Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities.In this study,apigenin,luteolin,and baicalein were chosen to evaluate their anti-diabetic effect in hig...Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities.In this study,apigenin,luteolin,and baicalein were chosen to evaluate their anti-diabetic effect in high-glucose and dexamethasone induced insulin-resistant(IR)HepG2 cells.All flavonoids improves the glucose consumption and glycogen synthesis abilities in IR-HepG2 cells via activating glucose transporter protein 4(GLUT4)and phosphor-glycogen synthase kinase(GSK-3β).These fl avonoids signifi cantly inhibited the production of reactive oxygen species(ROS)and advanced glycation end-products(AGEs),which were closely related to the suppression of the phosphorylation form of NF-κB and P65.The expression levels of insulin receptor substrate-1(IRS-1),insulin receptor substrate-2(IRS-2)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)pathway in IR-HepG2 cells were all partially activated by the fl avonoids,with variable effects.Furthermore,the intracellular metabolic conditions of the fl avonoids were also evaluated.展开更多
AIM To study the role and the possible mechanism of β-arrestin 2 in lipopolysaccharide(LPS)-induced liver injury in vivo and in vitro.METHODS Male β-arrestin 2^(+/+) and β-arrestin 2^(-/-)C57 BL/6 J mice were used ...AIM To study the role and the possible mechanism of β-arrestin 2 in lipopolysaccharide(LPS)-induced liver injury in vivo and in vitro.METHODS Male β-arrestin 2^(+/+) and β-arrestin 2^(-/-)C57 BL/6 J mice were used for in vivo experiments, and the mouse macrophage cell line RAW264.7 was used for in vitro experiments. The animal model was established via intraperitoneal injection of LPS or physiological sodium chloride solution. Blood samples and liver tissues were collected to analyze liver injury and levels of pro-inflammatory cytokines. Cultured cell extracts were collected to analyze the production of pro-inflammatory cytokines and expression of key molecules involved in the TLR4/NF-κB signaling pathway.RESULTS Compared with wild-type mice, the β-arrestin 2 knockout mice displayed more severe LPS-induced liver injury and significantly higher levels of proinflammatory cytokines, including interleukin(IL)-1β, IL-6, tumor necrosis factor(TNF)-α, and IL-10. Compared with the control group, pro-inflammatory cytokines(including IL-1β, IL-6, TNF-α, and IL-10) produced by RAW264.7 cells in the β-arrestin 2 si RNA group were significantly increased at 6 h after treatment with LPS. Further, key molecules involved in the TLR4/NF-κB signaling pathway, including phosphoIκBα and phosho-p65, were upregulated.CONCLUSION β-arrestin 2 can protect liver tissue from LPS-induced injury via inhibition of TLR4/NF-κB signaling pathwaymediated inflammation.展开更多
BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occu...BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occurrence and development of diabetic atheroscerosis have not been fully elucidated.AIM To summarize the potential role of retinol binding protein 4(RBP4) in the pathogenesis of diabetic atheroscerosis,particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.METHODS Male Wistar rats were randomly divided into three groups,including a control group(NC group),diabetic rat group(DM group),and diabetic atherosclerotic rat group(DA group).The contents of total cholesterol(TC), high-density lipoprotein cholesterol(HDL-c), triglycerides(TG), low-density lipoprotein cholesterol(LDLc), fasting insulin(FINS),fasting plasma glucose,and hemoglobin A1 c(HbA1 c)were measured.Moreover,the adipose and serum levels of RBP4,along with the expression levels of JAK2, phosphorylated JAK2(p-JAK2), STAT3,phosphorylated STAT3(p-STAT3), B-cell lymphoma-2(Bcl-2), and Cyclin D1 in aortic tissues were also measured.Besides,homeostasis model assessment of insulin resistance(HOMA-IR) and atherogenic indexes(AI) were calculated.RESULTS Compared with the NC and DM groups,the levels LDL-c,TG,TC,FINS,HOMAIR,RBP4,and AI were upregulated,whereas that of HDL-c was downregulated in the DA group(P <0.05);the mRNA levels of JAK2,STAT3,Cyclin D1,and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group;P-JAK2,p-JAK2/JAK2 ratio,p-STAT3,p-STAT3/STAT3 ratio,Cyclin D1,and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group.In addition,as shown by Pearson analysis,serum RBP4 had a positive correlation with TG,TC,LDL-c,FINS,HbA1 C,p-JAK2,p-STAT3,Bcl-2,Cyclin D1,AI,and HOMA-IR but a negative correlation with HDL-c.In addition,multivariable logistic regression analysis showed that serum RBP4,p-JAK2,p-STAT3,and LDL-c were predictors of the presence of diabetic atherosclerosis.CONCLUSION RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.展开更多
