Neuronal nitric oxide synthase/reactive oxygen species pathway is involved in apoptosis and pyroptosis in epilepsy

Dysfunction of neuronal nitric oxide synthase contributes to neurotoxicity,which triggers cell death in various neuropathological diseases,including epilepsy.Studies have shown that inhibition of neuronal nitric oxide synthase activity increases the epilepsy threshold,that is,has an anticonvulsant effect.However,the exact role and potential mechanism of neuronal nitric oxide synthase in seizures are still unclear.In this study,we performed RNA sequencing,functional enrichment analysis,and weighted gene coexpression network analysis of the hippocampus of tremor rats,a rat model of genetic epilepsy.We found damaged hippocampal mitochondria and abnormal succinate dehydrogenase level and Na+-K+-ATPase activity.In addition,we used a pilocarpine-induced N2a cell model to mimic epileptic injury.After application of neuronal nitric oxide synthase inhibitor 7-nitroindazole,changes in malondialdehyde,lactate dehydrogenase and superoxide dismutase,which are associated with oxidative stress,were reversed,and the increase in reactive oxygen species level was reversed by 7-nitroindazole or reactive oxygen species inhibitor N-acetylcysteine.Application of 7-nitroindazole or N-acetylcysteine downregulated the expression of caspase-3 and cytochrome c and reversed the apoptosis of epileptic cells.Furthermore,7-nitroindazole or N-acetylcysteine downregulated the abnormally high expression of NLRP3,gasdermin-D,interleukin-1βand interleukin-18.This indicated that 7-nitroindazole and N-acetylcysteine each reversed epileptic cell death.Taken together,our findings suggest that the neuronal nitric oxide synthase/reactive oxygen species pathway is involved in pyroptosis of epileptic cells,and inhibiting neuronal nitric oxide synthase activity or its induced oxidative stress may play a neuroprotective role in epilepsy.

Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies

Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.

Role of selenium in cell death

Selenium is an essential nutrient closely related to redox homeostasis in the body.A redox imbalance will adversely affect the microenvironment inside and outside the cell,leading to cell death.Various types of cell death have been discovered in recent years,but the role(s)of selenium and the associated mechanism(s)of action require further elaboration.We review the roles and mechanisms of action of selenium in cell necrosis,apoptosis,ferroptosis,autophagy,and pyroptosis.Under normal conditions,selenium inhibits cell necrosis,apoptosis,ferroptosis,autophagy,and pyroptosis by downregulating the nuclear factorκB pathway,upregulating antiapoptotic proteins,decreasing oxidative stress,increasing antioxidant enzyme activity,enhancing the mTOR pathway,and downregulating the NLRP3/caspase-1 pathway,thereby helping to maintain the normal physiological functions of cells.On the other hand,selenium deficiency leads to activation of the PI3K/AKT and Notch/Hes1 pathways,causing a significant increase in the level of oxidative stress in the organism,resulting in cell necrosis,apoptosis,and pyroptosis.In the case of malignancy,the in vivo metabolite of inorganic selenium,hydrogen selenide,plays an antitumor role by inducing apoptosis and ferroptosis in tumor cells because of its high redox activity.In conclusion,an adequate level of selenium in the body is essential for maintaining normal cellular physiological functions and reducing fibrotic alterations.Furthermore,the in vivo metabolites of inorganic selenium may have some clinical value in antitumor therapy.

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.

Cell-death-mode switch from necrosis to apoptosis in hydrogen peroxide treated macrophages

Cell death is typically defined either as apoptosis or necrosis. Because the consequences of apoptosis and necrosis are quite different for an entire organism, the investigation of the cell-death-mode switch has considerable clinical significance. The existence of a necrosis-to-apoptosis switch induced by hydrogen peroxide in macrophage cell line RAW 264.7 cells was confirmed by using flow cytometry and fluorescence microscopy. With the help of computational simulations, this study predicted that negative feedbacks between NF-κB and MAPKs are implicated in converting necrosis into apoptosis in macrophages exposed to hydrogen peroxide, which has significant implications.

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.

