Poly(ADP-ribose)(PAR),a polymer of ADP-ribose,is synthesized by PAR po-lymerase and is crucial for the survival of cancer cells due to its vital functions in DNA repair and post-translational modifications.Beyond its ...Poly(ADP-ribose)(PAR),a polymer of ADP-ribose,is synthesized by PAR po-lymerase and is crucial for the survival of cancer cells due to its vital functions in DNA repair and post-translational modifications.Beyond its supportive role,PAR also triggers cancer cell death by excessive accumulation of PAR leading to an energy crisis and parthanatos.This phenomenon underscores the potential of targeting PAR regulation as a novel anticancer strategy,and the rationale would present an engaging topic in the field of anticancer research.Therefore,this editorial provides an overview of the mechanisms determining cancer cell fate,emphasizing the central role of PAR.It further introduces promising methods for modulating PAR concentrations that may pave the way for innovative anticancer therapies.展开更多
BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breas...BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.展开更多
Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that jimit the pathological changes and improve the behavioral outcome have been w...Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that jimit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially per- oxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly（ADP-ribose） polymerase （PARP） upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neu- ronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the in- volvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.展开更多
The highly conserved abundant nuclear protein poly （ADP-ribose） polymerase-1 （PARP-1） is activated by DNA damage. PARP-1 activation is associated in DNA repair, cell death and inflammation. Since oxidative stress ...The highly conserved abundant nuclear protein poly （ADP-ribose） polymerase-1 （PARP-1） is activated by DNA damage. PARP-1 activation is associated in DNA repair, cell death and inflammation. Since oxidative stress induced robust DNA damage and wide spread inflamma- tory responses are common pathologies of various CNS diseases, the attention towards PARP-1 as a therapeutic target has been amplifying. This review highlights the multiple roles of PARP- 1 in neurological diseases and po- tential of PARP- 1 inhibitors to enter clinical translation.展开更多
The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult ...The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult to recognize in the early stages.Furthermore,at advanced stages,there are important challenges to achieve clinical benefit and symptom resolution,even with the use of an expanded spectrum of anticancer drugs.Recently,a point of reduced susceptibility to conventional chemotherapies by breast cancer susceptibility gene(BRCA)mutations led to a new perspective for overcoming the resistance of pancreatic cancer within the framework of increased genome instability.Poly(ADP-Ribose)polymerase(PARP)-1 is an enzyme that can regulate intrinsic functions,such as response to DNA damage.Therefore,in an environment where germline mutations in BRCAs(BRCAness)inhibit homologous recombination in DNA damage,resulting in a lack of DNA damage response,a key role of PARP-1 for the adaptation of the genome instability could be further emphasized.Here,we summarized the key functional role of PARP-1 in genomic instability of pancreatic cancer with the BRCAness phenotype and listed clinical applications and outcomes of PARP-1 inhibitors to highlight the importance of targeting PARP-1 activity.展开更多
Poly （ADP-ribose） polymerase-1 （PARP-1） can exacerbate ischemic brain injury and lessen ischemic neuronal death, which may be associated with PARP-1 polymorphisms. The present study investigated human PARP-1 gene ...Poly （ADP-ribose） polymerase-1 （PARP-1） can exacerbate ischemic brain injury and lessen ischemic neuronal death, which may be associated with PARP-1 polymorphisms. The present study investigated human PARP-1 gene polymorphisms in various Chinese nationalities, the results of which could potentially help in the treatment and prevention of neurologic diseases. Genetic polymorphisms of seven exons in the PARP-1 gene, in 898 Chinese Han, Buyi, Shui, Miao, and Zhuang subjects, were investigated by PCR-single-strand conformation polymorphism. A single-strand conformation polymorphism variant in exons 12, 13, 16, and 17 of the PARP-1 gene was identified in 148 people, with two stationary bands showing three degenerative single strands. Results showed that the PARP-1 gene polymorphisms exist in various nationalities, and may act as a biomarker for susceptibility to disease.展开更多
