Function of flavonoids on different types of programmed cell death and its mechanism:a review

Cell death in the living system plays a vital role in maintaining the homeostasis and balancing the cell count in the body.Programmed cell death(PCD)is a crucial component of several development and defense mechanisms.PCD is also important in terms of aging which avoids the accumulation of cellular damage by maintaining cell division.Depending on the execution of cell death and its role in destruction,PCD is categorized into several subtypes.The major different forms of PCD in animals are apoptosis,autophagy and necrosis,which can be distinct in morphological terms.More intense investigations of cell death have given close insight showing other important types of cellular destruction and their pivotal roles in treating disease conditions like cancer.Flavonoids have been acquired a great interest for disease therapies and chemoprevention through activation of several PCD mechanisms.The significant potential of natural flavonoids in the induction of distinct signaling cascades is being a massive approach for targeting uncontrolled cell growth.For these reasons,understanding PCD mechanisms is a promising approach for the interventions in treating cancer.Thus,it is intriguing that understanding the different forms of PCD mechanism induced by flavonoids with more accurate descriptions on the biochemical and cellular processes are gaining more significance in cancer research.Here,we provide a brief overview on the different types of PCD and aim to discuss the functional role of flavonoids in promoting different types of cell death as well as an extensive brief review on their mechanism of action has been highlighted.

Reduced Expression of Programmed Cell Death 5 Protein in Tissue of Human Prostate Cancer

Objective To investigate the expression of programmed cell death 5(PDCD5) in tissues of normal human prostate(NP),benign prostatic hyperplasia(BPH),and prostate cancer(PCa) in order to assess the clinical role of PDCD5 in PCa.Methods PDCD5 expression was determined by EnVision immunohistochemical staining in formalin-fixed and paraffin-embedded specimens obtained from 12 subjects with NP,22 with BPH,and 22 with PCa.In addition,PCa cases were classified as low/middle-risk(Gleason sum≤7) and high-risk(Gleason sum>7) on the basis of Gleason grade.Positive expression rates and intensity of PDCD5 protein were observed under light microscope and analyzed with computer imaging technique.Expression of PDCD5 was compared among different prostatic tissues.Results The expression of PDCD5 was significantly lower in tissue of PCa than in tissues of NP and BPH(P<0.01).However,there was no significant difference in PDCD5 expression between tissues of NP and BPH.In addition,the expression of PDCD5 was further downregulated with the increase of Gleason sum in PCa.Conclusions By downregulating apoptosis,low PDCD5 expression may play an important role in the occurrence and development of PCa.PDCD5 is supposed to have a potential clinical value to be a new predictor of progression and target of gene therapy in PCa.

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

Stem cell-based therapy raises hopes for a better approach to promoting tissue repair and functional recovery.However,transplanted stem cells show a high death percentage,creating challenges to successful transplantation and prognosis.Thus,it is necessary to investigate the mechanisms underlying stem cell death,such as apoptotic cascade activation,excessive autophagy,inflammatory response,reactive oxygen species,excitotoxicity,and ischemia/hypoxia.Targeting the molecular pathways involved may be an efficient strategy to enhance stem cell viability and maximize transplantation success.Notably,a more complex network of cell death receives more attention than one crucial pathway in determining stem cell fate,highlighting the challenges in exploring mechanisms and therapeutic targets.In this review,we focus on programmed cell death in transplanted stem cells.We also discuss some promising strategies and challenges in promoting survival for further study.

Programmed cell death protein 4 expression in renal cell carcinoma, penile carcinoma and testicular germ cell cancer

AIM:To investigate the expression of programmed cell death 4(Pdcd4)tumor suppressor gene in tissue specimen of renal cell carcinoma(RCC),testicular germ cell cancer and penile cancer.METHODS:Pdcd4 expression was studied using immunohistochemistry in 188 cases of RCC and 28 controls(including 9 oncocytoma);in 74 cases of penile carcinoma(including 17 metastatic tissue samples)and26 controls;in 11 cases of seminoma,in 14 cases of non-seminoma and 5 controls.RESULTS:Control tissues exhibited strong core and cytoplasmatic Pdcd4 staining.In contrast,core and cy-toplasmatic Pdcd4 levels were significantly decreased in cancer tissues.CONCLUSION:Our data support a role for Pdcd4(down-)regulation in urologic tumors.Interestingly,Pdcd4 expression seem to be a potential diagnostic marker for renal or penile tumors.

