Objective：To study the effects of Zuogui Pill（左归丸,ZGP）and Yougui Pill（右归丸,YGP）on the expressions of brain-derived neurotrophic factor（BDNF）and cyclic adenosine monophosphate（cAMP）/protein kinase A（PKA...Objective：To study the effects of Zuogui Pill（左归丸,ZGP）and Yougui Pill（右归丸,YGP）on the expressions of brain-derived neurotrophic factor（BDNF）and cyclic adenosine monophosphate（cAMP）/protein kinase A（PKA）signaling of axonal regeneration in the Lewis rats with experimental autoimmune encephalomyelitis（EAE）,in order to explore the possible mechanism of ZGP and YGP on promoting axonal regeneration.Methods：The rats were randomly divided into normal control（NC）,model（MO）,prednisone acetate（PA）,ZGP and YGP groups.The EAE model of rat was established by injecting antigen containing myelin basic protein（MBP）68-86.The brain and spinal cord were harvested on the 14th and 28th day postimmunization（PI）,the protein and mRNA expression of BDNF and PKA in the brain and spinal cord of rats were detected by Western blot analysis and real-time quantitative polymerase chain reaction（PCR）,and the cAMP levels were detected by using enzyme-immunoassay method.Results：（1）On the 28th day PI,the mRNA expression of BDNF in brain white matter and spinal cord of rats in ZGP and YGP groups were up-regulated,especially in YGP group（P〈0.05 or P〈0.01）.（2）On the 14th day PI,the cAMP levels in brain white matters significantly increased in PA and YGP groups compared with MO group（P〈0.05 or P〈0.01）,and the cAMP level in YGP group was higher than that in ZGP group（P〈0.05）.The cAMP level in spinal cord also significantly increased in YGP group compared with MO,PA and ZGP groups,respectively（P〈0.01）.（3）On the 14th day PI,the PKA expression in spinal cord of rats in ZGP group was significantly decreased compared with MO and YGP groups,respectively（P〈0.05）.（4）On the 28th day PI,there was a positive correlation between cAMP and PKA expression in the brain white matter of YGP rats.Conclusions：The results suggest that ZGP and YGP may promote axonal regeneration by modulating cAMP/PKA signal transduction pathway,but the targets of molecular mechanism of ZGP may be different from those of YGP.展开更多
Objectives: The objective of the study is to observe the effects of ginsenoside Rb1 on indexes of body weight, body composition, blood lipid, skeletal muscle endurance, and insulin sensitivity in obese mice, probe int...Objectives: The objective of the study is to observe the effects of ginsenoside Rb1 on indexes of body weight, body composition, blood lipid, skeletal muscle endurance, and insulin sensitivity in obese mice, probe into its pharmacological action, and further explore its effects on adenosine monophosphate-activated protein kinase(AMPK) signaling pathway in skeletal muscle. Materials and Methods: Eight-week-old C57 BL/6 J mice were fed with high-fat diet for 12 weeks to establish obese mouse model. The model-establishment obese mice were randomly divided into three groups including model control group, metformin group, and ginsenoside Rb1 group. In the normal control group, normal diet was administered. The intervention period was 8 weeks. Body weight and food intake of the mice were measured regularly every week. The treadmill test was performed at weeks 3 and 7, and the oral glucose tolerance test was carried out at weeks 4 and 8. Body composition of the mice was detected by applying NMR Animal Body Composition Analyzer at week 8. Four parameters of blood lipids and free fatty acid(FFA)levels were detected. The m RNA expression of AMPKα and proliferator-activated receptor gamma coactivator-1α(PGC-1α) in skeletal muscle was examined by real-time fluorescence quantitative polymerase chain reaction, and the influence of ginsenoside Rb1 on protein expression of AMPKα, p-AMPKα, and PGC-1α was observed by western blotting. Results: The body weight(since the 5 th week of drug administration)and food intake of the mice in the ginsenoside Rb1 group were significantly lower than those in the model control group(P < 0.05) in a time-dependent manner. Ginsenoside Rb1 could significantly reduce the levels of triglyceride and low-density lipoprotein cholesterol, while increase the high-density lipoprotein cholesterol level(P < 0.05). In addition, ginsenoside Rb1 could reduce the serum FFA level(P < 0.05).After the administration of ginsenoside Rb1 for 8 weeks, the body fat mass of obese mice decreased and the lean mass increased(P < 0.05).The skeletal muscle endurance and the oral glucose tolerance of the obese mice improved using ginsenoside Rb1. At the molecular level,ginsenoside Rb1 could up-regulate the mRNA and protein expression of AMPKα in skeletal muscle, and increase the content of p-AMPK protein significantly(P < 0.01). At the same time, the mRNA and protein level of PGC-1α was also un-regulated, correspondingly(P < 0.01).Conclusion: Ginsenoside Rb1 exerts effects on reducing body weight, decreasing blood lipid levels, enhancing the skeletal muscle endurance,and increasing the insulin sensitivity in obese mice by activating the related proteins in AMPK signaling pathway in skeletal muscle.展开更多
