Post-resuscitation myocardial dysfunction(PRMD)is the most severe myocardial ischemia-reperfusion injury(MIRI)and is characterized by difficult treatment and poor prognosis.Research has shown the protective effects of...Post-resuscitation myocardial dysfunction(PRMD)is the most severe myocardial ischemia-reperfusion injury(MIRI)and is characterized by difficult treatment and poor prognosis.Research has shown the protective effects of the rational use of ivabradine(IVA)against PRMD,however,the molecular mechanisms of IVA remain unknown.In this study,an ischemia-reperfusion injury(IRI)model was established using hypoxic chambers.The results demonstrated that pretreatment with IVA reduced IRI-induced cytotoxicity and apoptosis.IVA attenuated mitochondrial damage,eliminated excess reactive oxygen species(ROS),suppressed IRI-induced ATP and NAD+,and increased the AMP/ATP ratio.We further found that IVA increased the mRNA levels of sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)and upregulated the expression levels of phosphorylated AMP-activated protein kinase(p-AMPK)/AMPK,SIRT1,and PGC-1αproteins.Interestingly,no change in AMPK mRNA levels was observed.Cardiomyocyte energy metabolism significantly changed after IRI.The aim of this study was to demonstrate the cardioprotective effect of Ivabradine via the AMPK/SIRT1/PGC-1αsignaling pathway in myocardial ischemia/reperfusion injury-induced in H9c2 cell.展开更多
Poly(ADP-ribosyl)ation(PARylation)is a specific form of post-translational modification(PTM)predominantly triggered by the activation of poly-ADP-ribose polymerase 1(PARP1).However,the role and mechanism of PARylation...Poly(ADP-ribosyl)ation(PARylation)is a specific form of post-translational modification(PTM)predominantly triggered by the activation of poly-ADP-ribose polymerase 1(PARP1).However,the role and mechanism of PARylation in the advancement of acute kidney injury(AKI)remain undetermined.Here,we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI,consistent with renal biopsy findings in patients with AKI.This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4(H3K4me3).Furthermore,a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models.Mechanistically,liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1(RACK1),thereby facilitating its subsequent phosphorylation.Moreover,the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α(HIF-1α)degradation,thereby exacerbating kidney injury.Additionally,we identified a PARP1 proteolysis-targeting chimera(PROTAC),A19,as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34,a previously identified PARP1 inhibitor.Collectively,both genetic and drug-based inhibition of PARylation mitigated kidney injury,indicating that the PARylated RACK1/HIF-1αaxis could be a promising therapeutic target for AKI treatment.展开更多
HDAC7,a member of class IIa HDACs,plays a pivotal regulatory role in tumor,immune,fibrosis,and angiogenesis,rendering it a potential therapeutic target.Nevertheless,due to the high similarity in the enzyme active site...HDAC7,a member of class IIa HDACs,plays a pivotal regulatory role in tumor,immune,fibrosis,and angiogenesis,rendering it a potential therapeutic target.Nevertheless,due to the high similarity in the enzyme active sites of class IIa HDACs,inhibitors encounter challenges in discerning differences among them.Furthermore,the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes,leading to a limited impact of enzymatic inhibitors on their function.In this study,proteolysis targeting chimera(PROTAC)technology was employed to develop HDAC7 drugs.We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma(DLBCL)and acute myeloid leukemia(AML)cells.Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7,thereby exerting proliferative inhibition in DLBCL.Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies,particularly in DLBCL and AML.展开更多
Modern electric power systems have increased the usage of switching power converters.These tightly regulated switching power converters behave as constant power loads(CPLs).They exhibit a negative incremental impedanc...Modern electric power systems have increased the usage of switching power converters.These tightly regulated switching power converters behave as constant power loads(CPLs).They exhibit a negative incremental impedance in small signal analysis.This negative impedance degrades the stability margin of the interaction between CPLs and their feeders,which is known as the negative impedance instability problem.The feeder can be an LC input filter or an upstream switching converter.Active damping methods are preferred for the stabilization of the system.This is due to their higher power efficiency over passive damping methods.Based on different sources of damping effect,this paper summarizes and classifies existing active damping methods into three categories.The paper further analyzes and compares the advantages and disadvantages of each active damping method.展开更多
基金the National Natural Science Foundation Youth Science Foundation(No.81601661)the Science Foundation for Post-doctoral researchers in Anhui Province of China(No.2016B140).
