Programmed Cell Death Research Articles

Exploring tumor microenvironment interactions and apoptosis pathways in NSCLC through spatial transcriptomics and machine learning.

The most common type of lung cancer is non-small cell lung cancer (NSCLC), accounting for 85% of all cases. Programmed cell death (PCD), an important regulatory mechanism for cell survival and homeostasis, has become increasingly prominent in cancer research in recent years. As such, exploring the role of PCD in NSCLC may help uncover new mechanisms for therapeutic targets. We utilized the GEO database and TCGA NSCLC gene data to screen for co-expressed genes. To delve deeper, single-cell sequencing combined with spatial transcriptomics was employed to study the intrinsic mechanisms of programmed cell death in cells and their interaction with the tumor microenvironment. Furthermore, Mendelian randomization was applied to screen for causally related genes. Prognostic models were constructed using various machine learning algorithms, and multi-cohort multi-omics analyses were conducted to screen for genes. In vitro experiments were then carried out to reveal the biological functions of the genes and their relationship with apoptosis. Cells with high programmed cell death activity primarily activate pathways related to apoptosis, cell migration, and hypoxia, while also exhibiting strong interactions with smooth muscle cells in the tumor microenvironment. Based on a set of programmed cell death genes, the prognostic model NSCLCPCD demonstrates strong predictive capabilities. Moreover, laboratory experiments confirm that SLC7A5 promotes the proliferation of NSCLC cells, and the knockout of SLC7A5 significantly increases tumor cell apoptosis. Our data indicate that programmed cell death is predominantly associated with pathways related to apoptosis, tumor metastasis, and hypoxia. Additionally, it suggests that SLC7A5 is a significant risk indicator for the prognosis of non-small cell lung cancer (NSCLC) and may serve as an effective target for enhancing apoptosis in NSCLC tumor cells.

Potent Covalent Organic Framework Nanophotosensitizers with Staggered Type I/II Motifs for Photodynamic Immunotherapy of Hypoxic Tumors.

Photodynamic therapy (PDT) using oxygen-dependent type II photosensitizers is frequently limited by the hypoxic microenvironment of solid tumors. Type I photosensitizers show oxygen-independent reactive oxygen species (ROS) generation upon light irradiation but still face the challenges of aggregation-caused quenching (ACQ) and low efficiency to produce ROS. Herein, we first prepare an efficient type I photosensitizer from a perylene derivative via intramolecular donor-acceptor binding and sulfur substitution, which significantly enhance intersystem crossing between singlet and triplet states and electron transfer capability. After reaction with a type II photosensitizer, the covalent organic framework (COF) nanophotosensitizer is formed with alternated type I and II photosensitizer motifs in the same layer and staggered AB stacking between layers to avoid ACQ. The nanophotosensitizer exhibits high-efficiency generation of singlet oxygen (1O2) and superoxide anion radicals (O2•-) via type I and II mechanism under normoxia upon exposure to light irradiation. Under hypoxia, massive O2•- can be produced continuously. The potent ROS generation capability results in efficient cellular apoptosis and immunogenic cell death (ICD) efficiently. After combination with immune checkpoint inhibitors, tumor immunosuppressive microenvironment is reversed, which effectively ablates bulky hypoxic primary tumors and suppresses metastases via photodynamic immunotherapy. The COF nanophotosensitizers with staggered type I and II photosensitizer motifs represent a promising strategy to boost photodynamic immunotherapy of hypoxic tumors.

Cytotoxic effects of bee venom-loaded ZIF-8 nanoparticles on thyroid cancer cells: a promising strategy for targeted therapy.