The mammalian target of rapamycin （mTOR） pathway plays an important role in neuronal growth, proliferation and differentiation. To better understand the role of mTOR pathway involved in the induction of spinal cord ...The mammalian target of rapamycin （mTOR） pathway plays an important role in neuronal growth, proliferation and differentiation. To better understand the role of mTOR pathway involved in the induction of spinal cord injury, rat models of spinal cord injury were established by modified Allen＇s stall method and interfered for 7 days by intraperitoneal administration of mTOR activator adenosine triphosphate and mTOR kinase inhibitor rapamycin. At 1-4 weeks after spinal cord injury induction, the Basso, Beattie and Bresnahan locomotor rating scale was used to evaluate rat locomotor function, and immunohistochemical staining and western blot analysis were used to detect the expression of nestin （neural stem cell marker）, neuronal nuclei （neuronal marker）, neuron specific enolase, neurofilament protein 200 （axonal marker）, glial fibrillary acidic protein （astrocyte marker）, Akt, mTOR and signal transduction and activator of transcription 3 （STAT3）. Results showed that adenosine triphosphate-mediated Akt/mTOR/STAT3 pathway increased endogenous neural stem cells, induced neurogenesis and axonal growth, inhibited excessive astrogliosis and improved the locomotor function of rats with spinal cord injury.展开更多
Extracellular signal-regulated protein kinase 5 （ERK5）, also known as big mitogen-activated protein kinase 1 （MAPK1）, is an important member of ERK family, which is a subfamily of the large MAPK family. ERK5 is ex...Extracellular signal-regulated protein kinase 5 （ERK5）, also known as big mitogen-activated protein kinase 1 （MAPK1）, is an important member of ERK family, which is a subfamily of the large MAPK family. ERK5 is expressed in many tissues, including the dorsal root ganglion （DRG） neurons and the spinal cord. In this review, we focus on elaborating ERK5-associated pathway in pathological pain, in which the ERK5/CREB （cyclic adenosine monophos- phate （cAMP）-response element-binding protein） pathway plays a crucial role in the transduction of pain signal and contributes to pain hypersensitivity. ERK5 activation in the spinal dorsal horn occurs mainly in microglia. The activation of ERK5 can be mediated by N-methyI-D-aspartate （NMDA） receptors. We also elaborate the relationship between ERK5 activation and nerve growth factor-tyrosine kinase A （NGF-TrkA）, and the connection between ERK5 activation and brain-derived neurotrophic factor （BDNF） in pathological pain in detail.展开更多
BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors globally.Recent reports suggest that Fusobacterium nucleatum(F.nucleatum)contributes to the initiation,progression,and prognosis of CRC....BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors globally.Recent reports suggest that Fusobacterium nucleatum(F.nucleatum)contributes to the initiation,progression,and prognosis of CRC.Butyrate,a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber,is known to inhibit various cancers.This study is designed to explore whether F.nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid.AIM To investigate the mechanism by which F.nucleatum affects CRC occurrence and development.METHODS Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F.nucleatum.Additionally,DLD-1 and HCT116 cell lines were exposed to sodium butyrate(NaB)and F.nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function.RESULTS Our research indicates that the prevalence of F.nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts,while the prevalence of butyrate-producing bacteria is notably lower.In mice colonized with F.nucleatum,the population of butyrate-producing bacteria decreased,resulting in altered levels of butyric acid,a key intestinal metabolite of butyrate.Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells.Consequently,this leads to modulated production of adenosine triphosphate and reactive oxygen species,thereby inhibiting cancer cell prolif-eration.Additionally,NaB triggers the adenosine monophosphate-activated protein kinase(AMPK)signaling pathway,blocks the cell cycle in HCT116 and DLD-1 cells,and curtails the proliferation of CRC cells.The combined presence of F.nucleatum and NaB attenuated the effects of the latter.By employing small interfering RNA to suppress AMPK,it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell proliferation.CONCLUSION F.nucleatum can promote cancer progression through its inhibitory effect on butyric acid,via the AMPK signaling pathway.展开更多
基金Supported by the National Natural Science Foundation of China(No.30873230)Beijing Natural Science Foundation(No.7092014)+1 种基金Scientific Research Common Program of Beijing Municipal Education Commission(No.KM2007100025015)Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality(No.PHR201008401)