文摘Post-resuscitation myocardial dysfunction(PRMD)is the most severe myocardial ischemia-reperfusion injury(MIRI)and is characterized by difficult treatment and poor prognosis.Research has shown the protective effects of the rational use of ivabradine(IVA)against PRMD,however,the molecular mechanisms of IVA remain unknown.In this study,an ischemia-reperfusion injury(IRI)model was established using hypoxic chambers.The results demonstrated that pretreatment with IVA reduced IRI-induced cytotoxicity and apoptosis.IVA attenuated mitochondrial damage,eliminated excess reactive oxygen species(ROS),suppressed IRI-induced ATP and NAD+,and increased the AMP/ATP ratio.We further found that IVA increased the mRNA levels of sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)and upregulated the expression levels of phosphorylated AMP-activated protein kinase(p-AMPK)/AMPK,SIRT1,and PGC-1αproteins.Interestingly,no change in AMPK mRNA levels was observed.Cardiomyocyte energy metabolism significantly changed after IRI.The aim of this study was to demonstrate the cardioprotective effect of Ivabradine via the AMPK/SIRT1/PGC-1αsignaling pathway in myocardial ischemia/reperfusion injury-induced in H9c2 cell.
基金supported by the National Natural Science Foundation of China(No.82270738)National Key R&D Program(2022YFC2502503,China)Scientific Research Project of Education Department of Anhui Province(No.2023AH053398,China).
文摘Poly(ADP-ribosyl)ation(PARylation)is a specific form of post-translational modification(PTM)predominantly triggered by the activation of poly-ADP-ribose polymerase 1(PARP1).However,the role and mechanism of PARylation in the advancement of acute kidney injury(AKI)remain undetermined.Here,we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI,consistent with renal biopsy findings in patients with AKI.This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4(H3K4me3).Furthermore,a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models.Mechanistically,liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1(RACK1),thereby facilitating its subsequent phosphorylation.Moreover,the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α(HIF-1α)degradation,thereby exacerbating kidney injury.Additionally,we identified a PARP1 proteolysis-targeting chimera(PROTAC),A19,as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34,a previously identified PARP1 inhibitor.Collectively,both genetic and drug-based inhibition of PARylation mitigated kidney injury,indicating that the PARylated RACK1/HIF-1αaxis could be a promising therapeutic target for AKI treatment.
基金support from the National Natural Science Foundation of China(Nos.82173660,82103975)Zhejiang Provincial Key Research&Development Plan(No.2023C03111,China)+1 种基金the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province(Nos.LR21H300003,LR22H310002,China)the Natural Science Foundation of Zhejiang Province(No.LQ21H300005,China).
文摘HDAC7,a member of class IIa HDACs,plays a pivotal regulatory role in tumor,immune,fibrosis,and angiogenesis,rendering it a potential therapeutic target.Nevertheless,due to the high similarity in the enzyme active sites of class IIa HDACs,inhibitors encounter challenges in discerning differences among them.Furthermore,the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes,leading to a limited impact of enzymatic inhibitors on their function.In this study,proteolysis targeting chimera(PROTAC)technology was employed to develop HDAC7 drugs.We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma(DLBCL)and acute myeloid leukemia(AML)cells.Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7,thereby exerting proliferative inhibition in DLBCL.Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies,particularly in DLBCL and AML.
文摘Modern electric power systems have increased the usage of switching power converters.These tightly regulated switching power converters behave as constant power loads(CPLs).They exhibit a negative incremental impedance in small signal analysis.This negative impedance degrades the stability margin of the interaction between CPLs and their feeders,which is known as the negative impedance instability problem.The feeder can be an LC input filter or an upstream switching converter.Active damping methods are preferred for the stabilization of the system.This is due to their higher power efficiency over passive damping methods.Based on different sources of damping effect,this paper summarizes and classifies existing active damping methods into three categories.The paper further analyzes and compares the advantages and disadvantages of each active damping method.
