骨质疏松症(osteoporosis,OP)是以骨微观结构退化、骨量和骨矿物质密度下降为特征的骨代谢性疾病,表现为骨的脆性增加且易发生骨折,进而对患者的生活质量产生严重影响.泛凋亡(PANoptosis)是近年来新建立的一种独特的炎性程序性细胞死亡(programmed cell death,PCD)过程,涉及细胞焦亡(pyroptosis)、凋亡(apoptosis)和坏死性凋亡(necroptosis)之间的相互作用及串扰,其同时具有细胞焦亡、凋亡和(或)坏死性凋亡的关键特征,但不能单独用三种程序性细胞死亡途径中的任何一种来解释.近年来,国内外研究主要探究细胞焦亡、凋亡以及坏死性凋亡与OP机制之间的关系,而针对泛凋亡与OP病理生理过程的作用机制探究较少.本文旨在探讨泛凋亡与OP发病机制的潜在联系,为防治OP寻找潜在的靶点.

Regulated cell death (RCD), including apoptosis, pyroptosis, necroptosis, and ferroptosis, is regulated by a series of evolutionarily conserved pathways, and is required for development and tissue homeostasis. Based on previous genetic and biochemical explorations of cell death subroutines, the characteristics of each are generally considered distinctive. However, recent in-depth studies noted the presence of crosstalk between the different forms of RCD; hence, the concept of PANoptosis appeared. Cancer, a complex genetic disease, is characterized by stepwise deregulation of cell apoptosis and proliferation, with significant morbidity and mortality globally. At present, studies on the different RCD pathways, as well as the intricate relationships between different cell death subroutines, mainly focus on infectious diseases, and their roles in cancer remain unclear. As cancers are characterized by dysregulated cell death and inflammatory responses, most current treatment strategies aim to selectively induce cell death via different RCD pathways in cancer cells. In this review, we describe five types of RCD pathways in detail with respect to tumorigenesis and cancer progression. The potential value of some of these key effector molecules in tumor diagnosis and therapeutic response has also been raised. We then review and highlight recent progress in cancer treatment based on PANoptosis and ferroptosis induced by small-molecule compounds, immune checkpoint inhibitors, and nanoparticles. Together, these findings may provide meaningful evidence to fill in the gaps between cancer pathogenesis and RCD pathways to develop better cancer therapeutic strategies.

Background::Sepsis, a serious condition with high mortality, usually causes sepsis associated encephalopathy (SAE) that involves neuronal cell death. However, the cell death programs involved and their underlying mechanisms are not clear. This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.Methods::A neonatal rat model of SAE was established by cecal ligation and perforation. Survival rate and vital signs (mean arterial pressure and heart rate) were monitored, nerve reflexes were evaluated, and cortical pathological changes were observed by hematoxylin and eosin staining. The expression of pyroptosis, apoptosis, and necroptosis (PANoptosis)-related proteins, mitogen-activated protein kinase (MAPK), and its upstream regulator toll-like receptor 9 (TLR9) were detected. The expression of TLR9 in neurons was observed by immunofluorescence staining. The ultrastructure of neurons was observed by transmission electron microscope.Results::First, PANoptosis was found in cortical nerve cells of the SAE rats. Meanwhile, the subunits of MAPKs, p38 MAPK, Jun N-terminal kinase, and extracellular signal-regulated kinase (ERK) were activated. After pharmacologically inhibiting each of the subunits, only p38 MAPK was found to be associated with PANoptosis. Furthermore, blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis. When necroptosis was pharmacologically inhibited, apoptosis and pyroptosis were reactivated. Finally, we found that the expression of TLR9, a regulator of MAPKs, was significantly increased in this model. After down-regulation of TLR9, p38 MAPK, and ERK signaling pathways were inhibited, which led to the inhibition of PANoptosis. Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.Conclusions::Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats. TLR9 activated PANoptosis through the p38 MAPK signaling pathway. TLR9 may work as a potential target for SAE treatment.

