Mechanism Of Cell Death Research Articles

Mitophagy in Cell Death Regulation: Insights into Mechanisms and Disease Implications.

Mitophagy, a selective form of autophagy, plays a crucial role in maintaining optimal mitochondrial populations, normal function, and intracellular homeostasis by monitoring and removing damaged or excess mitochondria. Furthermore, mitophagy promotes mitochondrial degradation via the lysosomal pathway, and not only eliminates damaged mitochondria but also regulates programmed cell death-associated genes, thus preventing cell death. The interaction between mitophagy and various forms of cell death has recently gained increasing attention in relation to the pathogenesis of clinical diseases, such as cancers and osteoarthritis, neurodegenerative, cardiovascular, and renal diseases. However, despite the abundant literature on this subject, there is a lack of understanding regarding the interaction between mitophagy and cell death. In this review, we discuss the main pathways of mitophagy, those related to cell death mechanisms (including apoptosis, ferroptosis, and pyroptosis), and the relationship between mitophagy and cell death uncovered in recent years. Our study offers potential directions for therapeutic intervention and disease diagnosis, and contributes to understanding the molecular mechanism of mitophagy.

Exploring the diagnostic and immune infiltration roles of disulfidptosis related genes in pulmonary hypertension

BackgroundPulmonary hypertension (PH) is marked by elevated pulmonary artery pressures due to various causes, impacting right heart function and survival. Disulfidptosis, a newly recognized cell death mechanism, may play a role in PH, but its associated genes (DiGs) are not well understood in this context. This study aims to define the diagnostic relevance of DiGs in PH.MethodsUsing GSE11726 data, we analyzed DiGs and their immune characteristics to identify core genes influencing PH progression. Various machine learning models, including RF, SVM, GLM, and XGB, were compared to determine the most effective diagnostic model. Validation used datasets GSE57345 and GSE48166. Additionally, a CeRNA network was established, and a hypoxia-induced PH rat model was used for experimental validation with Western blot analysis.Results12 DiGs significantly associated with PH were identified. The XGB model excelled in diagnostic accuracy (AUC = 0.958), identifying core genes DSTN, NDUFS1, RPN1, TLN1, and MYH10. Validation datasets confirmed the model’s effectiveness. A CeRNA network involving these genes, 40 miRNAs, and 115 lncRNAs was constructed. Drug prediction suggested therapeutic potential for folic acid, supported by strong molecular docking results. Experimental validation in a rat model aligned with these findings.ConclusionWe uncovered the distinct expression patterns of DiGs in PH, identified core genes utilizing an XGB machine-learning model, and established a CeRNA network. Drugs targeting the core genes were predicted and subjected to molecular docking. Experimental validation was also conducted for these core genes.

Ferroptosis and pathogenesis of neuritic plaques in Alzheimer's Disease.

Neuritic plaques are pathognomonic and terminal lesions of Alzheimer's Disease (AD). They embody AD pathogenesis because they harbor in one space critical pathologic features of the disease: amyloid deposits, neurofibrillary degeneration (NFD), neuroinflammation, iron accumulation. Neuritic plaques are thought to arise from the conversion of diffuse extracellular deposits of amyloid beta protein (Aβ), and it is believed that during conversion amyloid toxicity creates the dystrophic neurites of neuritic plaques, as well as neurofibrillary tangles (NFTs). However, recent evidence from human post-mortem studies suggests a much different mechanism of neuritic plaque formation where the first step in their creation is neuronal degeneration driven by iron overload and ferroptosis. Similarly, NFTs represent corpses of iron-laden neurons that develop independent of Aβ deposits. In this review, we will focus on the role of free redox-active iron in the development of typical AD pathology, as determined largely by evidence obtained in human temporal lobe during early, preclinical stages of AD. The findings have allowed construction of a scheme of AD pathogenesis where brain iron is center stage and is involved in every step of the sequence of events that produce characteristic AD pathology. We will discuss how the study of preclinical AD has produced a fresh and revised assessment of AD pathogenesis that may be important for reconsidering current therapeutic efforts and guiding future ones. Significance Statement This review offers a novel perspective on AD pathogenesis where elevated brain iron plays a central role and is involved throughout the development of lesions. We review arguments against the amyloid cascade theory and explain how recent findings in humans during early preclinical disease support iron-mediated cell death and endogenous iron containment mechanisms as critical components of neuritic plaque formation and the ensuing dementia.

