Form Of Programmed Cell Death Research Articles

Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.

Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases.

No Time to Die: How Cytomegaloviruses Suppress Apoptosis, Necroptosis, and Pyroptosis.

Viruses are obligate intracellular pathogens as their replication depends on the metabolism of the host cell. The induction of cellular suicide, known as programmed cell death (PCD), has the potential to hinder viral replication and act as a first line of defense against viral pathogens. Apoptosis, necroptosis, and pyroptosis are three important PCD modalities. Different signaling pathways are involved in their execution, and they also differ in their ability to cause inflammation. Cytomegaloviruses (CMV), beta-herpesviruses with large double-stranded DNA genomes, encode a great variety of immune evasion genes, including several cell death suppressors. While CMV inhibitors of apoptosis and necroptosis have been known and studied for years, the first pyroptosis inhibitor has been identified and characterized only recently. Here, we describe how human and murine CMV interfere with apoptosis, necroptosis, and pyroptosis signaling pathways. We also discuss the importance of the different PCD forms and their viral inhibitors for the containment of viral replication and spread in vivo.

Emerging connectivity of programmed cell death pathways and pulmonary vascular remodelling during pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic progressive vascular disease characterized by abnormal pulmonary vascular resistance and pulmonary artery pressure. The major structural alteration during PH is pulmonary vascular remodelling, which is mainly caused by the imbalance between proliferation and apoptosis of pulmonary vascular cells. Previously, it was thought that apoptosis was the only type of programmed cell death (PCD). Soon afterward, other types of PCD have been identified, including autophagy, pyroptosis, ferroptosis and necroptosis. In this review, we summarize the role of the above five forms of PCD in mediating pulmonary vascular remodelling, and discuss their guiding significance for PH treatment. The current review could provide a better understanding of the correlation between PCD and pulmonary vascular remodelling, contributing to identify new PCD-associated drug targets for PH.

OTUB1 regulates ferroptosis to inhibit myoblast differentiation into myotubes by deubiquitinating P62

As the largest organ in the human body, skeletal muscle is essential for breathing support, movement initiation, and maintenance homeostasis. It has been shown that programmed cell death (PCD), which includes autophagy, apoptosis, and necrosis, is essential for the development of skeletal muscle. A novel form of PCD called ferroptosis is still poorly understood in relation to skeletal muscle. In this study, we observed that the activation of ferroptosis significantly impeded the differentiation of C2C12 myoblasts into myotubes and concurrently suppressed the expression of OTUB1, a crucial deubiquitinating enzyme. OTUB1-silenced C2C12 mouse myoblasts were used to investigate the function of OTUB1 in ferroptosis. The results show that OTUB1 knockdown in vitro significantly increased C2C12 ferroptosis and inhibited myogenesis. Interestingly, the induction of ferroptosis resulting from OTUB1 knockdown was concomitant with the activation of autophagy. Furthermore, OTUB1 interacted with the P62 protein and stabilized its expression by deubiquitinating it, thereby inhibiting autophagy-dependent ferroptosis and promoting myogenesis. All of these findings demonstrate the critical role that OTUB1 plays in controlling ferroptosis, and we suggest that focusing on the OTUB1-P62 axis may be a useful tactic in the treatment and prevention of disorders involving the skeletal muscle.

Apoptosis and NETotic cell death affect diabetic nephropathy independently: An study integrative study encompassing bioinformatics, machine learning, and experimental validation

