T3-1 Areca catechu L.ameliorates chronic unpredictable mil stress-induced depression behavior in rats by the promotion of the BDNF signaling pathway YAO Caihong1,ZHANG Yiwen1,SUN Xinran1,PEI Haiyue 1,WEI Shanshan1,WAN...T3-1 Areca catechu L.ameliorates chronic unpredictable mil stress-induced depression behavior in rats by the promotion of the BDNF signaling pathway YAO Caihong1,ZHANG Yiwen1,SUN Xinran1,PEI Haiyue 1,WEI Shanshan1,WANG Mengdi1,CHANG Qi1,LIU Xinmin2,JIANG Ning1(1.Research Center for Pharmacology and Toxicology,In⁃stitute of Medicinal Plant Development,Chinese Academy of Medical Sciences and Peking Union Medical Cllege,Beijing 100193,China;2.Institute of Drug Discovery Tech⁃nology,Ningbo University,Ningbo 315211,China)Abstract:OBJECTIVE To investigated the anti-de⁃pressant effects of the fruit Areca catechu L.(ACL)and elucidated its potential underlying mechanism using a rat model of chronic unpredictable mild stress(CUMS).METHODS CUMS was induced in rats to establish a depression animal model for 28 d.According to the baseline sucrose preference,the male rats were divided into six different groups.They were treated with parox⁃etine hydrochloride,ACL,and water once a day until the behavioral tests were performed.The levels of corticoste⁃rone(CORT),malondialdehyde(MDA),catalase(CAT),and total superoxide dismutase(T-SOD)in serum were de⁃tected using a commercial kit,and the concentrations of 5-hydroxytryptamine(5-HT)and dopamine(DA)mono⁃amine neurotransmitters in the brain tissues were detect⁃ed by liquid chromatography-tandem mass spectrometry.Doublecortin(DCX)expression in the hippocampal den⁃tate gyrus(DG)was determined by immunofluorescence,and the relative abundance of brain-derived neurotrophic factor(BDNF),TrkB,PI3K,p-Akt/Akt,PSD-95,and p-GSK-3β/GSK-3βof brain tissues were assayed by West⁃ern blotting.RESULTS ACL markedly increased sucrose preference,decreased the immobility time,and short⁃ened the feeding latency of CUMS-induced rats.CUMS induction resulted in marked changes in the contents of the monoamine neurotransmitters(5-HT and DA)in the hippocampus and cortex of brain tissues and the levels of CORT,MDA,CAT,and T-SOD in serum,whereas ACL administration alleviated these considerable changes.ACL promoted DCX expression in DG and increased the protein levels of BDNF,TrkB,PI3K,p-Akt/Akt,PSD-95,and p-GSK-3β/GSK-3βin the brains of CUMS-induced rats.CONCLUSION Our results indicated that ACL may improve depression-like behaviors in CUMS-induced rats by decreasing the hyperfunction and oxidative stress of the hypothalamic-pituitary-adrenal axis,stimulating hippo⁃campal neurogenesis,and activating the BDNF signaling pathway.展开更多
OBJECTIVE Progressive isch⁃emic stroke is characterized by aggravation of neurological dysfunction and poor prognosis.Neuroinflammation is involved in the pathological process of cerebral ischemia.Inflammasomes-activa...OBJECTIVE Progressive isch⁃emic stroke is characterized by aggravation of neurological dysfunction and poor prognosis.Neuroinflammation is involved in the pathological process of cerebral ischemia.Inflammasomes-activated caspase-1 has thus been considered a promising target for stroke therapy.However,it remains not fully understood how caspase-1 ag⁃gravates progressive functional impairment.We previously identified a novel caspase-1 inhibitor CZL-80,the present study is to explore whether CZL-80 protects against progressive ischemic stroke.METHODS Male C57/BL6 mice and cas⁃pase-1-/-mice were subjected to photothrombotic(PT)-induced cerebral ischemia.CZL-80 was in⁃traperitoneally injected daily during 1-7 d,1-4 d,4-7 d after PT.The grid-walking task and the cyl⁃inder task were used to determine the motor function.RESULTS Mice developed primary and the secondary neurological dysfunction at 1 d and 4-7 d after PT onset.The activation of cas⁃pase-1 peaked at 7 d after ischemic stroke and caspase-1 was mainly derived from activated microglia.Treatment with CZL-80(30 mg·kg-1)during 1-7 d significantly improved motor func⁃tion.Administration of CZL-80 during 1-4 d could not ameliorate motor function loss while administration during 4-7 d after PT onset signifi⁃cantly reduced foot faults and forelimb symme⁃try.Remarkably,treatment with CZL-80 during 4-7 d showed no significant difference in