Correlation of PDCD4 and telomerase expression with apoptosis molecule and interstitial molecule expression in myocardial tissue of sudden coronary death

Objective: To study the correlation of PDCD4 and telomerase expression with the expression of apoptosis molecules and interstitial molecules in myocardial tissue of sudden coronary death. Methods: The sudden death cases that underwent autopsy in the Fifth Affiliated Hospital of Southern Medical University between March 2014 and March 2017 were collected and divided into group A with sudden cardiac death of coronary heart disease, group B with sudden non-cardiac death of coronary heart disease and group C without coronary lesions according to the autopsy results and medicolegal expertise report. The myocardial tissue was collected to determine the mRNA expression of PDCD4 and telomerase as well as the protein expression of PDCD4, telomerase, apoptosis molecules and interstitial molecules. Results:The mRNA expression and protein expression of PDCD4 and telomerase in myocardial tissue of group A were significantly higher than those of group B and group C;Bax, p53 and SOCS1 protein expression in myocardial tissue of group A were higher than those in group B and group C and positively correlated with PDCD4 and telomerase protein expression whereas Bcl-2, N-cadherin, Cx40, Cx43, Cx45 and FN protein expression were lower than those of group B and group C and negatively correlated with PDCD4 and telomerase protein expression;the mRNA expression and protein expression of PDCD4 and telomerase as well as the protein expression of Bax, Bcl-2, p53, SOCS1, N-cadherin, Cx40, Cx43, Cx45 and FN in myocardial tissue were not significantly different between group B and Group C. Conclusion:The high expression of PDCD4 and telomerase is related to the sudden cardiac death of coronary heart disease, and it regulates the expression of apoptosis and interstitial molecules in myocardial tissue.

Staurosporine-Induced Cell Death in Trypanosoma brucei and the Role of Endonuclease G during Apoptosis

Apoptosis in single-cell organisms like Trypanosoma or Leishmania was characterized in several studies in the last few years [1]-[4]. Cell death in these caspase lacking protozoa is still poorly understood and a conclusive apoptotic pathway has not been identified so far. In the work presented here, we studied the effects of prostaglandin D2 and staurosporine induced cell death in blood-forms of Trypanosoma brucei in a time dependent manner and focused on the role of a nuclease similar to endonuclease G of higher eukaryotes. We found that these parasites undergo apoptotic cell death as demonstrated by the appearance of several canonical hallmarks of apoptosis in higher eukaryotes, but that different stimuli induce remarkable differences in the way these cells die. We compared the effects of prostaglandin D2 and staurosporine in trypanosomes with and without endonuclease G overexpression by flow cytometric and electron microscopic methods with the result that endonuclease G overexpression led to a significant modification of intracellular organelles and accelerated apoptotic cell death in prostaglandin D2 or staurosporine treated cells. Our results demonstrate that different stimuli induce apoptosis even in these ancient organisms in different caspase-independent ways. Whereas central processes of apoptosis like ROS formation, loss of mitochondrial membrane potential, endonuclease G release, phosphatidylserine exposure and DNA fragmentation appeared in the same chronology during treatment with either one of both drugs, other effects like cell cycle arrest or change of cell shape occurred only in the case of prostaglandin D2 or staurosporine treatment. We conclude from these results that trypanosomes react to stimuli of apoptosis with the concerted action of cellular responses but cannot control the final outcome if additional stress, as in the case of staurosporine, is superimposed.

