Cell Death Signaling Research Articles

The cyclophilin D (CypD) of Toxoplasma gondii is involved in the parasite's response to oxidative stress damage.

The mitochondrial permeability transition pore (mPTP) significantly impacts mitochondrial responses to cell death signals through its structural opening. Cyclophilin D (CypD) serves as a key regulator of the mPTP and plays a pivotal role in governing mitochondrial responses to cell death. In this study, we have demonstrated that Toxoplasma expresses a homolog of cyclophilin D, named TgCypD, which is localized in the mitochondria. Depletion of TgCypD resulted in a modest inhibition of tachyzoite invasion and proliferation, with no notable effect on mitochondrial morphology. However, TgCypD deficiency led to the inhibition of cytochrome c release from mitochondria into the cytosol, thereby imparting resistance to oxidative stress-induced cell death. Our findings suggest that T. gondii contains the mPTP component protein TgCypD, which is intricately involved in regulating mitochondrial responses to cell death.

3D in vitro modelling of post-partum cardiovascular health reveals unique characteristics and signatures following hypertensive disorders in pregnancy

BackgroundHypertensive disorders of pregnancy (HDP) affect 2–8% of pregnancies and are associated postpartum with increased cardiovascular disease (CVD) risk, although mechanisms are poorly understood.MethodsHuman induced pluripotent stem cells (iPSC)-derived cardiomyocytes, cardiac fibroblasts and coronary artery endothelial cells were cocultured to form cardiac spheroids (CSs) in collagen type-1 hydrogels containing 10% patient plasma collected five years postpartum [n = 5 per group: normotensive control, gestational hypertension (GH) and preeclampsia (PE)]. Plasma-treated CSs were assessed for cell viability and contractile function and subjected to immunofluorescence staining and imaging. A quantitative proteomic analysis of plasma samples was conducted (controls n = 21; GH n = 5; PE n = 12).ResultsContraction frequency (CF) was increased in PE-treated CSs (CF: 45.5 ± 3.4 contractions/minute, p < 0.001) and GH-treated CSs (CF: 45.7 ± 4.0 contractions/minute, p < 0.001), compared to controls (CF = 21.8 ± 2.6 contractions/min). Only PE-treated CSs presented significantly increased fractional shortening (FS) % (9.95 ± 1.8%, p < 0.05) compared to controls (3.7 ± 1.1%). GH-treated CSs showed a reduction in cell viability (p < 0.05) and an increase in α-SMA expression (p < 0.05). Proteomics analyses identified twenty differentially abundant proteins, with hemoglobin A2 being the only protein perturbed in both GH and PE versus control plasma (p < 0.05).ConclusionsThe innovative patient-relevant CS platforms led to the discovery of biomarkers/targets linked to cell death signaling and cardiac remodeling in GH-induced CVD and vascular/endothelial cell dysfunction in PE-induced CVD.

Biosynthesis and Characterization of Silver Nanoparticles Using Cleistanthus collinus; Investigation on Molecular Mechanism of Apoptosis Cell Death Against Lung Cancer Cells

Background: The discovery of novel molecular and cellular signaling pathways for cancer medicines would enhance the efficacy of cancer therapy. In the current study, we made an effort to explore the mitochondrial-mediated apoptosis cell death signaling pathway in A549 lung cancer cells by silver nanoparticles (AgNPs) synthesized from leaf extract of Cleistanthus collinus. Methods: In-depth, A549 lung cancer cells were treated with AgNPs, and further studies such as HOECHST 33342, AO/EB, Rhodamine-123 staining, flowcytometry, RT-PCR, and Western blotting techniques (24, 48, and 72 h) evidenced apoptosis pathway in cancer cells. Results: Indeed, the microscopic studies proved that AgNPs-treated lung cancer cells appeared with cell shrinkage, membrane swelling, and apoptotic body formation whereas the untreated cells (control) failed to show any morphological consequences. The flow cytometry analysis revealed the G2/M phase of cell cycle arrest by cells were accumulated in large numbers. The RT-PCR data confirmed the expression (Bax and p53) and suppression (Bcl 2) apoptosis-responsive genes in cancer cells. Finally, immunoblotting proved the increased expression of cytochrome c, initiator caspase 9, and executioner caspase 3, which are effective proteins of intrinsic apoptosis activation. Conclusion: Ultimately, the overall present investigations confirmed the mitochondrial signaling pathway played a key role in inducing apoptosis in A549 cancer cell death and demonstrated that AgNPs are novel therapeutic agents for cancer nanomedicine