ObjectiveAlthough programmed cell death (PCD) and diabetic nephropathy (DN) are intrinsically conneted, the interplay among various PCD forms remains elusive. In this study, We aimed at identifying independently DN-associated PCD pathways and biomarkers relevant to the related pathogenesis. MethodsWe acquired DN-related datasets from the GEO database and identified PCDs independently correlated with DN (DN-PCDs) through single-sample Gene Set Enrichment Analysis (ssGSEA) as well as, univariate and multivariate logistic regression analyses. Subsequently, applying differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Mfuzz cluster analysis, we filtered the DN-PCDs pertinent to DN onset and progression. The convergence of various machine learning techniques ultimately spotlighted hub genes, substantiated through dataset meta-analyses and experimental validations, thereby confirming hub genes and related pathways expression consistencies. ResultsWe harmonized four DN-related datasets (GSE1009, GSE142025, GSE30528, and GSE30529) post-batch-effect removal for subsequent analyses. Our differential expression analysis yielded 709 differentially expressed genes (DEGs), comprising 446 upregulated and 263 downregulated DEGs. Based on our ssGSEA as well as univariate and multivariate logistic regressions, apoptosis and NETotic cell death were appraised as independent risk factors for DN (Odds Ratio > 1, p < 0.05). Next, we further refined 588 apoptosis- and NETotic cell death-associated genes through WGCNA and Mfuzz analysis, resulting in the identification of 17 DN-PCDs. Integrating protein-protein interaction (PPI) network analyses, network topology, and machine learning, we pinpointed hub genes (e.g., IL33, RPL11, and CX3CR1) as significant DN risk factors with expression corroborating in subsequent meta-analyses and experimental validations. Our GSEA enrichment analysis discerned differential enrichments between DN and control samples within pathways such as IL2/STAT5, IL6/JAK/STAT3, TNF-α via NF-κB, apoptosis, and oxidative phosphorylation, with related proteins such as IL2, IL6, and TNFα, which we subsequently submitted to experimental verification. ConclusionInnovatively stemming from from PCD interactions, in this study, we discerned PCDs with an independent impact on DN: apoptosis and NETotic cell death. We further screened DN evolution- and progression-related biomarkers, i.e. IL33, RPL11, and CX3CR1, all of which we empirically validated. This study not only poroposes a PCD-centric perspective for DN studies but also provides evidence for PCD-mediated immune cell infiltration exploration in DN regulation. Our results could motivate further exploration of DN pathogenesis, such as how the inflammatory microenvironment mediates NETotic cell death in DN regulation, representing a promising direction for future research.

Crosstalk Between Cell Death and Spinal Cord Injury: Neurology and Therapy.

Spinal cord injury (SCI) often leads to neurological dysfunction, and neuronal cell death is one of the main causes of neurological dysfunction. After SCI, in addition to necrosis, programmed cell death (PCD) occurs in nerve cells. At first, studies recognized only necrosis, apoptosis, and autophagy. In recent years, researchers have identified new forms of PCD, including pyroptosis, necroptosis, ferroptosis, and cuproptosis. Related studies have confirmed that all of these cell death modes are involved in various phases of SCI and affect the direction of the disease through different mechanisms and pathways. Furthermore, regulating neuronal cell death after SCI through various means has been proven to be beneficial for the recovery of neural function. In recent years, emerging therapies for SCI have also provided new potential methods to restore neural function. Thus, the relationship between SCI and cell death plays an important role in the occurrence and development of SCI. This review summarizes and generalizes the relevant research results on neuronal necrosis, apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis after SCI to provide a new understanding of neuronal cell death after SCI and to aid in the treatment of SCI.

Mechanisms of persistent hemolysis-induced middle kidney injury in grass carp (Ctenopharyngodon idella)