efficacy compared with the its administration during 1-7 d,which indicated a key therapeutic window.More⁃over,the neuroprotective effect of CZL-80 during 4-7 d was available at least until 43 d after isch⁃emic stroke,indicating CZL-80 can improve the long-term neurological function after cerebral ischemia.Furthermore,administration of CZL-80(30 mg·kg-1)during 4-7 d after PT onset in cas⁃pase-1-/-mice failed to improve the motor func⁃tion,which suggested that the neuroprotective effect of CZL-80 was caspase-1-dependent.The results showed that CZL-80 did not inhibit the expression of GSDMD and failed to reduce neu⁃ronal loss after ischemia.These results indicated the effect of CZL-80 was not attributable to inhib⁃it pyroptosis.We further found that CZL-80 signif⁃icantly reduced the number of activated microglia in the peri-infarct brain cortex after ischemic stroke,which might be involved in its neuropro⁃tective effect.CONCLUSION CZL-80,a novel caspase-1 inhibitor,improved motor function after progressive ischemic stroke in mice.The effective therapeutic window of CZL-80 would be 4-7 d after ischemia,when the secondary neuro⁃logical dysfunction occurred.Therefore,the inter⁃vention by targeting caspase-1 in this window phase provides a novel strategy for the function⁃al recovery of stroke survivors.展开更多
Polygonati Rhizoma is the dry rhizome of Liliaceae plants Polygonatum kingianum coil ethemsl,Polygonatum sibiricum Redoute and Polygonatum cyrtonem Hua.It tastes sweet and has a flat nature.It belongs to the spleen,lu...Polygonati Rhizoma is the dry rhizome of Liliaceae plants Polygonatum kingianum coil ethemsl,Polygonatum sibiricum Redoute and Polygonatum cyrtonem Hua.It tastes sweet and has a flat nature.It belongs to the spleen,lung and kidney channels.Polygonati Rhizoma contains a variety of chemical components,including polysaccharides,alkaloids,steroidal saponins,lignans,phytosterols,and so on.Polygonati Rhizoma polysaccharide(PSP)is one of the main bioactive components of Polygonati Rhizoma.It is widely used.It has the effects of enhancing immunity,anti-inflammatory,anti-virus and regulating blood lipid.In recent years,the immunomodulatory function of PSP has been paid more and more attention by researchers.PSP can play an immunomodulatory role through a variety of mechanisms.(1)Effects of PSP on innate immunity.①Macrophages have a strong ability to phagocytize and clear foreign bodies.When polysaccharides bind to macrophage specific membrane receptors,the immune response will be officially activated.RAW264.7 cells can be activated by PSP MR and TLR4 mediated signal pathway to improve the pinocytosis and phagocytosis of RAW264.7 cells.②Natural killer cell(NK cell)is a very important immune cell in the body.It is a non-specific immune killer cell naturally existing in the body.It has the dual functions of immune regulation and cytotoxicity.It was found that the signal pathway mediated by PSP CR3 and TRL2 may play a major role in the stimulation of NK cells.(2)Effects of PSP on adaptive immune response.①Lymphocytes can be divided into two forms:T cells and B cells due to different differentiation and maturation sites.T lymphocytes are the general name of thymus dependent lymphocytes.B lymphocytes differentiate and mature from animal bone marrow cells and exert their humoral immune function by secreting different antibodies.It was found that PSP could activate T/B lymphocytes and increase the ratio of CD4+/CD8+in lymph cells to promote the regulation of immune system.②Thymus and spleen index refers to the level of body immunity through the development of immune organs and the functional status of immune cells.The higher the index of thymus and spleen,the higher the immune activity.A large number of studies have found that PSP can improve immune activity by promoting the proliferation of spleen lymphocytes and regulating organ index,so as to increase the weight and index of thymus and spleen induced by CY.③Antibody is a glycoprotein secreted by B cells after antigen stimulation and a series of proliferation and differentiation into plasma cells.Antibody production level is one of the main indicators of nonspecific immune function.PSP can not only improve the serum antibody level of mice by regulating the phagocytosis of mouse macrophages and the level of serum hemolysin,but also enhance the concentration of IL-2 secreted by spleen lymphocytes in vitro to increase the level of antibody response,and then improve the humoral immune function of the body.