7888 Mitotane Induces Different Modes Of Cell Death In Treatment Resistant And Sensitive Models Of Adrenocortical Carcinoma

Abstract Disclosure: S. Feely: None. N. Mullen: None. C. Hong: None. C. Hantel: None. W.E. Rainey: None. M.C. Dennedy: None. Adrenocortical carcinoma (ACC) is a rare aggressive cancer with poor survival. Adjuvant mitotane is the only approved drug for treatment of ACC. It improves survival but its use is limited by poor tolerability and drug resistance. For metastatic ACC, combination chemotherapy, using mitotane and etoposide, doxorubicin, and cisplatin improves survival, but efficacy is limited. Better understating the cytotoxic mechanisms of mitotane offers potential to develop improved therapeutic options for ACC. To investigate the underlying mechanisms in vitro, human ACC cells (HAC15 and H295R), in monolayer cell culture were treated with increasing concentrations of mitotane. Cell death was evaluated at 6 and 24 hours using flow cytometry analysis of Annexin V and Sytox Blue. This was complemented by Incucyte ® Live-Cell Analysis System imaging of annexin V and Sytox Blue staining. Expression of the markers of apoptosis, cleaved caspase 3, and necroptosis, phosphorylated MLKL and RIPK1 was measured at 6 and 24 hours. Mitotane significantly reduced the viability of H295R cells at 6 and 24 hours at the therapeutic concentration of 50uM (p>0.0001), thereby demonstrating treatment-sensitivity. In HAC15 cells, a supratherapeutic dose of 200uM was needed to significantly reduce viability (p>0.05) at 24 hours, indicating resistance to mitotane treatment at therapeutic concentrations. There was increasing Annexin V fluorescence with increasing mitotane concentration in H295R and HAC15 cells ar 6 and 24 hours without higher coinciding staining with Sytox Blue. Video analysis demonstrated these findings. Cleaved caspase 3 expression was associated with mitotane-induced cell death in H295R cells at 6 and 24 hours, indicating apoptosis. HAC15 cells demonstrated cleaved caspase 3 expression only at the highest concentration of mitotane exposure (600uM) at 6 hours, without appreciable expression at 24 hours. Phosphorylated-MLKL and RIPK1 expression was seen in controls and all mitotane doses in both cell lines at both timepoints, indicating necroptosis. In this study, H295R cells, representing a treatment-sensitive model of Mitotane undergo both apoptotic and necroptotic cell death at 6 and 24 hours of mitotane exposure. In contrast, HAC15 cells, demonstrated relative treatment resistance to mitotane, and undergo necroptotic cell death only. These results highlight the importance of understanding and targeting non-apoptotic and necroptotic cell death pathways, particularly when evaluating mechanisms of treatment resistance in ACC. Given the difference in the mechanism of cell death in treatment-sensitive and treatment-resistant cells, further exploration of necroptosis is necessary to better understand how ACC cells may manifest treatment resistance. Presentation: 6/1/2024

9316 Modulation Of Intracellular Lipid Access By ATGL Determines Ferroptosis Sensitivity In Castration-resistant Prostate Cancer

Abstract Disclosure: P. Cao: None. D. Awad: None. J. Han: None. D.E. Frigo: Grant Recipient; Self; GTx, Inc.. Other; Self; Familial relationship with Biocity Biopharmaceuticals, Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals and Barricade Therapeutics. Ferroptosis induction has recently been recognized as a novel therapeutic approach to alter the outcomes of drug-resistant cancer. Ferroptosis is cell death that is caused by the intracellular accumulation of toxic lipid hydroperoxides. Due to their elevated metabolism, castration-resistant prostate cancer (CRPCs) are highly prone to ferroptosis; yet, many of them manage to avert this cellular fate. We have identified a key enzyme involved in lipid metabolism, adipose triglyceride lipase (ATGL), that engenders CRPCs with the ability to resist ferroptosis. Our data has shown that ATGL deletion by CRISPR-Cas9 knockout method sensitized human CRPC cell lines such as C4-2, C4-2BLT, and PC3 cells to the ferroptosis inducer RSL3. In all cases, RSL3-mediated cell death could be blocked by the antioxidant Ferrostatin-1, confirming ferroptosis as the mechanism of cell death. Knocking out ATGL also augmented the ferroptosis inducer-mediated increase in lipid peroxides as indicated by the increased ratio of oxidized to non-oxidized C11-BODIPY 581/591. With regards to the mechanism for the sensitivity of ATGL KO to ferroptosis induction, previous research has established that the enzyme long-chain acyl-CoA synthetase 4 (ACSL4) is universally essential to facilitate ferroptosis. More specifically, ATGL(PNPLA2) was found to inversely correlate with ACSL4 in the Taylor et al., the TCGA PanCancer Atlas, and Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team) datasets in both primary and metastatic tumors. qPCR and western blot analysis of ACSL4 levels further showed that ACSL4 expression is closely tied to the lipase activity of ATGL. Addition of arachidonic acid significantly induced ferroptosis when combined with RSL3 in a dose-dependent manner only in ATGL KO cells. This indicates that PUFAs can render ATGL KO cells even more sensitive to RSL3-induced ferroptosis while cells with functional ATGL remain highly resistant, further reinforcing that ATGL is an essential safeguard of CRPC against ferroptosis. ATGL KO cells also demonstrated sensitivity to the antiandrogen Enzalutamide. The combination of Enzalutamide and RSL3 substantially decreased cell viability in ATGL KO cells as compared to control cells, indicating a strong synergy effect particularly seen in ATGL KO cells. In summary, this work demonstrates that ATGL is an important and novel regulator of ferroptosis in CRPC and supports the use of ferroptosis inducer as a new therapeutic approach in CRPC. Presentation: 6/2/2024

