Form Of Programmed Cell Death Research Articles

Targeting the programmed cell death (PCD) signaling mechanism with natural substances for the treatment of diabetic cardiomyopathy (DCM).

Diabetic cardiomyopathy (DCM) is one of the severe complications of diabetes, characterized by structural and functional abnormalities in the hearts of diabetic patients without hypertension, coronary heart disease, or valvular heart disease. DCM can progress to heart failure, which is a significant cause of death in diabetic patients, but currently, there is no effective treatment available. Programmed cell death (PCD) is a genetically regulated form of cell death that includes apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis. PCD is essential for tissue homeostasis and normal development of the body. DCM is a complex condition, and abnormalities in the cascade of PCD signaling have been observed in its pathological process, suggesting that targeting PCD could be a potential therapeutic strategy. Studies have shown that natural substances can effectively modulate PCD to intervene in the treatment of DCM, and their use is safe. This review explores the role of different forms of PCD in the pathogenesis of DCM and summarizes the research progress in targeting PCD with natural substances to treat DCM. It can serve as a basis for further research and drug development to provide new treatment strategies for DCM patients.

Ferroptosis of CD163+ tissue-infiltrating macrophages and CD10+ PC+ epithelial cells in lupus nephritis.

Dysregulation of cell death and defective clearance of dying cells are closely related to the pathogenesis of lupus nephritis (LN). However, the contribution of a recently discovered form of programmed cell death (PCD) called ferroptosis to LN has not been explored in detail. The purpose of this study was to investigate the role of ferroptosis and its associated metabolic pathways in the pathogenesis of LN. The composite gene expression scores were calculated by averaging the z-scored transformed log2 expressed genes within each form of PCD and pathway. Immunohistochemistry and immunofluorescence assays were used to verify the bioinformatics results. We determined that ferroptosis is prominently and specifically elevated in the glomerular compartment of LN patients compared to other forms of PCD and kidney disease. This finding was then verified by immunohistochemical staining of 4-HNE (a key indicator for ferroptosis) expression in our own cohort (P < 0.0001). Intercorrelation networks were observed between 4-HNE and blood urea nitrogen, SLE disease activity index, serum creatinine, and complement 4, and negatively correlated with glomerular filtration rate in our own LN cohort (P < 0.05). Furthermore, enhanced iron metabolism and reduced fatty acid synthesis may be the most important factors for ferroptosis within the glomerulus. Through analysis of a single cell sequencing dataset and verification of immunohistochemical and immunofluorescence staining, aberrantly activated lipid peroxidation in CD163+ macrophages and CD10+ PC+ (pyruvate carboxylase) epithelial cells indicated that they may be undergoing ferroptosis in the glomerular compartment. Two dysregulated genes, CD163 and PC, were identified and verified that were significantly associated with lipid peroxidation. Targeting ferroptosis in CD163+ macrophages and CD10+ PC+ epithelial cells may provide novel therapeutic approaches in LN.

Mass Spectrometry Detects Sphingolipid Metabolites for Discovery of New Strategy for Cancer Therapy from the Aspect of Programmed Cell Death.

Sphingolipids, a type of bioactive lipid, play crucial roles within cells, serving as integral components of membranes and exhibiting strong signaling properties that have potential therapeutic implications in anti-cancer treatments. However, due to the diverse group of lipids and intricate mechanisms, sphingolipids still face challenges in enhancing the efficacy of different therapy approaches. In recent decades, mass spectrometry has made significant advancements in uncovering sphingolipid biomarkers and elucidating their impact on cancer development, progression, and resistance. Primary sphingolipids, such as ceramide and sphingosine-1-phosphate, exhibit contrasting roles in regulating cancer cell death and survival. The evasion of cell death is a characteristic hallmark of cancer cells, leading to treatment failure and a poor prognosis. The escape initiates with long-established apoptosis and extends to other programmed cell death (PCD) forms when patients experience chemotherapy, radiotherapy, and/or immunotherapy. Gradually, supportive evidence has uncovered the fundamental molecular mechanisms underlying various forms of PCD leading to the development of innovative molecular, genetic, and pharmacological tools that specifically target sphingolipid signaling nodes. In this study, we provide a comprehensive overview of the sphingolipid biomarkers revealed through mass spectrometry in recent decades, as well as an in-depth analysis of the six main forms of PCD (apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis) in aspects of tumorigenesis, metastasis, and tumor response to treatments. We review the corresponding small-molecule compounds associated with these processes and their potential implications in cancer therapy.