Thyroid cancer continues to be a notable health issue, requiring the creation of novel treatment methods to enhance patient results. The objective of this study is to investigate the potential of utilizing bee venom (BV)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanoparticles as a novel strategy for specifically targeting and treating medullary thyroid cancer cells. Due to their wide surface area and configurable pore size, ZIF-8 nanoparticles are ideal for drug delivery. Bee venom's cytotoxic capabilities are used in ZIF-8 nanoparticles to target thyroid cancer cells more effectively. ZIF-8 nanoparticles containing bee venom were tested on TT medullary thyroid cancer cell lines. The effects of these nanoparticles on cell viability, proliferation, and apoptosis were investigated. IC50 value at 24h for BV-ZIF-8 nanoparticles in TT medullary thyroid carcinoma cells was determined to be 17.19µg/mL, while the IC50 value at 48h was determined to be 16.39µg/mL. It has been demonstrated that nanoparticle treatment upregulates the Bax and caspase-3 genes while downregulating the Bcl-2, CCND1, and CDK4 genes. Additionally, it was observed that oxidative stress was triggered in the nanoparticle-treated group. Furthermore, an examination of its mechanisms was conducted, with a specific emphasis on the modulation of critical signaling pathways that are implicated in the progression of cancer. In thyroid cancer cells, ZIF-8 nanoparticles infused with bee venom promote programmed cell death and impair key biological processes.

Construction of a prognostic model based on disulfidptosis-related genes and identification of CCNA2 as a novel biomarker for hepatocellular carcinoma

BackgroundDisulfidptosis, identified as an innovative form of cellular death subsequent to cuproptosis, is currently under investigation for its mechanisms in oncological contexts. In-depth analyses exploring the relationship between disulfidptosis-related genes (DRGs) and hepatocellular carcinoma (HCC) are currently limited.MethodsTranscriptomic data and clinical information were retrieved from the TCGA and GEO databases (GSE76427 and GSE54236), concentrating on the expression levels of 24 DRGs. Subsequently, multifactor and LASSO regression analyses were utilized to construct the 5-DRG prognostic signature. Immunohistochemistry (IHC) was employed to assess Cyclin A2 (CCNA2) protein expression levels. Quantitative real-time PCR (qRT-PCR) and western blot analyses were conducted to detect transcriptomic and protein expression of CCNA2-targeting short interfering RNA (siRNA). The Cell Counting Kit-8 (CCK-8) assay, EdU staining, and scratch experiments were employed to observe the proliferation and migration of hepatoma cell lines subsequent to CCNA2 inhibition.ResultsThree HCC patterns were identified, among which pattern B exhibited the the most unfavorable survival outcomes. Five DRGs (STC2, PBK, CCNA2, SERPINE1, and SLC6A1) were involved to establish the 5-DRG prognostic signature. High-risk groups (HRGs) exhibited prolonged survival durations in comparison to low-risk groups (LRGs). Both bioinformatics analyses and experimental methodologies corroborated the association of CCNA2 with poor prognosis in HCC patients. Functional studies elucidated that interference with CCNA2 significantly inhibited proliferation and migration, while simultaneously promoting apoptosis in hepatoma cells and resulting in the downregulation of epithelial-mesenchymal transition (EMT)-related protein markers.ConclusionsThe 5-DRG prognostic signature is proficient in predicting clinical outcomes, informing therapeutic strategies, and elucidating the characteristics of the immune microenvironment in HCC patients. Furthermore, this study elucidates the potential of CCNA2 as an innovative biomarker for HCC.

Identification of hub programmed cell death-related genes and immune infiltration in Crohn’s disease using bioinformatics