Ramulus Cinnamomi （RC）, a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide （LPS）-induced neur...Ramulus Cinnamomi （RC）, a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide （LPS）-induced neuroinflammation in BV2 microglial cells and the underlying mechanisms involved. BV2 cells were incubated with normal medium （control group）, LPS, LPS plus 30 pg/mL RC extract, or LPS plus 100 pg/mL RC extract. The BV2 cell morphology was observed under an optical microscope and cell viability was detected by MTT assay. Nitric oxide level in BV2 cells was detected using Griess regents, and the levels of interleukin-6, interleukin-1 β, and tumor necrosis factor u in BV2 cells were determined by ELISA. The expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 proteins were detected by western blot assay. Compared with the LPS group, both 30 and 100 μg/mL RC extract had no significant effect on the viability of BV2 cells. The levels of nitric oxide, interleukin-6, interleukin-1β and tumor necrosis factor ct in BV2 cells were all significantly increased after LPS induction, and the levels were significantly reversed after treatment with 30 and 100 μg/mL RC extract. Furthermore, RC extract significantly inhibited the protein expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 in LPS-induced BV2 cells. Our findings suggest that RC extract alleviates neuroinflammation by downregulating the TLR4/MyD88 signaling pathway.展开更多
NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with n...NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with neurological disorders such as Parkinson's disease.Recently,NR4A2 has been found to play a critical role in some inflammatory diseases and cancer.NR4A2 can be efficiently trans-activated by some proinflammatory cytokines,such as tumor necrosis factor-α,interleukin-1β,and vascular endothelial growth factor(VEGF).The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells.NR4A2 can trans-activate Foxp3,a hallmark specifically expressed in regulatory T(Treg) cells,and plays a critical role in the differentiation,maintenance,and function of Treg cells.NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions.High density of Foxp3 + Treg cells is significantly associated with gastrointestinal inflammation,tumor immune escape,and disease progression.NR4A2 is produced at high levels in CD133 + colorectal carcinoma(CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E 2 in a cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)-dependent manner in CRC cells.The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer.NR4A2 trans-activates osteopontin,a direct target of the Wnt/β-catenin pathway associated with CRC invasion,metastasis,and poor prognosis.Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation,migration and in vivo angiogenesis.Taken together,NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer,especially CRC,and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.展开更多
Due to its difficulty in early diagnosis and lack of sensitivity to chemotherapy and radiotherapy,renal cell carcinoma(RCC)remains to be a frequent cause of cancer-related death.Here,we probed into new targets for its ...Due to its difficulty in early diagnosis and lack of sensitivity to chemotherapy and radiotherapy,renal cell carcinoma(RCC)remains to be a frequent cause of cancer-related death.Here,we probed into new targets for its early diagnosis and treatment for RCC.microRNA(miRNA)data of M2-EVs and RCC were searched on the Gene Expression Omnibus database,followed by the prediction of the potential downstream target.Expression of target genes was measured via RT-qPCR and Western blot,respectively.M2 macrophage was obtained viaflow cytometry with M2-EVs extracted.The binding ability of miR-342-3p to NEDD4L and to CEP55 ubiquitination was studied with their roles in the physical abilities of RCC cells assayed.Subcutaneous tumor-bearing mouse models and lung metastasis models were prepared to observe in vivo role of target genes.M2-EVs induced RCC growth and metastasis.miR-342-3p showed high expression in both M2-EVs and RCC cells.M2-EVs carrying miR-342-3p promoted RCC cell abilities to proliferate,invade and migrate.In RCC cells,M2-EV-derived miR-342-3p could specifically bind to NEDD4L and consequently elevate CEP55 protein expression via suppressing NEDD4L,thereby exerting tumor-promoting effects.CEP55 could be degraded by ubiquitination under the function of NEDD4L,and miR-342-3p delivered by M2-EVs facilitated the RCC occurrence and development by activating the PI3K/AKT/mTOR signaling pathway.In conclusion,M2-EVs promote RCC growth and metastasis by delivering miR-342-3p to suppress NEDD4L and subsequently inhibit CEP55 ubiquitination and degradation via activation of the PI3K/AKT/mTOR signaling pathway,strongly driving the proliferative,migratory and invasive of RCC cells.展开更多