Correlation of PDCD5 and Apoptosis in Hair Cells and Spiral Ganglion Neurons of Different Age of C57BL/6J Mice

This study examined the expression pattern of programmed cell death 5 (PDCD5) in co-chlear hair cells and spiral ganglion neurons (SGNs) and its association with age-related hearing loss in mice.Sixty C57BL/6J (C57) mice at different ages were divided into four groups (3,6,9 or 12 months).PDCD5 expression was detected by using immunohistochemistry,real-time PCR and Western blot.Morphological change of the cochleae was also evaluated by using immunoassay.The results showed that the expression of PDCD5 had a gradual increase with ageing in both protein and RNA levels in C57 mice,as well as gradually increased apoptosis of cochlear hair cells and SGNs.In addition,we also found that caspase-3 activity was enhanced and its expression was enhanced with ageing.It is implied that overexpression of PDCD5 causes the increase in caspase-3 activity and the subsequent increase of apoptosis in cochlear hair cells and SGNs,and thereby plays a role in the pathogenesis of presbycusis.Thus,PDCD5 may be a new target site for the treatment and prevention of age-related hearing loss.

Apoptosis and autophagy control cell proliferation in the dentate gyrus following hippocampal lesion

Brain injuries often result in the promotion of cell proliferation in the hippocampal dentate gyrus（DG）,but the number of newborn cells declines with time.However,the cause of this decline remains poorly understood.Elucidation of the fate of these newborn cells will further the understanding of the pathological process and treatment of brain injury.In the present study,the number of newborn cells was quantitatively analyzed using an unbiased stereological method following hippocampal lesion by kainic acid,in combination with detection of apoptosis and autophagy.Results revealed that hippocampal lesion resulted in a significantly increased number of 5-bromo-2-deoxyuridine（BrdU）-positive cells in the DG,which subsequently decreased with time.BrdU/cleaved caspase-3 double-labeled cells were detected in the granular cell layer and hilus of DG.However,expressions of LC3-11,Beclin 1,and p53 were upregulated,and pro-caspase-3 and Bcl-2 were downregulated.Results indicated that hippocampal lesion in adult rats resulted in significant cell proliferation in the DG,which subsequently reduced with time.In addition,results suggested that apoptosis and autophagic processes could regulate cell proliferation in the DG following hippocampal lesion.

Relationship of PDCD5 expression with apoptosis, inflammatory factors and MMPs/TIMPs expression in degenerated intervertebral disc tissue

Objective: To study the relationship of PDCD5 expression with apoptosis, inflammatory factors and MMPs/TIMPs expression in degenerated intervertebral disc tissue. Methods:Patients with lumbar disc herniation who were treated in the Seventh People's Hospital of Shanghai between March 2015 and February 2017 were selected as the LDH group and patients with violent thoracolumbar vertebral fracture were selected as the control group. The intervertebral disc tissue was collected to determine the mRNA expression of PDCD5 as well as the protein levels of apoptosis molecules, inflammatory factors and MMPs/TIMPs molecules. Results: PDCD5 mRNA expression in intervertebral disc tissue of LDH group was significantly higher than that of control group;Caspase-3, Caspase-8, Fas, Caspase-9, Bax, SDF-1, CXCR-4, TNF-α, PGE2, MMP1, MMP2, MMP8 and MMP9 protein levels in intervertebral disc tissue of LDH group were significantly higher than those of control group and positively correlated with PDCD5 mRNA expression while TIMP1 and TIMP2 protein levels were significantly lower than those of control group and negatively correlated with PDCD5 mRNA expression. Conclusion: The high expression of PDCD5 in degenerated intervertebral disc tissue can activate apoptosis and inflammatory response and cause MMPs/TIMPs imbalance.

Pretreatment can alleviate programmed cell death in mesenchymal stem cells

In this editorial,we delved into the article titled“Cellular preconditioning and mesenchymal stem cell ferroptosis.”This groundbreaking study underscores a pivotal discovery:Ferroptosis,a type of programmed cell death,drastically reduces the viability of donor mesenchymal stem cells(MSCs)after engraftment,thereby undermining the therapeutic value of cell-based therapies.Furthermore,the article proposes that by manipulating ferroptosis mechanisms through preconditioning,we can potentially enhance the survival rate and functionality of MSCs,ultimately amplifying their therapeutic potential.Given the crucial role ferroptosis plays in shaping the therapeutic outcomes of MSCs,we deem it im-perative to further investigate the intricate interplay between programmed cell death and the therapeutic effectiveness of MSCs.