BackgroundCrohn’s disease (CD) is an immune-mediated disorder characterized by immune cell infiltration that induces persistent chronic inflammation of the gastrointestinal tract. Programmed cell death (PCD) plays a critical role in the pathogenesis of CD. This study identified vital PCD-related genes in CD based on immune infiltration using bioinformatic analysis.MethodsWe obtained two CD datasets from the Gene Expression Omnibus (GEO) database and examined immune cell infiltration to investigate immune cell dysregulation in CD. PCD-related genes were retrieved from the GeneCards database. Based on the differentially expressed genes (DEGs) and PCD gene sets, PCD-related DEGs were identified. Candidate hub genes were identified using a protein-protein interaction (PPI) network, and their diagnostic effectiveness was predicted using receiver operating characteristic (ROC) curve analysis. Functional enrichment and immune infiltration analyses were used to assess the distinct roles of the hub genes. Finally, the miRWalk and ENCORI databases were used to predict which microRNAs (miRNAs) regulated the hub genes and to verify gene expression in CD colonic tissues via transcriptome sequencing.ResultsA total of 335 PCD-related DEGs and 3 hub genes (MMP1, SAA1, and PLAU) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses indicated the enrichment of these genes in the immune response. Infiltration analysis of immune cells showed abundant endothelial cells, plasma cells, dendritic cells, and monocytes in the CD samples. Based on the correlation analysis, the three hub genes were positively correlated with monocytes and negatively correlated with CD8 naïve T-cells. MMP1, SAA1, and PLAU correlated with the pathogenicity of CD and had good diagnostic value for CD. The three hub genes were highly expressed in the CD tissues, as confirmed using transcriptome sequencing.ConclusionThis study identified MMP1, SAA1, and PLAU as hub genes involved in PCD in patients with CD. These genes regulate immune cell function and their expression levels are closely related to immune cell infiltration. These findings provide novel insights into the mechanisms underlying CD pathogenesis. The identified PCD genes and regulatory miRNAs are potential biomarkers and therapeutic targets for CD.

Pathologic function and therapeutic potential of extracellular vesicle miRNA in sepsis

Sepsis is a systemic inflammatory response initiated by an infection, which can lead to multi-organ dysfunction. The pathophysiology of sepsis is complex, and treatment options are limited. Traditional antibiotic therapies have shown limitations, such as promoting the emergence of antibiotic-resistant bacteria and disrupting the natural microbiota. Consequently, there is a pressing need to explore diverse therapeutic approaches for sepsis management. Extracellular vesicles, which play a crucial role in cell-to-cell communication, are released by various cell types throughout the body and possess a membrane structure composed of a lipid bilayer. MicroRNAs may be encapsulated within these structures and can be selectively delivered to target recipient cells through the activation of cell surface receptors or via endocytosis and fusion, thereby modulating the biological functions of target cells. The article examines the pathological alterations that happen as sepsis progresses and the biological control of extracellular vesicles and microRNAs in sepsis. This review focuses on the role of extracellular vesicles and their microRNAs on controlling the inflammatory response, macrophage polarization, programmed cell death, endothelial dysfunction, and microcirculatory changes in sepsis. Furthermore, the obstacles encountered by this novel therapy are also examined.

Trans-differentiation of Jdp2-depleted Gaba-receptor-positive cerebellar granule cells to Purkinje cells

The Jun dimerization protein (Jdp2) gene is active in mouse cerebellar granule cells and its protein product plays a crucial role in the formation of the cerebellum lobes through programmed cell death. However, the role of Jdp2 in cellular differentiation and pluripotency in the cerebellum, and the effect of the antioxidation reaction on cell plasticity, remain unknown. N-acetyl-l-cysteine (NAC) induced the early commitment of the differentiation of granule cell precursors (GCPs) to neurons, especially Purkinje cells, via the γ-aminobutyric acid type A receptor α6 subunit (Gabra6) axis; moreover, Jdp2 depletion enhanced this differentiation program of GCPs. The antioxidative effect of NAC was the main driving force of this decision toward the neural differentiation of the GCP population in the presence of Gabra6 in vitro. This implies that antioxidative drugs are effective agents for rescuing oxidative-stress-induced GCP damages in the cerebellum and commit this Gabra6-positive cell population toward differentiation into Purkinje cells.