Abstract 4137296: Single-cell Atlas of Human Epicardial Adipose Tissue Reveals Aging IL4R + Naive B cell Contributing To Atrial Fibrillation

Background: Numerous recent evidence suggested a role of epicardial adipose tissue (EAT), the visceral fat depot of the heart, in the development of Atrial Fibrillation (AF). However, the cellular and molecular mechanisms underlying the association remain elusive. Methods: We performed single-nucleus RNA sequencing on eleven EAT samples collected from 2 groups of subjects: patients with nonvalvular AF undergoing coronary bypass surgery for severe CAD (n=7), and a control group of patients without concomitant AF (n=4). Comparative analyses were performed between the groups, including cellular compositional analysis, cell type–resolved transcriptomic changes, and functional analysis. Results: Unsupervised clustering of 92734 nuclei identified 11 clusters, encompassing all known cell types in the adipose tissue. Pseudobulk differential expression analysis between the AF and control groups revealed pronounced differences in a select subset of genes located on the X and Y chromosomes, including XIST and TSIX. Subsequent pathway analysis identified that the most significantly impacted pathways were those associated with immune cell functions. Meanwhile, differences in cellular composition and transcriptomic profiles, particularly concerning B cells, were observed between normal and AF conditions, highlighting distinct immune cell dynamics. Comparison of pathways across different B cell states revealed the enrichment of distinct pathways within each state, including those involved in cellular senescence, antigen processing and presentation, and programmed cell death signatures. Notably, aging IL4R + naive B cell and inflammatory ITGB1 + memory B cell were identified as important regulators potentially involved in functional changes of EAT and AF pathogenesis. Conclusions: We built a complete single-nucleus transcriptomic atlas of human EAT in normal and AF conditions. Our study lays the foundation for developing novel therapeutic strategies for treating AF by targeting and modifying B cell functions within EAT.

Single-cell RNA sequencing analysis identifies acute changes in the tumor microenvironment induced by interferon α gene therapy in a murine bladder cancer model.

Nadofaragene firadenovec (Ad-IFNα/Syn3) is now approved for BCG-unresponsive bladder cancer (BLCA). IFNα is a pleiotropic cytokine that causes direct tumor cell killing via TRAIL-mediated apoptosis, angiogenesis inhibition, and activation of the innate and adaptive immune system. We established an immunocompetent murine BLCA model to study the effects of murine adenoviral IFNα (muAd-Ifnα) gene therapy on cancer cells and the tumor microenvironment using a novel murine equivalent of Nadofaragene firadenovec (muAd-Ifnα). Tumors were induced by instilling MB49 cells into the bladders of mice; luciferase imaging confirmed tumor development. Mice were treated with adenovirus control (Ad-Ctrl; empty vector), or muAd-Ifnα (3x1011 VP/mL), and survival analysis was performed. For single-cell sequencing (scRNAseq) analysis (72h), bladders were harvested and treated with collagenase/hyaluronidase and TrypLE for cell dissociation. Single cells were suspended in PBS/1% FBS buffer; viability was assessed with Vicell cell counter. scRNAseq analysis was performed using 10X genomics 3' sequencing. Raw RNAseq data were pre-processed using Cell Ranger single-cell software. Seurat (R package) was used to normalize and cluster the scRNA data. Pooled differential gene expression analysis in specific cell clusters was performed with DESeq2. We identified 16 cell clusters based on marker expression which were grouped into epithelial (tumor), uroplakin-enriched, endothelial, T-cells, neutrophils, and macrophage clusters. Top differentially expressed genes between muAd-Ifnα and Ad-Ctrl were identified. Within the specific cell clusters, IPA analysis revealed significant differences between muAd-Ifnα and control. IFNα signaling and hypercytokinemia/chemokinemia were upregulated in all clusters. Cell death pathways were upregulated in tumor and endothelial clusters. T-cells demonstrated upregulation of the immunogenic cell death signaling pathway and a decrease in the Th2 pathway genes. Macrophages showed upregulation of PD1/PD-L1 pathways along with downregulation of macrophage activation pathways (alternate and classical). Multiplex immunofluorescence confirmed increased infiltration with macrophages in muAd-Ifnα treated tumors compared to controls. PD1/PD-L1 expression was reduced at 72h. This single-cell analysis builds upon our understanding of the impact of Ad-IFNα on tumor cells and other compartments of the microenvironment. These data will help identify mechanisms to improve patient selection and therapeutic efficacy of Nadofaragene firadenovec.

