Objective To test the resuscitative effects from prolonged ventricular fibrillation by epinephrine combined with sodium hydrogen exchanger isoform 1 inhibitor Cariporide. Methods 16 rats were received a 3 mg/kg bolu...Objective To test the resuscitative effects from prolonged ventricular fibrillation by epinephrine combined with sodium hydrogen exchanger isoform 1 inhibitor Cariporide. Methods 16 rats were received a 3 mg/kg bolus of Cariporide or the same volume of 0.9%NaCl solution (control) 15 seconds before completion 12 minutes untreated VF. Chest compression (CC) was started for a total of 8 minutes. Adjusted the depth of compressor so that the aortic diastolic pressure to 25～28 mmHg during the 2nd minute of CC. Fix the depth of the piston and this depth was used throughout the remaining 6 minutes of CC. 10 seconds before starting the 3rd minute of chest compression, injected epinephrine (30 μg/kg). Recorded the time at which restoration of spontaneous circulation (ROSC) occurred in Cariporide treated rats. Electrical defibrillation was timed in control group to match the time of spontaneous defibrillation in Cariporide treated rats. To the rats, which cant be defibrillated spontaneously, received chest compression and rescues electrical shocks. Results compared with control group, with the same CC depth, Cariporide treated rats received the higher and longer lasting coronary perfusion pressure (P< 0.05), higher resuscitative rate (P< 0.05), less post resuscitative ventricular ectopic activities (P< 0.001), better hemodynamic effects and longer survival time (P< 0.05). Conclusion Epinephrine combined with sodium hydrogen exchanger isoform 1 inhibitor Cariporide may represent a novel and remarkably effective intervention for resuscitation from prolonged VF.展开更多
The Na+/Ca2+ exchanger plays an important role in regulation of airway smooth muscle contraction by regulating intracellular calcium, and is a potential target for treatment of asthma. To test modulation of exchanger ...The Na+/Ca2+ exchanger plays an important role in regulation of airway smooth muscle contraction by regulating intracellular calcium, and is a potential target for treatment of asthma. To test modulation of exchanger activity, we used Xenopus oocytes as model system. Na+/Ca2+ exchanger was expressed in the cells by microinjection of cRNA of the exchanger isoform NCX1. The activity of NCX1 was determined as Ni2+-sensitive current under voltage clamp in low Cl– medium and in the presence of the Cl–-channel inhibitor niflumic acid. Only this composition of solution allowed determining NCX1-mediated current with sufficient accuracy. Among a few tested Chinese herbal drugs, glycyrrhizic acid turned out to be a potent inhibitor of NCX1 with an apparent IC50 value of 40 μM. Previous work had revealed elevated cyclophylin A concentration in serum of asthmatic rats after receiving acupuncture treatment. Extracellular incubation of the oocytes in cyclophylin A for one day led to significant inhibition with an apparent IC50 value of about 1 μM. We suggest that effects of acupuncture and application of glycyrrhizic acid as an active constituent of Chinese medicine for treatment of asthma symptoms may partially be attributed to inhibition of the reversed mode of NCX1 and that these compounds may stimulate the search for new anti-asthmatic drugs.展开更多
A series of novel derivatives of ligustrazine linked with substituted benzoyl guanidine were synthesized. These compounds have not been reported in literature, and their chemical structures were confirmed by IR, ^1H N...A series of novel derivatives of ligustrazine linked with substituted benzoyl guanidine were synthesized. These compounds have not been reported in literature, and their chemical structures were confirmed by IR, ^1H NMR and MS. The results of NHE1 inhibitory activity test showed that compounds I2, I3, I4, I6, and I7 possess more potent NHE1 inhibitory activity than cariporide.展开更多
Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug,the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors(SGLT2i)showed efficacy in decreasing overall mort...Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug,the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors(SGLT2i)showed efficacy in decreasing overall mortality,hospitalization,and sudden death in patients of this very population,in whom chronic or acute ischemia count among the first cause.Remarkably,this benefit was observed independently from diabetic status,and benefited both preserved and altered ventricular ejection fraction.This feature,observed in several large randomized controlled trials,suggests additional effects from SGLT2i beyond isolated glycemia control.Indeed,both in-vitro and animal models suggest that inhibiting the Na+/H+exchanger(NHE)may be key to preventing ischemia/reperfusion injuries,and by extension may hold a similar role in ischemic damage control and ischemic preconditioning.Yet,several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules.Because of a large therapeutic margin with few adverse events,ease of prescription and potential pharmacological efficacity,SGLT2i could be candidate for wider indications.In this review,we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation,by first listing known mechanisms,including metabolic switch,prevention of lethal arrythmias and others,which portend the latter,and second,hypothesize how the former may interact with these mechanisms.展开更多
Guanine nucleotide exchange factors(GEFs)and guanine nucleotide-dissociation inhibitors(GDIs)regulate small GTPase proteins,which function as molecular switches in various signaling pathways,but their identification a...Guanine nucleotide exchange factors(GEFs)and guanine nucleotide-dissociation inhibitors(GDIs)regulate small GTPase proteins,which function as molecular switches in various signaling pathways,but their identification and functions in plants are not well understood.Using in-silico analysis and transgenic approaches,respectively,we dissected the evolutionary relationships and functions of all GEF and GDI genes in rice.Intron-exon distribution and phylogenetic analyses identified 30 GEF and 10 GDI genes in rice that shared close evolutionary relationships with other eukaryotes.Tissue-specific expression and co-expression analyses revealed that phylogenetically related genes had similar expression patterns.GEF and GDI genes were highly expressed in panicles,hulls,and stamens.Co-expression network analysis identified panicle and stamen-specific modules of co-expressed genes in both families.Mapping of these genes in known protein interactomes further identified two and one small G-protein sub-networks.A mutant library of GEF and GDI families was constructed by CRISPR knockout of each gene,and their genotypes and phenotypes were confirmed.Phenotype changes occurred with the mutation of only three genes(OsGEF5,OsGDI1,and OsGEF3).OsGEF5 and OsGDI1 single mutants exhibited significantly reduced height and longer and thinner grains,whereas OsGEF3 mutants had reduced grain length compared to the wild type.Haplotype and eGWAS analyses showed that natural variations in the three genes affected gene expression in reproductive tissues that were significantly associated with the phenotypic variation.BiFC assays demonstrated that GDI1 and GEF3 interacted with grain-size protein GS3,pointing to a role of these genes in the regulation of grain size and plant architecture connected to heterotrimeric G-proteins in rice.展开更多
文摘Objective To test the resuscitative effects from prolonged ventricular fibrillation by epinephrine combined with sodium hydrogen exchanger isoform 1 inhibitor Cariporide. Methods 16 rats were received a 3 mg/kg bolus of Cariporide or the same volume of 0.9%NaCl solution (control) 15 seconds before completion 12 minutes untreated VF. Chest compression (CC) was started for a total of 8 minutes. Adjusted the depth of compressor so that the aortic diastolic pressure to 25～28 mmHg during the 2nd minute of CC. Fix the depth of the piston and this depth was used throughout the remaining 6 minutes of CC. 10 seconds before starting the 3rd minute of chest compression, injected epinephrine (30 μg/kg). Recorded the time at which restoration of spontaneous circulation (ROSC) occurred in Cariporide treated rats. Electrical defibrillation was timed in control group to match the time of spontaneous defibrillation in Cariporide treated rats. To the rats, which cant be defibrillated spontaneously, received chest compression and rescues electrical shocks. Results compared with control group, with the same CC depth, Cariporide treated rats received the higher and longer lasting coronary perfusion pressure (P< 0.05), higher resuscitative rate (P< 0.05), less post resuscitative ventricular ectopic activities (P< 0.001), better hemodynamic effects and longer survival time (P< 0.05). Conclusion Epinephrine combined with sodium hydrogen exchanger isoform 1 inhibitor Cariporide may represent a novel and remarkably effective intervention for resuscitation from prolonged VF.