Background Poly（ADP-ribose） polymerase （PARP） plays an important role in the death of retinal capillary cells in diabetic retinopathy （DR） partly via its regulation of nuclear factor kappa B （NF-κB）. The curr...Background Poly（ADP-ribose） polymerase （PARP） plays an important role in the death of retinal capillary cells in diabetic retinopathy （DR） partly via its regulation of nuclear factor kappa B （NF-κB）. The current study investigated the effect of the regimen of Gaoshan Hongjingtian （RG） on the mechanism of PARP regulation of NF-κB, and demonstrated the possible impact of the RG and Gaoshan Hongjingtian （Rhodiola sachalinensis, RS） on diabetic retinopathy. Methods Wistar rats were made diabetic by administering streptozotocin. They were then assigned to three groups at random. After 2 months, the three groups of these diabetic rats were treated with RS or RG, or untreated. Analyses of expression levels of PARP, NF-κB, and intercellular adhesion molecule-1 （ICAM-1） in the retinas of rats in different groups were performed by Western blotting and immunohistochemical assays, and mRNA levels of NF-κB and ICAM-1 were determined by real-time polymerase chain reaction （PCR）. In addition, the basement membranes of capillaries in the rats＇ retinas were observed using electron microscopy, and diabetes-induced capillary degeneration （ghost pericytes and acellular capillaries） were quantitated. Results From the third month after the injection of streptozotocin, the diabetic rats were given daily RG, RS or tap water separately. The diabetic rats failed to gain weight compared with normal age-matched rats, whereas their glycated hemoglobin levels were significantly increased. After 5 months, the mRNA levels of NF-KB and ICAM-1 and the protein expression of PARP, NF-κB, and ICAM-1 were significantly increased in the retinas of diabetic rats in the untreated group compared with the nondiabetic controls. After 8 months, the number of degenerated retinal capillaries （ghost pericytes and acellular capillaries） was significantly increased in the diabetic rats in the untreated group compared with normal age-matched rats. RG and RS inhibited diabetes-induced over-expression of PARP, NF-KB, and ICAM-1 in the retinas of diabetic rats at the end of 5-month diabetic duration. Treatment using RG and RS significantly inhibited increases in the number of acellular capillaries and pericyte ghosts and suppressed the basement membrane thickening in the retinas of rats with diabetes for 8 months compared with the control diabetic rats. Conclusions These results indicate that PARP plays an important role in the pathogenesis of diabetic retinopathy. RS and RG may have acted on the mechanism of PARP regulation of NF-κB, which suppressed the expression of NF-KB and ICAM-1, and led to the inhibition of retinal capillary degeneration.展开更多
A new method has been developed to assay poly(ADP-ribose) polymerase (PARP) activity in plant tissues through determining the content of nicotinamide (NIC) produced by enzymatic reaction by linear sweeping polarograph...A new method has been developed to assay poly(ADP-ribose) polymerase (PARP) activity in plant tissues through determining the content of nicotinamide (NIC) produced by enzymatic reaction by linear sweeping polarographic method. The detection limit of NIC was 0.03μmol/L, the calibration graph was linear up to 5μmol/L ( r = 0.999). The recoveries were approximately in the range of 92% to 98% and the relative standard deviations were less展开更多
Background Poly （ADP-ribose） polymerase （PARP） has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion （I/R） injury. 3,4-dihydro-5-[4-（1-piperidinyl）butoxy]-l（2H）-isoqu...Background Poly （ADP-ribose） polymerase （PARP） has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion （I/R） injury. 