Identification of Vascular Genes Differentially Expressed in the Brain of Patients with Alzheimer's Disease.

Alzheimer's disease (AD) plays a prominent role as the most common form of dementia. Moreover, the traditional mechanism of AD does not explain the microvascular damage observed in about 25-30 years between the onset of AD, which results in late application treatment that inhibits or delays neurodegeneration. Our objective was to identify differentially expressed genes in human brain samples associated with vascular disruption in AD. We analyzed 1633 post-mortem brain samples in the GEO database and, after applying clinical and bioinformatic exclusion criteria, worked with 581 prefrontal and frontal samples. All datasets were analyzed using GEO2R from NCBI. We identified common genes using the Venny tool, and their metabolic relevance associated with AD and the vascular system was analyzed using MetaboAnalyst tools. Our bioinformatic analysis identified PRKCB, MAP2K2, ADCY1, GNA11, GNAQ, PRKACB, KCNMB4, CALD1, and GNAS as potentially involved in AD pathogenesis. These genes are associated with signal transductions, cell death signaling, and cytoskeleton, suggesting potential modulation of cellular physiology, including endoplasmic reticulum and mitochondrial activity. This study generates hypotheses regarding the roles of novel genes over critical pathways relevant to AD and its relation with vascular dysfunction. These findings suggest potential new targets for further investigation into the pathogenesis of dementia and AD.

TLR2 Activation as a Marker of Severe COVID-19 and a Potential Therapeutic Target.

SARS-CoV-2-induced COVID-19 has been a serious public health problem, resulting in millions of lives lost over the previous three years. Although the direct infection caused by virus invasion is important for the pathobiology of COVID-19, the hyperinflammatory response and tissue injury are major contributors in critically ill patients. As a host sensor, toll-like receptor 2 (TLR2) recognizes multiple pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), producing various inflammatory cytokines and inflammatory cell death signals, which are central to the inflammatory pathology observed in COVID-19. The objectives of this narrative review are to summarize the role of TLR2 activation during SARS-CoV-2 infection and emphasize the importance of SARS-CoV-2 viral proteins in TLR2 activation. Additionally, we presented some compounds related to TLR2 regulation clinically or experimentally, which may provide new insights into targets for pharmaceutical discovery and development.

Potential Anticancer Effects of Isoflavone Prunetin and Prunetin Glycoside on Apoptosis Mechanisms.

Cancer is a deadly disease caused by cells that deviate from the normal differentiation and proliferation behaviors and continue to multiply. There is still no definitive cure, and many side effects occur even after treatment. However, apoptosis, one of the programs imprinted on cells, is becoming an important concept in controlling cancer. Flavonoids are polyphenolic compounds found in plants, are naturally bioactive compounds, have been studied for their anticancer effects, and have fewer side effects than chemical treatments. Isoflavones are phytoestrogens belonging to the flavonoid family, and this review discusses in depth the potential anticancer effects of prunetin, one of the many flavonoid families, via the apoptotic mechanism. In addition, a glycoside called prunetin glucoside has been investigated for its anticancer effects through apoptotic mechanisms. The primary intention of this review is to identify the effects of prunetin and its glycoside, prunetin glucoside, on cell death signaling pathways in various cancers to enhance the potential anticancer effects of these natural compounds.

Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway

Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S-palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases.

Follicle-intrinsic and spatially distinct molecular programs drive follicle rupture and luteinization during ex vivo mammalian ovulation

During ovulation, the apical wall of the preovulatory follicle breaks down to facilitate gamete release. In parallel, the residual follicle wall differentiates into a progesterone-producing corpus luteum. Disruption of ovulation, whether through contraceptive intervention or infertility, has implications for women’s health. In this study, we harness the power of an ex vivo ovulation model and machine-learning guided microdissection to identify differences between the ruptured and unruptured sides of the follicle wall. We demonstrate that the unruptured side exhibits clear markers of luteinization after ovulation while the ruptured side exhibits cell death signals. RNA-sequencing of individual follicle sides reveals 2099 differentially expressed genes (DEGs) between follicle sides without ovulation induction, and 1673 DEGs 12 h after induction of ovulation. Our model validates molecular patterns consistent with known ovulation biology even though this process occurs in the absence of the ovarian stroma, vasculature, and immune cells. We further identify previously unappreciated pathways including amino acid transport and Jag-Notch signaling on the ruptured side and glycolysis, metal ion processing, and IL-11 signaling on the unruptured side of the follicle. This study yields key insights into follicle-inherent, spatially-defined pathways that underlie follicle rupture, which may further understanding of ovulation physiology and advance women’s health.

Elucidation of Medusozoan (Jellyfish) Venom Constituent Activities Using Constellation Pharmacology.

Within the phylum Cnidaria, sea anemones (class Anthozoa) express a rich diversity of ion-channel peptide modulators with biomedical applications, but corollary discoveries from jellyfish (subphylum Medusozoa) are lacking. To bridge this gap, bioactivities of previously unexplored proteinaceous and small molecular weight (~15 kDa to 5 kDa) venom components were assessed in a mouse dorsal root ganglia (DRG) high-content calcium-imaging assay, known as constellation pharmacology. While the addition of crude venom led to nonspecific cell death and Fura-2 signal leakage due to pore-forming activity, purified small molecular weight fractions of venom demonstrated three main, concentration-dependent and reversible effects on defined heterogeneous cell types found in the primary cultures of mouse DRG. These three phenotypic responses are herein referred to as phenotype A, B and C: excitatory amplification (A) or inhibition (B) of KCl-induced calcium signals, and test compound-induced disturbances to baseline calcium levels (C). Most notably, certain Alatina alata venom fractions showed phenotype A effects in all DRG neurons; Physalia physalis and Chironex fleckeri fractions predominantly showed phenotype B effects in small- and medium-diameter neurons. Finally, specific Physalia physalis and Alatina alata venom components induced direct excitatory responses (phenotype C) in glial cells. These findings demonstrate a diversity of neuroactive compounds in jellyfish venom potentially targeting a constellation of ion channels and ligand-gated receptors with broad physiological implications.

Leveraging programmed cell death signature to predict clinical outcome and immunotherapy benefits in postoperative bladder cancer

Bladder cancer is the fourth most common malignancy in men with poor prognosis. Programmed cell death (PCD) exerts crucial functions in many biological processes and immunotherapy responses of cancers. Cell death signature (CDS) is novel gene signature comprehensively considering the characteristics of 15 patterns of programmed cell death, which could affect the prognosis and immunotherapy benefits of cancer patients. Integrative machine learning procedure including 10 algorithms was conducted to construct a prognostic CDS using TCGA, GSE13507, GSE31684, GSE32984 and GSE48276 datasets. Immunophenoscore, intratumor heterogeneity (ITH), tumor immune dysfunction and exclusion (TIDE) score and five immunotherapy cohorts were used to evaluate the predictive value of CDS in immunotherapy response. The prognostic CDS constructed by StepCox[backward] + Ridge algorithms was regarded as the optimal prognostic model. The CDS had a stable and powerful performance in predicting overall survival of bladder cancer patients with the AUCs at 3-year, 5-year, and 7-year ROC of 0.740, 0.763 and 0.820 in TCGA cohort. Moreover, CDS score acted as an independent risk factor for overall survival rate of bladder cancer patients. Low CDS score had a higher abundance of immuno-activated cells, higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score, lower immune escape score, lower ITH score, lower cancer-related hallmarks score in bladder cancer. The CDS score was higher in non-responders in pan-cancer patients receiving immunotherapy. Our study constructed a novel prognostic CDS, which could serve as an indicator for predicting the prognosis in postoperative bladder cancer cases and immunotherapy benefits in pan-cancer. Low CDS score indicated a better prognosis and immunotherapy benefits.