Infection-induced hemolysis results in intravascular hemolysis, which releases hemoglobin (Hb) into the tissues. Free Hb exhibits cytotoxic, oxidative, and pro-inflammatory effects, leading to systemic inflammation, vascular constriction dysfunction, thrombosis, and proliferative vascular lesions. Currently, the impact of intravascular hemolysis on the middle kidney in fish is unclear. Here, the injection of phenylhydrazine (PHZ) was used to establish a persistent hemolysis model in grass carp. The determination results revealed that the PHZ-induced hemolysis caused conspicuous tissue damage in the kidneys of grass carp, increased the levels of Cr in the serum and the expression indicators of kidney injury-related genes in the middle kidney. Prussian blue staining indicated that PHZ-induced hemolysis significantly increased the deposition of iron ions in the kidneys of grass carp, and activated the expression levels of iron metabolism-related genes. The results of oxidative damage-related experiments indicate that under PHZ treatment, the activity of middle kidney cells decreases, and the production of oxidative damage markers malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) increases, simultaneously inhibiting the activity of antioxidant enzymes and upregulating the transcription levels of antioxidant enzyme-related genes. Additionally, the analysis of inflammatory factors revealed a significant upregulation of genes associated with inflammation induced by PHZ-induced hemolysis. The transcriptome analysis was performed to further explore the molecular regulatory effects of hemolysis on tissues, the analysis revealed the treatment of PHZ activated various of programmed cell death (PCD) pathways, including ferroptosis, apoptosis, and autophagy. In summary, this study found that sustained hemolysis in fish results in Hb and iron ion deposition in middle kidney, promoting oxidative damage, ultimately inducing various forms of PCD.

The role of programmed cell death in osteosarcoma: From pathogenesis to therapy.

Osteosarcoma (OS) is a prevalent bone solid malignancy that primarily affects adolescents, particularly boys aged 14-19. This aggressive form of cancer often leads to deadly lung cancer due to its high migration ability. Experimental evidence suggests that programmed cell death (PCD) plays a crucial role in the development of osteosarcoma. Various forms of PCD, including apoptosis, ferroptosis, autophagy, necroptosis, and pyroptosis, contribute significantly to the progression of osteosarcoma. Additionally, different signaling pathways such as STAT3/c-Myc signal pathway, JNK signl pathway, PI3k/AKT/mTOR signal pathway, WNT/β-catenin signal pathway, and RhoA signal pathway can influence the development of osteosarcoma by regulating PCD in osteosarcoma cell. Therefore, targeting PCD and the associated signaling pathways could offer a promising therapeutic approach for treating osteosarcoma.

Nicotinic and Muscarinic Acetylcholine Receptor Agonists Counteract Cognitive Impairment in a Rat Model of Doxorubicin-Induced Chemobrain via Attenuation of Multiple Programmed Cell Death Pathways.

Chemotherapy causes undesirable long-term neurological sequelae, chemotherapy-induced cognitive impairment (CICI), or chemobrain in cancer survivors. Activation of programmed cell death (PCD) has been proposed to implicate in the development and progression of chemobrain. Neuronal apoptosis has been extensively recognized in experimental models of chemobrain, but little is known about alternative forms of PCD in response to chemotherapy. Activation of acetylcholine receptors (AChRs) is emerging as a promising target in attenuating a wide variety of the neuronal death associated with neurodegeneration. Thus, this study aimed to investigate the therapeutic capacity of AChR agonists on cognitive function and molecular hallmarks of multiple PCD against chemotherapy neurotoxicity. To establish the chemobrain model, male Wistar rats were assigned to receive six doses of doxorubicin (DOX: 3mg/kg) via intraperitoneal injection. The DOX-treated rats received either an a7nAChR agonist (PNU-282987: 3mg/kg/day), mAChR agonists (bethanechol: 12mg/kg/day), or the two as a combined treatment. DOX administration led to impaired cognitive function via neuroinflammation, glial activation, reduced synaptic/blood-brain barrier integrity, defective mitochondrial ROS-detoxifying capacity, and dynamic imbalance. DOX insult also mediated hyperphosphorylation of Tau and simultaneously induced various PCD, including apoptosis, necroptosis, and pyroptosis in the hippocampus. Concomitant treatment with either PNU-282987, bethanechol, or a combination of the two potently attenuated neuroinflammation, mitochondrial dyshomeostasis, and Tau hyperphosphorylation, thereby suppressing excessive apoptosis, necroptosis, and pyroptosis and improving cognitive function in DOX-treated rats. Our findings suggest that activation of AChRs using their agonists effectively protected against DOX-induced neuronal death and chemobrain.

