BACKGROUND The biochemical phenomenon defined as poly adenosine diphosphate(ADP)-ribosylation(PARylation)is essential for the progression of pancreatic cancer.However,the excessive accumulation of poly ADP-ribose(PAR)...BACKGROUND The biochemical phenomenon defined as poly adenosine diphosphate(ADP)-ribosylation(PARylation)is essential for the progression of pancreatic cancer.However,the excessive accumulation of poly ADP-ribose(PAR)induces apoptosis-inducing factor(AIF)release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer cells.AIM To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR accumulation.METHODS Two pancreatic cancer cell lines,AsPC-1 and CFPAC-1 were used for the study.Calcium influx and mitochondrial reactive oxygen species(ROS)were observed by fluorescence staining.Changes in enzyme levels,as well as PAR accumulation and energy metabolism,were measured using assay kits.AIF-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium administration.RESULTS Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer cells.Then,excess PAR accumulation,decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels,and energy deprivation were observed.In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels.CONCLUSION This study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer,however elucidating a clear mode of action remains a challenge,and it should be accompanied by further studies to assess its potential for clinical application.展开更多
The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor microenvironment.Particularly,it is primarily associated with genomic instability that is the gradual ...The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor microenvironment.Particularly,it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression.Based on this background,the potential to focus on poly[adenosine diphosphate(ADP)-ribose]polymerase(PARP)-1 and poly-ADP ribosylation(PARylation)as the main causes of malignant formation of CRC may be considered.One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid(DNA)repair function,which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide.PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes.Given the high importance of these processes in CRC,it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression.Therefore,this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles;furthermore,it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC.This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC,which may present the potential to identify various research topics that can be challenged both nonclinically and clinically.展开更多
目的:系统评价PARPi治疗转移性去势抵抗性前列腺癌(mCRPC)的有效性及安全性,以期为临床决策供循证医学证据。方法:依据纳入和排除标准,网络检索2015年1月~2023年6月PubMed、Web of Science、Embace、Clinicial.gov中有关PARPi治疗mCRPC...目的:系统评价PARPi治疗转移性去势抵抗性前列腺癌(mCRPC)的有效性及安全性,以期为临床决策供循证医学证据。方法:依据纳入和排除标准,网络检索2015年1月~2023年6月PubMed、Web of Science、Embace、Clinicial.gov中有关PARPi治疗mCRPC的随机对照试验文献,使用RevMan5.4及Stata17.0软件对数据进行Meta分析。结果:纳入7篇随机对照试验文献,共1888例患者。Meta分析结果表明,与非PARPi组比较,PARPi组(PARPi联合或不联合抗激素治疗)可提高mCRPC的放射学无进展生存期(HR=0.52,95%CI=0.34~0.78)和总生存期(HR=0.72,95%CI=0.60~0.86),差异均有统计学意义(P<0.05)。在安全性方面,PARPi组1~2级骨痛、背痛、贫血、中性粒细胞减少、恶心、呕吐、腹泻、乏力不良反应发生率明显高于非PARPi组,差异均有统计学意义(P<0.05);≥3级上述不良反应中与非PARPi组比较,PARPi组中只有恶心和贫血不良反应发生率较高,差异均有统计学意义(P<0.05),而骨痛、背痛、中性粒细胞减少、呕吐、腹泻、乏力两组间比较差异均无统计学意义(P>0.05)。结论:与非PARPi比较,PARPi联合或不联合抗激素治疗可提高mCRPC的放射学无进展生存期和总生存期,3级及以上不良反应发生率低,值得在临床上推广应用。展开更多