(3)Effect of PSP on cytokines.①A large number of experiments have proved that PSP has a significant effect on promoting the production of interleukin(IL).PSP can combine with specific receptors on the surface of immune cells to activate various intracellular signal transduction pathways,enhance the secretion of cytokines such as IL-2,IL-4,IL-6 and IL^(-1)0 by spleen lymphocytes in vitro,make them directly kill target cells and regulate the immune function of the body at the molecular level.②Interferon(IFN)is a special protein or glycoprotein produced by human or animal cells in response to various stimuli.It plays an important role in anti-virus,immune regulation and cell proliferation control.It was found that PSP could increase IFN-γsecreted by T cells and NK cells,activate macrophages to regulate immune function.③Tumor necrosis factor(TNF)is mainly produced by activated macrophages,NK cells and activated T cells.It is a cytokine with important biological activity in antitumor immune response.④Tumor necrosis factor(TNF)is mainly produced by activated macrophages,NK cells and activated T cells.It is a cytokine with important biological activity in antitumor immune response.PSP can promote the proliferation and phagocytic activity of macrophage RAW264.7 to reduce its apoptosis rate.By increasing the secretion of TNF-α,PSP can promote the dissociation between NF-κВprotein and IκВp65 protein after phosphorylation,so as to start the expression and transcription of related immune genes.In conclusion,PSP can improve immunity and has a good application prospect in the development of immunomodulatory drugs.展开更多
文摘T3-1 Areca catechu L.ameliorates chronic unpredictable mil stress-induced depression behavior in rats by the promotion of the BDNF signaling pathway YAO Caihong1,ZHANG Yiwen1,SUN Xinran1,PEI Haiyue 1,WEI Shanshan1,WANG Mengdi1,CHANG Qi1,LIU Xinmin2,JIANG Ning1(1.Research Center for Pharmacology and Toxicology,In⁃stitute of Medicinal Plant Development,Chinese Academy of Medical Sciences and Peking Union Medical Cllege,Beijing 100193,China;2.Institute of Drug Discovery Tech⁃nology,Ningbo University,Ningbo 315211,China)Abstract:OBJECTIVE To investigated the anti-de⁃pressant effects of the fruit Areca catechu L.(ACL)and elucidated its potential underlying mechanism using a rat model of chronic unpredictable mild stress(CUMS).METHODS CUMS was induced in rats to establish a depression animal model for 28 d.According to the baseline sucrose preference,the male rats were divided into six different groups.They were treated with parox⁃etine hydrochloride,ACL,and water once a day until the behavioral tests were performed.The levels of corticoste⁃rone(CORT),malondialdehyde(MDA),catalase(CAT),and total superoxide dismutase(T-SOD)in serum were de⁃tected using a commercial kit,and the concentrations of 5-hydroxytryptamine(5-HT)and dopamine(DA)mono⁃amine neurotransmitters in the brain tissues were detect⁃ed by liquid chromatography-tandem mass spectrometry.Doublecortin(DCX)expression in the hippocampal den⁃tate gyrus(DG)was determined by immunofluorescence,and the relative abundance of brain-derived neurotrophic factor(BDNF),TrkB,PI3K,p-Akt/Akt,PSD-95,and p-GSK-3β/GSK-3βof brain tissues were assayed by West⁃ern blotting.RESULTS ACL markedly increased sucrose preference,decreased the immobility time,and short⁃ened the feeding latency of CUMS-induced rats.CUMS induction resulted in marked changes in the contents of the monoamine neurotransmitters(5-HT and DA)in the hippocampus and cortex of brain tissues and the levels of CORT,MDA,CAT,and T-SOD in serum,whereas ACL administration alleviated these considerable changes.ACL promoted DCX expression in DG and increased the protein levels of BDNF,TrkB,PI3K,p-Akt/Akt,PSD-95,and p-GSK-3β/GSK-3βin the brains of CUMS-induced rats.CONCLUSION Our results indicated that ACL may improve depression-like behaviors in CUMS-induced rats by decreasing the hyperfunction and oxidative stress of the hypothalamic-pituitary-adrenal axis,stimulating hippo⁃campal neurogenesis,and activating the BDNF signaling pathway.