基于细胞程序性死亡探讨中药治疗子宫内膜异位症研究进展

子宫内膜异位症(endometriosis,EMs)是一种临床上常见的炎症性、免疫性和激素依赖性疾病。该疾病的机制尚未完全确定,近年来发现细胞程序性死亡(programmed cell death,PCD)在EMs的发生发展中起到重要作用。PCD是一种由基因调控的自主细胞死亡行为,包括:凋亡、自噬、焦亡、铁死亡和坏死性凋亡。在凋亡中,中药主要通过上调caspase-3表达,增强异位内膜的凋亡干预EMs进展。自噬过程中,中药可以抑制PI3K-AKT-mTOR通路促进异位病灶的自噬,也可以下调Beclin-1、p62水平抑制正常内膜细胞自噬。焦亡是依赖caspase引起以炎症反应为主的死亡方式,而产生的炎症环境可能也是影响EMs的原因,中药可通过抑制炎症因子的释放而治疗疾病。铁死亡反应中,中药可以增强细胞抗氧化能力而对抗铁死亡。坏死性凋亡是一种高度免疫原性的细胞死亡模式,迄今为止还未有研究探讨其在EMs中的作用机制,感染是引发此反应的条件之一,而EMs会使体内处于慢性炎症状态,因此推断坏死性凋亡也影响着疾病的发生发展。故该文对国内外应用中药干预PCD治疗EMs的相关研究进行综述,并探讨中药及其有效成分调控PCD治疗EMs作用机制。

基于调控足细胞程序性死亡的中药治疗膜性肾病药理机制研究进展

膜性肾病(membranous nephropathy,MN)是一种以上皮下免疫复合物沉积为典型病理特征的原发性肾小球疾病,其核心机制为免疫复合物沉积进而所造成的足细胞损伤。目前包括糖皮质激素联合免疫抑制药物或生物制剂在内的MN主流治疗方案,存在疗效个体差异较大、停药容易复发及不良反应多等局限性。近年来MN中的足细胞程序性死亡异常在疾病发生发展过程中的潜在作用越来越被重视。中医药对此相关的基础研究也大量展开。当前研究表明,中药单体、中药复方、中成药等可通过磷脂酰肌醇-3-激酶(phosphatidylin-ositol-3-kinase,PI3K)/蛋白激酶B(protein kinase B,AKT)信号通路、核因子E2相关因子(nuclear factor erythroid-derived factor 2-related factor,Nrf2)信号通路、丝裂原活化蛋白激酶(mitogen activated protein kinase,MAPK)信号通路、细胞核转录因子(nuclear factor kappa-B,NF-κB)信号通路、富含亮氨酸重复蛋白3(leucine-rich repetitive protein 3,NLRP3)/天冬氨酸蛋白水解酶1(Caspase-1)信号通路等,调控包括足细胞自噬、调亡、焦亡、铁死亡等一系列细胞程序性死亡过程,进而缓解足细胞损伤,保护肾脏功能。本文从中药单体、中药复方和中成药的角度对干预相关靶点通路治疗MN有关文献进行总结,旨在为中医药抗MN的临床治疗、基础研究及靶向药物的研发提供一定的参考依据。

程序性细胞死亡在青光眼视网膜神经节细胞中的研究进展

程序性细胞死亡(PCD)不同于传统意义上的细胞坏死,是涉及效应分子参与的独特的细胞死亡方式,包括细胞凋亡、自噬和焦亡等多种形式。PCD参与人类正常生理活动的诸多环节,更与多种疾病的发生发展密切相关。青光眼是全球不可逆失明的主要原因。相关研究表明,青光眼的发生与多种PCD的相关蛋白异常表达有关。文章将对青光眼发病过程中视网膜神经节细胞的凋亡、自噬、焦亡、铁死亡及依赖性细胞死亡相关机制及其相互作用作一综述,为青光眼的防治提供新思路。