3,4-dihydro-5-[4-（1-piperidinyl）butoxy]-l（2H）-isoquinolinone （DPQ）, a potent PARP inhibitor, has cardiac protective effects. Because the underlying mechanisms are not understood, we investigated the effect of DPQ on heart I/R injury and its mechanisms. Methods Studies were performed with I/R rats＇ hearts. DPQ was used to inhibit the activation of PARP. Cardiac function and cellular apoptosis were assessed. The activation of PARP, transcription factor nuclear factor-kappaB （NF-KB）, intercellular adhesion molecule-1 （ICAM-1）, cyclooxygenase-2 （COX-2） and matrix metalloproteinase-9 （MMP-9） were evaluated. We also evaluated expression of Akt and two of its downstream targets, glycogen synthase kinase-313 （GSK- 3β） and forkhead transcription factor FOXO3a. Results Administration of DPQ significantly decreased the activation of PARP and cellular apoptosis from （35±5）% to （20±4）% and simultaneously improved the cardiac function. DPQ reduced the expressions of NF-KB, ICAM-1, COX-2 and MMP-9 in rat heart and facilitated the activations of phosphor-Akt, phosphor-GSK-3β and phosphor-FOXO3a. Conclusion The protective effects of DPQ were associated with the suppression of inflammation and the activation of the Akt signalling pathways suggesting that the inhibition of poly （ADP-ribose） polymerase reduced heart I/R injury in rats.展开更多
Background Severe sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients.This study aimed to investigate the association of poly（ADP-ribose） polymerase-1 （PARP-1） activi...Background Severe sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients.This study aimed to investigate the association of poly（ADP-ribose） polymerase-1 （PARP-1） activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock.Methods A total of 64 patients with septic shock were divided into the survival group （n=41） and the nonsurvival group （n=23） according to mortality at 28 days after enrollments.PARP-1 activity in circulating mononuclear cells,brain natriuretic peptide,Acute Physiology and Chronic Health Evaluation Ⅱ score,the cardiac index （CI）,the cardiac function index （CFI）,global ejection fraction （GEF）,and the left ventricular contractility index （dp/dt max） were measured after admission to the intensive care unit.Results PARP-1 activity in circulating mononuclear cells of nonsurvival patients with septic shock was significantly higher than that in survival patients.PARP-1 activity in circulating mononuclear cells was strongly,negatively correlated with the CI,the CFI,GEE and dp/dt max.Multiple Logistic regression analysis showed that PARP-1 activity in circulating mononuclear cells was an independent risk factor of myocardial dysfunction.The optimal cutoff point of PARP-1 activity for predicting 28-day mortality was 942 nmol/L with a sensibility of 78.2% and specificity of 65.1%.Conclusion PARP-1 activity in circulating mononuclear cells is significantly associated with myocardial dysfunction and may have prognostic value in patients with septic shock.展开更多
The aim of this paper is to study the changes of apoptosis and cell cycle progression in HeLa cells after the poly(ADP-ribose)polymerase(PARP)was inhibited by its inhibitor 3-aminobenzamide(3-AB)and the mechan-isms of...The aim of this paper is to study the changes of apoptosis and cell cycle progression in HeLa cells after the poly(ADP-ribose)polymerase(PARP)was inhibited by its inhibitor 3-aminobenzamide(3-AB)and the mechan-isms of PARP action on HeLa cells damaged by irra-diation.Flow cytometry(FCM)was used to examine the PARP expression and the percentage of apoptotic cells and cell cycle progression.The percentage of HeLa cells with positive expression of PARP protein 2,4,8 and 12 h after administrated with 3-AB was significantly lower than that of the control(P<0.01).The percentages of apoptotic cells in the 3-AB plus irradiation group at the time points of 2,8,12 and 24 h after 2 Gy irradiation were higher than that in the irradiation group(P<0.01 or P<0.05)and the percentage of G2 cells decreased signifi-cantly(P<0.01 or P<0.05).It indicates that 3-AB can rapidly inhibit PARP expression of HeLa cells,promote cell apoptosis and block G2 arrest induced by irradiation.展开更多
Programmed cell death (PCD) during secondary xylem differentiation in Eucommia ulmoides Oliv. was examined using electron microscopy and by investigation of DNA fragmentation and degradation of caspase-like proteases ...Programmed cell death (PCD) during secondary xylem differentiation in Eucommia ulmoides Oliv. was examined using electron microscopy and by investigation of DNA fragmentation and degradation of caspase-like proteases (CLPs). DNA ladders were detected in developing secondary xylem by gel electrophoresis. DNA fragmentation was further confirmed by using the TdT-mediated dUTP nick-end labeling (TUNEL) method. Western blotting analysis showed that CLPs (caspase-8- and caspase-3-like proteases) and PARP (poly (ADP-ribose) polymerase) were degraded during secondary xylem differentiation. The results thus indicated that secondary xylem differentiation in E ulmoides was a typical process of PCD and the degradation of CLPs might be a constitutive PCD event during secondary xylem differentiation.展开更多