Programmed Cell Death in Asthma: Apoptosis, Autophagy, Pyroptosis, Ferroptosis, and Necroptosis.

Bronchial asthma is a complex heterogeneous airway disease, which has emerged as a global health issue. A comprehensive understanding of the different molecular mechanisms of bronchial asthma may be an efficient means to improve its clinical efficacy in the future. Increasing research evidence indicates that some types of programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, contributed to asthma pathogenesis, and may become new targets for future asthma treatment. This review briefly discusses the molecular mechanism and signaling pathway of these forms of PCD focuses on summarizing their roles in the pathogenesis and treatment strategies of asthma and offers some efficient means to improve clinical efficacy of therapeutics for asthma in the near future.

Anoikis-Related Gene Signature for Prognostication of Pancreatic Adenocarcinoma: A Multi-Omics Exploration and Verification Study

Anoikis, a form of apoptosis that occurs due to detachment of cells from the extracellular matrix, has been linked to the development of cancer in several studies. However, its role in pancreatic cancer remains incompletely understood. In this study, we utilized univariate Cox regression and LASSO regression analyses to establish a prognostic model for pancreatic adenocarcinoma based on anoikis-related genes in the TCGA database. Additionally, we performed univariate and multifactorial Cox analyses of protein expression results for TCGA pancreatic adenocarcinoma. We further explored the difference in immune infiltration between the high-risk and low-risk groups and verified the expression of the screened genes using quantitative real-time PCR (qRT-PCR). Our findings indicate that numerous anoikis-related genes are linked to pancreatic adenocarcinoma prognosis. We identified seven prognostic genes (MET, DYNLL2, CDK1, TNFSF10, PIP5K1C, MSLN, GKN1) and validated that their related proteins, such as EGFR and MMP2, have a significant impact on the prognosis of pancreatic adenocarcinoma. Based on clustering analyses of the seven prognostic genes, patients could be classified into three distinct categories, for which somatic mutations varied significantly across the groups. High-risk and low-risk groups also exhibited significant differences in immune infiltration. All genes were found to be highly expressed in pancreatic cancer cell lines (ASPC-1, CFPAC-1) as compared to a normal pancreatic cell line (HPDE). Based on the seven anoikis-related genes, we formulated a robust prognostic model with high predictive accuracy. We also identified the significant impact of KRAS, P53, and CDKN2A mutations on the prognosis of this fatal disease. Therefore, our study highlights the crucial role of anoikis in the development of the pancreatic adenocarcinoma tumor microenvironment.

From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors.

Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1) emerged as an important driver of inflammation and, consequently, inflammatory pathologies. The enzymatic activity of RIPK1 is known to indirectly promote inflammation by triggering cell death, in the form of apoptosis, necroptosis and pyroptosis. Small molecule Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors have therefore recently entered clinical trials for the treatment of a subset of inflammatory pathologies. We previously identified GSK2656157 (GSK'157), a supposedly specific inhibitor of protein kinase R (PKR)-like ER kinase (PERK), as a much more potent type II Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitor. We now performed further structural optimisation on the GSK'157 scaffold in order to develop a novel class of more selective Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors. Based on a structure-activity relationship (SAR) reported in the literature, we anticipated that introducing a substituent on the para-position of the pyridinyl ring would decrease the interaction with PERK. Herein, we report a series of novel GSK'157 analogues with different para-substituents with increased selectivity for Receptor-Interacting serine/threonine-Protein Kinase 1. The optimisation led to UAMC-3861 as the best compound of this series in terms of activity and selectivity for Receptor-Interacting serine/threonine-Protein Kinase 1 over PERK. The most selective compounds were screened in vitro for their ability to inhibit RIPK1-dependent apoptosis and necroptosis. With this work, we successfully synthesised a novel series of potent and selective type II Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors based on the GSK'157 scaffold.