Ruthenium complexes with abiraterone acetate as antiproliferative agents

This study is dedicated to the development of multimodal anticancer agents. We have obtained ruthenium complexes conjugated with the steroid-type antitumor drug abiraterone acetate in order to take advantage of the dual antitumor properties of both ruthenium and abiraterone. The compounds exhibit good antiproliferative activity against cancer cells, with selectivity over primary fibroblasts. Real-time cell analysis revealed that compound dichlorido(η66-p-cymene)(abiraterone acetate)ruthenium(II) had pronounced antiproliferation activity compared to abiraterone acetate. Flow cytometric studies on the mechanism of cell death have revealed that the most active compound induces apoptosis more effectively than abiraterone acetate. Our findings demonstrate the potential of this novel dual-action compound as promising candidates for further development as anticancer agents.

Oral toxicity assessment and the mitigation of lung carcinogenesis by phytol and α-bisabolol combination treatment in swiss albino mice: insights into redox enzyme modulation and caspase-dependent cell death mechanisms.

This study examined the safety and potential anti-lung cancer effects of combinations of phytol and α-bisabolol in Swiss albino mice. Both acute and subacute toxicity assessments showed that the combination of phytol and α-bisabolol is safe, with no adverse effects observed at higher concentrations. Hematological, biochemical, and histopathological tests showed no signs of toxicity in the heart, lungs, liver, spleen, and kidneys. The LD50 was greater than 2000mg/kg, indicating a large safety margin. Histopathological analysis confirmed cancer induction in the B(a)P-induced group, which had significantly altered relative lung weights. Lung weight increased slightly pre and post-treatment, but histopathology showed normal alveolar epithelium. GSH and SOD levels increased significantly in B(a)P-exposed groups, indicating an adaptive antioxidant response. CAT levels increased significantly in the post-treatment group, demonstrating the role of combination of phytol and α-bisabolol in protecting against B(a)P-induced oxidative damage. Upregulation of Bax and downregulation of Bcl-2 caused a pro-apoptotic environment, suggesting a way to inhibit malignant cell survival. Modulation of caspase-3 and caspase-9 showed the complexity of carcinogen-induced apoptotic signaling. In conclusion, phytol and α-bisabolol were found to be safe and organ-protective, and demonstrated no acute or subacute toxicity. They modulate antioxidant defenses and apoptotic pathways, which may help prevent and treat lung cancer.

Intricate Role of the Cyclic Guanosine Monophosphate Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway in Traumatic Brain Injury-Generated Neuroinflammation and Neuronal Death.

The secondary insult in the aftermath of traumatic brain injury (TBI) causes detrimental and self-perpetuating alteration in cells, resulting in aberrant function and the death of neuronal cells. The secondary insult is mainly driven by activation of the neuroinflammatory pathway. Among several classical pathways, the cGAS-STING pathway, a primary neuroinflammatory route, encompasses the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptor. Recently, the cGAS-STING research domain has gained exponential attention. The aberrant stimulation of cGAS-STING machinery and corresponding neuroinflammation have also been reported after TBI. In addition to the critical contribution to neuroinflammation, the cGAS-STING signaling also provokes neuronal cell death through various cell death mechanisms. This review highlights the structural and molecular mechanisms of the cGAS-STING machinery associated with TBI. We also focus on the intricate relationship and framework between cGAS-STING signaling and cell death mechanisms (autophagy, apoptosis, pyroptosis, ferroptosis, and necroptosis) in the aftermath of TBI. We suggest that the targeting of cGAS-STING signaling may open new therapeutic strategies to combat neuroinflammation and neurodegeneration in TBI.

Research Progress on the Role of Autophagy Pathway in the Pharmacological Treatment of Multiple Myeloma --Review

Multiple myeloma (MM) is a malignant hematological tumour for which pharmacological treatments such as protease inhibitors, immunomodulators, and steroids are commonly used, but most MM cases still relapsed or become refractory. Autophagy is a type 2 cell death mechanism that plays a key role in MM progression, including biphasic regulation that promotes MM cell survival or facilitates its death. In this paper, we review the changes of MM cells' autophagic activity and its effect on cell proliferation and apoptosis during drug action, aiming to analyse the role of autophagy pathway in drug treatment of MM and provide relevant ideas for targeting autophagy in the treatment of MM.

