Molecular mechanism and therapeutic targeting of necrosis,apoptosis, pyroptosis,and autophagy in cardiovascular disease

Cell death occurs in various tissues and organs in the body. It is a physiological or pathological process that has different effects. It is of great significance in maintaining the morphological function of cells and clearing abnormal cells. Pyroptosis, apoptosis, and necrosis are all modes of cell death that have been studied extensively by many experts and scholars, including studies on their effects on the liver, kidney, the heart, other organs, and even the whole body. The heart, as the most important organ of the body, should be a particular focus. This review summarizes the mechanisms underlying the various cell death modes and the relationship between the various mechanisms and heart diseases. The current research status for heart therapy is discussed from the perspective of pathogenesis.     

Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies

Sepsis is defined as organ dysfunction due to a dysregulated systemic host response to infection. During gram-negative bacterial infection and other acute illness such as absorption from the gut infection, lipopolysaccharide (LPS) is a major mediator in sepsis. LPS is able to trigger inflammation through both intracellular and extracellular pathways. Classical interactions between LPS and host cells first involve LPS binding to LPS binding protein (LBP), a carrier. The LPS-LBP complex then binds to a receptor complex including the CD14, MD2, and toll-like receptor 4 (TLR4) proteins, initiating a signal cascade which triggers the secretion of pro-inflammatory cytokines. However, it has been established that LPS is also internalized by macrophages and endothelial cells through TLR4-independent pathways. Once internalized, LPS is able to bind to the cytosolic receptors caspases-4/5 in humans and the homologous caspase-11 in mice. Bound caspases-4/5 oligomerize and trigger the assembly of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome followed by the activation of inflammatory caspase-1 resulting in subsequent release of interleukin-1β. Caspases-4/5 also activate the perforin gasdermin D and purinergic receptor P2X7, inducing cell lysis and pyroptosis. Pyroptosis is a notable source of inflammation and damage to the lung endothelial barrier during sepsis. Thus, inhibition of caspases-4/5/1 or downstream effectors to block intracellular LPS signaling may be a promising therapeutic approach in adjunction with neutralizing extracellular LPS for treatment of sepsis.     

线粒体在针刺治疗脑卒中后认知功能障碍中的作用研究进展

卒中后认知功能障碍(PSCI)是卒中后常见的并发症,严重影响患者的生命质量。尽管其发病机制还未完全阐明,但研究表明线粒体参与了其发病过程,因此基于线粒体的保护措施可能是治疗PSCI颇具前途的一种策略。针刺的作用具有多靶点、多途径的特点,在PSCI治疗方面显示出独特的优势。针刺基于线粒体功能保护作用治疗PSCI的机制涵盖了线粒体生物能学、线粒体通透性、线粒体质量、线粒体氧化还原系统和线粒体生物发生等多个方面。针对线粒体的进一步研究将为针刺治疗PSCI提供理论支持,并推进针刺治疗方案的优化。     

Tongxinluo promotes endothelium-dependent arteriogenesis to attenuate diabetic peripheral arterial disease

BACKGROUND Peripheral arterial disease(PAD) has become one of the leading causes of disability and death in diabetic patients. Restoring blood supply to the hindlimbs,especially by promoting arteriogenesis, is currently the most effective strategy, in which endothelial cells play an important role. Tongxinluo(TXL) has been widely used for the treatment of cardio-cerebrovascular diseases and extended for diabetes-related vascular disease.AIM To investigate the effect of TXL on diabetic PAD and it...     

小胶质细胞焦亡在缺氧缺血性脑损伤中的作用

目的 初步探讨小胶质细胞焦亡在缺氧缺血性脑损伤中的作用。方法 建立体外培养大鼠小胶质细胞系氧糖剥夺再灌注（OGD/R）模型,用Western blot法检测OGD/R后0、1、3、6、12及24 h焦亡相关蛋白半胱氨酸天冬氨酸蛋白酶-l（caspase-1）、白细胞介素-1β（IL-1β）、Gasdermin D蛋白N端（GSDMD-N）的表达情况。用慢病毒构建的沉默Gasdermin D（GSDMD）序列转染小胶质细胞,使用免疫荧光和Western blot法检测GSDMD转染效率。将小胶质细胞系分为正常对照组、阴性对照组、LV-sh_GSDMD组（慢病毒沉默GSDMD）,使用CCK-8和LDH试剂盒检测沉默GSDMD对OGD/R后24 h小胶质细胞活性和毒性的影响;通过Western blot法检测沉默GSDMD对OGD/R后24 h小胶质细胞中caspase-1、GSDMD-N、IL-1β含量变化的影响。结果 在OGD/R后0 h起小胶质细胞内焦亡相关蛋白caspase-1、GSDMD-N、IL-1β的表达水平即较OGD/R前发生了上调,并且在24 h达到高峰（P < 0.05）。成功地构建慢病毒沉默GSDMD转染小胶质细胞模型。OGD/R后24 h,与正常对照组相比,沉默GSDMD可提高细胞活性和降低细胞毒性（P < 0.05）,降低小胶质细胞内caspase-1、GSDMD-N、IL-1β蛋白水平（P < 0.05）。结论 慢病毒沉默细胞焦亡关键底物蛋白GSDMD可减轻缺氧缺血性脑损伤,提示小胶质细胞焦亡加重缺氧缺血性脑损伤。     