Static magnetic field reduces cisplatin resistance via increasing apoptosis pathways and genotoxicity in cancer cell lines

Cisplatin is a chemotherapy drug widely used in cancer treatment. Alongside its clinical benefits, however, it may inflict intolerable toxicity and other adverse effects on healthy tissues. Due to the limitation of administering a high dose of cisplatin as well as cancer drug resistance, it is necessary to utilize new methods optimizing treatment modalities through both higher therapeutic efficacy and reduced administered doses of radiation and drugs. In this study, sensitive (A2780) and resistant (A2780CP) ovarian carcinoma cells underwent treatment with cisplatin + static magnetic field (SMF). First, the levels of genotoxicity after treatment were evaluated by Comet assay. Then, cell cycle analysis and apoptosis assay were conducted by a flow cytometer. Lastly, the expression levels of genes involved in apoptosis and cellular drug uptake were investigated by PCR. After treating different groups of cells for 24, 48, and 96 h, the co-treatment of SMF and cisplatin as a combination managed to increase the amount of DNA damage in both sensitive and resistant cell lines. A considerable increase in mortality of cells was also observed mostly in the form of apoptosis, which was caused by inhibition of the cell cycle. The combination also increased the expression levels of apoptotic genes, namely P53 and P21; however, it did not have much effect on the expression levels of BCL2. Besides, the levels of CTR1 gene expression increased significantly in the groups receiving the aforementioned combination. Our study suggests that the combination of cisplatin + SMF might have clinical potential which needs further investigations through future studies.

The Long Non-Coding RNA NR3C2-8:1 Promotes p53-Mediated Apoptosis through the miR-129-5p/USP10 Axis in Amyotrophic Lateral Sclerosis

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms underlying this neuronal cell death remain unclear. Numerous studies demonstrate abnormally elevated and active p53 in the central nervous system of ALS patients. Activation of p53-regulated pro-apoptotic signaling pathways may trigger motor neuron death. We previously reported decreased expression of the long non-coding RNA NR3C2-8:1 (Lnc-NR3C) in leukocytes of ALS patients. Here, we show lnc-NR3C promotes p53-mediated cell death in ALS by upregulating USP10 and promoting lnc-NR3C-triggered p53 activation, resulting in cell death. Conversely, lnc-NR3C knockdown inhibited USP10-triggered p53 activation, thereby protecting cells against oxidative stress. As a competitive endogenous RNA, lnc-NR3C competitively binds miR-129-5p, regulating the usp10/p53 axis. Elucidating the link between Lnc-NR3C and the USP10/p53 axis in an ALS cell model reveals a role for long non-coding RNAs in activating apoptosis. This provides new therapeutic opportunities in ALS.

Validation and identification of anoikis-related lncRNA signatures for improving prognosis in clear cell renal cell carcinoma.

Clear cell carcinoma (ccRCC) usually has a high metastasis rate and high mortality rate. To enable precise risk stratification, there is a need for novel biomarkers. As one form of apoptosis, anoikis results from the disruption of cell-cell connection or cell-ECM attachment. However, the impact of anoikis-related lncRNAs on ccRCC has not yet received adequate attention. The study utilized univariate Cox regression analysis in order to identify the overall survival (OS) associated anoikis-related lncRNAs (ARLs), followed by the LASSO algorithm for selection. On this basis, a risk model was subsequently established using five anoikis-related lncRNAs. To dig the inner molecular mechanism, KEGG, GO, and GSVA analyses were conducted. Additionally, the immune infiltration landscape was estimated using the ESTIMATE, CIBERSORT, and ssGSEA algorithms. The study constructed a novel risk model based on five ARLs (AC092611.2, AC027601.2, AC103809.1, AL133215.2, and AL162586.1). Patients categorized as low-risk exhibited significantly better OS. Notably, the study observed marked different immune infiltration landscapes and drug sensitivity by risk stratification. Additionally, the study preliminarily explored potential signal pathways associated with risk stratification. The study exhibited the crucial role of ARLs in the carcinogenesis of ccRCC, potentially through differential immune infiltration. Furthermore, the established risk model could serve as a valuable stratification factor for predicting OS prognosis.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer.

