Necrostatin-1对雨蛙肽诱导的小鼠急性胰腺炎的保护作用

目的观察Necrostatin-1(Nec-1)对雨蛙肽诱导的小鼠急性胰腺炎(AP)的影响。方法 C57BL/6小鼠予以50μg/kg的雨蛙肽腹腔注射7次,间隔1 h,建立AP模型。于第1次雨蛙肽注射后3 h、6 h、9 h和12 h,取出胰腺组织,HE染色。Western blot检测RIP1和RIP3蛋白的表达;C57BL/6小鼠随机分为:Control组、Vehicle组、Nec-1组和Nec-1i组,予以50μg/kg的雨蛙肽腹腔注射10次,间隔1 h,第1次雨蛙肽注射2 h前,腹腔注射Nec-1(1 mg/kg,每6 h 1次)、Nec-1i或等体积溶剂和空白对照。于第1次雨蛙肽注射后12 h、18 h和24 h,收集血清和胰腺组织。检测血清淀粉酶和脂肪酶。HE染色评估胰腺损伤程度。Real-time RT-PCR检测胰腺组织IL-1β和TNF-αmRNA的表达。结果 RIP1和RIP3蛋白在雨蛙肽诱导的AP中逐渐升高,且与胰腺腺泡细胞的坏死呈正相关;应用Nec-1后,与Vehicle组和Nec-1i组比较,于12 h、18 h和24 h,小鼠血清淀粉酶和脂肪酶水平明显降低,胰腺组织病理评分也明显减少,同时胰腺组织中IL-1β和TNF-αmRNA的水平也明显降低。结论 Nec-1对实验性胰腺炎具有明显的保护作用;程序性坏死可能促进了急性胰腺炎的损伤。     

程序性坏死在骨关节炎病理机制和治疗中的作用

骨关节炎是一种由多种病因引起的进行性关节疾病,其发病机制尚未明确,目前临床上尚未有根治性的治疗方法。程序性坏死是一种新的细胞程序性死亡方式,是一种高度促炎症的细胞死亡模式。近年研究结果显示,程序性坏死相关因子与骨关节炎的进展密不可分,如损伤相关分子模式促进各类炎症因子的释放,从而募集巨噬细胞,促进骨关节局部炎症;抑制受体相互作用蛋白激酶可减少关节细胞死亡及炎症因子表达,从而减少软骨破坏。本文综述了骨关节炎中程序性坏死的调控机制,以期进一步揭示骨关节炎的发病机制,为骨关节炎的治疗提供潜在作用靶点。     

坏死性凋亡的机制及其治疗白血病的研究进展

白血病是造血干细胞恶性克隆性疾病.近年来,随着化疗、造血干细胞移植、分子靶向治疗等多种治疗方法的快速发展,使白血病患者的完全缓解(CR)率及5年无病生存(EFS)率均较前有所改善,但仍有大部分白血病患者出现耐药和复发.目前,临床上大部分化疗药物及分子靶向药物都是通过诱导白血病细胞发生凋亡,以达到治疗目的.因此,寻找有效逆转凋亡耐受的方法改善白血病患者的预后,成为当务之急.坏死性凋亡(necroptosis)为近年来新发现的一种细胞死亡形式,以细胞出现程序性坏死样改变为特征.诱导白血病细胞发生坏死性凋亡,有望成为凋亡诱导失败,以及其他形式的耐药白血病患者的新治疗策略.笔者将针对近年来坏死性凋亡与白血病治疗的相关研究进展进行阐述.     

Association of anti-HER2 antibody with graphene oxide for curative treatment of osteosarcoma

The finding of HER2 overexpression in osteosarcoma (OS) makes HER2 a potential therapeutic target. However, studies indicate OS cells are nonresponsive to anti-HER2 antibody trastuzumab (TRA) therapy. We established stable, non-covalent association of TRA with nanomaterial graphene oxide (GO) to generated multivalent TRA/GO complexes that demonstrated markedly enhanced HER2-binding activity and capacity to rapidly kill OS cells. TRA/GO simultaneously induced oxidative stress and HER2 signaling in the target cells, leading to rapid depletion of the cellular inhibitors of apoptosis protein (cIAP) and caspase-8, formation of RIP1/RIPK3/MLKL necroptosome and necroptosis of the OS cells. Intravenous administration of TRA/GO eradicated established xenograft the OS in immunodeficient mice, resulting in indefinite survival of the animals, whereas TRA in its original form failed to do so. No appreciable side effects were observed with TRA/GO therapy. The results demonstrate a novel, nontoxic, curative therapy for a HER2^pos cancer in a preclinical animal model.     