BACKGROUND Genetic screening for breast cancer gene 1(BRCA)1/2 mutations can inform breast/ovarian/pancreatic cancer patients of suitable therapeutic interventions.Four to seven percent of pancreatic cancer patients h...BACKGROUND Genetic screening for breast cancer gene 1(BRCA)1/2 mutations can inform breast/ovarian/pancreatic cancer patients of suitable therapeutic interventions.Four to seven percent of pancreatic cancer patients have germline BRCA mutations.BRCA genes aid in DNA repair,especially homologous recombination,which impacts genomic stability and cancer cell growth.BRCA1 regulates the cell cycle,ubiquitination,and chromatin remodeling,whereas BRCA2 stimulates the immune response.They predict the efficacy of platinum chemotherapy or polymerase(PARP)inhibitors such as olaparib.AIM To determine the trends and future directions in the use of olaparib for pancreatic cancer treatment.METHODS To evaluate the trends in how olaparib works in pancreatic cancer,we performed a bibliometric analysis.One hundred and ninety-six related publications were accessed from the Web of Science Core Collection and were published between 2009 and 2022.The analytic parameters included publications,related citations,productive countries and institutes,influential authors,and keyword development.RESULTS This study visualizes and discusses the current research,including the present global trends and future directions in olaparib and pancreatic cancer.Overall,this study sheds light on optimizing the use of olaparib in pancreatic cancer treatment,Feng X et al.The use of olaparib in pancreatic cancer WJGO https://www.wjgnet.com 4490 November 15,2024 Volume 16 Issue 11 offering valuable guidance for researchers in this field.CONCLUSION Our findings identified trends in olaparib and pancreatic cancer,with China and the USA leading and with global cooperation tightening.O'Reilly EM's team and Memorial Sloan-Kettering had the highest output.The Journal of Clinical Oncology was the most cited journal.More PARP inhibitors are emerging,and combination therapy is suggested for future therapeutic trends.展开更多
目的研究连豆清脉方对大鼠动脉粥样硬化(AS)形成的预防作用,以及对核因子-κB(NF-κB)炎症信号通路中Toll样受体-4(TLR-4)、NF-κB、多聚二磷酸腺苷核糖聚合酶-1(PARP-1)的影响。方法 50只大鼠随机分为基础组10只、空白预防组(空预组)1...目的研究连豆清脉方对大鼠动脉粥样硬化(AS)形成的预防作用,以及对核因子-κB(NF-κB)炎症信号通路中Toll样受体-4(TLR-4)、NF-κB、多聚二磷酸腺苷核糖聚合酶-1(PARP-1)的影响。方法 50只大鼠随机分为基础组10只、空白预防组(空预组)10只、模型组10只、辛伐他汀预防组(辛预组)10只、连豆清脉方预防组(连预组)10只;后4组大鼠通过高脂饲料喂养建立早期AS模型,同步采用连豆清脉方、辛伐他汀,分别对大鼠AS模型进行预防性干预。并对主动脉血管壁厚度、组织PARP-1阳性细胞表达率、外周血单个核细胞TLR-4 m RNA表达、血清NF-κB水平检测计算。结果 1)光镜下大鼠主动脉血管壁厚度存在差异(P<0.01),连预组和辛预组大鼠主动脉血管壁厚度明显薄于模型组(P<0.01),但是和空预组比较差异无统计学意义。免疫组化染色光镜下大鼠左心室组织PARP-1表达具有显著差异,PARP-1阳性细胞表达率存在统计学差异(P<0.01),连预组和辛预组PARP-1阳性细胞表达率明显低于模型组(P<0.01),但是明显高于空预组(P<0.01),具有统计学差异。2)大鼠外周血单个核细胞TLR-4 m RNA表达各组间存在统计学差异(P<0.01),连预组和辛预组TLR-4 m RNA表达明显低于模型组(P<0.01),且连预组低于空预组(P<0.05)。大鼠血清NF-κB水平各组间存在差异(P=0.001);其中连预组NF-κB水平明显低于模型组(P<0.01),但与空预组比较差异无统计学意义。结论连豆清脉方可预防高脂饮食导致的AS形成;其机制与抑制NF-κB炎症信号通路PARP-1、TLR-4、NF-κB等环节有关。展开更多
Minocylcine, a tetracycline derivate, has been shown to cross the blood-brain barrier and enter the central nervous system. In this study, cerebral ischemia-reperfusion injury models were established using the suture ...Minocylcine, a tetracycline derivate, has been shown to cross the blood-brain barrier and enter the central nervous system. In this study, cerebral ischemia-reperfusion injury models were established using the suture method, and minocycline was immediately injected intraperitoneally after cerebral ischemia-repeffusion （22.5 mg/kg, initially 45 mg/kg） at a 12-hour interval. Results showed that after minocycline treatment, the volume of cerebral infarction was significantly reduced, the number