Mammalian Ste20-like kinase 1 inhibition as a cellular mediator of anoikis in mouse bone marrow mesenchymal stem cells

The low survival rate of mesenchymal stem cells (MSCs) caused by anoikis, a form of apoptosis, limits the therapeutic efficacy of MSCs. As a proapoptotic molecule, mammalian Ste20-like kinase 1 (Mst1) can increase the production of reactive oxygen species (ROS), thereby promoting anoikis. Recently, we found that Mst1 inhibition could protect mouse bone marrow MSCs (mBMSCs) from H2O2-induced cell apoptosis by inducing autophagy and reducing ROS production. However, the influence of Mst1 inhibition on anoikis in mBMSCs remains unclear. To investigate the mechanisms by which Mst1 inhibition acts on anoikis in isolated mBMSCs. Poly-2-hydroxyethyl methacrylate-induced anoikis was used following the silencing of Mst1 expression by short hairpin RNA (shRNA) adenovirus transfection. Integrin (ITGs) were tested by flow cytometry. Autophagy and ITGα5β1 were inhibited using 3-methyladenine and small interfering RNA, respectively. The alterations in anoikis were measured by Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling and anoikis assays. The levels of the anoikis-related proteins ITGα5, ITGβ1, and phospho-focal adhesion kinase and the activation of caspase 3 and the autophagy-related proteins microtubules associated protein 1 light chain 3 II/I, Beclin1 and p62 were detected by Western blotting. In isolated mBMSCs, Mst1 expression was upregulated, and Mst1 inhibition significantly reduced cell apoptosis, induced autophagy and decreased ROS levels. Mechanistically, we found that Mst1 inhibition could upregulate ITGα5 and ITGβ1 expression but not ITGα4, ITGαv, or ITGβ3 expression. Moreover, autophagy induced by upregulated ITGα5β1 expression following Mst1 inhibition played an essential role in the protective efficacy of Mst1 inhibition in averting anoikis. Mst1 inhibition ameliorated autophagy formation, increased ITGα5β1 expression, and decreased the excessive production of ROS, thereby reducing cell apoptosis in isolated mBMSCs. Based on these results, Mst1 inhibition may provide a promising strategy to overcome anoikis of implanted MSCs.

GSDMD knockdown exacerbates hippocampal damage and seizure susceptibility by crosstalk between pyroptosis and apoptosis in kainic acid-induced temporal lobe epilepsy

BackgroundNeuronal loss is a vital pathological feature of temporal lobe epilepsy (TLE). However, the exact mechanism of neuronal loss in TLE is not fully understood. Pyroptosis, a novel form of programmed cell death (PCD), has been considered a contributor to the pathogenesis of TLE. However, recent studies have implicated extensive molecular crosstalk among pyroptosis, apoptosis, and necroptosis in various diseases, and they can be transformed to each other according to different contexts. This study aimed to investigate whether gasdermin D (GSDMD)-mediated pyroptosis is involved in the pathogenesis of TLE and whether crosstalk exists in the process of the modulation of pyroptosis. MethodsThe TLE model was established by intra-amygdala injection of kainic acid. The Racine score and local field potential (LFP) recordings were used to assess seizure severity. Western blotting and immunofluorescence were applied to detect the levels and cellular localization of GSDMD. The neuronal loss and type of neuronal death in the bilateral hippocampus were assessed by Nissl staining and flow cytometry analysis. The underlying crosstalk among pyroptosis, apoptosis, and necroptosis was explored by western blot and verified by VX765. ResultsGSDMD was significantly upregulated and mainly expressed within the neurons of the hippocampus in the TLE model. Inhibition of pyroptosis by GSDMD knockdown triggered caspase-3-mediated apoptosis, leading to excess neuronal loss and deterioration of epileptic behaviors. Blocking caspase-1 markedly inhibited caspase-3-mediated apoptosis and improved epileptic behaviors under GSDMD knockdown. ConclusionsOur results demonstrate that GSDMD-mediated pyroptosis is involved in the pathogenesis of TLE. However, inhibition of GSDMD triggers caspase-1-mediated crosstalk between pyroptosis and apoptosis, which exacerbates neuronal loss and seizure susceptibility. Therefore, the complex crosstalk among different forms of PCD should be considered when a potential molecular target in the single PCD pathway is modulated. On the other hand, along with further studies of molecular crosstalk among the PCD pathways, taking advantage of crosstalk to attenuate neuronal loss may provide new insight for the clinical therapy of TLE.

The Involvement of Natural Polyphenols in Molecular Mechanisms Inducing Apoptosis in Tumor Cells: A Promising Adjuvant in Cancer Therapy.