文摘Poly(ADP-ribose)(PAR),a polymer of ADP-ribose,is synthesized by PAR po-lymerase and is crucial for the survival of cancer cells due to its vital functions in DNA repair and post-translational modifications.Beyond its supportive role,PAR also triggers cancer cell death by excessive accumulation of PAR leading to an energy crisis and parthanatos.This phenomenon underscores the potential of targeting PAR regulation as a novel anticancer strategy,and the rationale would present an engaging topic in the field of anticancer research.Therefore,this editorial provides an overview of the mechanisms determining cancer cell fate,emphasizing the central role of PAR.It further introduces promising methods for modulating PAR concentrations that may pave the way for innovative anticancer therapies.
文摘BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.
基金Department of Biotechnology Govt of India,for their financial support to Dr.Ashutosh Kumar via grant BT/527/NE/TBP/2013the financial support from Department of Pharmaceuticals,Ministry of Chemical and Fertilizers and NIPER Hyderabad for their support
文摘Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that jimit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially per- oxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly（ADP-ribose） polymerase （PARP） upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neu- ronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the in- volvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.
文摘The highly conserved abundant nuclear protein poly （ADP-ribose） polymerase-1 （PARP-1） is activated by DNA damage. PARP-1 activation is associated in DNA repair, cell death and inflammation. Since oxidative stress induced robust DNA damage and wide spread inflamma- tory responses are common pathologies of various CNS diseases, the attention towards PARP-1 as a therapeutic target has been amplifying. This review highlights the multiple roles of PARP- 1 in neurological diseases and po- tential of PARP- 1 inhibitors to enter clinical translation.
文摘The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult to recognize in the early stages.Furthermore,at advanced stages,there are important challenges to achieve clinical benefit and symptom resolution,even with the use of an expanded spectrum of anticancer drugs.Recently,a point of reduced susceptibility to conventional chemotherapies by breast cancer susceptibility gene(BRCA)mutations led to a new perspective for overcoming the resistance of pancreatic cancer within the framework of increased genome instability.Poly(ADP-Ribose)polymerase(PARP)-1 is an enzyme that can regulate intrinsic functions,such as response to DNA damage.Therefore,in an environment where germline mutations in BRCAs(BRCAness)inhibit homologous recombination in DNA damage,resulting in a lack of DNA damage response,a key role of PARP-1 for the adaptation of the genome instability could be further emphasized.Here,we summarized the key functional role of PARP-1 in genomic instability of pancreatic cancer with the BRCAness phenotype and listed clinical applications and outcomes of PARP-1 inhibitors to highlight the importance of targeting PARP-1 activity.
基金the National Natural Science Foundation of China, No. 30972500the Natural Science Foundation of Guangdong Province, No. 7301507
文摘Poly （ADP-ribose） polymerase-1 （PARP-1） can exacerbate ischemic brain injury and lessen ischemic neuronal death, which may be associated with PARP-1 polymorphisms. The present study investigated human PARP-1 gene polymorphisms in various Chinese nationalities, the results of which could potentially help in the treatment and prevention of neurologic diseases. Genetic polymorphisms of seven exons in the PARP-1 gene, in 898 Chinese Han, Buyi, Shui, Miao, and Zhuang subjects, were investigated by PCR-single-strand conformation polymorphism. A single-strand conformation polymorphism variant in exons 12, 13, 16, and 17 of the PARP-1 gene was identified in 148 people, with two stationary bands showing three degenerative single strands. Results showed that the PARP-1 gene polymorphisms exist in various nationalities, and may act as a biomarker for susceptibility to disease.