Genomic and Transcriptional Analysis of the Necroptosis Pathway Elements RIPK and MLKL in Sea Cucumber, Holothuria leucospilota.

Background: Receptor-interacting protein kinases (RIPKs) and mixed-lineage kinase domain-like protein (MLKL) are crucial in regulating innate immune responses and cell death signaling (necroptosis and apoptosis), and are potential candidates for genetic improvement in breeding programs. Knowledge about the RIPK family and MLKL in sea cucumber remains limited. Methods: We searched the genomes of sea cucumber Holothuria leucospilota for genes encoding RIPKs and MLKL, performed phylogenetic tree, motif and functional domain analyses, and examined tissue distribution and embryonic development patterns using qPCR. Results: RIPK5 (Hl-RIPK5), RIPK7 (Hl-RIPK7) and MLKL (Hl-MLKL) were identified in sea cucumber H. leucospilota. Hl-RIPK5 and Hl-RIPK7 were mainly expressed in coelomocytes, suggesting that they play a role in innate immunity, whereas Hl-MLKL exhibited relatively low expression across tissues. During embryonic development, Hl-MLKL was highly expressed from the 2-cell stage to the morula stage, while Hl-RIPK5 and Hl-RIPK7 were primarily expressed after the morula stage, indicating different roles in embryonic development. In primary coelomocytes, Hl-RIPK5 transcriptional activity was significantly depressed by LPS, poly(I:C), or pathogen Vibrio harveyi. Hl-RIPK7 expression levels were unchanged following the same challenges. Hl-MLKL mRNA levels were significantly decreased with poly(I:C) or V. harveyi, but did not change with LPS. Conclusions: These findings provide valuable insights into the evolutionary tree and characterization of RIPK and MLKL genes in sea cucumber, contributing to the broader understanding of the RIPK gene family and MLKL in ancient echinoderms.

Immunogenic cell death signatures from on-treatment tumor specimens predict immune checkpoint therapy response in metastatic melanoma

Melanoma is a highly malignant form of skin cancer that typically originates from abnormal melanocytes. Despite significant advances in treating metastatic melanoma with immune checkpoint blockade (ICB) therapy, a substantial number of patients do not respond to this treatment and face risks of recurrence and metastasis. This study collected data from multiple datasets, including cohorts from Riaz et al., Gide et al., MGH, and Abril-Rodriguez et al., focusing on on-treatment samples during ICB therapy. We used the single-sample gene set enrichment analysis (ssGSEA) method to calculate immunogenic cell death scores (ICDS) and employed an elastic network algorithm to construct a model predicting ICB efficacy. By analyzing 18 ICD gene signatures, we identified 9 key ICD gene signatures that effectively predict ICB treatment response for on-treatment metastatic melanoma specimens. Results showed that patients with high ICD scores had significantly higher response rates to ICB therapy compared to those with low ICD scores. ROC analysis demonstrated that the AUC values for both the training and validation sets were around 0.8, indicating good predictive performance. Additionally, survival analysis revealed that patients with high ICD scores had longer progression-free survival (PFS). This study used an elastic network algorithm to identify 9 ICD gene signatures related to the immune response in metastatic melanoma. These gene features can not only predict the efficacy of ICB therapy but also provide references for clinical decision-making. The results indicate that ICD plays an important role in metastatic melanoma immunotherapy and that expressing ICD signatures can more accurately predict ICB treatment response and prognosis for on-treatment metastatic melanoma specimens, thus providing a basis for personalized treatment.

