AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction...AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS:Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer.Isometric tension was recorded.Cumulative concentration-response curves were obtained for(+)-cis- dioxolane(cD),a nonspecific muscarinic agonist,at 10^(-8)- 10^(-4)mol/L,in the presence of tetrodotoxin(TTX,10^(-7)mol/L). Results were normalized to cross sectional area.A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1(pirenzepine), M2(methoctramine)and M3(darifenadn)muscarinic receptor subtypes.The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment.The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS:A dose-dependent contractile response observed with bethanechol,was not affected by TTx.The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol.Lack of calcium as well as the presence of the L-type calcium channel blocker,nifedipine,also inhibited the cholinergic contraction,with a reduction in response from 2.5±0.4 g/mm^2 to 1.2±0.4 g/mm^2(P<0.05).The dose- response curves were shifted to the right by muscarinic antagonists in the following order of affinity:darifenacin (M_3)>methocramine(M_2)>pirenzepine(M_1). CONCLUSION:The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s)involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels.The presence of the residual contractile response after the treatment with nifedipine,sugges展开更多
Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides andβ-trifluoromethyl-substituted alkenyl heteroarenes was developed for the first time.A wide range of enantioenriched pyrrolidines containin...Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides andβ-trifluoromethyl-substituted alkenyl heteroarenes was developed for the first time.A wide range of enantioenriched pyrrolidines containing both heteroarenes and trifluoromethyl group with multiple stereogenic centers could be readily accessible by this method with good to high yields and excellent levels of both stereo-and regioselectivity(up to 99%yield,>20:1 rr,>20:1 dr,and up to 95%ee).Notably,substratecontrolled umpolung-type dipolar cycloaddition was also disclosed in this protocol to achieve regiodivergent synthesis withα-aryl substituted aldimine esters as the dipole precursors.Systematic DFT studies were conducted to explore the origin of the stereo-and regioselectivity of this 1,3-dipolar cycloaddition,and suggest that copper(Ⅱ)salt utilized in this catalytic system could be reduced in-situ to the active copper(Ⅰ)species and might be responsible for the observed high stereo-and regioselectivity.展开更多
OBJECTIVE:To evaluate the therapeutic effectiveness of salidroside(Sal)and pyrrolidine dithiocarbamate(PDTC)against severe acute pancreatitis(SAP)in a rat model.METHODS:Rat models of SAP were established by retrograde...OBJECTIVE:To evaluate the therapeutic effectiveness of salidroside(Sal)and pyrrolidine dithiocarbamate(PDTC)against severe acute pancreatitis(SAP)in a rat model.METHODS:Rat models of SAP were established by retrograde infusion of sodium taurocholate solution.SAP rats were randomly divided into 6 groups:SAP 3 h group,SAP 24 h group,low-dose Sal treatment group(Sal L+S),middle-dose Sal treatment group(Sal M+S),high-dose Sal treatment group(Sal H+S)and PDTC treatment group(PDTC+S).The serum amylase,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and interleukin-10(IL-10)levels were determined by optical turbidimetry and enzyme-linked immunosorbent assay.The expression of Beclin-1,microtubule-associated protein light chain 3Ⅱ(LC3Ⅱ),lysosome associated membrane protein 2(LAMP2),interleukin-1 receptor associated kinase 1(IRAK1),inhibitorαof nuclear transcription factor-κB(IκBα),nuclear transcription factor-κB 65(p65)in the pancreas tissues were detected by quantitative real-time polymerase chain reaction and Western blot,while the pIκBαand p-p65 levels were detected by Western blot.Pathological changes of the pancreas and all the other indexes were observed at 3 and 24 h after operation.RESULTS:The serum IL-10 level,IκBαand LAMP2 levels in Sal M+S,Sal H+S and PDTC+S groups were higher than those in SAP 24 h group,while all the other indexes in these three groups were all lower significantly than those in SAP 24 h group.There was no significant difference in all indexes between Sal H+S and PDTC+S groups.CONCLUSION:High-dose Sal has an effectively therapeutic effect on SAP in rats,which was similar to PDTC.展开更多