基金This study was supported by a grant from the National Natural Science Foundation of China （No. 81072844）.
文摘Background Poly（ADP-ribose） polymerase （PARP） plays an important role in the death of retinal capillary cells in diabetic retinopathy （DR） partly via its regulation of nuclear factor kappa B （NF-κB）. The current study investigated the effect of the regimen of Gaoshan Hongjingtian （RG） on the mechanism of PARP regulation of NF-κB, and demonstrated the possible impact of the RG and Gaoshan Hongjingtian （Rhodiola sachalinensis, RS） on diabetic retinopathy. Methods Wistar rats were made diabetic by administering streptozotocin. They were then assigned to three groups at random. After 2 months, the three groups of these diabetic rats were treated with RS or RG, or untreated. Analyses of expression levels of PARP, NF-κB, and intercellular adhesion molecule-1 （ICAM-1） in the retinas of rats in different groups were performed by Western blotting and immunohistochemical assays, and mRNA levels of NF-κB and ICAM-1 were determined by real-time polymerase chain reaction （PCR）. In addition, the basement membranes of capillaries in the rats＇ retinas were observed using electron microscopy, and diabetes-induced capillary degeneration （ghost pericytes and acellular capillaries） were quantitated. Results From the third month after the injection of streptozotocin, the diabetic rats were given daily RG, RS or tap water separately. The diabetic rats failed to gain weight compared with normal age-matched rats, whereas their glycated hemoglobin levels were significantly increased. After 5 months, the mRNA levels of NF-KB and ICAM-1 and the protein expression of PARP, NF-κB, and ICAM-1 were significantly increased in the retinas of diabetic rats in the untreated group compared with the nondiabetic controls. After 8 months, the number of degenerated retinal capillaries （ghost pericytes and acellular capillaries） was significantly increased in the diabetic rats in the untreated group compared with normal age-matched rats. RG and RS inhibited diabetes-induced over-expression of PARP, NF-KB, and ICAM-1 in the retinas of diabetic rats at the end of 5-month diabetic duration. Treatment using RG and RS significantly inhibited increases in the number of acellular capillaries and pericyte ghosts and suppressed the basement membrane thickening in the retinas of rats with diabetes for 8 months compared with the control diabetic rats. Conclusions These results indicate that PARP plays an important role in the pathogenesis of diabetic retinopathy. RS and RG may have acted on the mechanism of PARP regulation of NF-κB, which suppressed the expression of NF-KB and ICAM-1, and led to the inhibition of retinal capillary degeneration.
文摘A new method has been developed to assay poly(ADP-ribose) polymerase (PARP) activity in plant tissues through determining the content of nicotinamide (NIC) produced by enzymatic reaction by linear sweeping polarographic method. The detection limit of NIC was 0.03μmol/L, the calibration graph was linear up to 5μmol/L ( r = 0.999). The recoveries were approximately in the range of 92% to 98% and the relative standard deviations were less
基金This study was supported by grants from the Natural Science Foundation of Shandong Province, China （No.ZR2010HM069） and the Technology Development Projects of Taian City （No. 20093077）.
文摘Background Poly （ADP-ribose） polymerase （PARP） has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion （I/R） injury. 3,4-dihydro-5-[4-（1-piperidinyl）butoxy]-l（2H）-isoquinolinone （DPQ）, a potent PARP inhibitor, has cardiac protective effects. Because the underlying mechanisms are not understood, we investigated the effect of DPQ on heart I/R injury and its mechanisms. Methods Studies were performed with I/R rats＇ hearts. DPQ was used to inhibit the activation of PARP. Cardiac function and cellular apoptosis were assessed. The activation of PARP, transcription factor nuclear factor-kappaB （NF-KB）, intercellular adhesion molecule-1 （ICAM-1）, cyclooxygenase-2 （COX-2） and matrix metalloproteinase-9 （MMP-9） were evaluated. We also evaluated expression of Akt and two of its downstream targets, glycogen synthase kinase-313 （GSK- 3β） and forkhead transcription factor FOXO3a. Results Administration of DPQ significantly decreased the activation of PARP and cellular apoptosis from （35±5）% to （20±4）% and simultaneously improved the cardiac function. DPQ reduced the expressions of NF-KB, ICAM-1, COX-2 and MMP-9 in rat heart and facilitated the activations of phosphor-Akt, phosphor-GSK-3β and phosphor-FOXO3a. Conclusion The protective effects of DPQ were associated with the suppression of inflammation and the activation of the Akt signalling pathways suggesting that the inhibition of poly （ADP-ribose） polymerase reduced heart I/R injury in rats.