细胞凋亡与慢性肾脏病

细胞凋亡属于细胞程序性死亡,有助于细胞更替、免疫系统的正常功能和胚胎发育,细胞凋亡主要由内源性途径、外源性途径、内质网应激等途径介导,在疾病的发生和发展中发挥重要的作用。慢性肾脏病(chronic kidney disease,CKD)为肾结构或功能异常超过3个月且对健康产生影响的疾病,细胞凋亡与其有一定的关联。揭示肾内皮细胞、足细胞、肾小管上皮细胞、肾小球系膜细胞、肾间质成纤维细胞等肾不同类型的细胞凋亡情况,以及CKD中的凋亡相关途径,可为发现治疗CKD新靶点提供参考。

N^(6)-甲基腺苷修饰在肿瘤程序性细胞死亡中的作用

非突变表观遗传重编程是肿瘤的关键特征之一,抵抗程序性细胞死亡是肿瘤的另一关键特征。作为体内最丰富的转录后表观遗传修饰方式,N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)通过靶向调节程序性细胞死亡关键因子在肿瘤细胞凋亡、自噬、焦亡、铁死亡、坏死性凋亡、铜死亡中发挥重要作用。现已有靶向异常DNA甲基化、组蛋白修饰的表观遗传调节剂应用于临床,靶向m^(6)A修饰调控药物仍待探索。本文阐述了m^(6)A修饰调控肿瘤细胞程序性死亡的机制,旨在为通过调节m^(6)A修饰水平介导肿瘤细胞死亡这一潜在肿瘤治疗策略提供理论基础。

Necroptosis:An emerging type of cell death in liver diseases

Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ’s physiological function.For long,only apoptosis was considered as a sole form of programmed cell death.Recently necroptosis,a RIP1/RIP3-dependent programmed cell death,has been identified as an apoptotic backup cell death mechanism with necrotic morphology.The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past.However,only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions.Although the number of necroptosis initiators is increasing;however,interestingly,it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules.Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance.By targeting necroptosis and/or other parallel death pathways,a significant cell loss and thus a decrement in an organ’s physiological function can be prevented.

Regulation of cell survival and death during Flavivirus infections

Flaviviruses, ss(+) RNA viruses, include many of mankind's most important pathogens. Their pathogenicity derives from their ability to infect many types of cells including neurons, to replicate, and eventually to kill the cells. Flaviviruses can activate tumor necrosis factor α and both intrinsic(Bax-mediated) and extrinsic pathways to apoptosis. Thus they can use many approaches for activating these pathways. Infection can lead to necrosis if viral load is extremely high or to other types of cell death if routes to apoptosis are blocked. Dengue and Japanese Encephalitis Virus can also activate autophagy. In this case the autophagy temporarily spares the infected cell, allowing a longer period of reproduction for the virus, and the autophagy further protects the cell against other stresses such as those caused by reactive oxygen species. Several of the viral proteins have been shown to induce apoptosis or autophagy on their own, independent of the presence of other viral proteins. Given the versatility of these viruses to adapt to and manipulate the metabolism, and thus to control the survival of, the infected cells, we need to understand much better how the specific viral proteins affect the pathways to apoptosis and autophagy. Only in this manner will we be able to minimize the pathology that they cause.