程序性细胞死亡主要包括焦亡、凋亡和坏死性凋亡等途径，在宿主防御病原体入侵和维持体内平衡中发挥重要作用。虽然之前的研究认为各种程序性细胞死亡之间是相互独立的通路，但随着研究的深入，越来越多的证据表明各程序性细胞死亡之间存在广泛的相互作用，研究者把各程序性细胞死亡通路之间存在的串扰现象称为泛凋亡（PANoptosis），且PANoptosis受到上游泛凋亡小体复合物（PANoptosome）调控。文章通过对PANoptosis及PANoptosome的成分来源、刺激因素、形成机制以及在急性肺损伤（acute lung injury, ALI）/急性呼吸窘迫综合征（acute respiratory distress syndrome, ARDS）中的研究进展进行描述，旨在为ALI/ARDS的预防和治疗提供更广泛的思路。

近年来，随着细胞死亡分子机制方面的研究取得进展，人们才逐渐发现有多种新型的细胞程序性死亡方式，包括非凋亡性(10种)及凋亡性(2种)二大类。它们广泛参与感染性疾病和肿瘤等疾病的发生、发展，是目前热门研究的前沿课题，为临床防治提供了新思路。本文通过对程序性细胞死亡文献的梳理，围绕细胞坏死、凋亡、焦亡、铁死亡、中性粒细胞的炎性细胞死亡、铜死亡及细胞广泛凋亡等特征性表现，以及与若干感染性疾病相关性研究进展作一综述。

目的:利用生物信息学对癌症基因组图谱(TCGA)数据库进行挖掘并筛选对肝细胞癌(HCC)患者预后有显著影响的泛凋亡(PANoptosis)相关长链非编码RNA(lncRNA)，构建HCC中PANoptosis相关lncRNA(PANRlncRNA)的预后风险模型。方法:在TCGA数据库下载377例HCC患者临床数据，在多种数据库中检索关键词"PANoptosis"并从文献中获取泛凋亡相关基因(PANR-Gs)，通过对PANR-Gs和lncRNAs进行共表达分析确定PANRlncRNAs，在癌组织及癌旁组织中进行差异性分析。对377例患者的临床数据预处理后筛选到符合标准的343例样本(全集)，将全集随机分组为训练集(172例)和测试集(171例)，通过单因素Cox、LASSO、多因素Cox风险回归分析建立训练集的预后风险模型，得到每个患者的风险评分，按风险评分的中位值将其分为高、低风险组，采用Kaplan-Meier方法对两组患者进行生存分析，绘制受试者工作特征(ROC)曲线对模型进行效能评估。分析高、低风险组的生存时间和免疫功能，通过Wilcoxon检验完成两组间比较。结果:共筛选到147个PANRlncRNAs，108个差异表达的PANRlncRNAs，最终确定4个PANRlncRNAs构成HCC预后风险模型，该模型在训练集患者的1年、3年和5年生存预测性能曲线下面积(AUC)值分别为0.740、0.774和0.791；高风险组患者的总生存期明显低于低风险组( P<0.05)，测试集和全集中也呈现出良好的预测效能，进一步分析表明在高、低风险组中，免疫细胞及其功能差异有统计学意义( P<0.05)。 结论:基于4个PANRlncRNAs建立预后风险模型有良好的预测能力，可有效预测HCC患者的生存预后，其风险评分可能成为HCC独立的预后因素。

目的:观察平喘颗粒对METTL3介导的气道上皮细胞中miR-29a-3p的m6A修饰的影响,明确其抑制哮喘气道炎症的分子机制.方法:16HBE采用LPS诱导(50 mg/L)构建细胞模型,并给予平喘颗粒含药血清和地塞米松进行干预.分别采用CCK8法检测细胞活性、ELISA法检测炎症因子(TNF-α、IL-6和IL-8)的含量和miR-29a-3p的m6A修饰水平、Western blot检测METTL3与泛凋亡蛋白的表达和qRT-PCR检测METTL3与miR-29a-3p的表达.结果:与模型组相比,平喘颗粒能够显著增加16HBE的活力,抑制炎症因子TNF-α、IL-6 和IL-8 的含量,下调泛凋亡相关蛋白p-RIPK3、p-MLKL、cleaved Caspase-1、cleaved Caspase-3的表达和GSDMD-NT/FL-GSDMD与GSDME-NT/FL-GSDME的比值,差异均具有统计学意义(P<0.01).此外,平喘颗粒能够显著上调细胞中miR-29a-3p和METTL3的表达水平,促进miR-29a-3p的m6A修饰水平,与模型组相比差异均具有统计学意义(P<0.01).结论:平喘颗粒主要通过METTL3增强miR-29a-3p的m6A修饰水平,抑制气道上皮细胞泛凋亡,改善气道炎症.