Intramolecular cyclization of N-alkoxyl amines are studied for the stereoselective preparation of 2, 4-disubstituted pyrrolidine derivatives. Reduction of oximes under acidic conditions by NaBH3CN afforded the corres...Intramolecular cyclization of N-alkoxyl amines are studied for the stereoselective preparation of 2, 4-disubstituted pyrrolidine derivatives. Reduction of oximes under acidic conditions by NaBH3CN afforded the corresponding nucleophilic hydroxylamine derivatives, which subsequently cyclized via SN2' mechanism to give the desired N-alkoxyl pyrrolidines.展开更多
An efficient methodology for the stereoselective synthesis of cis-2,5-disubstituted pyrrolidines using copper catalyst was developed. The corresponding cis-2,5-disubstituted pyrrolidines could be obtained in reasonabl...An efficient methodology for the stereoselective synthesis of cis-2,5-disubstituted pyrrolidines using copper catalyst was developed. The corresponding cis-2,5-disubstituted pyrrolidines could be obtained in reasonable yields and with good stereoselectivities in the presence of 4,4＇-di-tert-butyl-2,2＇-bipyridine as ligand and l-methyl-2-pyrrolidinone as solvent.展开更多
（1S、2R、3R、5R、7aR）-1,2-Dihydroxy-3-hydroxy methyl-5-methylpyrrolizidine（hyacinthacine A6, I） was synthesized by Wittig＇s methodology via the reaction of aldehyde 6, prepared from the partially protected deriva...（1S、2R、3R、5R、7aR）-1,2-Dihydroxy-3-hydroxy methyl-5-methylpyrrolizidine（hyacinthacine A6, I） was synthesized by Wittig＇s methodology via the reaction of aldehyde 6, prepared from the partially protected derivative of polyhydroxylated pyrrolidine, with appropriated ylides, followed by cyclization through the intemal reductive amination process of the resulting a,B-unsaturated ketone 7, and total deprotection.展开更多
文摘AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS:Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer.Isometric tension was recorded.Cumulative concentration-response curves were obtained for(+)-cis- dioxolane(cD),a nonspecific muscarinic agonist,at 10^(-8)- 10^(-4)mol/L,in the presence of tetrodotoxin(TTX,10^(-7)mol/L). Results were normalized to cross sectional area.A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1(pirenzepine), M2(methoctramine)and M3(darifenadn)muscarinic receptor subtypes.The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment.The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS:A dose-dependent contractile response observed with bethanechol,was not affected by TTx.The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol.Lack of calcium as well as the presence of the L-type calcium channel blocker,nifedipine,also inhibited the cholinergic contraction,with a reduction in response from 2.5±0.4 g/mm^2 to 1.2±0.4 g/mm^2(P<0.05).The dose- response curves were shifted to the right by muscarinic antagonists in the following order of affinity:darifenacin (M_3)>methocramine(M_2)>pirenzepine(M_1). CONCLUSION:The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s)involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels.The presence of the residual contractile response after the treatment with nifedipine,sugges
基金supported by the National Natural Science Foundation of China(22071186,22071187,22073067,22101216,22271226,21933003,22193020,22193023)the National Youth Talent Support Program+3 种基金the Natural Science Foundation of Hubei Province(2020CFA0362021CFA069)the Fundamental Research Funds for the Central Universities(2042022kf1180,2042022kf1040)the Shenzhen Nobel Prize Scientists Laboratory Project(C17783101)the Guangdong Provincial Key Laboratory of Catalytic Chemistry(2020B121201002)。
文摘Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides andβ-trifluoromethyl-substituted alkenyl heteroarenes was developed for the first time.A wide range of enantioenriched pyrrolidines containing both heteroarenes and trifluoromethyl group with multiple stereogenic centers could be readily accessible by this method with good to high yields and excellent levels of both stereo-and regioselectivity(up to 99%yield,>20:1 rr,>20:1 dr,and up to 95%ee).Notably,substratecontrolled umpolung-type dipolar cycloaddition was also disclosed in this protocol to achieve regiodivergent synthesis withα-aryl substituted aldimine esters as the dipole precursors.Systematic DFT studies were conducted to explore the origin of the stereo-and regioselectivity of this 1,3-dipolar cycloaddition,and suggest that copper(Ⅱ)salt utilized in this catalytic system could be reduced in-situ to the active copper(Ⅰ)species and might be responsible for the observed high stereo-and regioselectivity.