GSDME maintains hematopoietic stem cells by balancing pyroptosis and apoptosis

GSDME contains a pore-forming domain at its N-terminal region to execute pyroptosis.Our previous study has reported that forced expression of Gsdme impairs the reconstitution capacity of hematopoietic stem cells(HSCs).While,how GSDME-mediated pyroptosis regulates HSCs remains unknown.Here,we show that hematopoietic stem and progenitor cells are capable to undergo pyroptosis in response to cisplatin treatment and GSDME is one of the genes mediating such process.Gsdme^(-/-)mice revealed no difference in the steady state of blood system while Gsdme^(-/-)HSCs exhibited compromised reconstitution capacity due to increased apoptosis.Briefly,this study reveals that GSDME modulates HSC function by coordinating pyroptosis and apoptosis.

M^(6)A modification in cardiovascular disease:With a focus on programmed cell death

N^(6)-methyladenosine(m^(6)A)methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years.Cardiovascular diseases(CVDs)are a leading cause of death globally.Emerging evidence demonstrates that RNA modifications,such as the m^(6)A modification,are associated with the development and progression of many diseases,including CVDs.An increasing body of studies has indicated that programmed cell death(PCD)plays a vital role in CVDs.However,the molecular mechanisms underlying m^(6)A modification and PCD in CVDs remain poorly understood.Herein,elaborating on the highly complex connections between the m^(6)A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m^(6)A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs.There is great potential for clinical application.

Regulated cell death in cancer:from pathogenesis to treatment

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.

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.

Autophagic activity in neuronal cell death

As post-mitotic cells with great energy demands, neurons depend upon the homeostatic and waste-recycling functions provided by autophagy. In addition, autophagy also promotes survival during periods of harsh stress and targets aggregate-prone proteins associated with neurodegeneration for degradation. Despite this, autophagy has also been controversially described as a mechanism of programmed cell death. Instances of autophagic cell death are typically associated with elevated numbers of cytoplasmic autophagosomes, which have been assumed to lead to excessive degradation of cellular components. Due to the high activity and reliance on autophagy in neurons, these cells may be particularly susceptible to autophagic death. In this review, we summarize and assess current evidence in support of autophagic cell death in neurons, as well as how the dysregulation of autophagy commonly seen in neurodegeneration can contribute to neuron loss. From here, we discuss potential treatment strategies relevant to such cell-death pathways.

Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy

Diabetic mellitus(DM) is a common degenerative chronic metabolic disease often accompanied by severe cardiovascular complications(DCCs) as major causes of death in diabetic patients with diabetic cardiomyopathy(DCM) as the most common DCC. The metabolic disturbance in DCM generates the conditions/substrates and inducers/triggers and activates the signaling molecules and death executioners leading to cardiomyocyte death which accelerates the development of DCM and the degeneration of DCM to heart failure.Various forms of programmed active cell death including apoptosis, pyroptosis, autophagic cell death, autosis,necroptosis, ferroptosis and entosis have been identified and characterized in many types of cardiac disease.Evidence has also been obtained for the presence of multiple forms of cell death in DCM. Most importantly,published animal experiments have demonstrated that suppression of cardiomyocyte death of any forms yields tremendous protective effects on DCM. Herein, we provide the most updated data on the subject of cell death in DCM, critical analysis of published results focusing on the pathophysiological roles of cell death, and pertinent perspectives of future studies.

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.

调节性细胞死亡在胃癌发生发展中的作用

胃癌是全球最常见的恶性肿瘤之一,其发病率和死亡率在我国恶性肿瘤中均位居第3。调节性细胞死亡(regulated cell death,RCD)是由信号转导模块激活而引起的一种细胞死亡形式,与胃癌的进展和治疗密切相关。RCD包括多种形式,如凋亡、焦亡、铁死亡、铜死亡、自噬等。这些形式不仅在清除受损细胞中发挥作用,还在抑制胃癌扩散中扮演着重要角色。本文综述了不同RCD形式在胃癌发生发展中的作用,旨在为胃癌的新型诊疗方法提供参考。

