Compared to their linear counterparts,cyclic peptides show better biological activities,such as antibacterial,immunosuppressive,and anti-tumor activities,and pharmaceutical properties due to their conformational rigid...Compared to their linear counterparts,cyclic peptides show better biological activities,such as antibacterial,immunosuppressive,and anti-tumor activities,and pharmaceutical properties due to their conformational rigidity.However,cyclic peptides could form numerous putative metabolites from potential hydrolytic cleavages and their fragments are very difficult to interpret.These characteristics pose a great challenge when analyzing metabolites of cyclic peptides by mass spectrometry.This study was to assess and apply a software-aided analytical workflow for the detection and structural characterization of cyclic peptide metabolites.Insulin and atrial natriuretic peptide(ANP)as model cyclic peptides were incubated with trypsin/chymotrypsin and/or rat liver S9,followed by data acquisition using TripleTOF?5600.Resultant full-scan MS and MS/MS datasets were automatically processed through a combination of targeted and untargeted peak finding strategies.MS/MS spectra of predicted metabolites were interrogated against putative metabolite sequences,in light of a,b,y and internal fragment series.The resulting fragment assignments led to the confirmation and ranking of the metabolite sequences and identification of metabolic modification.As a result,29 metabolites with linear or cyclic structures were detected in the insulin incubation with the hydrolytic enzymes.Sequences of twenty insulin metabolites were further determined,which were consistent with the hydrolytic sites of these enzymes.In the same manner,multiple metabolites of insulin and ANP formed in rat liver S9 incubation were detected and structurally characterized,some of which have not been previously reported.The results demonstrated the utility of software-aided data processing tool in detection and identification of cyclic peptide metabolites.展开更多
Diabetes mellitus(DM)is one of the major causes of mortality worldwide,with inflammation being an important factor in its onset and development.This review summarizes the specific mechanisms of the cyclic guanosine mo...Diabetes mellitus(DM)is one of the major causes of mortality worldwide,with inflammation being an important factor in its onset and development.This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway in mediating inflammatory responses.Furthermore,it compre-hensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM,diabetic gastroenteropathy,diabetic cardiomyopathy,non-alcoholic fatty liver disease,and other complic-ations.Additionally,the role of cGAS-STING in autonomic dysfunction and intes-tinal dysregulation,which can lead to digestive complications,has been discuss-ed.Altogether,this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.展开更多
AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the ...AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.展开更多
本试验旨在模拟夏季蛋鸡舍内的循环高温,研究不同温度对蛋鸡生产性能、蛋壳品质及钙磷代谢的影响。选取28周龄高产海兰褐蛋鸡288只,随机分为21℃适温组(自由采食)、27~30℃循环高温组(自由采食)、29~35℃循环高温组(自由采食)和21℃采...本试验旨在模拟夏季蛋鸡舍内的循环高温,研究不同温度对蛋鸡生产性能、蛋壳品质及钙磷代谢的影响。选取28周龄高产海兰褐蛋鸡288只,随机分为21℃适温组(自由采食)、27~30℃循环高温组(自由采食)、29~35℃循环高温组(自由采食)和21℃采食配对组(按前1 d 29~35℃循环高温组的采食量饲喂),每个组6个重复,每个重复12只鸡,分别饲养于4个人工环境控制舱内,试验期4周。结果表明:与21℃适温组相比,27~30℃循环高温组蛋鸡平均日采食量、体增重和平均蛋重显著降低(P<0.05),蛋壳强度显著降低(P<0.05),蛋鸡钙、磷的代谢率差异不显著(P>0.05),但钙、磷的吸收量显著降低(P<0.05),除蛋黄颜色显著降低(P<0.05)外,鸡蛋品质其他相关指标差异不显著(P>0.05);而29~35℃循环高温组除平均日采食量、体增重和平均蛋重显著降低(P<0.05)外,产蛋率同样显著降低(P<0.05),蛋壳厚度和蛋壳强度均显著降低(P<0.05),破蛋率显著升高(P<0.05),蛋鸡钙、磷的代谢率差异不显著(P>0.05),而钙、磷吸收量同样显著降低(P<0.05),鸡蛋蛋白高度和蛋黄颜色均显著降低(P<0.05)。与21℃采食配对组相比,29~35℃循环高温组平均蛋重显著降低(P<0.05),料蛋比显著提高(P<0.05),蛋壳强度显著降低(P<0.05),钙、磷的代谢率和吸收量差异不显著(P>0.05),鸡蛋品质差异不显著(P>0.05)。结果提示,夏季鸡舍内温度在27~30℃波动即可显著降低蛋鸡的体增重、平均蛋重和蛋壳品质;而29~35℃不仅显著降低蛋鸡的体增重、产蛋率、平均蛋重以及蛋壳品质,还显著影响鸡蛋的蛋白高度和蛋黄颜色。高温对蛋鸡产蛋性能及蛋白高度和蛋黄颜色的影响可能与降低采食量有关;高温可能直接影响蛋壳的形成,也可能由于降低钙、磷吸收量影响蛋壳品质。展开更多