Various literature data show how a diet rich in vegetables could reduce the incidence of several cancers due to the contribution of the natural polyphenols contained in them. Polyphenols are attributed multiple pharmacological actions such as anti-inflammatory, anti-oxidant, antibiotic, antiseptic, anti-allergic, cardioprotective and even anti-tumor properties. The multiple mechanisms involved in their anti-tumor action include signaling pathways modulation associated with cell proliferation, differentiation, migration, angiogenesis, metastasis and cell death. Since the dysregulation of death processes is involved in cancer etiopathology, the natural compounds able to kill cancer cells could be used as new anticancer agents. Apoptosis, a programmed form of cell death, is the most potent defense against cancer and the main mechanism used by both chemotherapy agents and polyphenols. The aim of this review is to provide an update of literature data on the apoptotic molecular mechanisms induced by some representative polyphenol family members in cancer cells. This aspect is particularly important because it may be useful in the design of new therapeutic strategies against cancer involving the polyphenols as adjuvants.

The role of ferroptosis in chronic intermittent hypoxia-induced cognitive impairment.

Obstructive sleep apnea (OSA) is a sleep disorder that may lead to cognitive impairment. The primary pathophysiological feature of OSA is chronic intermittent hypoxia (CIH), but the underlying mechanisms of CIH are not known. There have been few studies on the role of ferroptosis, a novel form of programmedcell death, during CIH-induced cognitive impairment. Therefore, this paper examined ferroptosis' effect on CIH-mediated cognitive impairment. The study randomized twenty-four Sprague-Dawley (SD) male rats to control or CIH group. CIH rats were subjected to intermittent hypoxia for 4weeks. Rat learning and memory were analyzed by the Morris water maze (MWM) test. Alterations of hippocampal neuronal ultrastructure were observed by transmission electron microscopy (TEM). Malondialdehyde (MDA) and ferrous iron (Fe2+) levels and superoxide dismutase (SOD) and reduced glutathione (GSH) contents were determined. Ferroptosis-associated protein levels were examined by Western blotting. The MWM test indicated that rats in the CIH group exhibited neurocognitive impairment. TEM showed that CIH induced mitochondrial damage. Significant increases in Fe2+ and MDA levels were observed in the CIH group, and GSH and SOD levels were decreased. Expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4) increased, and glutathione peroxidase 4 (GPX4) protein levels were decreased, suggesting that ferroptosis was induced in CIH model rats. The NF-E2-related factor 2 (Nrf2) protein level in the CIH group was decreased. Ferroptosis had an essential effect on CIH-mediated cognitive impairment, and it may occur via Nrf2 dysregulation. These findings lay a solid foundation for the subsequent study of OSA-associated cognitiveimpairment offering potential evidence for the development of therapeutic strategies.

Transcriptome analysis constructed the necroptosis associated prognostic signature in endometrial cancer and identified EZH2 as a potential biomarker

Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system, but our understanding of the tumor microenvironment of EC remains unclear. Programmed cell death (PCD) plays an important role in the genesis and progression of tumors. Necroptosis is a novel form of PCD that does not rely on the caspase system. However, the role of necroptosis in EC is unclear. Transcriptome data of endometrial cancer were downloaded from The Cancer Genome Atlas (TCGA) database and log2 conversion was performed. Expression analysis and correlation analysis were performed to explore necroptosis gene expression and interaction in EC. Lasso regression was used to construct necroptosis-related prognostic signature. Finally, immunocorrelation analysis and single cell sequencing analysis were used to explore the significance of this signature in EC tumor microenvironment. A total of 15 of the 17 necroptosis genes were differentially expressed in EC. Subsequently, necroptosis related prognostic signature was constructed through Lasso regression. Riskscore = (−0.0999) × Toll-likereceptor4 (TLR4) + (−0.0528) × tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) + (0.1208) × Enhancer of Zeste Homolog 2 (EZH2) + (−0.004) × N-myc Down-stream Regulated Gene 2 (NDRG2). EC patients can be divided into high-risk group and low-risk group based on the median riskscore and the high-risk group has a worse prognosis. Survival analysis showed a worse prognosis for patients in the high-risk group (p &lt; 0.05). Immunomicroenvironment analysis showed a significant negative correlation between risk score and infiltration levels of B cells, CD4+ T cells, CD8+ T cells, Endothelial cells, macrophages, and NK cells. Subsequent cell experiments showed that knockdown of the key gene EZH2 in signature significantly reduced the invasion, migration and healing abilities of EC cell lines, proving that EZH2 is a promising marker of EC.