文摘OBJECTIVE Progressive isch⁃emic stroke is characterized by aggravation of neurological dysfunction and poor prognosis.Neuroinflammation is involved in the pathological process of cerebral ischemia.Inflammasomes-activated caspase-1 has thus been considered a promising target for stroke therapy.However,it remains not fully understood how caspase-1 ag⁃gravates progressive functional impairment.We previously identified a novel caspase-1 inhibitor CZL-80,the present study is to explore whether CZL-80 protects against progressive ischemic stroke.METHODS Male C57/BL6 mice and cas⁃pase-1-/-mice were subjected to photothrombotic(PT)-induced cerebral ischemia.CZL-80 was in⁃traperitoneally injected daily during 1-7 d,1-4 d,4-7 d after PT.The grid-walking task and the cyl⁃inder task were used to determine the motor function.RESULTS Mice developed primary and the secondary neurological dysfunction at 1 d and 4-7 d after PT onset.The activation of cas⁃pase-1 peaked at 7 d after ischemic stroke and caspase-1 was mainly derived from activated microglia.Treatment with CZL-80(30 mg·kg-1)during 1-7 d significantly improved motor func⁃tion.Administration of CZL-80 during 1-4 d could not ameliorate motor function loss while administration during 4-7 d after PT onset signifi⁃cantly reduced foot faults and forelimb symme⁃try.Remarkably,treatment with CZL-80 during 4-7 d showed no significant difference in efficacy compared with the its administration during 1-7 d,which indicated a key therapeutic window.More⁃over,the neuroprotective effect of CZL-80 during 4-7 d was available at least until 43 d after isch⁃emic stroke,indicating CZL-80 can improve the long-term neurological function after cerebral ischemia.Furthermore,administration of CZL-80(30 mg·kg-1)during 4-7 d after PT onset in cas⁃pase-1-/-mice failed to improve the motor func⁃tion,which suggested that the neuroprotective effect of CZL-80 was caspase-1-dependent.The results showed that CZL-80 did not inhibit the expression of GSDMD and failed to reduce neu⁃ronal loss after ischemia.These results indicated the effect of CZL-80 was not attributable to inhib⁃it pyroptosis.We further found that CZL-80 signif⁃icantly reduced the number of activated microglia in the peri-infarct brain cortex after ischemic stroke,which might be involved in its neuropro⁃tective effect.CONCLUSION CZL-80,a novel caspase-1 inhibitor,improved motor function after progressive ischemic stroke in mice.The effective therapeutic window of CZL-80 would be 4-7 d after ischemia,when the secondary neuro⁃logical dysfunction occurred.Therefore,the inter⁃vention by targeting caspase-1 in this window phase provides a novel strategy for the function⁃al recovery of stroke survivors.