基金Supported by the Traditional Chinese Medicine Technology Development Plan Project of Jiangsu Province in 2020:Basic and Clinical Study on Salidroside in the Adjuvant Treatment of Severe Acute Pancreatitis(No.YB2020088)the Health Innovation Project of Lvyang Jinfeng Plan of Yangzhou City in 2020:Basic and Clinical Study on Salidroside in the Adjuvant Treatment of Severe Acute Pancreatitis(No.LJ202037)。
文摘OBJECTIVE:To evaluate the therapeutic effectiveness of salidroside(Sal)and pyrrolidine dithiocarbamate(PDTC)against severe acute pancreatitis(SAP)in a rat model.METHODS:Rat models of SAP were established by retrograde infusion of sodium taurocholate solution.SAP rats were randomly divided into 6 groups:SAP 3 h group,SAP 24 h group,low-dose Sal treatment group(Sal L+S),middle-dose Sal treatment group(Sal M+S),high-dose Sal treatment group(Sal H+S)and PDTC treatment group(PDTC+S).The serum amylase,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and interleukin-10(IL-10)levels were determined by optical turbidimetry and enzyme-linked immunosorbent assay.The expression of Beclin-1,microtubule-associated protein light chain 3Ⅱ(LC3Ⅱ),lysosome associated membrane protein 2(LAMP2),interleukin-1 receptor associated kinase 1(IRAK1),inhibitorαof nuclear transcription factor-κB(IκBα),nuclear transcription factor-κB 65(p65)in the pancreas tissues were detected by quantitative real-time polymerase chain reaction and Western blot,while the pIκBαand p-p65 levels were detected by Western blot.Pathological changes of the pancreas and all the other indexes were observed at 3 and 24 h after operation.RESULTS:The serum IL-10 level,IκBαand LAMP2 levels in Sal M+S,Sal H+S and PDTC+S groups were higher than those in SAP 24 h group,while all the other indexes in these three groups were all lower significantly than those in SAP 24 h group.There was no significant difference in all indexes between Sal H+S and PDTC+S groups.CONCLUSION:High-dose Sal has an effectively therapeutic effect on SAP in rats,which was similar to PDTC.
文摘Intramolecular cyclization of N-alkoxyl amines are studied for the stereoselective preparation of 2, 4-disubstituted pyrrolidine derivatives. Reduction of oximes under acidic conditions by NaBH3CN afforded the corresponding nucleophilic hydroxylamine derivatives, which subsequently cyclized via SN2' mechanism to give the desired N-alkoxyl pyrrolidines.
基金We gratefully acknowledge the funding support of the State Key Program of National Natural Science Foundation of China （No. 21432009） and the National Natural Science Foundation of China （No. 21372210）. The authors are grateful to Miss Jun Kee Cheng for her careful proofreading of the final manuscript.
文摘An efficient methodology for the stereoselective synthesis of cis-2,5-disubstituted pyrrolidines using copper catalyst was developed. The corresponding cis-2,5-disubstituted pyrrolidines could be obtained in reasonable yields and with good stereoselectivities in the presence of 4,4＇-di-tert-butyl-2,2＇-bipyridine as ligand and l-methyl-2-pyrrolidinone as solvent.
基金the National Basic Research Program(973 Program)of China(No.2007CB108903)the National Natural Science Foundation of China(No.20621091)
文摘（1S、2R、3R、5R、7aR）-1,2-Dihydroxy-3-hydroxy methyl-5-methylpyrrolizidine（hyacinthacine A6, I） was synthesized by Wittig＇s methodology via the reaction of aldehyde 6, prepared from the partially protected derivative of polyhydroxylated pyrrolidine, with appropriated ylides, followed by cyclization through the intemal reductive amination process of the resulting a,B-unsaturated ketone 7, and total deprotection.