Toxicity Effect of Holothuria Lessoni Sea Cucumber on Cancerous Mitochondria Obtained from Rat Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a significant type of liver cancer. In spite of many treatment approaches, its treatment is still associated with challenges. Therefore, new approaches with minimal side effects are necessary for its treatment. Sea cucumbers are marine animals that have many biologically active compounds. They are rich in useful compounds and have high nutritional value. It has been reported to have many pharmacological effects, including anticancer. This research was designed to investigate the effects of Holothuria lessoni (H. lessoni) sea cucumber toxicity in HCC model rats. Cancer was induced in rats using diethyl nitrosamine (200 mg/kg DEN/single dose) + 2-acetylaminofluorene (2-AAF/ dietary/ 0.02% w/w for two weeks). After 15 weeks, hepatocytes and mitochondria were isolated to evaluate toxicity tests. The results of the study showed that H. lessoni (62.5, 125, and 250 µg/ml) were able to cause toxicity only in cancerous mitochondria by increasing the level of free radicals, disrupting the permeability of the mitochondrial membrane, and initiating cell death signaling (p<0.05). It was suggested that H. lessoni sea cucumber may be beneficial in the treatment of HCC along with selected drugs. However, more studies are needed.

P2X7R-primed keratinocytes are susceptible to apoptosis via GPCR-Gβγ-pERK signal pathways

BackgroundCell death constitutes a pivotal biological phenomenon essential for the preservation of homeostasis within living organisms. In the context of maintaining a functional skin barrier, keratinocytes exert positively and negatively control cell death signals. However, in patients with severe drug eruptions, anomalous overexpression of the formyl peptide receptor 1 (FPR1) in keratinocytes elicits a distinctive mode of cell death known as necroptosis, thereby suffering a loss of the skin barrier. The precise molecular mechanisms connecting FPR1 activation to this cell death remain unclear. ObjectiveWe have investigated the intracellular signal transduction cascade governing FPR1-mediated cell death in cultured keratinocytes. MethodsWe used HaCaT cells as a model keratinocyte. The expression of FPR1 was detected with qPCR. The presence of cell death events was monitored through live-cell fluorescent staining and LDH release assays. Furthermore, the phosphorylation of ERK was assessed via Western blot analysis. Intracellular signal pathways were investigated using specific inhibitors. ResultsLigand stimulation of an endogenous ion channel, purinergic receptor P2X7 (P2X7R), increased the FPR1 expression level. This upregulated FPR1 demonstrated functional competence in the phosphorylation of downstream MAP kinase and the initiation of cell death. Notably, this cell death was ameliorated upon the administration of inhibitors targeting Gβγ, ERK, and caspases. ConclusionThe induction and stimulation of FPR1 initiated apoptosis in keratinocytes via the Gβγ-pERK signaling pathway. Our findings postulate that the downstream components of FPR1 represent an alternative therapeutic target for preventing unintended keratinocyte cell death.

Piperine, a black pepper compound, induces autophagy and cellular senescence mediated by NF-κB and IL-6 in acute leukemia

Acute leukemia is characterized by abnormal white blood cell proliferation with rapid onset and severe complications. Natural compounds, which are alternative treatments, are widely used in cancer treatment. Piperine, an alkaloid compound from black pepper, exerts anticancer effects through the cell death signaling pathway. Autophagy and senescence signaling pathways are considered target signaling pathways for cancer treatment. In this study, we investigated the effects of piperine via autophagy and senescence signaling pathways in NB4 and MOLT-4 cells. The MTT assay results demonstrated that piperine significantly decreased the viability of NB4 and MOLT-4 cells. Piperine induced autophagy by increasing LC3, Beclin-1 and ULK1 and decreasing mTOR and NF-κB1 expression in NB4 and MOLT-4 cells. In addition, piperine increased senescence-associated beta-galactosidase fluorescence intensity by increasing p21 and IL-6 expression while decreasing CDK2 expression in NB4 and MOLT-4 cells. In conclusion, our study provides additional information about the induction of autophagy and senescence by piperine in acute leukemia.