Mode of Actions of Bile Acids in Avoidance of Colorectal Cancer Development; and their Therapeutic Applications in Cancers - A Narrative Review

Bile Acids (BAs) possess a considerably significant part in the form of emulsifiers in digestion besides absorption of dietary lipids. BAs represent amphiphilic molecules, that are primary metabolites formed from cholesterol by the aid of enzymes acting on cholesterol. Earlier BAs were believed to be tumor repressors. The tumor repressive actions of BAs are correlated with programmed cell death (PCD). Furthermore, dependent on this observation different Synthetic BAs products have been generated along with their utilization regarding induction of PCD (in the form of apoptosis, autophagy or necroptosis in variable kinds of human cancers. Thus we conducted a narrative review till August 2022. The present article might form the basis of generationof such innovative therapies even for cancers/tumors that are cisplatin resistant. With time these therapies might be used for the treatment of neurodegenerative diseases (NDD), amyotrophic sclerosis, and numerous metabolic and haematological diseases as described for use of TUDCA.

Biodegradable Carbon Dioxide-Derived Non-Viral Gene Vectors for Osteosarcoma Gene Therapy.

Osteosarcoma often occurs in children and adolescents with high invasiveness and high mortality. Polo-like kinase 1 (PLK1) overexpressed in most tumors promotes cancer cell proliferation and transformation. PLK1 is considered as a therapeutic target for osteosarcoma. RNA interference-based therapies are employed to combat osteosarcoma through silencing PLK1 gene expression. However, the treatment results remain unsatisfactory due to the lack of a safe and efficient nonviral gene vector. To tackle this hurdle, biodegradable and CO2 -derivative cationic poly(vinylcyclohexene carbonates) (CPCHCs) are used as gene vectors to perform a siPLK1 therapeutic strategy for osteosarcoma treatment. Of those CPCHCs, CPCHC60 demonstrates the most excellent performance in gene transfection efficiency, endo-lysosome escaping, biodegradability, and biosafety. With the treatment of CPCHCs/siRNA nanoparticles, the expression level of PLK1 gene in osteosarcoma cells is significantly down-regulated. Subsequently, cells are arrested in the G2 /M phase and subsequently dead in the form of apoptosis, resulting in significant tumor regression both in vitro and in vivo. This study brings a new insight into the development of superior nonviral gene vectors for practical cancer treatment. Based on the results, the resulting nanoparticle-based gene drug formation is considered to have a highly successful chance in further translational nanomedicine applications.

Leonurine inhibits cardiomyocyte pyroptosis to attenuate cardiac fibrosis via the TGF-β/Smad2 signalling pathway.

Cardiac fibrosis is a common cause of most cardiovascular diseases. Leonurine, an alkaloid from Herba leonuri, had been indicated to treat cardiovascular diseases due to its cardioprotective effects. Recently, pyroptosis, a programmed form of cell death that releases inflammatory factors, has been shown to play an important role in cardiovascular diseases, especially cardiac fibrosis. This study examined the novel mechanism by which leonurine protects against cardiac fibrosis. In rats with isoprenaline-induced cardiac fibrosis, leonurine inhibited the expression of proteins related to pyroptosis and improved cardiac fibrosis. In vitro, leonurine inhibited the expression of proteins related to pyroptosis and fibrosis. Additionally, leonurine regulated the TGF-β/Smad2 signalling pathway and inhibited pyroptosis to protect cardiomyocytes and improve cardiac fibrosis. Therefore, leonurine might improve cardiac fibrosis induced by isoprenaline by inhibiting pyroptosis via the TGF-β/Smad2 signalling pathway.

Comprehensive investigation into cuproptosis in the characterization of clinical features, molecular characteristics, and immune situations of clear cell renal cell carcinoma.