文摘The Na+/Ca2+ exchanger plays an important role in regulation of airway smooth muscle contraction by regulating intracellular calcium, and is a potential target for treatment of asthma. To test modulation of exchanger activity, we used Xenopus oocytes as model system. Na+/Ca2+ exchanger was expressed in the cells by microinjection of cRNA of the exchanger isoform NCX1. The activity of NCX1 was determined as Ni2+-sensitive current under voltage clamp in low Cl– medium and in the presence of the Cl–-channel inhibitor niflumic acid. Only this composition of solution allowed determining NCX1-mediated current with sufficient accuracy. Among a few tested Chinese herbal drugs, glycyrrhizic acid turned out to be a potent inhibitor of NCX1 with an apparent IC50 value of 40 μM. Previous work had revealed elevated cyclophylin A concentration in serum of asthmatic rats after receiving acupuncture treatment. Extracellular incubation of the oocytes in cyclophylin A for one day led to significant inhibition with an apparent IC50 value of about 1 μM. We suggest that effects of acupuncture and application of glycyrrhizic acid as an active constituent of Chinese medicine for treatment of asthma symptoms may partially be attributed to inhibition of the reversed mode of NCX1 and that these compounds may stimulate the search for new anti-asthmatic drugs.
文摘A series of novel derivatives of ligustrazine linked with substituted benzoyl guanidine were synthesized. These compounds have not been reported in literature, and their chemical structures were confirmed by IR, ^1H NMR and MS. The results of NHE1 inhibitory activity test showed that compounds I2, I3, I4, I6, and I7 possess more potent NHE1 inhibitory activity than cariporide.
文摘Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug,the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors(SGLT2i)showed efficacy in decreasing overall mortality,hospitalization,and sudden death in patients of this very population,in whom chronic or acute ischemia count among the first cause.Remarkably,this benefit was observed independently from diabetic status,and benefited both preserved and altered ventricular ejection fraction.This feature,observed in several large randomized controlled trials,suggests additional effects from SGLT2i beyond isolated glycemia control.Indeed,both in-vitro and animal models suggest that inhibiting the Na+/H+exchanger(NHE)may be key to preventing ischemia/reperfusion injuries,and by extension may hold a similar role in ischemic damage control and ischemic preconditioning.Yet,several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules.Because of a large therapeutic margin with few adverse events,ease of prescription and potential pharmacological efficacity,SGLT2i could be candidate for wider indications.In this review,we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation,by first listing known mechanisms,including metabolic switch,prevention of lethal arrythmias and others,which portend the latter,and second,hypothesize how the former may interact with these mechanisms.
基金supported by the National Natural Science Foundation of China(32072042,31821005,32000370)Ten-Thousand Talents Programs,Fundamental Research Funds for the Central Universities(2662020SKPY006)+1 种基金Wuhan Applied Foundational Frontier Project(2020020601012257)Hubei Hongshan Laboratory(2021hszd005).
文摘Guanine nucleotide exchange factors(GEFs)and guanine nucleotide-dissociation inhibitors(GDIs)regulate small GTPase proteins,which function as molecular switches in various signaling pathways,but their identification and functions in plants are not well understood.Using in-silico analysis and transgenic approaches,respectively,we dissected the evolutionary relationships and functions of all GEF and GDI genes in rice.Intron-exon distribution and phylogenetic analyses identified 30 GEF and 10 GDI genes in rice that shared close evolutionary relationships with other eukaryotes.Tissue-specific expression and co-expression analyses revealed that phylogenetically related genes had similar expression patterns.GEF and GDI genes were highly expressed in panicles,hulls,and stamens.Co-expression network analysis identified panicle and stamen-specific modules of co-expressed genes in both families.Mapping of these genes in known protein interactomes further identified two and one small G-protein sub-networks.A mutant library of GEF and GDI families was constructed by CRISPR knockout of each gene,and their genotypes and phenotypes were confirmed.Phenotype changes occurred with the mutation of only three genes(OsGEF5,OsGDI1,and OsGEF3).OsGEF5 and OsGDI1 single mutants exhibited significantly reduced height and longer and thinner grains,whereas OsGEF3 mutants had reduced grain length compared to the wild type.Haplotype and eGWAS analyses showed that natural variations in the three genes affected gene expression in reproductive tissues that were significantly associated with the phenotypic variation.BiFC assays demonstrated that GDI1 and GEF3 interacted with grain-size protein GS3,pointing to a role of these genes in the regulation of grain size and plant architecture connected to heterotrimeric G-proteins in rice.
