Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regul...Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.展开更多
由cAMP激活的交换蛋白分子(exchange protein activated by c AMP,Epac)是近年来新发现的鸟嘌呤核苷酸交换因子,参与一系列cAMP介导的信号通路。纤维化疾病是临床上常见的一类疾病,是在正常生理学(如衰老)或不同致病因素持续刺激下,使...由cAMP激活的交换蛋白分子(exchange protein activated by c AMP,Epac)是近年来新发现的鸟嘌呤核苷酸交换因子,参与一系列cAMP介导的信号通路。纤维化疾病是临床上常见的一类疾病,是在正常生理学(如衰老)或不同致病因素持续刺激下,使得细胞外基质过度沉积的结果。有研究表明,Epac在纤维化疾病中发挥重要作用,因此,该文对Epac在纤维化疾病中的作用进行综述,以促进对于Epac相关机制及药物的研究与开发。展开更多
Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemi...Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.展开更多
Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hip...Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.展开更多
Objective:To investigate the effect of down-regulation of matrix metalloproteinase-2(MMP-2)by down-regulating the cyclic adenosine monophosphate(cAMP)signaling pathway on the migration and invasion of uterine fibroids...Objective:To investigate the effect of down-regulation of matrix metalloproteinase-2(MMP-2)by down-regulating the cyclic adenosine monophosphate(cAMP)signaling pathway on the migration and invasion of uterine fibroids cells.Methods:A total of 65 female SD rats were randomly divided into five groups after being adaptively fed for 7 d.Except for the blank group,the remaining four groups of rats were injected with 0.05 mg/(100 g·d)estradiol benzoate and 0.5 mg/(100g·d)progesterone into the muscle to establish a uterine fibroids rat model.After successful modeling,the blank group and model group were given 200 mg/(kg·d)physiological saline by gavage,the low-dose group was given 100 mg/(kg·d)mifepristone by gavage,the medium-dose group was given 200 mg/(kg·d)mifepristone by gavage,and the high-dose group was given 300 mg/(kg·d)mifepristone by gavage.After continuous gavage treatment for 21 d,serum and uterine tissues were collected from rats to observe and compare the expression levels of MMP-2 mRNA,TIMP-2 mRNA,estradiol(E2),cAMP signaling pathway related proteins,and the migration and invasive ability of uterine fibroids cells in the five groups of rats.Results:The expression levels of MMP-2 mRNA and E2in the high-dose group were lower than those in the low-dose group and the medium-dose group,and the expression level of TIMP-2 mRNA was higher than that in the low-dose group and the medium-dose group(P<0.05).The number of cell migration in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The number of cell invasion in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The mRNA expression levels of cAMP,PDE and PK in the high-dose group were higher than those in the low-dose group,and the mRNA expression levels of AC in the high-dose group were lower than those in the low-dose group(P<0.05).The mRNA expression levels of cAMP and PDE in the high-dose group were higher than those in the mediumdose group(P<0.05).Conclusion:Letrozole may down-regulate the expression level of MMP-2 through the cAMP signaling pathway to inhibit the migration and invasion of uterine fibroids cells.With increasing doses of letrozole,its inhibitory effect on the migration and invasion of uterine fibroids cells will be enhanced.However,the optimal dosage of letrozole for inhibiting the migration and invasion of uterine fibroids cells is yet to be determined.展开更多
慢性咳嗽属于临床疑难杂症,气道炎症、咳嗽神经通路敏感性增强以及炎性疼痛是其主要病理学基础。环磷酸腺苷(cyclic adenosine monophosphate,cAMP)/cAMP直接激活的交换蛋白分子(exchange protein activated by cAMP,Epac)信号通路广泛...慢性咳嗽属于临床疑难杂症,气道炎症、咳嗽神经通路敏感性增强以及炎性疼痛是其主要病理学基础。环磷酸腺苷(cyclic adenosine monophosphate,cAMP)/cAMP直接激活的交换蛋白分子(exchange protein activated by cAMP,Epac)信号通路广泛参与气道炎症(特别是气道神经源性炎症)、咳嗽神经兴奋性以及炎性疼痛等生理病理过程。本文就近年来cAMP/Epac信号通路调控气道炎症、咳嗽通路增敏、炎性疼痛而影响慢性咳嗽以及中药干预作用研究进行综述,为研究慢性咳嗽以及镇咳药的开发应用提供理论基础。展开更多
Vesicle-based traffi cking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal,submembrane co...Vesicle-based traffi cking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal,submembrane compartment,followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane,the transporters usually undergo recycling between the plasma membrane and the endosomal compartment,which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence,it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters,which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis,and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation,with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition,the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally,several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP,tauroursodeoxycholate) are described.展开更多
基金supported by the National Natural Science Foundation of China(31972217 and 32072369)the Central Government Guides Local Science and Technology Development Projects,China(206Z6501G and 216Z6502G)the Research Project of Basic Scientific Research Business Fees in Provincial Universities of Hebei Province,China(KY2021043 and KY2021044)。
文摘Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.