Neuregulin 1 Signaling Attenuates Tumor Necrosis Factor α-Induced Female Rat Luteal Cell Death.

The corpus luteum (CL) is a transient ovarian endocrine structure that maintains pregnancy in primates during the first trimester and in rodents during the entire pregnancy by producing steroid hormone progesterone (P4). CL lifespan, growth, and differentiation are tightly regulated by survival and cell death signals through luteotrophic and luteolytic factors, including the epidermal growth factor (EGF)-like factor family. Neuregulin 1 (NRG1), a member of the EGF family, mediates its effect through ErbB2/3 receptors. However, the functional role of NRG1 in luteal cells (LCs) is unknown. Thus, this study investigated the role of NRG1 and its molecular mechanism of action in rat LC. Our experimental results suggest a strong positive correlation between steroidogenic acute regulatory protein (StAR) and NRG1 expression in mid-CL and serum P4 and estrogen (E2) production. In contrast, there was a decrease in StAR and NRG1 expression and P4 and E2 production with an increase in tumor necrosis factor α (TNFα) expression in regressing CL. Further in vitro studies in LCs showed that the knockdown of endogenous Nrg1 promoted the expression of proinflammatory and proapoptotic factors and decreased prosurvival factor expression. Subsequently, treatment with exogenous TNFα under these experimental conditions profoundly elevated proinflammatory and proapoptotic factors. Further analysis demonstrated that the phosphorylation status of ErbB2/3, PI3K, Ak strain transforming or protein kinase B (Akt), and ErK1/2 was significantly inhibited under these experimental conditions, whereas the treatment of TNFα further inhibited the phosphorylation of ErbB2/3, PI3K, Akt, and ErK1/2. Collectively, these studies provide new insights into the NRG1-mediated immunomodulatory and prosurvival role in LCs, which may maintain the function of CL.

Drug-induced oxidative stress actively prevents caspase activation and hepatocyte apoptosis

Cell death is a fundamental process in health and disease. Emerging research shows the existence of numerous distinct cell death modalities with similar and intertwined signaling pathways, but resulting in different cellular outcomes, raising the need to understand the decision-making steps during cell death signaling. Paracetamol (Acetaminophen, APAP)-induced hepatocyte death includes several apoptotic processes but eventually is executed by oncotic necrosis without any caspase activation. Here, we studied this paradoxical form of cell death and revealed that APAP not only fails to activate caspases but also strongly impedes their activation upon classical apoptosis induction, thereby shifting apoptosis to necrosis. While APAP intoxication results in massive drop in mitochondrial respiration, low cellular ATP levels could be excluded as an underlying cause of missing apoptosome formation and caspase activation. In contrast, we identified oxidative stress as a key factor in APAP-induced caspase inhibition. Importantly, caspase inhibition and the associated switch from apoptotic to necrotic cell death was reversible through the administration of antioxidants. Thus, exemplified by APAP-induced cell death, our study stresses that cellular redox status is a critical component in the decision-making between apoptotic and necrotic cell death, as it directly affects caspase activity.

Immune-related cell death index and its application for hepatocellular carcinoma

Regulated cell death (RCD) plays a crucial role in the immune microenvironment, development, and progression of hepatocellular carcinoma (HCC). However, reliable immune-related cell death signatures have not been explored. In this study, we collected 12 RCD modes (e.g., apoptosis, ferroptosis, and cuproptosis), including 1078 regulators, to identify immune-related cell death genes based on HCC immune subgroups. Using a developed competitive machine learning framework, nine genes were screened to construct the immune-related cell death index (IRCDI), which is available for online application. Multi-omics data, along with clinical features, were analyzed to explore the HCC malignant heterogeneity. To validate the efficacy of this model, more than 18 independent cohorts, including survival and diverse treatment cohorts and datasets, were utilized. These findings were further validated using in-house samples and molecular biological experiments. Overall, the IRCDI may have a wide application in individual therapeutic decision-making and improving outcomes for HCC patients.