Colorectal cancer (CRC) presents a significant global health burden, characterized by a heterogeneous molecular landscape and various genetic and epigenetic alterations. Programmed cell death (PCD) plays a critical role in CRC, offering potential targets for therapy by regulating cell elimination processes that can suppress tumor growth or trigger cancer cell resistance. Understanding the complex interplay between PCD mechanisms and CRC pathogenesis is crucial. This study aims to construct a PCD-related prognostic signature in CRC using machine learning integration, enhancing the precision of CRC prognosis prediction. We retrieved expression data and clinical information from the Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Fifteen forms of PCD were identified, and corresponding gene sets were compiled. Machine learning algorithms, including Lasso, Ridge, Enet, StepCox, survivalSVM, CoxBoost, SuperPC, plsRcox, random survival forest (RSF), and gradient boosting machine, were integrated for model construction. The models were validated using six GEO datasets, and the programmed cell death score (PCDS) was established. Further, the model's effectiveness was compared with 109 transcriptome-based CRC prognostic models. Our integrated model successfully identified differentially expressed PCD-related genes and stratified CRC samples into four subtypes with distinct prognostic implications. The optimal combination of machine learning models, RSF + Ridge, showed superior performance compared with traditional methods. The PCDS effectively stratified patients into high-risk and low-risk groups, with significant survival differences. Further analysis revealed the prognostic relevance of immune cell types and pathways associated with CRC subtypes. The model also identified hub genes and drug sensitivities relevant to CRC prognosis. The current study highlights the potential of integrating machine learning models to enhance the prediction of CRC prognosis. The developed prognostic signature, which is related to PCD, holds promise for personalized and effective therapeutic interventions in CRC.

Exploring diverse programmed cell-death patterns to develop a novel gene signature for predicting the prognosis of lung adenocarcinoma patients.

Programmed cell death (PCD) plays a critical role in tumor progression and malignancy, and exploring its relationship with lung adenocarcinoma (LUAD)'s survival outcomes is important for personalized diagnosis and treatment. This study aimed to identify survival-related genes and construct an effective prognostic indicator for LUAD based on 12 forms of PCD. A total of 1,933 candidate genes related to PCD were collected from published studies and public data center. A prognostic gene signature, called the cell death index (CDI), was established based on RNA-Seq and immunohistochemistry (IHC). IHC staining on tissue microarray was applied for the validation of protein level. Moreover, GSE42127, GSE72094 were used as validation datasets. The CDI based on expression level of nine genes (CCNB2, HMGA1, CACNA2D2, BUB1B, BTG2, KIF14, PTGDS, SERPINB5, BRCA1) was highly predictive for overall survival (OS) of LUAD in our cohort [36-month area under the curve (AUC): 0.750, 60-month AUC: 0.809]. The CDI was further validated in independent cohorts (GSE72094, 36-month AUC: 0.717, 60-month AUC: 0.737; GSE42127, 12-month AUC: 0.829, 60-month AUC: 0.663). And the CDI was found to be an independent prognostic factor after adjusting for other clinical characteristics. Furthermore, the high-CDI group was associated with upregulated tumor immune infiltration compared to the low-CDI group. This study identified a 9-gene signature (CDI) based on PCD-related genes that accurately predicted the prognosis of LUAD patients. The CDI could serve as a valuable prognostic indicator and guide personalized therapeutic strategies for LUAD.

Programmed cell death in tumor immunity: mechanistic insights and clinical implications.