文摘由cAMP激活的交换蛋白分子(exchange protein activated by c AMP,Epac)是近年来新发现的鸟嘌呤核苷酸交换因子,参与一系列cAMP介导的信号通路。纤维化疾病是临床上常见的一类疾病,是在正常生理学(如衰老)或不同致病因素持续刺激下,使得细胞外基质过度沉积的结果。有研究表明,Epac在纤维化疾病中发挥重要作用,因此,该文对Epac在纤维化疾病中的作用进行综述,以促进对于Epac相关机制及药物的研究与开发。
基金supported by Scottish Rugby Union funding to WH and DSthe NRB PhD scholarship from the International Spinal Rsesarch Trust to AGBa Hot-Start Scholarship from the University of aberdeen to DD。
文摘Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.
基金supported by the National Natural Science Foundation of China,No.91849104(to YW)。
文摘Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.
文摘Objective:To investigate the effect of down-regulation of matrix metalloproteinase-2(MMP-2)by down-regulating the cyclic adenosine monophosphate(cAMP)signaling pathway on the migration and invasion of uterine fibroids cells.Methods:A total of 65 female SD rats were randomly divided into five groups after being adaptively fed for 7 d.Except for the blank group,the remaining four groups of rats were injected with 0.05 mg/(100 g·d)estradiol benzoate and 0.5 mg/(100g·d)progesterone into the muscle to establish a uterine fibroids rat model.After successful modeling,the blank group and model group were given 200 mg/(kg·d)physiological saline by gavage,the low-dose group was given 100 mg/(kg·d)mifepristone by gavage,the medium-dose group was given 200 mg/(kg·d)mifepristone by gavage,and the high-dose group was given 300 mg/(kg·d)mifepristone by gavage.After continuous gavage treatment for 21 d,serum and uterine tissues were collected from rats to observe and compare the expression levels of MMP-2 mRNA,TIMP-2 mRNA,estradiol(E2),cAMP signaling pathway related proteins,and the migration and invasive ability of uterine fibroids cells in the five groups of rats.Results:The expression levels of MMP-2 mRNA and E2in the high-dose group were lower than those in the low-dose group and the medium-dose group,and the expression level of TIMP-2 mRNA was higher than that in the low-dose group and the medium-dose group(P<0.05).The number of cell migration in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The number of cell invasion in a single visual field of rats in the high-dose group was lower than that in the low-dose group and the medium-dose group(P<0.05).The mRNA expression levels of cAMP,PDE and PK in the high-dose group were higher than those in the low-dose group,and the mRNA expression levels of AC in the high-dose group were lower than those in the low-dose group(P<0.05).The mRNA expression levels of cAMP and PDE in the high-dose group were higher than those in the mediumdose group(P<0.05).Conclusion:Letrozole may down-regulate the expression level of MMP-2 through the cAMP signaling pathway to inhibit the migration and invasion of uterine fibroids cells.With increasing doses of letrozole,its inhibitory effect on the migration and invasion of uterine fibroids cells will be enhanced.However,the optimal dosage of letrozole for inhibiting the migration and invasion of uterine fibroids cells is yet to be determined.
文摘慢性咳嗽属于临床疑难杂症,气道炎症、咳嗽神经通路敏感性增强以及炎性疼痛是其主要病理学基础。环磷酸腺苷(cyclic adenosine monophosphate,cAMP)/cAMP直接激活的交换蛋白分子(exchange protein activated by cAMP,Epac)信号通路广泛参与气道炎症(特别是气道神经源性炎症)、咳嗽神经兴奋性以及炎性疼痛等生理病理过程。本文就近年来cAMP/Epac信号通路调控气道炎症、咳嗽通路增敏、炎性疼痛而影响慢性咳嗽以及中药干预作用研究进行综述,为研究慢性咳嗽以及镇咳药的开发应用提供理论基础。
基金Supported by Grants from CONICET (PIP 6442)Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT PICT 05-26115 and 05-26306),Argentina
文摘Vesicle-based traffi cking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal,submembrane compartment,followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane,the transporters usually undergo recycling between the plasma membrane and the endosomal compartment,which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence,it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters,which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis,and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation,with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition,the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally,several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP,tauroursodeoxycholate) are described.