文摘Polygonati Rhizoma is the dry rhizome of Liliaceae plants Polygonatum kingianum coil ethemsl,Polygonatum sibiricum Redoute and Polygonatum cyrtonem Hua.It tastes sweet and has a flat nature.It belongs to the spleen,lung and kidney channels.Polygonati Rhizoma contains a variety of chemical components,including polysaccharides,alkaloids,steroidal saponins,lignans,phytosterols,and so on.Polygonati Rhizoma polysaccharide(PSP)is one of the main bioactive components of Polygonati Rhizoma.It is widely used.It has the effects of enhancing immunity,anti-inflammatory,anti-virus and regulating blood lipid.In recent years,the immunomodulatory function of PSP has been paid more and more attention by researchers.PSP can play an immunomodulatory role through a variety of mechanisms.(1)Effects of PSP on innate immunity.①Macrophages have a strong ability to phagocytize and clear foreign bodies.When polysaccharides bind to macrophage specific membrane receptors,the immune response will be officially activated.RAW264.7 cells can be activated by PSP MR and TLR4 mediated signal pathway to improve the pinocytosis and phagocytosis of RAW264.7 cells.②Natural killer cell(NK cell)is a very important immune cell in the body.It is a non-specific immune killer cell naturally existing in the body.It has the dual functions of immune regulation and cytotoxicity.It was found that the signal pathway mediated by PSP CR3 and TRL2 may play a major role in the stimulation of NK cells.(2)Effects of PSP on adaptive immune response.①Lymphocytes can be divided into two forms:T cells and B cells due to different differentiation and maturation sites.T lymphocytes are the general name of thymus dependent lymphocytes.B lymphocytes differentiate and mature from animal bone marrow cells and exert their humoral immune function by secreting different antibodies.It was found that PSP could activate T/B lymphocytes and increase the ratio of CD4+/CD8+in lymph cells to promote the regulation of immune system.②Thymus and spleen index refers to the level of body immunity through the development of immune organs and the functional status of immune cells.The higher the index of thymus and spleen,the higher the immune activity.A large number of studies have found that PSP can improve immune activity by promoting the proliferation of spleen lymphocytes and regulating organ index,so as to increase the weight and index of thymus and spleen induced by CY.③Antibody is a glycoprotein secreted by B cells after antigen stimulation and a series of proliferation and differentiation into plasma cells.Antibody production level is one of the main indicators of nonspecific immune function.PSP can not only improve the serum antibody level of mice by regulating the phagocytosis of mouse macrophages and the level of serum hemolysin,but also enhance the concentration of IL-2 secreted by spleen lymphocytes in vitro to increase the level of antibody response,and then improve the humoral immune function of the body.(3)Effect of PSP on cytokines.①A large number of experiments have proved that PSP has a significant effect on promoting the production of interleukin(IL).PSP can combine with specific receptors on the surface of immune cells to activate various intracellular signal transduction pathways,enhance the secretion of cytokines such as IL-2,IL-4,IL-6 and IL^(-1)0 by spleen lymphocytes in vitro,make them directly kill target cells and regulate the immune function of the body at the molecular level.②Interferon(IFN)is a special protein or glycoprotein produced by human or animal cells in response to various stimuli.It plays an important role in anti-virus,immune regulation and cell proliferation control.It was found that PSP could increase IFN-γsecreted by T cells and NK cells,activate macrophages to regulate immune function.③Tumor necrosis factor(TNF)is mainly produced by activated macrophages,NK cells and activated T cells.It is a cytokine with important biological activity in antitumor immune response.④Tumor necrosis factor(TNF)is mainly produced by activated macrophages,NK cells and activated T cells.It is a cytokine with important biological activity in antitumor immune response.PSP can promote the proliferation and phagocytic activity of macrophage RAW264.7 to reduce its apoptosis rate.By increasing the secretion of TNF-α,PSP can promote the dissociation between NF-κВprotein and IκВp65 protein after phosphorylation,so as to start the expression and transcription of related immune genes.In conclusion,PSP can improve immunity and has a good application prospect in the development of immunomodulatory drugs.