Research progress of immune checkpoint inhibitors in ovarian cancer

Ovarian cancer is the deadliest malignant tumor in the female reproductive system. Despite advancements in standard treatments such as tumor debulking surgery and platinum-based chemotherapy, the overall survival rate remains low. The emergence of targeted therapies, including Poly(ADP-ribose) polymerase (PARP) inhibitors and anti-angiogenic agents, has provided new avenues for treatment. However, drug resistance and disease heterogeneity continue to pose significant challenges. Immune checkpoint inhibitors (ICIs), as an emerging therapeutic approach, primarily target the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways to restore anti-tumor immune responses. Although ICIs have shown significant efficacy in other malignancies, their effectiveness in ovarian cancer is limited, with a response rate of only 10–15% for monotherapy. Recent studies have focused on combining ICIs with chemotherapy, anti-angiogenic agents, or PARP inhibitors to enhance therapeutic outcomes. This article reviews the progress of ICIs in ovarian cancer, including monotherapy and combination treatment strategies, and explores emerging therapeutic targets and strategies aimed at improving patient prognosis and achieving personalized treatment. By gaining a deeper understanding of the tumor microenvironment and its immune evasion mechanisms, there is hope for developing more effective treatment options in the future, ultimately improving the survival rates and quality of life for ovarian cancer patients.

Inhibition of Pyroptosis by Hydroxychloroquine as a Neuroprotective Strategy in Ischemic Stroke.

Hydroxychloroquine (HCQ), a well-known antimalarial and anti-inflammatory drug, has demonstrated potential neuroprotective effects in ischemic stroke by inhibiting pyroptosis, a programmed cell death associated with inflammation. This study investigates the impact of HCQ on ischemic stroke pathology using both in vivo and in vitro models. In vivo, C57BL/6 mice subjected to middle cerebral artery occlusion (MCAO) were treated with HCQ. Neurological deficits, infarct volume, and the expression of pyroptosis markers were evaluated. The results demonstrated that HCQ significantly improved motor function and reduced infarct volume in the MCAO mouse model. In vitro, BV2 microglial cells exposed to lipopolysaccharide (LPS) and oxygen-glucose deprivation (OGD) were treated with HCQ. Western blot and immunofluorescence analyses revealed that HCQ effectively suppressed the expression of pyroptosis markers GSDMD and NLRP3 in both in vivo and in vitro models. These findings suggest that HCQ mitigates ischemic stroke damage by inhibiting pyroptosis, highlighting its potential as a therapeutic agent for ischemic stroke. This study provides novel insights into the molecular mechanisms by which HCQ exerts its neuroprotective effects, offering a promising new avenue for developing safe, cost-effective, and widely applicable stroke treatments. The potential of HCQ to modulate neuroinflammatory pathways presents a significant advancement in ischemic stroke therapy, emphasizing the importance of targeting pyroptosis in stroke management and the broader implications for treating neuroinflammatory conditions.Significance Statement Ischemic stroke remains a leading cause of disability and death globally, with limited effective treatments. This study reveals that HCQ significantly mitigates ischemic stroke damage by inhibiting pyroptosis, a form of programmed cell death. Using in vivo and in vitro models, HCQ was shown to improve motor function and reduce infarct volume, highlighting its potential as a neuroprotective agent. These findings offer a promising new therapeutic approach for ischemic stroke, emphasizing the importance of targeting pyroptosis in stroke treatment.