of surviving cell in the hippocampal CA1 region increased, the number of apoptotic cells decreased, the expression of caspase-3 and poly（adenosine diphosphate-ribose） polymerase-1 protein was down-regulated, and the escape latency in the water maze test was significantly shortened compared with the ischemia-reperfusion group. Our experimental findings indicate that minocycline can protect against neuronal injury induced by focal ischemia-reperfusion, which may be mediated by the inhibition of caspase-3 and poly（adenosine diphosphate-ribose） polymerase-1 protein expression.展开更多
文摘BACKGROUND The biochemical phenomenon defined as poly adenosine diphosphate(ADP)-ribosylation(PARylation)is essential for the progression of pancreatic cancer.However,the excessive accumulation of poly ADP-ribose(PAR)induces apoptosis-inducing factor(AIF)release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer cells.AIM To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR accumulation.METHODS Two pancreatic cancer cell lines,AsPC-1 and CFPAC-1 were used for the study.Calcium influx and mitochondrial reactive oxygen species(ROS)were observed by fluorescence staining.Changes in enzyme levels,as well as PAR accumulation and energy metabolism,were measured using assay kits.AIF-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium administration.RESULTS Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer cells.Then,excess PAR accumulation,decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels,and energy deprivation were observed.In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels.CONCLUSION This study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer,however elucidating a clear mode of action remains a challenge,and it should be accompanied by further studies to assess its potential for clinical application.
文摘The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor microenvironment.Particularly,it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression.Based on this background,the potential to focus on poly[adenosine diphosphate(ADP)-ribose]polymerase(PARP)-1 and poly-ADP ribosylation(PARylation)as the main causes of malignant formation of CRC may be considered.One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid(DNA)repair function,which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide.PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes.Given the high importance of these processes in CRC,it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression.Therefore,this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles;furthermore,it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC.This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC,which may present the potential to identify various research topics that can be challenged both nonclinically and clinically.
文摘目的:系统评价PARPi治疗转移性去势抵抗性前列腺癌(mCRPC)的有效性及安全性,以期为临床决策供循证医学证据。方法:依据纳入和排除标准,网络检索2015年1月~2023年6月PubMed、Web of Science、Embace、Clinicial.gov中有关PARPi治疗mCRPC的随机对照试验文献,使用RevMan5.4及Stata17.0软件对数据进行Meta分析。结果:纳入7篇随机对照试验文献,共1888例患者。Meta分析结果表明,与非PARPi组比较,PARPi组(PARPi联合或不联合抗激素治疗)可提高mCRPC的放射学无进展生存期(HR=0.52,95%CI=0.34~0.78)和总生存期(HR=0.72,95%CI=0.60~0.86),差异均有统计学意义(P<0.05)。在安全性方面,PARPi组1~2级骨痛、背痛、贫血、中性粒细胞减少、恶心、呕吐、腹泻、乏力不良反应发生率明显高于非PARPi组,差异均有统计学意义(P<0.05);≥3级上述不良反应中与非PARPi组比较,PARPi组中只有恶心和贫血不良反应发生率较高,差异均有统计学意义(P<0.05),而骨痛、背痛、中性粒细胞减少、呕吐、腹泻、乏力两组间比较差异均无统计学意义(P>0.05)。结论:与非PARPi比较,PARPi联合或不联合抗激素治疗可提高mCRPC的放射学无进展生存期和总生存期,3级及以上不良反应发生率低,值得在临床上推广应用。
基金the Zhejiang Provincial Medical and Health Science and Technology Program,No.2024KY1109.
