal cord after spinal cord injury(SCI)induced tail spasticity in rats.[Methods]Adult male Wistar rats...[Objectives]To investigate the spasticity of rat tail and the expression of dopamine receptor-1(DRD1)mRNA in the spinal cord after spinal cord injury(SCI)induced tail spasticity in rats.[Methods]Adult male Wistar rats were randomly divided into Sham group and SCI group.The second sacral spinal cord(S2)segment of SCI rats was completely transected.60 d after operation,the rat tail spasticity was scored,and then the spinal cord tissues below the level of S2 spinal cord transection were taken.The expression of DRD1 mRNA in the sacrococcygeal spinal cord was detected by qPCR.In addition,3 normal rats were used for DAR/neuronal nuclei(NeuN)and DRD1/choline acetyltransferase(ChAT)immunofluorescence staining to study the distribution of DRD1 in spinal cord and the properties of DRD1 positive cells.[Results]60 d after operation in SCI group,the tail spasticity of rats developed fully,and the symptoms of spasticity were typical.qPCR results showed that the expression of DRD1 mRNA in SCI group was significantly lower than that in Sham group(P<0.05).DRD1 was widely distributed in the dorsal horn,intermediate zone and ventral horn at the sacrococcygeal end of the rat spinal cord.[Conclusions]The decrease of DRD1 mRNA expression after SCI may be related to the occurrence and development of spasticity.展开更多
基金Supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,No.2021-I2M-1-061 and 2021-I2M-1-003Chinese Society of Clinical Oncology-Hengrui Cancer Research Fund,No.Y-HR2019-0239+1 种基金Chinese Society of Clinical Oncology-MSD Cancer Research Fund,No.Y-MSDZD2021-0213National Ten-thousand Talent Program.
文摘BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.
基金supported by the Key Project of the National Natural Science Foundation of China,No.81930070(to SF)the National Natural Science Foundation of China,No.81972074(to XY)the Key Program of Natural Science Foundation of Tianjin,No.19JCZDJC34900(to XY)。
文摘Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.
基金Supported by the National Natural Science Foundation of China,No.81570543 and No.81560104
文摘BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.
文摘The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors' histological features and angiogenesis were investigated by means of immunohistochemical technique. The expression of bFGF and FGFR-1 was detected by antibody of bFGF or FGFR-1. The tumors' angiogenesis was evaluated by microvascular density (MVD) and, which was observed by use of CD34-antibody immunohistochemically. The results showed that there were varied degrees of the expression of bFGF and FGFR-1 proteins in meningiomas. The expression was correlated with the tumors' histological characters and angiogenesis. It was concluded that bFGF and FGFR-1 might play important roles in meningiomas' angiogenesis and proliferation. The expression positive rate of bFGF and FGFR-1 may provide an indication of evaluating the histological and malignant degree of the tumor.
基金Supported by Heilongjiang Provincial Health and Family Planning Commission Research Project,No.2017-413
文摘BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.
基金supported by a grant-in-aid from the Ministry of Education,Culture,Sports,Science and Technology of Japangrants for Research and Development project of Yokohama City University
文摘Glia-derived axonal growth inhibitory proteins limit functional repair following damage to the adult cen- tral nervous system （CNS）. Nogo proteins, myelin-as- sociated glycoprotein （MAG）, oligodendrocyte myelin glycoprotein （OMgp） and B lymphocyte stimulator （BLyS）, are 4 inhibitors that commonly interact with the neuronal receptor, Nogo receptor-1 （NgR1）, lead- ing to inhibition of axonal growth. Here, we demon- strate that lateral olfactory tract usher substance （LOTUS） binds to NgR1 and blocks the binding of all four ligands to NgR1, resulting in the suppression of axonal growth inhibition induced by these NgR1 li- gands. LOTUS allows neurons to overcome NgRl-me- diated axonal growth inhibition, raising the possibility that LOTUS may be useful in future therapeutic ap- proaches as an endogenous potent inhibitor of NgR1 for promoting neuronal regeneration.
基金supported by the National Natural Science Foundation of ChinaNo.81971826 (to AG)+5 种基金the China Postdoctoral Science FoundationNo.2020M681 689 (to YH)the Scientific Research Project of The Health Commission of Jiangsu ProvinceNo.ZDB2020003 (to AG)the Basic Scientific Research Projects of NantongNo.JC2020041 (to YH)
文摘Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.
文摘There is evidence that the expression of members of the fibroblast growth factor （FGF） protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined whether the expression of fibroblast growth factor-2 （FGF2） and fibroblast growth factor receptor-1 （FGFR1） protein is altered following chronic stress in an animal model. Rats were exposed to 35 days of chronic unpredictable mild stress, and then tested using open-field and sucrose consumption tests. Compared with the control group, rats in the chronic stress group exhibited obvious depressive-like behaviors, including anhedonia, anxiety and decreased mobility. The results of western blot analysis and immunohistochemical analysis revealed a downregulation of the expression of FGF2 and FGFR1 in the hippocampus of rats, particularly in the CA1, CA3 and dentate gyrus. This decreased expression is in accord with the results of post-mortem studies in humans with major depressive disorder. These findings suggest that FGF2 and FGFR1 proteins participate in the pathophysiology of depressive-like behavior, and may play an important role in the mechanism of chronic stress-induced depression.
基金Supported by Youth Project of National Natural Science Foundation of China(81501080)Funding Project for Introducing Overseas Students in Hebei Provincial Department of Human Resources and Social Security(C20190174)Construction of Chengde Biomedical Industry Research Institute(202205B086)。
文摘[Objectives]To investigate the spasticity of rat tail and the expression of dopamine receptor-1(DRD1)mRNA in the spinal cord after spinal cord injury(SCI)induced tail spasticity in rats.[Methods]Adult male Wistar rats were randomly divided into Sham group and SCI group.The second sacral spinal cord(S2)segment of SCI rats was completely transected.60 d after operation,the rat tail spasticity was scored,and then the spinal cord tissues below the level of S2 spinal cord transection were taken.The expression of DRD1 mRNA in the sacrococcygeal spinal cord was detected by qPCR.In addition,3 normal rats were used for DAR/neuronal nuclei(NeuN)and DRD1/choline acetyltransferase(ChAT)immunofluorescence staining to study the distribution of DRD1 in spinal cord and the properties of DRD1 positive cells.[Results]60 d after operation in SCI group,the tail spasticity of rats developed fully,and the symptoms of spasticity were typical.qPCR results showed that the expression of DRD1 mRNA in SCI group was significantly lower than that in Sham group(P<0.05).DRD1 was widely distributed in the dorsal horn,intermediate zone and ventral horn at the sacrococcygeal end of the rat spinal cord.[Conclusions]The decrease of DRD1 mRNA expression after SCI may be related to the occurrence and development of spasticity.