Astragaloside IV attenuates podocyte apoptosis via regulating TXNIP/NLRP3/GSDMD signaling pathway in diabetic nephropathy

ObjectivesAmong all the diabetes complications brought on by persistent inflammation is diabetic kidney disease (DKD). One essential method of the inflammatory response's programmed cell death is anthrax. One of the main causes of diabetic renal disease progression in a high-glycemic environment is the lysis of renal resident cells.MethodThis investigation sought to determine whether Astragaloside IV (AS-IV)'s anti-pyroptosis action provides a protective function for the kidneys. For 12 weeks, db/db mice received 40 mg/kg of AS-IV by transgastric gavage. To validate the possible in vitro mechanism, mouse podocytes were cultivated for additional experiments.ResultsIn vitro, AS-IV led to a significant reduction in blood urea nitrogen (BUN), urine albumen-to-creatinine ratio (UACR), serum creatinine (CREA), and hyperglycemia in db/db mice and lessen the pathological alterations in the kidney. Moreover, pyrin structural domain of the NLR family pyrin domain containing 3 (NLRP3), cleaved-caspase-1, gasdermin D (GSDMD), IL-18, and IL-1β were down-expressed and podocyte markers podocin and nphs1 were up-regulated following AS-IV intervention. By silencing GSDMD, we demonstrated in vitro that HG-stimulated podocytes undergo pyroptosis. We also discovered that AS-IV can mitigate this pyroptosis. To confirm that AS-IV prevented the NLRP3 inflammasome from activating, the NLRP3 inhibitor CY-09 was employed. It was also discovered that AS-IV prevents the expression of TXNIP and NLRP3 as well as their interaction. GSDMD expression was significantly downregulated following TXNIP-siRNA treatment, whereas GSDMD expression was upregulated in TXNIP overexpression cells; this upregulation could be undone with AS-IV.ConclusionsThe anti-pyroptosis effect of AS-IV via the TXNIP-NLRP3-GSDMD axis improves the renal function and podocyte damage of db/db mice and delays the onset of DKD, according to in vivo and in vitro experimental data.

Insights into the molecular underlying mechanisms and therapeutic potential of endoplasmic reticulum stress in sensorineural hearing loss

Sensorineural hearing loss (SNHL) is characterized by a compromised cochlear perception of sound waves. Major risk factors for SNHL include genetic mutations, exposure to noise, ototoxic medications, and the aging process. Previous research has demonstrated that inflammation, oxidative stress, apoptosis, and autophagy, which are detrimental to inner ear cells, contribute to the pathogenesis of SNHL; however, the precise mechanisms remain inadequately understood. The endoplasmic reticulum (ER) plays a key role in various cellular processes, including protein synthesis, folding, lipid synthesis, cellular calcium and redox homeostasis, and its homeostatic balance is essential to maintain normal cellular function. Accumulation of unfolded or misfolded proteins in the ER leads to endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) signaling pathway. The adaptive UPR has the potential to reestablish protein homeostasis, whereas the maladaptive UPR, associated with inflammation, oxidative stress, apoptosis, and autophagy, can lead to cellular damage and death. Recent evidence increasingly supports the notion that ERS-mediated cellular damage responses play a crucial role in the initiation and progression of various SNHLs. This article reviews the research advancements on ERS in SNHL, with the aim of elucidating molecular biological mechanisms underlying ERS in SNHL and providing novel insights for the treatment.

Integrating bioinformatics and machine learning to uncover lncRNA LINC00269 as a key regulator in Parkinson's disease via pyroptosis pathways

BackgroundPyroptosis, a specific type of programmed cell death, which has become a significant factor to Parkinson's disease (PD). Concurrently, long non-coding RNAs (lncRNAs) have garnered attention for their regulatory roles in neurodegenerative disorders. This study was designed to ascertain the key lncRNAs in pyroptosis pathways of PD and elucidate their regulatory mechanisms.MethodsEmploying a combination of bioinformatics and machine learning, we analyzed PD data sets GSE133347 and GSE110716. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) recognized different lncRNAs. Through various algorithms such as Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest (RF), and Weighted Gene Co-expression Network Analysis (WGCNA), we recognized LINC01606 and LINC00269, which are key factors during the emergence and development of PD. Furthermore, experimental validation was conducted in PD mouse models to confirm these bioinformatics findings.ResultsThe analysis showed that there were a large number of apoptosis-related gene expression changes in Parkinson's syndrome, for example, CASP1 and GSDME were up-regulated, and CASP9 and AIM2 were down-regulated. Among the lncRNAs, LINC01606 and LINC00269 were identified as potential modulators of pyroptosis. Notably, LINC00269 was observed to be significantly downregulated in the brain tissues of a PD mouse model, supporting its involvement in PD. The study also highlighted potential interactions of these lncRNAs with genes like ONECUT2, PRLR, CTNNA3, and LRP2.ConclusionsThis study identifies LINC00269 as a potential contributor to pyroptosis pathways in PD. While further investigation is required to fully elucidate its role, these findings provide new insights into PD pathogenesis and suggest potential avenues for future research on diagnostic and therapeutic targets. The study underscores the importance of integrating bioinformatics with experimental validation in neurodegenerative disease research.