文摘Compared to their linear counterparts,cyclic peptides show better biological activities,such as antibacterial,immunosuppressive,and anti-tumor activities,and pharmaceutical properties due to their conformational rigidity.However,cyclic peptides could form numerous putative metabolites from potential hydrolytic cleavages and their fragments are very difficult to interpret.These characteristics pose a great challenge when analyzing metabolites of cyclic peptides by mass spectrometry.This study was to assess and apply a software-aided analytical workflow for the detection and structural characterization of cyclic peptide metabolites.Insulin and atrial natriuretic peptide(ANP)as model cyclic peptides were incubated with trypsin/chymotrypsin and/or rat liver S9,followed by data acquisition using TripleTOF?5600.Resultant full-scan MS and MS/MS datasets were automatically processed through a combination of targeted and untargeted peak finding strategies.MS/MS spectra of predicted metabolites were interrogated against putative metabolite sequences,in light of a,b,y and internal fragment series.The resulting fragment assignments led to the confirmation and ranking of the metabolite sequences and identification of metabolic modification.As a result,29 metabolites with linear or cyclic structures were detected in the insulin incubation with the hydrolytic enzymes.Sequences of twenty insulin metabolites were further determined,which were consistent with the hydrolytic sites of these enzymes.In the same manner,multiple metabolites of insulin and ANP formed in rat liver S9 incubation were detected and structurally characterized,some of which have not been previously reported.The results demonstrated the utility of software-aided data processing tool in detection and identification of cyclic peptide metabolites.
基金Supported by the Natural Science Foundation of Shandong Province,No.ZR2022MH153“Clinical+X”Project Fund of Binzhou Medical College,No.BY2021LCX11.
文摘Diabetes mellitus(DM)is one of the major causes of mortality worldwide,with inflammation being an important factor in its onset and development.This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway in mediating inflammatory responses.Furthermore,it compre-hensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM,diabetic gastroenteropathy,diabetic cardiomyopathy,non-alcoholic fatty liver disease,and other complic-ations.Additionally,the role of cGAS-STING in autonomic dysfunction and intes-tinal dysregulation,which can lead to digestive complications,has been discuss-ed.Altogether,this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.
文摘AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.
文摘本试验旨在模拟夏季蛋鸡舍内的循环高温,研究不同温度对蛋鸡生产性能、蛋壳品质及钙磷代谢的影响。选取28周龄高产海兰褐蛋鸡288只,随机分为21℃适温组(自由采食)、27~30℃循环高温组(自由采食)、29~35℃循环高温组(自由采食)和21℃采食配对组(按前1 d 29~35℃循环高温组的采食量饲喂),每个组6个重复,每个重复12只鸡,分别饲养于4个人工环境控制舱内,试验期4周。结果表明:与21℃适温组相比,27~30℃循环高温组蛋鸡平均日采食量、体增重和平均蛋重显著降低(P<0.05),蛋壳强度显著降低(P<0.05),蛋鸡钙、磷的代谢率差异不显著(P>0.05),但钙、磷的吸收量显著降低(P<0.05),除蛋黄颜色显著降低(P<0.05)外,鸡蛋品质其他相关指标差异不显著(P>0.05);而29~35℃循环高温组除平均日采食量、体增重和平均蛋重显著降低(P<0.05)外,产蛋率同样显著降低(P<0.05),蛋壳厚度和蛋壳强度均显著降低(P<0.05),破蛋率显著升高(P<0.05),蛋鸡钙、磷的代谢率差异不显著(P>0.05),而钙、磷吸收量同样显著降低(P<0.05),鸡蛋蛋白高度和蛋黄颜色均显著降低(P<0.05)。与21℃采食配对组相比,29~35℃循环高温组平均蛋重显著降低(P<0.05),料蛋比显著提高(P<0.05),蛋壳强度显著降低(P<0.05),钙、磷的代谢率和吸收量差异不显著(P>0.05),鸡蛋品质差异不显著(P>0.05)。结果提示,夏季鸡舍内温度在27~30℃波动即可显著降低蛋鸡的体增重、平均蛋重和蛋壳品质;而29~35℃不仅显著降低蛋鸡的体增重、产蛋率、平均蛋重以及蛋壳品质,还显著影响鸡蛋的蛋白高度和蛋黄颜色。高温对蛋鸡产蛋性能及蛋白高度和蛋黄颜色的影响可能与降低采食量有关;高温可能直接影响蛋壳的形成,也可能由于降低钙、磷吸收量影响蛋壳品质。