Overexpression of receptor-interacting protein 140（RIP140） promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2（ERK1/2） signaling.However,involvement of RIP140 in human neural dif...Overexpression of receptor-interacting protein 140（RIP140） promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2（ERK1/2） signaling.However,involvement of RIP140 in human neural differentiation remains unclear.We found both RIP140 and ERK1/2 expression increased during neural differentiation of H1 human embryonic stem cells.Moreover,RIP140 negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation,and positively correlated with the neural stem cell marker Nestin during later stages.Thus,ERK1/2 signaling may provide the molecular mechanism by which RIP140 takes part in neural differentiation to eventually affect the number of neurons produced.展开更多
Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4...Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.展开更多
基金supported by National Natural Science Foundation of China(32072212)Multi-Year Research Grant of University of Macao(MYRG2018-00169-ICMS)+5 种基金Science and Technology Development Fund of Macao(FDCT)(0098/2020/A)MICINN supporting the Ramón y Cajal grant for M.A.Prieto(RYC-201722891)Jianbo Xiao(RYC2020-030365-I)Xunta de Galicia supporting the Axudas Conecta Peme,the IN852A 2018/58 Neuro Food Project,the program EXCELENCIA-ED431F 2020/12the pre-doctoral grants of P.García-Oliveira(ED481A-2019/295)to Ibero-American Program on Science and Technology(CYTED-AQUA-CIBUS,P317RT0003).
文摘Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities.In this study,apigenin,luteolin,and baicalein were chosen to evaluate their anti-diabetic effect in high-glucose and dexamethasone induced insulin-resistant(IR)HepG2 cells.All flavonoids improves the glucose consumption and glycogen synthesis abilities in IR-HepG2 cells via activating glucose transporter protein 4(GLUT4)and phosphor-glycogen synthase kinase(GSK-3β).These fl avonoids signifi cantly inhibited the production of reactive oxygen species(ROS)and advanced glycation end-products(AGEs),which were closely related to the suppression of the phosphorylation form of NF-κB and P65.The expression levels of insulin receptor substrate-1(IRS-1),insulin receptor substrate-2(IRS-2)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)pathway in IR-HepG2 cells were all partially activated by the fl avonoids,with variable effects.Furthermore,the intracellular metabolic conditions of the fl avonoids were also evaluated.
基金Supported by the National Natural Science Foundation of China,No.81470848the Breeding Foundation for Young Pioneers’Research of Sun Yat-sen University,No.14ykpy27
文摘AIM To study the role and the possible mechanism of β-arrestin 2 in lipopolysaccharide(LPS)-induced liver injury in vivo and in vitro.METHODS Male β-arrestin 2^(+/+) and β-arrestin 2^(-/-)C57 BL/6 J mice were used for in vivo experiments, and the mouse macrophage cell line RAW264.7 was used for in vitro experiments. The animal model was established via intraperitoneal injection of LPS or physiological sodium chloride solution. Blood samples and liver tissues were collected to analyze liver injury and levels of pro-inflammatory cytokines. Cultured cell extracts were collected to analyze the production of pro-inflammatory cytokines and expression of key molecules involved in the TLR4/NF-κB signaling pathway.RESULTS Compared with wild-type mice, the β-arrestin 2 knockout mice displayed more severe LPS-induced liver injury and significantly higher levels of proinflammatory cytokines, including interleukin(IL)-1β, IL-6, tumor necrosis factor(TNF)-α, and IL-10. Compared with the control group, pro-inflammatory cytokines(including IL-1β, IL-6, TNF-α, and IL-10) produced by RAW264.7 cells in the β-arrestin 2 si RNA group were significantly increased at 6 h after treatment with LPS. Further, key molecules involved in the TLR4/NF-κB signaling pathway, including phosphoIκBα and phosho-p65, were upregulated.CONCLUSION β-arrestin 2 can protect liver tissue from LPS-induced injury via inhibition of TLR4/NF-κB signaling pathwaymediated inflammation.