Identification of a pyroptosis-related prognostic model for colorectal cancer and validation of the core gene SPTBN5

BackgroundPyroptosis, an emerging type of programmed cell death. The mechanisms of pyroptosis mainly include inflammasome-activated pyroptosis and non-inflammasome-activated pyroptosis. Multiple prognostic scoring systems that utilize pyroptosis-related gene expression have been validated as effective predictors of patient outcomes. But the relationship between pyroptosis and colorectal cancer remains unclear. This study has established a gene signature associated with pyroptosis to forecast the prognosis of CRC patients. MethodsAn analysis of 52 pyroptosis genes was conducted in both CRC and normal colorectal tissues, leading to the discovery of differentially expressed genes (DEGs). Core pyroptosis-related genes were identified using least absolute shrinkage and selection operator (LASSO) Cox regression to establish a prognostic risk score (PRS) for predicting CRC patient outcomes. The TCGA cohort was split into high-risk and low-risk groups based on the PRS, followed by Gene Ontology (GO) and KEGG pathway analyses. Additionally, differences in the enrichment scores of 16 immune cell types and the activity of 13 immune-related pathways were compared. The role of SPTBN5, a core pyroptosis-related gene, was validated through functional experiments on human colorectal adenocarcinoma cells (SW480).Results40 differentially expressed genes were identified from 52 pyroptosis genes. A risk model was subsequently developed using 25 core pyroptosis-related genes identified through LASSO Cox regression analysis, and this model was validated in GEO cohorts. GO and KEGG pathway analyses showed that the DEGs are predominantly associated with mineral absorption, thyroid hormone synthesis, and pancreatic secretion. Functional experiments demonstrated that down-regulation of SPTBN5 expression through transfection led to significant decreases in the proliferation, migration, and clonogenicity of SW480 cells.ConclusionThe PRS can identify high-risk CRC patient groups and predict patient prognosis. SPTBN5 may present a potential therapeutic target for CRC.

Prognostic significance of programmed death ligand 2 expression in tumor-infiltrating lymphocytes of triple-negative breast cancer

Objectives: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and overexpression of human epidermal growth factor receptor 2 protein. Patients with high expression of programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been found to have better prognosis and increased response to anti-PD-1/PDL1 immunotherapy. However, the role programmed death ligand 2 (PD-L2), the other known ligand of PD-1, plays in PD-1/PD-L1 checkpoint pathway has not been well studied. Therefore, this project aims to investigate (1) the relationship between PD-L2 expression in tumor infiltrating lymphocytes (TILs) and patient clinicopathological features, (2) whether PD-L2 can serve as a predictor of patient survival, and (3) the association of PD-L2 expression with the infiltration of relevant immune cell types in the tumor microenvironment. Materials and Methods: Two hundred and ninety-six (296) TNBC cases diagnosed between 2003 and 2013 in Singapore General Hospital were used in this study to create tissue microarray for immunohistochemistry with several antibodies. Results: Patients with PD-L2 expression were found to have significantly improved disease-free survival (hazard ratio [HR] 0.51; P = 0.0362) and overall survival (HR 0.43; P = 0.0379) compared to patients who have negative PD-L2 expression. PD-L2+ TILs correlate significantly with CD3+ T-cells (P = 0.00776) and CD20+ B-cells (P = 0.001019) infiltration in the stromal compartments and intratumoral CD38+ plasma cells (P = 0.048869) infiltration. Conclusion: Like PD-L1, PD-L2 positivity in TILs was found in our study to indicate a better prognosis compared to PD-L2-negative patients.

