Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of ...Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of α3- nAChR in the inflammatory responses of atherosclerosis. Methods The inflammatory indicators were detected in mouse macrophage, adipocytes and mouse aortic endothelial cells （MAECs） after the α3-nAChR was antagonized or after the α3-nAChR gene was silenced. Meanwhile, atherogenesis was induced in the apolipoprotein E knock-out （ ApoE^ -/- ） mice after fed with an atherogenic high-fat diet for 7 weeks. Results In MAECs, the lipopolysaccha- ride （LPS）-stimulated secretions of the adhesion molecules and inflammatory cytokines were significantly enhanced （30%± 80% ） after pretreatment with α-Conotoxin MII （an antagonist for α3-nAChR） or after knock-down with α3-nAChR gene. In adipocytes, the knock-down of α3 gene promoted the generations of the proin？ ammatory adi- pokines or cytokines but decreased the production of adiponectin, an anti-inflammatory adipokine, by 29.29 ± 9.43%. In macrophage silenced with α3-nAChR gene, the M1 （classical） activation was predominantly stimula- ted, whereas the M2 （alternative） activation was suppressed. In addition, the amount of the atherosclerotic lesions and the infiltration of the M1 type activated macrophages into the arterial wall were markedly elevated in the α- Conotoxin MII-treated ApoE -/- mice. Conclusion The α3-nAChR may play a pivotal role in regulating the atherogenesis through influencing the inflammatory responses of ECs, macrophages and adipocytes. The mecha- nisms involve the regulations of multiple cell signaling pathways.展开更多
Leber's congenital amaurosis(LCA)and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE,Pub Med and EMBASE. Adeno-associated viral vectors were th...Leber's congenital amaurosis(LCA)and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE,Pub Med and EMBASE. Adeno-associated viral vectors were the most utilised vectors for ocular gene therapy. Cone photoreceptor cells might use an alternate pathway which was not reliant of the retinal pigment epithelium(RPE)derived retinoid isomerohydrolase(RPE65)to access the 11-cis retinal dehydechromophore. Research efforts dedicated on the progression of a gene-based therapy for the treatment of LCA2. Such gene therapy approaches were extremely successful in canine,porcine and rodent LCA2 models. The recombinant AAV2.h RPE65v2 adenoassociated vector contained the RPE65 cDNA and was replication deficient. Its in vitro injection in target cells induced RPE65 protein production. The gene therapy trials that were so far conducted for inherited retinopathies have generated promising results. Phase I clinical trials to cure LCA and choroideremia demonstrated that adeno-associated viral vectors containing RPE genes and photoreceptors respectively,could be successfully administered to inherited retinopathy patients. A phase III trial is presently ongoing and if successful,it will lead the way to additional gene therapy attempts to cure monogenic,inherited retinopathies.展开更多
Objective:To investigate the effects of Δ^(9)-tetrahydrocannabinol,the principal psychoactive compound of Cannabis sativa,and cannabinol,a Δ^(9)-tetrahydrocannabinol degradative product,on human non-small cell lung ...Objective:To investigate the effects of Δ^(9)-tetrahydrocannabinol,the principal psychoactive compound of Cannabis sativa,and cannabinol,a Δ^(9)-tetrahydrocannabinol degradative product,on human non-small cell lung cancer cells.Methods:Δ^(9)-Tetrahydrocannabinol and cannabinol were tested for anticancer activity in human non-small cell lung cancer(A549)cells.The effects on cell proliferation,apoptosis,and phosphorylation profiles were examined.The effects of Δ^(9)-tetrahydrocannabinol and cannabinol on tumor growth were also investigated using a xenograft nude mouse model.Apoptosis and targeted phosphorylation were verified by immunohistochemistry.Results:Δ^(9)-Tetrahydrocannabinol and cannabinol significantly inhibited cell proliferation and increased the number of apoptotic cells in a concentration-dependent manner.The Δ^(9)-tetrahydrocannabinol-and cannabinol-treated cells had lower levels of phosphorylated protein kinase B[AKT(S473)],glycogen synthase kinase 3 alpha/beta,and endothelial nitric oxide synthase compared to the controls.The study of xenograft mice revealed that tumors treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly smaller than those of the control mice.The tumor progression rates in mice treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly slower than in the control group.Conclusions:These findings indicate that Δ^(9)-tetrahydrocannabinol and cannabinol inhibit lung cancer cell growth by inhibiting AKT and its signaling pathways,which include glycogen synthase kinase 3 alpha/beta and endothelial nitric oxide synthase.展开更多