基金Supported by National Natural Science Foundation of China,No.81800713 and No.81971264The Project of Natural Science Foundation of Anhui Province,No.1808085QH292Fundamental Research Funds for the Central Universities,No.WK9110000041。
文摘BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occurrence and development of diabetic atheroscerosis have not been fully elucidated.AIM To summarize the potential role of retinol binding protein 4(RBP4) in the pathogenesis of diabetic atheroscerosis,particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.METHODS Male Wistar rats were randomly divided into three groups,including a control group(NC group),diabetic rat group(DM group),and diabetic atherosclerotic rat group(DA group).The contents of total cholesterol(TC), high-density lipoprotein cholesterol(HDL-c), triglycerides(TG), low-density lipoprotein cholesterol(LDLc), fasting insulin(FINS),fasting plasma glucose,and hemoglobin A1 c(HbA1 c)were measured.Moreover,the adipose and serum levels of RBP4,along with the expression levels of JAK2, phosphorylated JAK2(p-JAK2), STAT3,phosphorylated STAT3(p-STAT3), B-cell lymphoma-2(Bcl-2), and Cyclin D1 in aortic tissues were also measured.Besides,homeostasis model assessment of insulin resistance(HOMA-IR) and atherogenic indexes(AI) were calculated.RESULTS Compared with the NC and DM groups,the levels LDL-c,TG,TC,FINS,HOMAIR,RBP4,and AI were upregulated,whereas that of HDL-c was downregulated in the DA group(P <0.05);the mRNA levels of JAK2,STAT3,Cyclin D1,and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group;P-JAK2,p-JAK2/JAK2 ratio,p-STAT3,p-STAT3/STAT3 ratio,Cyclin D1,and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group.In addition,as shown by Pearson analysis,serum RBP4 had a positive correlation with TG,TC,LDL-c,FINS,HbA1 C,p-JAK2,p-STAT3,Bcl-2,Cyclin D1,AI,and HOMA-IR but a negative correlation with HDL-c.In addition,multivariable logistic regression analysis showed that serum RBP4,p-JAK2,p-STAT3,and LDL-c were predictors of the presence of diabetic atherosclerosis.CONCLUSION RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.
基金supported by a grant from the National Natural Science Foundation of China,No.81473383a grant from the Medical and Health Innovation Project of Chinese Academy of Medical Sciences,No.2016-I2M-3-007a grant from Key Project of New-Drugs Creation of Science and Technology of China,No.2012ZX09103101-078 and 2017ZX09101003-003-019
文摘Ramulus Cinnamomi （RC）, a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide （LPS）-induced neuroinflammation in BV2 microglial cells and the underlying mechanisms involved. BV2 cells were incubated with normal medium （control group）, LPS, LPS plus 30 pg/mL RC extract, or LPS plus 100 pg/mL RC extract. The BV2 cell morphology was observed under an optical microscope and cell viability was detected by MTT assay. Nitric oxide level in BV2 cells was detected using Griess regents, and the levels of interleukin-6, interleukin-1 β, and tumor necrosis factor u in BV2 cells were determined by ELISA. The expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 proteins were detected by western blot assay. Compared with the LPS group, both 30 and 100 μg/mL RC extract had no significant effect on the viability of BV2 cells. The levels of nitric oxide, interleukin-6, interleukin-1β and tumor necrosis factor ct in BV2 cells were all significantly increased after LPS induction, and the levels were significantly reversed after treatment with 30 and 100 μg/mL RC extract. Furthermore, RC extract significantly inhibited the protein expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 in LPS-induced BV2 cells. Our findings suggest that RC extract alleviates neuroinflammation by downregulating the TLR4/MyD88 signaling pathway.