Programmed cell death (PCD) is an evolutionarily conserved mechanism of cell suicide that is controlled by various signaling pathways. PCD plays an important role in a multitude of biological processes, such as cell turnover, development, tissue homeostasis and immunity. Some forms of PCD, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis and necroptosis, contribute to carcinogenesis and cancer development, and thus have attracted increasing attention in the field of oncology. Recently, increasing research-based evidence has demonstrated that PCD acts as a critical modulator of tumor immunity. PCD can affect the function of innate and adaptive immune cells, which leads to distinct immunological consequences, such as the priming of tumor-specific T cells, immunosuppression and immune evasion. Targeting PCD alone or in combination with conventional immunotherapy may provide new options to enhance the clinical efficacy of anticancer therapeutics. In this review, we introduce the characteristics and mechanisms of ubiquitous PCD pathways (e.g., apoptosis, autophagy-dependent cell death, pyroptosis and ferroptosis) and explore the complex interaction between these cell death mechanisms and tumor immunity based on currently available evidence. We also discuss the therapeutic potential of PCD-based approaches by outlining clinical trials targeting PCD in cancer treatment. Elucidating the immune-related effects of PCD on cancer pathogenesis will likely contribute to an improved understanding of oncoimmunology and allow PCD to be exploited for cancer treatment.

Programmed cell death and Salmonella pathogenesis: an interactive overview.

Programmed cell death (PCD) is the collective term for the intrinsically regulated death of cells. Various types of cell death are triggered by their own programmed regulation during the growth and development of organisms, as well as in response to environmental and disease stresses. PCD encompasses apoptosis, pyroptosis, necroptosis, autophagy, and other forms. PCD plays a crucial role not only in the growth and development of organisms but also in serving as a component of the host innate immune defense and as a bacterial virulence strategy employed by pathogens during invasion. The zoonotic pathogen Salmonella has the ability to modulate multiple forms of PCD, including apoptosis, pyroptosis, necroptosis, and autophagy, within the host organism. This modulation subsequently impacts the bacterial infection process. This review aims to consolidate recent findings regarding the mechanisms by which Salmonella initiates and controls cell death signaling, the ways in which various forms of cell death can impede or restrict bacterial proliferation, and the interplay between cell death and innate immune pathways that can counteract Salmonella-induced suppression of host cell death. Ultimately, these insights may contribute novel perspectives for the diagnosis and treatment of clinical Salmonella-related diseases.

Caspase-Linked Programmed Cell Death in Prostate Cancer: From Apoptosis, Necroptosis, and Pyroptosis to PANoptosis.

Prostate cancer (PCa) is a complex disease and the cause of one of the highest cancer-related mortalities in men worldwide. Annually, more than 1.2 million new cases are diagnosed globally, accounting for 7% of newly diagnosed cancers in men. Programmed cell death (PCD) plays an essential role in removing infected, functionally dispensable, or potentially neoplastic cells. Apoptosis is the canonical form of PCD with no inflammatory responses elicited, and the close relationship between apoptosis and PCa has been well studied. Necroptosis and pyroptosis are two lytic forms of PCD that result in the release of intracellular contents, which induce inflammatory responses. An increasing number of studies have confirmed that necroptosis and pyroptosis are also closely related to the occurrence and progression of PCa. Recently, a novel form of PCD named PANoptosis, which is a combination of apoptosis, necroptosis, and pyroptosis, revealed the attached connection among them and may be a promising target for PCa. Apoptosis, necroptosis, pyroptosis, and PANoptosis are good examples to better understand the mechanism underlying PCD in PCa. This review aims to summarize the emerging roles and therapeutic potential of apoptosis, necroptosis, pyroptosis, and PANoptosis in PCa.

NLRP3 Inflammasome: Key Role in the Pathophysiology of Cardiac Disorders and its Potential as a Therapeutic Target