BackgroundCopper-induced cell death has been widely investigated in human diseases as a form of programmed cell death (PCD). The newly recognized mechanism underlying copper-induced cell death provided us creative insights into the copper-related toxicity in cells, and this form of PCD was termed cuproptosis.MethodsThrough consensus clustering analysis, ccRCC patients from TCGA database were classified into different subgroups with distinct cuproptosis-based molecular patterns. Analyses of clinical significance, long-term survival, and immune features were performed on subgroups accordingly. The cuproptosis-based risk signature and nomogram were constructed and validated relying on the ccRCC cohort as well. The cuproptosis scoring system was generated to better characterize ccRCC patients. Finally, in vitro validation was conducted using ccRCC clinical samples and cell lines.ResultPatients from different subgroups displayed diverse clinicopathological features, survival outcomes, tumor microenvironment (TME) characteristics, immune-related score, and therapeutic responses. The prognostic model and cuproptosis score were well validated and proved to efficiently distinguish the high risk/score and low risk/score patients, which revealed the great predictive value. The cuproptosis score also tended out to be intimately associated with the prognosis and immune features of ccRCC patients. Additionally, the hub cuproptosis-associated gene (CAG) FDX1 presented a dysregulated expression pattern in human ccRCC samples, and it was confirmed to effectively promote the killing effects of copper ionophore elesclomol as a direct target. In vitro functional assays revealed the prominent anti-cancer role of FDX1 in ccRCC.ConclusionCuproptosis played an indispensable role in the regulation of TME features, tumor progression, and long-term prognosis of ccRCC.

Comprehensive analysis of cuproptosis in immune response and prognosis of osteosarcoma

Copper-induced cell death, a form of apoptosis, has been extensively investigated in human diseases. Recent studies on the mechanisms underlying copper-induced cell death have provided innovative insights into copper-related toxicity in cells, and this form of programmed cell death was termed cuproptosis. Herein, we conducted a comprehensive analysis to determine the specific role of cuproptosis in osteosarcoma. Using consensus clustering analysis, patients with osteosarcoma from the TARGET database were classified into subgroups with distinct cuproptosis-based molecular patterns. Accordingly, these patients displayed diverse clinicopathological features, survival outcomes, tumor microenvironment (TME) characteristics, immune-related scores, and therapeutic responses. Furthermore, we constructed a cuproptosis-based risk signature and nomogram, as well as developed a cuproptosis score for improved patient characterization. The prognostic model and cuproptosis score were well validated and confirmed to efficiently distinguish high- and low-risk patients, thereby affording great predictive value. Finally, we verified the abnormal expression of prognostic CUG in OS patients by immunohistochemistry. In conclusion, we suggest that cuproptosis may play an important role in regulating the tumor microenvironment features, tumor progression and the long-term prognosis of osteosarcoma.

Cuproptosis identifies respiratory subtype of renal cancer that confers favorable prognosis.

Cuproptosis is a newly discovered cell death induced by excessive copper in mitochondria distinct from any known forms of apoptosis. Role of cuproptosis has not been well-reported in cancer, especially in clear-cell renal cell carcinoma (ccRCC). We comprehensively interrogated cuproptotic gene signature in ccRCC by reproducing multi-omics datasets and found cuproptosis was decreased in ccRCC compared with normal kidney. Cuproptosis identified a subgroup with significantly better prognosis. Functional annotation supported increased tricarboxylic acid cycle activity and decreased hypoxia signaling corroborated by metabolomics. Cuproptotic tumors showed decreased angiogenesis but were sensitive to Sunitinib and Sorafenib. Cuproptotic level in ccRCC cell lines showed robust negative correlation with copper ionophore Elesclomol. All findings support a respiratory subtype of ccRCC identified by cuproptosis.

Crosstalk of three novel types of programmed cell death defines distinct microenvironment characterization and pharmacogenomic landscape in breast cancer.