文摘Aim The expression of α3 subunit of nicotinic acetylcholine receptor （α3-nAChR） has been demonstra- ted in aorta, adipocyte and macrophage. The objective of the present study was to verify the regulatory roles of α3- nAChR in the inflammatory responses of atherosclerosis. Methods The inflammatory indicators were detected in mouse macrophage, adipocytes and mouse aortic endothelial cells （MAECs） after the α3-nAChR was antagonized or after the α3-nAChR gene was silenced. Meanwhile, atherogenesis was induced in the apolipoprotein E knock-out （ ApoE^ -/- ） mice after fed with an atherogenic high-fat diet for 7 weeks. Results In MAECs, the lipopolysaccha- ride （LPS）-stimulated secretions of the adhesion molecules and inflammatory cytokines were significantly enhanced （30%± 80% ） after pretreatment with α-Conotoxin MII （an antagonist for α3-nAChR） or after knock-down with α3-nAChR gene. In adipocytes, the knock-down of α3 gene promoted the generations of the proin？ ammatory adi- pokines or cytokines but decreased the production of adiponectin, an anti-inflammatory adipokine, by 29.29 ± 9.43%. In macrophage silenced with α3-nAChR gene, the M1 （classical） activation was predominantly stimula- ted, whereas the M2 （alternative） activation was suppressed. In addition, the amount of the atherosclerotic lesions and the infiltration of the M1 type activated macrophages into the arterial wall were markedly elevated in the α- Conotoxin MII-treated ApoE -/- mice. Conclusion The α3-nAChR may play a pivotal role in regulating the atherogenesis through influencing the inflammatory responses of ECs, macrophages and adipocytes. The mecha- nisms involve the regulations of multiple cell signaling pathways.
文摘Leber's congenital amaurosis(LCA)and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE,Pub Med and EMBASE. Adeno-associated viral vectors were the most utilised vectors for ocular gene therapy. Cone photoreceptor cells might use an alternate pathway which was not reliant of the retinal pigment epithelium(RPE)derived retinoid isomerohydrolase(RPE65)to access the 11-cis retinal dehydechromophore. Research efforts dedicated on the progression of a gene-based therapy for the treatment of LCA2. Such gene therapy approaches were extremely successful in canine,porcine and rodent LCA2 models. The recombinant AAV2.h RPE65v2 adenoassociated vector contained the RPE65 cDNA and was replication deficient. Its in vitro injection in target cells induced RPE65 protein production. The gene therapy trials that were so far conducted for inherited retinopathies have generated promising results. Phase I clinical trials to cure LCA and choroideremia demonstrated that adeno-associated viral vectors containing RPE genes and photoreceptors respectively,could be successfully administered to inherited retinopathy patients. A phase III trial is presently ongoing and if successful,it will lead the way to additional gene therapy attempts to cure monogenic,inherited retinopathies.
基金the Research Institute,Rangsit University(grant number 103/2561,2018)and by the College of Pharmacy,Rangsit University.
文摘Objective:To investigate the effects of Δ^(9)-tetrahydrocannabinol,the principal psychoactive compound of Cannabis sativa,and cannabinol,a Δ^(9)-tetrahydrocannabinol degradative product,on human non-small cell lung cancer cells.Methods:Δ^(9)-Tetrahydrocannabinol and cannabinol were tested for anticancer activity in human non-small cell lung cancer(A549)cells.The effects on cell proliferation,apoptosis,and phosphorylation profiles were examined.The effects of Δ^(9)-tetrahydrocannabinol and cannabinol on tumor growth were also investigated using a xenograft nude mouse model.Apoptosis and targeted phosphorylation were verified by immunohistochemistry.Results:Δ^(9)-Tetrahydrocannabinol and cannabinol significantly inhibited cell proliferation and increased the number of apoptotic cells in a concentration-dependent manner.The Δ^(9)-tetrahydrocannabinol-and cannabinol-treated cells had lower levels of phosphorylated protein kinase B[AKT(S473)],glycogen synthase kinase 3 alpha/beta,and endothelial nitric oxide synthase compared to the controls.The study of xenograft mice revealed that tumors treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly smaller than those of the control mice.The tumor progression rates in mice treated with 15 mg/kg Δ^(9)-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly slower than in the control group.Conclusions:These findings indicate that Δ^(9)-tetrahydrocannabinol and cannabinol inhibit lung cancer cell growth by inhibiting AKT and its signaling pathways,which include glycogen synthase kinase 3 alpha/beta and endothelial nitric oxide synthase.