Abstract: The NLRP3 inflammasome holds a pivotal position in the pathophysiological landscape of cardiac disorders, presenting itself as a promising therapeutic target. Central to this role are the proinflammatory cytokines Interleukin (IL)-1 and IL-18, which emerge as major players orchestrated by the activation of the NLRP3 inflammasome. This activation culminates in pyroptosis, a programmed form of cell death. While controlled activation of NLRP3 supports tissue repair, its excessive activation yields adverse consequences. Within the spectrum of cardiovascular diseases, ranging from abdominal aortic aneurysm to calcific aortic valve disease, the NLRP3 inflammasome is notably implicated. Atherosclerosis, myocardial infarction, diabetic cardiomyopathy, heart failure, and dilated cardiomyopathy collectively contribute to the genesis of inflammatory conditions. Key to this process is the nucleotide oligomerization domain-containing leucine-rich repeat protein 3 (NLRP3) inflammation, necessitating both priming and activation signals to orchestrate inflammation. Extensive scientific evidence substantiates the critical role of the NLRP3 inflammasome in cardiac disorders. Experimental models and clinical studies converge, highlighting its contribution to the intricate web of inflammatory pathways that underlie cardiac pathologies. This deeper understanding has spurred interest in targeting the NLRP3 inflammasome as a therapeutic avenue. Efforts to modulate the NLRP3 inflammasome are underway, aiming to temper its hyperactivity without disrupting its beneficial functions. Strategies involve small molecule inhibitors and biological agents, targeting various points along the signaling cascade. By selectively intervening in the NLRP3 pathway, researchers aspire to mitigate inflammatory responses, potentially ameliorating the progression of cardiac disorders. In conclusion, the NLRP3 inflammasome is a central orchestrator in the pathophysiology of diverse cardiac disorders. Its dual nature, capable of both driving repair and provoking harm, accentuates its significance as a therapeutic target. Scientific endeavors are actively unraveling its complexities, fostering the development of innovative interventions that could potentially revolutionize the management of cardiac inflammatory conditions.

The chromatin remodeling protein BRG1 contributes to liver ischemia-reperfusion injury by regulating NOXA expression

AimsHepatic ischemia-reperfusion injury (IRI) is a common complication secondary to liver transplantation. Extensive death of hepatocytes, typically in the form of apoptosis, is observed in and contributes to IRI. In the present study we investigated the role of BRG1 (encoded by Smarca4), a chromatin remodeling protein, in the pathogenesis of liver IRI focusing on the transcriptional mechanism and translational potential. MethodsSmarca4f/f mice were crossed to Alb-Cre mice to generate hepatocytes-specific BRG1 knockout mice (CKO). Alterations in cellular transcriptome were evaluated by RNA-seq. ResultsBRG1 expression was up-regulated in liver tissues of mice subjected to I/R and in hepatocytes exposed to hypoxia-reoxygenation (H/R). Compared to wild type (WT) littermates, the BRG1 CKO mice displayed significant amelioration of liver injury following ischemia-reperfusion as evidenced by decreased ALT/AST levels and cell apoptosis. Primary hepatocytes isolated from the CKO mice were protected from H/R-induced apoptosis compared to those from the WT mice. RNA-seq analysis revealed phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA) as a novel target for BRG1. Consistently, NOXA knockdown attenuated liver IRI in mice. More importantly, administration of a small-molecule BRG1 inhibitor (PFI-3) protected the mice from liver IRI. ConclusionsOur data uncover a pivotal role for BRG1 in liver IRI and suggest that targeting BRG1 with small-molecule inhibitors can be considered as a reasonable therapeutic strategy.

PANoptosis: Mechanism and Role in Pulmonary Diseases.

PANoptosis is a newly defined programmed cell death (PCD) triggered by a series of stimuli, and it engages three well-learned PCD forms (pyroptosis, apoptosis, necroptosis) concomitantly. Normally, cell death is recognized as a strategy to eliminate unnecessary cells, inhibit the proliferation of invaded pathogens and maintain homeostasis; however, vigorous cell death can cause excessive inflammation and tissue damage. Acute lung injury (ALI) and chronic obstructive pulmonary syndrome (COPD) exacerbation is related to several pathogens (e.g., influenza A virus, SARS-CoV-2) known to cause PANoptosis. An understanding of the mechanism and specific regulators may help to address the pathological systems of these diseases. This review presents our understanding of the potential mechanism of PANoptosis and the role of PANoptosis in different pulmonary diseases.