基金This study was supported by the grants from the National Natural Science Foundation of China （No. 81171784） and Zhejiang Province Natural Science Fotmdation （No. Z2100237 and No. Y2110801）.
文摘Background Severe sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients.This study aimed to investigate the association of poly（ADP-ribose） polymerase-1 （PARP-1） activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock.Methods A total of 64 patients with septic shock were divided into the survival group （n=41） and the nonsurvival group （n=23） according to mortality at 28 days after enrollments.PARP-1 activity in circulating mononuclear cells,brain natriuretic peptide,Acute Physiology and Chronic Health Evaluation Ⅱ score,the cardiac index （CI）,the cardiac function index （CFI）,global ejection fraction （GEF）,and the left ventricular contractility index （dp/dt max） were measured after admission to the intensive care unit.Results PARP-1 activity in circulating mononuclear cells of nonsurvival patients with septic shock was significantly higher than that in survival patients.PARP-1 activity in circulating mononuclear cells was strongly,negatively correlated with the CI,the CFI,GEE and dp/dt max.Multiple Logistic regression analysis showed that PARP-1 activity in circulating mononuclear cells was an independent risk factor of myocardial dysfunction.The optimal cutoff point of PARP-1 activity for predicting 28-day mortality was 942 nmol/L with a sensibility of 78.2% and specificity of 65.1%.Conclusion PARP-1 activity in circulating mononuclear cells is significantly associated with myocardial dysfunction and may have prognostic value in patients with septic shock.
基金supported by the National Natural Science Foundation of China(Grant No.30570546).
文摘The aim of this paper is to study the changes of apoptosis and cell cycle progression in HeLa cells after the poly(ADP-ribose)polymerase(PARP)was inhibited by its inhibitor 3-aminobenzamide(3-AB)and the mechan-isms of PARP action on HeLa cells damaged by irra-diation.Flow cytometry(FCM)was used to examine the PARP expression and the percentage of apoptotic cells and cell cycle progression.The percentage of HeLa cells with positive expression of PARP protein 2,4,8 and 12 h after administrated with 3-AB was significantly lower than that of the control(P<0.01).The percentages of apoptotic cells in the 3-AB plus irradiation group at the time points of 2,8,12 and 24 h after 2 Gy irradiation were higher than that in the irradiation group(P<0.01 or P<0.05)and the percentage of G2 cells decreased signifi-cantly(P<0.01 or P<0.05).It indicates that 3-AB can rapidly inhibit PARP expression of HeLa cells,promote cell apoptosis and block G2 arrest induced by irradiation.
文摘Programmed cell death (PCD) during secondary xylem differentiation in Eucommia ulmoides Oliv. was examined using electron microscopy and by investigation of DNA fragmentation and degradation of caspase-like proteases (CLPs). DNA ladders were detected in developing secondary xylem by gel electrophoresis. DNA fragmentation was further confirmed by using the TdT-mediated dUTP nick-end labeling (TUNEL) method. Western blotting analysis showed that CLPs (caspase-8- and caspase-3-like proteases) and PARP (poly (ADP-ribose) polymerase) were degraded during secondary xylem differentiation. The results thus indicated that secondary xylem differentiation in E ulmoides was a typical process of PCD and the degradation of CLPs might be a constitutive PCD event during secondary xylem differentiation.