文摘BACKGROUND Genetic screening for breast cancer gene 1(BRCA)1/2 mutations can inform breast/ovarian/pancreatic cancer patients of suitable therapeutic interventions.Four to seven percent of pancreatic cancer patients have germline BRCA mutations.BRCA genes aid in DNA repair,especially homologous recombination,which impacts genomic stability and cancer cell growth.BRCA1 regulates the cell cycle,ubiquitination,and chromatin remodeling,whereas BRCA2 stimulates the immune response.They predict the efficacy of platinum chemotherapy or polymerase(PARP)inhibitors such as olaparib.AIM To determine the trends and future directions in the use of olaparib for pancreatic cancer treatment.METHODS To evaluate the trends in how olaparib works in pancreatic cancer,we performed a bibliometric analysis.One hundred and ninety-six related publications were accessed from the Web of Science Core Collection and were published between 2009 and 2022.The analytic parameters included publications,related citations,productive countries and institutes,influential authors,and keyword development.RESULTS This study visualizes and discusses the current research,including the present global trends and future directions in olaparib and pancreatic cancer.Overall,this study sheds light on optimizing the use of olaparib in pancreatic cancer treatment,Feng X et al.The use of olaparib in pancreatic cancer WJGO https://www.wjgnet.com 4490 November 15,2024 Volume 16 Issue 11 offering valuable guidance for researchers in this field.CONCLUSION Our findings identified trends in olaparib and pancreatic cancer,with China and the USA leading and with global cooperation tightening.O'Reilly EM's team and Memorial Sloan-Kettering had the highest output.The Journal of Clinical Oncology was the most cited journal.More PARP inhibitors are emerging,and combination therapy is suggested for future therapeutic trends.
文摘目的研究连豆清脉方对大鼠动脉粥样硬化(AS)形成的预防作用,以及对核因子-κB(NF-κB)炎症信号通路中Toll样受体-4(TLR-4)、NF-κB、多聚二磷酸腺苷核糖聚合酶-1(PARP-1)的影响。方法 50只大鼠随机分为基础组10只、空白预防组(空预组)10只、模型组10只、辛伐他汀预防组(辛预组)10只、连豆清脉方预防组(连预组)10只;后4组大鼠通过高脂饲料喂养建立早期AS模型,同步采用连豆清脉方、辛伐他汀,分别对大鼠AS模型进行预防性干预。并对主动脉血管壁厚度、组织PARP-1阳性细胞表达率、外周血单个核细胞TLR-4 m RNA表达、血清NF-κB水平检测计算。结果 1)光镜下大鼠主动脉血管壁厚度存在差异(P<0.01),连预组和辛预组大鼠主动脉血管壁厚度明显薄于模型组(P<0.01),但是和空预组比较差异无统计学意义。免疫组化染色光镜下大鼠左心室组织PARP-1表达具有显著差异,PARP-1阳性细胞表达率存在统计学差异(P<0.01),连预组和辛预组PARP-1阳性细胞表达率明显低于模型组(P<0.01),但是明显高于空预组(P<0.01),具有统计学差异。2)大鼠外周血单个核细胞TLR-4 m RNA表达各组间存在统计学差异(P<0.01),连预组和辛预组TLR-4 m RNA表达明显低于模型组(P<0.01),且连预组低于空预组(P<0.05)。大鼠血清NF-κB水平各组间存在差异(P=0.001);其中连预组NF-κB水平明显低于模型组(P<0.01),但与空预组比较差异无统计学意义。结论连豆清脉方可预防高脂饮食导致的AS形成;其机制与抑制NF-κB炎症信号通路PARP-1、TLR-4、NF-κB等环节有关。
基金supported by the National Natural Science Foundation of China, No. 81160157the Key Program of the Science and Technology Department of Guizhou Province, No. SY20093075Nomarch Foundation for Excellent Talents in Science, Technology and Education Field of Guizhou Province, No. 201209
文摘Minocylcine, a tetracycline derivate, has been shown to cross the blood-brain barrier and enter the central nervous system. In this study, cerebral ischemia-reperfusion injury models were established using the suture method, and minocycline was immediately injected intraperitoneally after cerebral ischemia-repeffusion （22.5 mg/kg, initially 45 mg/kg） at a 12-hour interval. Results showed that after minocycline treatment, the volume of cerebral infarction was significantly reduced, the number of surviving cell in the hippocampal CA1 region increased, the number of apoptotic cells decreased, the expression of caspase-3 and poly（adenosine diphosphate-ribose） polymerase-1 protein was down-regulated, and the escape latency in the water maze test was significantly shortened compared with the ischemia-reperfusion group. Our experimental findings indicate that minocycline can protect against neuronal injury induced by focal ischemia-reperfusion, which may be mediated by the inhibition of caspase-3 and poly（adenosine diphosphate-ribose） polymerase-1 protein expression.