目的 探讨I型糖尿病(T1DM)睾丸组织发生泛凋亡(PANoptosis)的可能机制.方法 SPF级SD大鼠50只随机分为对照组(n=15)和I型糖尿病组(n=35).I型糖尿病大鼠造模成功 8 周后,取睾丸组织检测PANoptosis相关指标以及PI3K、AKT和NF-κB.GC-1 spg细胞分为Control组、高糖组(HG)和LY294002+高糖组(LY294002+HG);CCK-8 实验确定PI3K的抑制剂LY294002 最佳干预浓度和时间;检测细胞内PANoptosis相关指标以及PI3K、AKT、NF-κB等.结果 与Control相比,T1DM组大鼠睾丸组织PANoptosis相关的免疫组化指标、mRNA和蛋白表达均较正常组显著升高;T1DM组大鼠睾丸组织内PI3K/AKT/NF-κB信号通路相关指标表达升高.Western blotting实验证明HG组GC-1 spg细胞PANoptosis相关蛋白和PI3K、AKT、NF-κB蛋白表达升高;LY294002+HG组与HG组相比上述蛋白表达下降.结论 I型糖尿病大鼠睾丸组织中PANoptosis的发生可能是由PI3K/AKT/NF-κB信号通路激活介导的.

认知功能障碍是2型糖尿病的严重并发症之一,运动干预改善糖尿病认知具有一定的疗效,但具体作用机制尚不清楚.本研究旨在探究跑台运动干预改善2型糖尿病小鼠认知功能障碍的作用及分子机制.取雄性8周龄m/m小鼠10只作为对照组,db/db小鼠40只随机分为4组,每组10只,分别为db/db组(模型组)、db+Exe组(运动组)、db+Exe+SB203580组(运动联合p38 MAPK 抑制剂组)、db+SB203580 组(p38 MAPK 抑制剂组).db+Exe 组和 db+Exe+SB203580 组进行运动干预(40 min/次,5次/周,共8周);db+Exe+SB203580组和db+SB203580组在运动干预前2 h腹腔注射SB203580,(5 mg/kg,5次/周,共8周).体重及空腹血糖测量结果显示,8周跑台运动干预可降低糖尿病小鼠体重及空腹血糖(P＜0.01);水迷宫结果显示,跑台运动改善了糖尿病小鼠的认知功能障碍(P＜0.05);免疫荧光染色结果显示,跑台运动降低了海马组织NLRP3的荧光强度,其中CA1区和CA3区具有显著性差异(P＜0.05);跑台运动降低了海马组织PI的荧光强度,其中DG区具有显著性差异(P＜0.01).qRT-PCR结果显示,跑台运动降低了小鼠海马组织中IL-1β和IL-18 mRNA的表达,其中IL-1β mRNA的表达具有显著性差异(P＜0.05);Western印迹结果显示,跑台运动减少了海马组织中凋亡相关蛋白质胱天蛋白酶3、胱天蛋白酶9和Bax的表达(P＜0.01);降低了 TXNIP(P＜0.01)和焦亡相关蛋白质NLRP3、GSDMD-N、IL-1β、IL-18、切割胱天蛋白酶1和 胱天蛋白酶1的表达(P＜0.05);减少了坏死性凋亡相关蛋白质p-RIPK1、RIPK1、p-RIPK3、RIPK3的表达(P＜0.05).加入p38抑制剂后,跑台运动联合p38抑制剂干预更进一步地抑制了胱天蛋白酶 3、TXNIP、GSDMD-N、IL-18 的表达(P＜0.05),胱天蛋白酶 9、Bax、NLRP3、IL-1β、切割胱天蛋白酶1、胱天蛋白酶 1的表达水平也呈现下降趋势;RIPK1、p-RIPK3的表达显著增加(P＜0.05),p-p38、p-RIPK1、RIPK3的蛋白质表达水平呈上升趋势.综上所述,跑台运动干预可有效改善2型糖尿病小鼠的认知功能障碍,其作用机制部分是通过p38 MAPK信号通路调控细胞泛凋亡.

脑卒中后认知障碍(post-stroke cognitive impairment,PSCI)是脑卒中后常见并发症之一,对卒中患者的生活质量影响较大,但发病机制尚未能完全解释清楚.越来越多的证据表明,程序性细胞死亡(programmed cell death,PCD)机制与PSCI有关,包括细胞凋亡、坏死性凋亡、细胞焦亡、泛凋亡、PARP-1依赖性细胞死亡和铁死亡等.因此,清楚了解各种PCD机制及其与PSCI的关系,阐明PCD在疾病发病机制中的作用至关重要.文章综述了与PSCI相关的6种PCD途径,总结其在PSCI中的作用机制,并阐述了不同途径之间可能存在的串扰,以期为临床靶向PCD途径的调节因子来治疗PSCI提供资料依据.