Ferroptosis and its role in osteoarthritis: mechanisms, biomarkers, and therapeutic perspectives

Osteoarthritis (OA) is one of the leading causes of disability worldwide, characterized by a complex pathological process involving cartilage degradation, synovial inflammation, and subchondral bone remodeling. In recent years, ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, has been recognized as playing a critical role in the onset and progression of OA. Investigating the molecular mechanisms of ferroptosis and its involvement in OA may offer novel strategies for diagnosing and treating this disease. This review first outlines the core mechanisms of ferroptosis, with a particular focus on the roles of critical molecules such as Glutathione Peroxidase 4 (GPX4), Transferrin Receptor 1 (TfR1), and Nuclear Receptor Coactivator 4 (NCOA4). Subsequently, this study examines the specific impacts of ferroptosis on the pathophysiology of OA. Building on this, the potential of ferroptosis-related biomarkers for OA diagnosis and treatment is highlighted, along with proposed therapeutic strategies targeting ferroptosis regulation. This review aims to deepen the understanding of ferroptosis mechanisms and advance the clinical application of regulatory therapies for OA.

Identification of key necroptosis-related genes and immune landscape in patients with immunoglobulin A nephropathy

BackgroundImmunoglobulin A nephropathy (IgAN) is a major cause of chronic kidney disease (CKD) and kidney failure. Necroptosis is a novel type of programmed cell death that has been proved to be associated with the pathogenesis of infectious disease, cardiovascular disease, neurological disorders and so on. However, the role of necroptosis in IgAN remains unclear.MethodsIn this study, we explored the role of necroptosis-related genes in the pathogenesis of IgAN using a comprehensive bioinformatics method. Microarray datasets GSE93798 and GSE115857 were downloaded from Gene Expression Omnibus (GEO). “limma” package of R software was employed to identify necroptosis-related differentially expressed genes (NRDEGs) between IgAN and healthy controls. GO and KEGG functional enrichment analysis was performed by Clusterprofiler. Least absolute shrinkage and selection operator (LASSO) regression analysis identified hub NRDEGs. We further established a diagnostic model consisting of 7 diagnostic hub NRDEGs and validated the efficacy by an external dataset. The expression of hub genes was confirmed in sc-RNA dataset GSE171314. Immune infiltration, gene set enrichment analysis and transcription factor binding motifs enrichment analysis were conducted to further uncover their roles.Results1076 differentially expressed genes were identified between healthy individuals and IgAN patients from RNA-seq dataset GSE9379. Then we cross-linked them with necroptosis-related genes to obtain 9 NRDEGs. LASSO regression analysis screened out 7 hub genes (JUN, CD274, SERTAD1, NFKBIA, H19, UCHL1 and EZH2) of IgAN. We further conducted functional enrichment analysis and constructed the diagnostic model based on dataset GSE93798. GSE115857 was used as the independent validation cohort and indicated a great predictive efficacy. Immune infiltration, gene set enrichment analysis and transcription factor binding motifs enrichment analysis revealed their potential function. Finally, we screened out four drugs that were predicted to have therapeutic value of IgAN.ConclusionsIn summary, we identified 7 hub necroptosis-associated genes, which can be used as potential genetic biomarkers for IgAN prediction and treatment. Four drugs were predicted as the potential therapeutic solutions. Collectively, we provided insights into the necroptosis-related mechanisms and treatment of IgAN at the transcriptome level.