文摘Objective：To study the effects of Zuogui Pill（左归丸,ZGP）and Yougui Pill（右归丸,YGP）on the expressions of brain-derived neurotrophic factor（BDNF）and cyclic adenosine monophosphate（cAMP）/protein kinase A（PKA）signaling of axonal regeneration in the Lewis rats with experimental autoimmune encephalomyelitis（EAE）,in order to explore the possible mechanism of ZGP and YGP on promoting axonal regeneration.Methods：The rats were randomly divided into normal control（NC）,model（MO）,prednisone acetate（PA）,ZGP and YGP groups.The EAE model of rat was established by injecting antigen containing myelin basic protein（MBP）68-86.The brain and spinal cord were harvested on the 14th and 28th day postimmunization（PI）,the protein and mRNA expression of BDNF and PKA in the brain and spinal cord of rats were detected by Western blot analysis and real-time quantitative polymerase chain reaction（PCR）,and the cAMP levels were detected by using enzyme-immunoassay method.Results：（1）On the 28th day PI,the mRNA expression of BDNF in brain white matter and spinal cord of rats in ZGP and YGP groups were up-regulated,especially in YGP group（P〈0.05 or P〈0.01）.（2）On the 14th day PI,the cAMP levels in brain white matters significantly increased in PA and YGP groups compared with MO group（P〈0.05 or P〈0.01）,and the cAMP level in YGP group was higher than that in ZGP group（P〈0.05）.The cAMP level in spinal cord also significantly increased in YGP group compared with MO,PA and ZGP groups,respectively（P〈0.01）.（3）On the 14th day PI,the PKA expression in spinal cord of rats in ZGP group was significantly decreased compared with MO and YGP groups,respectively（P〈0.05）.（4）On the 28th day PI,there was a positive correlation between cAMP and PKA expression in the brain white matter of YGP rats.Conclusions：The results suggest that ZGP and YGP may promote axonal regeneration by modulating cAMP/PKA signal transduction pathway,but the targets of molecular mechanism of ZGP may be different from those of YGP.
基金supported by Natural Science Foundation of China (NSFC81503540&NSFC81274041)Chaoyang District Science and Technology Commission Collaborative Innovation Project (CYXC1513)+1 种基金Major New Drug Creation Sub-project (2012ZX09103201-005)Beijing Joint Construction Project (0101216-14&0101216-2013)
文摘Objectives: The objective of the study is to observe the effects of ginsenoside Rb1 on indexes of body weight, body composition, blood lipid, skeletal muscle endurance, and insulin sensitivity in obese mice, probe into its pharmacological action, and further explore its effects on adenosine monophosphate-activated protein kinase(AMPK) signaling pathway in skeletal muscle. Materials and Methods: Eight-week-old C57 BL/6 J mice were fed with high-fat diet for 12 weeks to establish obese mouse model. The model-establishment obese mice were randomly divided into three groups including model control group, metformin group, and ginsenoside Rb1 group. In the normal control group, normal diet was administered. The intervention period was 8 weeks. Body weight and food intake of the mice were measured regularly every week. The treadmill test was performed at weeks 3 and 7, and the oral glucose tolerance test was carried out at weeks 4 and 8. Body composition of the mice was detected by applying NMR Animal Body Composition Analyzer at week 8. Four parameters of blood lipids and free fatty acid(FFA)levels were detected. The m RNA expression of AMPKα and proliferator-activated receptor gamma coactivator-1α(PGC-1α) in skeletal muscle was examined by real-time fluorescence quantitative polymerase chain reaction, and the influence of ginsenoside Rb1 on protein expression of AMPKα, p-AMPKα, and PGC-1α was observed by western blotting. Results: The body weight(since the 5 th week of drug administration)and food intake of the mice in the ginsenoside Rb1 group were significantly lower than those in the model control group(P < 0.05) in a time-dependent manner. Ginsenoside Rb1 could significantly reduce the levels of triglyceride and low-density lipoprotein cholesterol, while increase the high-density lipoprotein cholesterol level(P < 0.05). In addition, ginsenoside Rb1 could reduce the serum FFA level(P < 0.05).After the administration of ginsenoside Rb1 for 8 weeks, the body fat mass of obese mice decreased and the lean mass increased(P < 0.05).The skeletal muscle endurance and the oral glucose tolerance of the obese mice improved using ginsenoside Rb1. At the molecular level,ginsenoside Rb1 could up-regulate the mRNA and protein expression of AMPKα in skeletal muscle, and increase the content of p-AMPK protein significantly(P < 0.01). At the same time, the mRNA and protein level of PGC-1α was also un-regulated, correspondingly(P < 0.01).Conclusion: Ginsenoside Rb1 exerts effects on reducing body weight, decreasing blood lipid levels, enhancing the skeletal muscle endurance,and increasing the insulin sensitivity in obese mice by activating the related proteins in AMPK signaling pathway in skeletal muscle.