BackgroundPrior studies have highlighted that novel programmed cell death (PCD) modalities, including ferroptosis, pyroptosis, and necroptosis, are correlated with tumor progression and antitumor immunity. Nonetheless, comprehensive analysis of tumor microenvironment (TME) profiles mediated by the crosstalk of distinct PCD forms has not been conducted in breast cancer (BC).MethodsHere, we curated 34 identified PCD-associated genes (PCDAGs) and applied the consensus clustering algorithm to establish PCD-mediated tumor patterns in BC. Subsequently, based on prognostic differentially expressed genes extracted from distinct PCD-mediated patterns, we applied the LASSO algorithm to construct CD_Score. Furthermore, the correlation analysis between CD_Score and TME features, molecular subtypes, clinicopathological characteristics, drug response, and immunotherapeutic efficacy was performed.ResultsThree distinct PCD-clusters were determined among 2,038 BC samples, which did not only display different clinical outcomes but highly correlated to the established immunological tumor phenotypes: “desert,” “excluded,” and “inflamed” immune profiles. Based on the CD_Score derived from the PCD-related gene signature, BC patients could be stratified into CD_Score-low and -high group, of which the former displayed satisfactory survival outcome and enhanced immune infiltration. Further exploration identified that the CD_Score-high group significantly correlated with elevated neoantigen load and higher mutation frequency in SMGs (e.g., TP53 and MAP3K1) and reduced expression of immune checkpoint proteins.ConclusionsThis research is the first to emphasize the close relationship between distinct cell death modalities and the diversity and complexity of immune infiltration in TME. We established the CD_Score, which could help enhance our cognition of TME features and facilitate the clinical application of immunotherapy.

Development and validation of a robust necroptosis related classifier for colon adenocarcinoma.

Background: Necroptosis, a novel form of apoptosis, plays a crucial function in the progression of colon adenocarcinoma (COAD) and is expected to be triggered in cancer therapy for enhancing anti-tumor immunity. However, the function of necroptosis in tumors and its relationship with the tumor microenvironment (TME) remains largely unclear. Methods: Necroptosis-related genes (NRGs) were collected from high-quality literature. Using The Cancer Genome Atlas (TCGA) (https://cancergenome.nih.gov) and the Gene Expression Omnibus (GEO) (www.ncbi.nlm.nih.gov/geo) meta-cohorts, a robust risk model was constructed to systematically examine the clinical value, functional status, the role of TME based on the risk model, as also the genomic variations. Results: A risk model containing nine NRGs, including TNF receptor-associated factor (TRAF2), TNF receptor 1 associated via death domain (TRADD), ubiquitin carboxyl-terminal hydrolase 21 (USP21), TNF receptor superfamily, member 6 (FAS), tumor necrosis factor receptor superfamily 10B (TNFRSF10B), mitogen-activated protein kinase 8 (MAPK8), mixed lineage kinase domain-like (MLKL), TNF receptor-associated factor 5 (TRAF5), and recombinant receptor-interacting serine-threonine kinase 3 (RIPK3), was constructed. The risk model’s stability and accuracy were demonstrated in training, as also the validation cohorts; it was verified as an independent prognostic model for COAD. High-risk group patients developed “cold” tumors having active tumor proliferation and immunosuppression, while those in the low-risk group developed “hot” tumors with active immune and cell killing functions. Moreover, a higher number of copy number variations in the genome and fewer somatic mutations were found in high-risk group patients. Furthermore, higher sensitivity towards immunotherapy and chemotherapy was seen in patients of the low-risk group. Conclusion: A reliable risk model based on NRGs to assess patient prognosis and guide clinical decision-making was constructed and validated. Our findings may contribute to the understanding of necroptosis and are expected to aid clinical management and guide precision treatment for patients with COAD.

Azadirachta indica Seed Derived Carbon Nanocapsules: Cell Imaging, Depolarization of Mitochondrial Membrane Potential, and Dose-Dependent Control Death of Breast Cancer.

In this work, a series of mesoporous carbon nanocapsules (mCNS) of size below 10 nm have been prepared from Azadirachta indica seeds with a very easy and cost-effective approach. These nanocapsules can emit red and green light and are effective for cell imaging. Further, these carbon nanocapsules are biocompatible toward the normal healthy cells, however, they possess modest cytotoxicity against the MCF-7 (human breast cancer) and triple-negative breast cancer (TNBC) (MDA- MB-231 breast cancer cells), and the rate of killing cancer cells strongly depends on the dose of mCNCs. Further, the mitochondrial membrane potential and apoptosis assay were performed to analyze the therapeutic significance of these nanocapsules to kill breast cancer. Results showed that these carbon nanocapsules can depolarize the mitochondrial membrane potential alone (without using conventional drugs) and can change the physiological parameters and cellular metabolic energy of the cancer cells and kill them. The apoptosis results confirmed the death of breast cancer cells in the form of apoptosis and necrosis. Moreover, the results suggested that the porous carbon nanocapsules (mCNCs) reported herein can be used as a potential candidate and useful for the theranostic applications such as for cancer cell detection and therapy without using any conventional drugs.