Exogenous recombinant human thioredoxin‐1 prevents acetaminophen‐induced liver injury by scavenging oxidative stressors,restoring the thioredoxin‐1 system and inhibiting receptor interacting protein‐3 overexpression

Thioredoxin‐1 (Trx‐1) is a potent therapeutic agent against a variety of diseases because of its actions as an antioxidant and regulator of apoptosis. N‐acetyl‐p‐aminophenol (APAP), commonly known as acetaminophen, generates excessive oxidative stress and triggers hepatocyte cell death, exemplified by regulated necrosis. In the present study, we investigated whether APAP‐induced liver injury in a mouse model is associated with “necroptosis,” and if pretreatment with recombinant Trx‐1 prevents the hepatic injury caused by APAP overdose. We also explored the mechanism underlying the preventive action of Trx‐1 against APAP‐induced hepatic injury. In a prevention study, C3H/he mice received different doses (0, 10, 50 or 100 mg kg^–1 body weight) of recombinant human Trx‐1 intraperitoneally, followed by a single oral dose of 300 mg kg^–1 of APAP. In this experimental paradigm, liver injury and lethality were markedly decreased in rhTrx‐1–pretreated mice. In survival experiments, mice received rhTrx‐1 followed by oral administration of a lethal dose of APAP. APAP overdose caused a series of liver toxicity‐associated events, beginning with overexpression of c‐fos, excessive production of reactive oxygen species and reactive nitrogen species (RNS) and leading to decreased endogenous Trx‐1 expression and activation of JNK signaling pathways. Pretreatment with rhTrx‐1 inhibited all of these toxicological manifestations of APAP. In addition, rhTrx‐1 significantly reduced the expression of RIP‐3, a critical necrosome component. Taken together, our findings indicate that rhTrx‐1 prevents APAP‐induced liver injury through multiple action mechanisms, including scavenging reactive oxygen species and reactive nitrogen species, restoring endogenous Trx‐1 levels and inhibiting RIP‐3 overexpression.     

Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis

Aging-elevated DNMT3A R882H-driven clonal hematopoiesis (CH) is a risk factor for myeloid malignancies remission and overall survival. Although some studies were conducted to investigate this phenomenon, the exact mechanism is still under debate. In this study, we observed that DNMT3A R878H bone marrow cells (human allele: DNMT3A R882H) displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult. DNMT3A R878H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation, especially TNFα insults. Mechanistically, we identified that RIPK1–RIPK3–MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNFα insults. Briefly, we elucidated the molecular mechanism driving DNMT3A R878H-based clonal hematopoiesis, which raises clinical value for treating DNMT3A R882H-driven clonal hematopoiesis and myeloid malignancies with aging.     

小鼠胚胎肾脏细胞坏死性凋亡的超微结构

目的 观察小鼠胚胎肾脏发育过程中细胞坏死性凋亡的超微结构变化.方法 应用电子显微镜技术对不同胚龄(E12、14、16、18d)胎鼠(各3例)的肾脏的细胞坏死性凋亡进行系统观察.结果 细胞坏死性凋亡确实出现在胚胎肾脏中,它同时具有坏死的细胞质和凋亡的细胞核.细胞肿胀,细胞膜破溃,细胞器也肿胀空泡化.核染色质高密度固缩,边聚,多呈月牙状.细胞凋亡被发现的机会大于坏死性凋亡和细胞胀亡.结论 细胞坏死性凋亡与细胞凋亡及细胞胀亡共同构成了小鼠胚胎肾脏发育过程中的程序性细胞死亡,但坏死性凋亡和胀亡为辅,而以细胞凋亡为主.     

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.     

Connections Between Various Trigger Factors and the RIP1/RIP3 Signaling Pathway Involved in Necroptosis

Programmed cell death is a basic cellular process that is critical to maintaining tissue homeostasis. In contrastto apoptosis, necrosis was previously regarded as an unregulated and uncontrollable process. However, as researchhas progressed, necrosis, also known as necroptosis or programmed necrosis, is drawing increasing attention,not least becasu of its possible impications for cancer research. Necroptosis exhibits a unique signaling pathwaythat requires the involvement of receptor interaction protein kinases 1 and 3 (RIP1 and RIP3), mixed lineagekinase domain-like (MLKL), and phosphoglycerate mutase 5 (PGAM5) and can be specifically inhibited bynecrostatins. Not only does necroptosis serve as a backup cell death program when apoptosis is inhibited, but itis now recognized to play a pivotal role in regulating various physiological processes and the pathogenesis of avariety of human diseases such as ischemic brain injury, immune system disorders and cancer. The control ofnecroptosis by various defined trigger factors and signaling pathways now offers the opportunity to target thiscellular process for therapeutic purposes. The purpose of this paper is to review current findings concerning theconnections between various trigger factors and the RIP1/RIP3 signaling pathway as it relates to necroptosis.     

对放射性肠炎的认识及其可能的机制探讨

放射性肠炎严重影响盆腔肿瘤放疗患者的生活质量,作为一种放疗相关的肠道炎症,相关的基础研究显示放射性肠炎本质上是一种黏膜的炎症,由于程序性坏死可能介导了炎症性肠病的发生,因此,同样作为肠道炎症性疾病的一种,程序性坏死可能也介导了放射性肠炎的发生发展。本文拟对放射性肠炎的本质以及可能的发生机制进行综述,期待能够指导放射性肠炎的治疗,进而有望提高患者的生活质量。