不同类型程序性细胞死亡在牙周炎中的研究进展

牙菌斑是牙周炎的始动因子,而宿主免疫细胞的招募和多种炎症介质的产生导致了牙周组织损伤与破坏。程序性细胞死亡包括细胞凋亡、细胞坏死性凋亡、细胞自噬、细胞焦亡、细胞铁死亡、细胞铜死亡等,其在牙周炎发生发展过程中作用也不尽相同。该文总结了不同类型程序性细胞死亡在牙周炎中的作用特点和研究进展,以期为牙周炎的发病机制提供新的研究思路,并且为牙周炎的精准治疗提供更多参考。

调节性细胞死亡在扩张型心肌病中的研究进展

扩张型心肌病(dilated cardiomyopathy,DCM)起病隐匿,以左心扩大甚至全心扩大为主要影像学表现,是心力衰竭与心律失常的常见原发疾病之一。随着近年来研究的不断深入,调节性细胞死亡(regulatory cell death,RCD)的内在分子机制逐渐清晰,研究者们发现RCD方式在DCM的发生发展过程中扮演了十分重要的角色。目前已知DCM中所涉及的RCD方式主要包括凋亡、坏死性凋亡、焦亡、铁死亡、自噬、铜死亡等,并且它们之间具有一定的相关性,可相互作用和调控。本文就上述6种RCD方式参与DCM的机制研究现况进行概述,以期为未来基础研究及临床应用提供参考。

成骨细胞调节性细胞死亡在牙周病中的作用研究进展

牙周病是以牙槽骨渐进性破坏为特征的慢性炎症性疾病。牙槽骨破坏最关键的机制是骨稳态失衡,而成骨细胞介导的骨基质合成在骨稳态调节中发挥重要作用。在炎性微环境和骨稳态调控中调节性细胞死亡举足轻重。慢性炎症、氧化应激等因素可直接参与线粒体、死亡受体介导的信号通路,调节B细胞淋巴瘤蛋白2家族和胱天蛋白酶(caspase)的活性,调节成骨细胞凋亡,从而影响牙槽骨稳态;慢性炎症与细胞损伤可经由RIPK1/RIPK3/MLKL信号通路诱发成骨细胞坏死性凋亡,从而加剧炎症反应并加速牙槽骨破坏;病原微生物、细胞损伤等刺激可通过caspase-1依赖或非依赖性信号通路及GSDMD家族蛋白活化,促进成骨细胞焦亡,并释放促炎性细胞因子,介导牙槽骨破坏;牙周病中铁过载和脂质过氧化可诱发成骨细胞铁死亡,影响成骨细胞的存活和功能,从而导致骨稳态失衡。本文围绕牙周病通过调节性细胞死亡影响骨稳态的机制,以期探讨调控牙周病患者牙槽骨稳态失衡的对策。

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。

Pyroptosis:一种新的细胞死亡方式

Pyroptosis是一种不同于凋亡和坏死的新型细胞死亡途径,在多种疾病模型中发挥着重要作用。Pyroptosis是一种依赖caspase-1的炎性细胞死亡,在控制微生物感染方面发挥着重要作用。本文从Pyroptosis的发生机制,与凋亡和坏死不同的形态和生化特征,以及宿主细胞和病原体相互作用以调节Pyroptosis等方面进行综述。

受体结合苏氨酸/丝氨酸蛋白激酶3及其抑制剂的研究进展

受体结合苏氨酸/丝氨酸蛋白激酶3(receptor-interacting serine/threonine-protein kinase 3,RIPK3)是RIP激酶家族的成员之一,在细胞死亡,特别是在坏死样凋亡中发挥着重要的作用。此外,RIPK3还参与细胞凋亡和焦亡的发生,提示RIPK3可能是多种细胞死亡方式的交汇点,有可能成为精准调控细胞死亡方式的靶点。根据激酶结合模式,目前RIPK3抑制剂可分为Ⅰ型、Ⅱ型和其它类型。该文总结了RIPK3在细胞死亡中的作用及其抑制剂开发的研究进展,对寻找治疗损伤相关性疾病的药物具有重要意义。