Pyroptosis-inducing active caspase-1 as a genetic adjuvant in anti-cancer DNA vaccination

Pyroptosis is a recently discovered form of inflammatory programmed necrosis characterized by caspase-1-mediated and gasdermin D-dependent cell death leading to the release of pro-inflammatory cytokines such as Interleukin-1 beta (IL-1β). Here, we evaluated whether pyroptosis could be exploited in DNA vaccination by incorporating a constitutively active variant of caspase-1 to the antigen-expressing DNA. In vitro, transfection with constitutively active caspase-1 DNA induced pro-IL-1β maturation and IL-1β release as well as gasdermin D-dependent cell death. To test active caspase-1 as a genetic adjuvant for the induction of antigen-specific T cell responses, mice were vaccinated intradermally with a DNA vaccine consisting of the active caspase-1 plasmid together with a plasmid encoding an ovalbumin-derived CD8 T cell epitope. Active caspase-1 accelerated and amplified antigen-specific CD8 T cell responses when administered simultaneously with the DNA vaccine at an equimolar dose. Moreover, upon challenge with melanoma cells expressing ovalbumin, mice vaccinated with the antigen vaccine adjuvanted with active caspase-1 showed significantly better survival compared to the non-adjuvanted group. In conclusion, we have developed a novel genetic adjuvant that for the first time employs the pyroptosis pathway to improve DNA vaccination against cancer.     

Combating pancreatic cancer chemoresistance by triggering multiple cell death pathways

Pancreatic cancer is the fourth most common cause of cancer-associated death in western countries, where the incidence and number of deaths are increasing every year. Intrinsic or acquired resistance of tumor cells to chemotherapy agents is the major reason for failure of traditional cancer treatment. Several factors are implicated in this impressive resistance; however, of these, it is important to highlight the extensive cellular heterogeneity of these tumors. This heterogeneity is linked to a wide range of sensitivity that different clones in the same tumor display to chemotherapeutic agents. Accordingly, recent findings in this field have discovered new therapeutic targets in order to develop new combinatory treatments, as well as to induce several cell death pathways and reduce therapy-threshold and likelihood of future resistance. Accordingly, recent research has focused on targeting mitochondria, an organelle with key roles regulating cell death signaling pathways, such as apoptosis, necroptosis, autophagy, ferroptosis, or parthanatos. These findings — identifying new compounds, alone or in combination, that can target pancreatic ductal adenocarcinoma cell resistance — could be the key to future treatments.     

The role of lysosome in regulated necrosis

Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules, particles, and organelles. Currently, the pivotal role of lysosome in regulating cell death is drawing great attention. Over the past decades, we largely focused on how lysosome influences apoptosis and autophagic cell death. However, extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis (RN). Different types of RN have been uncovered, among which, necroptosis, ferroptosis, and pyroptosis are under the most intensive investigation. It becomes a hot topic nowadays to target RN as a therapeutic intervention, since it is important in many patho/physiological settings and contributing to numerous diseases. It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases. Therefore, we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN, especially in that of necroptosis, ferroptosis, and pyroptosis.     

Ghrelin alleviates traumatic brain injury-induced acute lung injury through pyroptosis/NF-κB pathway

Acute lung injury (ALI) is one of the severe complications in patients with traumatic brain injury (TBI), contributing to the high mortality. Ghrelin has protective effects against various inflammatory diseases, but the effects of Ghrelin on TBI-induced ALI and its mechanisms remain unknown. In this study, Ghrelin administration was performed on the mice with TBI, then histological change in cortex and lung tissues, lung vascular permeability and macrophage number in bronchoalveolar lavage fluid (BALF) were examined, respectively. Simultaneously, the alterations of proinflammatory factors and pyroptosis-related proteins in lung tissues were detected. As a result, TBI-induced ALI was ameliorated after Ghrelin treatment, which was demonstrated by improved histology, reduced lung vascular permeability, and peripheral macrophage number. Furthermore, Ghrelin decreased the mRNA levels of proinflammatory factors (IL-1β, IL-6, TNF-α and IL-18), the protein levels of pyroptosis-related proteins (NLRP3, Caspase1-P20, HMGB1 and Gasdermin D), and the phosphorylation levels of NF-κB in lung tissues. These results showed that Ghrelin attenuating TBI-induced ALI might be via ameliorating inflammasome-induced pyroptosis by blocking NF-κB signal, which are important for the prevention and treatment of TBI-induced ALI.