文摘The mammalian target of rapamycin （mTOR） pathway plays an important role in neuronal growth, proliferation and differentiation. To better understand the role of mTOR pathway involved in the induction of spinal cord injury, rat models of spinal cord injury were established by modified Allen＇s stall method and interfered for 7 days by intraperitoneal administration of mTOR activator adenosine triphosphate and mTOR kinase inhibitor rapamycin. At 1-4 weeks after spinal cord injury induction, the Basso, Beattie and Bresnahan locomotor rating scale was used to evaluate rat locomotor function, and immunohistochemical staining and western blot analysis were used to detect the expression of nestin （neural stem cell marker）, neuronal nuclei （neuronal marker）, neuron specific enolase, neurofilament protein 200 （axonal marker）, glial fibrillary acidic protein （astrocyte marker）, Akt, mTOR and signal transduction and activator of transcription 3 （STAT3）. Results showed that adenosine triphosphate-mediated Akt/mTOR/STAT3 pathway increased endogenous neural stem cells, induced neurogenesis and axonal growth, inhibited excessive astrogliosis and improved the locomotor function of rats with spinal cord injury.
基金supported by the Medical and Healthcare Project of Zhejiang Province(No.2015119381),China
文摘Extracellular signal-regulated protein kinase 5 （ERK5）, also known as big mitogen-activated protein kinase 1 （MAPK1）, is an important member of ERK family, which is a subfamily of the large MAPK family. ERK5 is expressed in many tissues, including the dorsal root ganglion （DRG） neurons and the spinal cord. In this review, we focus on elaborating ERK5-associated pathway in pathological pain, in which the ERK5/CREB （cyclic adenosine monophos- phate （cAMP）-response element-binding protein） pathway plays a crucial role in the transduction of pain signal and contributes to pain hypersensitivity. ERK5 activation in the spinal dorsal horn occurs mainly in microglia. The activation of ERK5 can be mediated by N-methyI-D-aspartate （NMDA） receptors. We also elaborate the relationship between ERK5 activation and nerve growth factor-tyrosine kinase A （NGF-TrkA）, and the connection between ERK5 activation and brain-derived neurotrophic factor （BDNF） in pathological pain in detail.
基金Supported by the Key Discipline of Zhejiang Province in Medical Technology(First Class,Category A)and the Health Project of the Science and Technology Department of Wenzhou,No.Y20220029.
文摘BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors globally.Recent reports suggest that Fusobacterium nucleatum(F.nucleatum)contributes to the initiation,progression,and prognosis of CRC.Butyrate,a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber,is known to inhibit various cancers.This study is designed to explore whether F.nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid.AIM To investigate the mechanism by which F.nucleatum affects CRC occurrence and development.METHODS Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F.nucleatum.Additionally,DLD-1 and HCT116 cell lines were exposed to sodium butyrate(NaB)and F.nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function.RESULTS Our research indicates that the prevalence of F.nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts,while the prevalence of butyrate-producing bacteria is notably lower.In mice colonized with F.nucleatum,the population of butyrate-producing bacteria decreased,resulting in altered levels of butyric acid,a key intestinal metabolite of butyrate.Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells.Consequently,this leads to modulated production of adenosine triphosphate and reactive oxygen species,thereby inhibiting cancer cell prolif-eration.Additionally,NaB triggers the adenosine monophosphate-activated protein kinase(AMPK)signaling pathway,blocks the cell cycle in HCT116 and DLD-1 cells,and curtails the proliferation of CRC cells.The combined presence of F.nucleatum and NaB attenuated the effects of the latter.By employing small interfering RNA to suppress AMPK,it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell proliferation.CONCLUSION F.nucleatum can promote cancer progression through its inhibitory effect on butyric acid,via the AMPK signaling pathway.