基金Supported by National Natural Science Foundation of China, No.81025015,30921006,91129301
文摘NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with neurological disorders such as Parkinson's disease.Recently,NR4A2 has been found to play a critical role in some inflammatory diseases and cancer.NR4A2 can be efficiently trans-activated by some proinflammatory cytokines,such as tumor necrosis factor-α,interleukin-1β,and vascular endothelial growth factor(VEGF).The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells.NR4A2 can trans-activate Foxp3,a hallmark specifically expressed in regulatory T(Treg) cells,and plays a critical role in the differentiation,maintenance,and function of Treg cells.NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions.High density of Foxp3 + Treg cells is significantly associated with gastrointestinal inflammation,tumor immune escape,and disease progression.NR4A2 is produced at high levels in CD133 + colorectal carcinoma(CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E 2 in a cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)-dependent manner in CRC cells.The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer.NR4A2 trans-activates osteopontin,a direct target of the Wnt/β-catenin pathway associated with CRC invasion,metastasis,and poor prognosis.Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation,migration and in vivo angiogenesis.Taken together,NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer,especially CRC,and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.
基金supported by the Science and Technology Department of Sichuan Province(2015SZ0117,2019YJ0701,and 2021YJ0239).
文摘Due to its difficulty in early diagnosis and lack of sensitivity to chemotherapy and radiotherapy,renal cell carcinoma(RCC)remains to be a frequent cause of cancer-related death.Here,we probed into new targets for its early diagnosis and treatment for RCC.microRNA(miRNA)data of M2-EVs and RCC were searched on the Gene Expression Omnibus database,followed by the prediction of the potential downstream target.Expression of target genes was measured via RT-qPCR and Western blot,respectively.M2 macrophage was obtained viaflow cytometry with M2-EVs extracted.The binding ability of miR-342-3p to NEDD4L and to CEP55 ubiquitination was studied with their roles in the physical abilities of RCC cells assayed.Subcutaneous tumor-bearing mouse models and lung metastasis models were prepared to observe in vivo role of target genes.M2-EVs induced RCC growth and metastasis.miR-342-3p showed high expression in both M2-EVs and RCC cells.M2-EVs carrying miR-342-3p promoted RCC cell abilities to proliferate,invade and migrate.In RCC cells,M2-EV-derived miR-342-3p could specifically bind to NEDD4L and consequently elevate CEP55 protein expression via suppressing NEDD4L,thereby exerting tumor-promoting effects.CEP55 could be degraded by ubiquitination under the function of NEDD4L,and miR-342-3p delivered by M2-EVs facilitated the RCC occurrence and development by activating the PI3K/AKT/mTOR signaling pathway.In conclusion,M2-EVs promote RCC growth and metastasis by delivering miR-342-3p to suppress NEDD4L and subsequently inhibit CEP55 ubiquitination and degradation via activation of the PI3K/AKT/mTOR signaling pathway,strongly driving the proliferative,migratory and invasive of RCC cells.
基金supported by the National Natural Science Foundation of China,No.31340024
文摘Overexpression of receptor-interacting protein 140（RIP140） promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2（ERK1/2） signaling.However,involvement of RIP140 in human neural differentiation remains unclear.We found both RIP140 and ERK1/2 expression increased during neural differentiation of H1 human embryonic stem cells.Moreover,RIP140 negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation,and positively correlated with the neural stem cell marker Nestin during later stages.Thus,ERK1/2 signaling may provide the molecular mechanism by which RIP140 takes part in neural differentiation to eventually affect the number of neurons produced.
基金supported by the National Natural Science Foundation of China(No.81603100)the Drug Innovation Major Project(2018ZX09711001-003-005,2018ZX09711001-012,China)+1 种基金CAMS Innovation Fund for Medical Sciences(2017-I2M1-010,China)Peking Union Medical College Graduate Innovation Fund Project(2017-1007-11,China)
文摘Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.