Development and validation of a programmed cell death index to predict the prognosis and drug sensitivity of gastric cancer

AimProgrammed cell death (PCD) critically influences the tumor microenvironment (TME) and is intricately linked to tumor progression and patient prognosis. This study aimed to develop a novel prognostic indicator and marker of drug sensitivity in patients with gastric cancer (GC) based on PCD.MethodsWe analyzed genes associated with 14 distinct PCD patterns using bulk transcriptome data and clinical information from TCGA-STAD for model construction with univariate Cox regression and LASSO regression analyses. Microarray data from GSE62254, GSE15459, and GSE26901 were used for validation. Single-cell transcriptome data from GSE183904 were analyzed to explore the relationship between TME and the newly constructed model, named PCD index (PCDI). Drug sensitivity comparisons were made between patients with high and low PCDI scores.ResultsWe developed a novel twelve-gene signature called PCDI. Upon validation, GC patients with higher PCDI scores had poorer prognoses. A high-performance nomogram integrating the PCDI with clinical features was also established. Additionally, single-cell transcriptome data analysis suggested that PCDI might be linked to critical components of the TME. Patients with high PCDI scores exhibited resistance to standard adjuvant chemotherapy and immunotherapy but might benefit from targeted treatments with NU7441, Dasatinib, and JQ1.ConclusionThe novel PCDI model shows significant potential in predicting clinical prognosis and drug sensitivity of GC, thereby facilitating personalized treatment strategies for patients with GC.

Mechanisms and Therapeutic Potential of Multiple Forms of Cell Death in Myocardial Ischemia–Reperfusion Injury

Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia–reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy.

PARP1 Inhibitors: An Important Part in Cancer Treatment

Abstract: Cancer is a highly fatal disease that is typified by aberrant cells proliferating out of control. The properties of acquired cells, including as genomic instability and mutations, cellular death evasion, and proliferative signaling sustenance, are evidenced by the hallmarks of cancer and contribute to the establishment of malignant tumors. A protein called poly(ADP-ribose) polymerase- 1 (PARP1) is essential for both cell survival and DNA damage repair, two processes that affect cellular control. Since homologous recombination deficient cells exhibit cellular death upon suppression of PARP1, the PARP protein has gained attention as a potential target for anticancer treatments. The Food and Drug Administration (FDA) has already approved a number of effective PARP1 inhibitors, including olaparib and niraparib. The final chemical has a 1,3,4- thiadiazole core in its structure. In fact, heterocyclic moieties have gained attention due to their numerous medicinal advantages, which include their capacity to combat cancer. The compounds derived from these substances have been studied as PARP1 inhibitors, with promising results. Thus, the goal of this study is to go over the importance of PARP1 in cancer as well as its role in cell regulation. It also attempts to offer a comprehensive assessment of the literature that has been published in the previous fifteen years about PARP1 inhibitors, including the different scaffolds, with an emphasis on features of the structure-activity relationship. This will provide vital information for the creation of fresh, more effective PARP1 inhibitors.

VISTA in hematological malignancies: a review of the literature

In recent years, tumor immunotherapy has become an active research area, with the emergence of immune checkpoint inhibitors (ICIs) revolutionizing immunotherapy. Clinical evidence indicates that programmed cell death protein 1 (PD-1) monoclonal antibodies and other drugs have remarkable therapeutic effects. V-domain Ig suppressor of T-cell activation (VISTA) is a new type of immune checkpoint receptor that is highly expressed in various tumors. It is co-expressed with PD-1, T-cell immunoglobulin domain, mucin domain-3 (Tim-3), T-cell immunoglobulin, and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and is associated with prognosis, which suggests that it may be a target for immunotherapy. As an immune checkpoint receptor with no mature drugs, VISTA is highly expressed in acute myeloid leukemia (AML), multiple myeloma (MM), and other hematological malignancies; however, its pathogenic mechanism should be defined to better guide treatment.