lncRNA SNHG1靶向miR-145-5p/PDCD4轴对缺氧/复氧诱导的心肌细胞凋亡的影响

目的探讨长链非编码RNA(lncRNA)核内小RNA宿主基因1(SNHG1)靶向miR-145-5p/程序性细胞死亡因子4(PDCD4)轴对缺氧/复氧(H/R)诱导的心肌细胞凋亡的影响。方法将H9c2细胞分为对照组(NC组)、H/R组、si-NC组、si-SNHG1组、mimic NC组、miR-145-5p mimic组、si-SNHG1+inhibitor NC组、si-SNHG1+miR-145-5p inhibitor组。除NC组外,其他组H9c2细胞均需转染对应物质后构建H/R模型。实时定量PCR(qRT-PCR)检测H9c2细胞中SNHG1、miR-145-5p表达;CCK-8法、流式细胞术分别检测细胞增殖、凋亡;试剂盒检测H9c2细胞中超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量;Western blotting检测H9c2细胞中PDCD4、caspase 3、Bcl-2、Bax蛋白表达;双荧光素酶报告基因实验验证SNHG1与miR-145-5p、miR-145-5p与PDCD4的关系。结果沉默SNHG1或过表达miR-145-5p可促进H/R诱导的H9c2细胞中miR-145-5p表达和细胞增殖,抑制PDCD4蛋白表达、细胞凋亡和氧化应激。miR-145-5p inhibitor减弱了沉默SNHG1对H/R诱导的H9c2细胞中miR-145-5p表达和细胞增殖的促进作用,以及对PDCD4蛋白表达、细胞凋亡、氧化应激的抑制作用。SNHG1靶向调控miR-145-5p/PDCD4轴。结论沉默SNHG1可能通过调控miR-145-5p/PDCD4轴抑制H/R诱导的H9c2细胞凋亡。

LncRNA TUG1通过调节miR-181b-5p/PDCD4轴对高糖诱导的心肌细胞凋亡的影响

目的 探讨长链非编码RNA(LncRNA)牛磺酸上调基因1(TUG1)通过调节miR-181b-5p/程序性细胞死亡蛋白4(PDCD4)轴对高糖诱导的心肌细胞凋亡的影响。方法 采用高糖(25 mmol/L葡萄糖)在体外构建糖尿病心肌病(DCM)细胞模型。AC16细胞分为NG组、HG组、HG+sh-NC组、HG+sh-TUG1组、HG+miR-NC组、HG+miR-181b-5p组、HG+sh-TUG1+anti-miR-NC组、HG+sh-TUG1+anti-miR-181b-5p组、HG+miR-181b-5p+pcDNA组、HG+miR-181b-5p+pc-PDCD4组。细胞计数试剂盒-8(CCK-8)法检测细胞活力;乳酸脱氢酶(LDH)测定试剂盒检测LDH释放总量;采用实时定量聚合酶链反应(q RT-PCR)检测TUG1、miR-181b-5p和PDCD4 mRNA表达;流式细胞术检测细胞凋亡;Western blot检测B细胞淋巴瘤2-相关X(Bax)、活化的胱天蛋白酶3(cleaved caspase 3)和PDCD4蛋白表达;caspase-Glo3检测试剂盒评估caspase 3活性;双萤光素酶报告基因实验验证TUG1或PDCD4与miR-181b-5p的靶向关系。结果 与NG组比较,HG组细胞活性降低,LDH释放总量、凋亡率、Bax、cleaved caspase 3表达及caspase 3活性升高(P<0.05),敲低TUG1或上调miR-181b-5p表达可拮抗上述变化(P<0.05)。抑制miR-181b-5p可减轻TUG1沉默对高糖处理下心肌细胞活力和凋亡的影响(P<0.05)。PDCD4过表达可减弱miR-181b-5p上调对高糖处理的心肌细胞活力的促进作用和对凋亡的抑制作用。TUG1可通过吸附miR-181b-5p上调PDCD4表达(P<0.05)。结论TUG1通过下调miR-181b-5p、上调PDCD4表达促进高糖诱导的心肌细胞凋亡。

不同类型程序性细胞死亡途径在肾癌中的研究进展

程序性细胞死亡(PCD)是机体内由遗传基因决定的细胞主动、有序的死亡方式,它在机体进化、维持机体稳态以及多个组织器官的发育中发挥重要作用,而这一过程的调控异常还与包括癌症在内的多种人类疾病密切相关。目前发现的PCD途径有细胞凋亡、自噬、坏死性凋亡、细胞焦亡和铁死亡,这些途径可在细胞受到各种内外部环境因素的刺激时被激活。研究表明,这些途径可以在多种信号分子的调控下诱导肾癌细胞死亡或维持细胞存活,从而影响肿瘤的进展或治疗效果。本文结合近年来的研究进展,针对以上多种PCD途径在肾癌发生发展中的作用进行综述,以期为深入研究肾癌的发病机制以及研发抗肿瘤靶向药物提供新方向。