Ferroptosis - a potential feature underlying neratinib-induced colonic epithelial injury.

Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear. Real-time quantitative polymerase chain reaction (RT-qPCR) and histology were integrated to study the effect of, and type of cell death induced by neratinib on colonic tissues collected from female Albino Wistar rats dosed with neratinib (50mg/kg) daily for 28 days. Additionally, previously published bulk RNA-sequencing and CRISPR-screening datasets on human glioblastoma SF268 cell line and glioblastoma T895 xenograft, and mouse TBCP1 breast cancer cell line were leveraged to elucidate potential mechanisms of neratinib-induced cell death. The severity of colonic epithelial injury, especially degeneration of surface lining colonocytes and infiltration of immune cells, was more pronounced in the distal colon than the proximal colon. Sequencing showed that apoptotic gene signature was enriched in neratinib-treated SF268 cells while ferroptotic gene signature was enriched in neratinib-treated TBCP1 cells and T895 xenograft. However, we found that ferroptosis, but less likely apoptosis, was a potential histopathological feature underlying colonic injury in rats treated with neratinib. Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity.

Leveraging mitochondrial-programmed cell death dynamics to enhance prognostic accuracy and immunotherapy efficacy in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is a highly heterogeneous disease, posing significant challenges to accurate prognosis prediction. Mitochondria play a central role in the energy metabolism of eukaryotic cells and can influence...

Transcriptional Downregulation of Methanol Metabolism Key Genes During Yeast Death in Engineered Pichia pastoris.

Pichia pastoris possesses the unique ability to utilize methanol as its sole carbon source, which makes it a proper host for producing various high-value-added products via metabolic engineering. Nevertheless, cell death has been observed during the fermentation of modified P. pastoris, with limited literature elucidating the underlying causes and mechanisms. Understanding the death mechanisms during methanol-based fermentation is crucial for optimizing fermentation strategies, enhancing the accumulation of target products, and reducing production costs. Here, we first sought to eliminate the potential causes of cell death during fermentation, such as inadequate inorganic salts and toxic by-product accumulation. The elimination of these potential causes was achieved efficiently utilizing the high-throughput fermentation equipment. Subsequently, we established a correlation between yeast cell death and the duration of the methanol metabolism period by monitoring the growth of the yeast at different fermentation stages. A critical revelation from this work came from analyzing the yeast's transcriptomic data at various stages of methanol metabolism. It was observed that a significant characteristic of yeast cell death during fermentation was the marked down-regulation of transcript levels of key enzymes involved in the methanol assimilation pathway and genes related to their biosynthesis process. The findings of this work are crucial for better understanding the causes and mechanisms of cell death for engineered P. pastoris during methanol-utilized fermentation.

The Activation of PKM2 Induces Pyroptosis in Hippocampal Neurons via the NLRP3/Caspase-1/GSDMD Pathway in Neonatal Rats With Hypoxic-Ischemic Brain Injury.

The presence of hypoxic-ischemic brain damage (HIBD) in neonates triggers a strong neuroinflammatory reaction. Pyroptosis, a programmed cell death mechanism associated with inflammation, plays a crucial role in HIBD. Pyruvate kinase M2 (PKM2) plays a significant role in connecting metabolic processes and inflammatory responses, but whether it affects hippocampus pyroptosis in HIBD is unclear. The aim of this study is to elucidate the role of PKM2 in HIBD and to propose a novel therapeutic approach for neonatal ischemic-hypoxic encephalopathy. In this study, we employed neonatal 7-day-old Sprague Dawley rats to establish a model of HIBD using the Rice-Vannucci surgical technique and a hypoxia device. To inhibit the elevation of PKM2, we utilized the PKM2 inhibitor shikonin. The rats were categorized into four groups: Sham, Shikonin, HIBD, and Shikonin+HIBD. Behavioral tests, hematoxylin eosin staining, immunofluorescence staining, ELISA (IL-1β, IL-18), and LDH were conducted in each group to evaluate neurological function, hippocampal damage, the occurrence of neuronal pyroptosis, and the neuroinflammation. Western blot was used to assess the expression levels of PKM2, NLRP3, Caspase-1, Cleaved Caspase-1, GSDMD, GSDMDN, and IL-1β. The expression of PKM2 elevated in hippocampal tissues of the HIBD model and the localization of PKM2 in the hippocampus was activated in neurons instead of microglia during the HIBD. Meanwhile, the inhibition of PKM2 improved the behavioral test scores and the body weight of rats, the neuronal damage in the CA1 region of hippocampal tissue was also attenuated. In addition, inhibiting PKM2 alleviated neuronal pyroptosis by decreasing the expression of PKM2, NLRP3, Caspase-1, Cleaved Caspase-1, GSDMD, GSDMDN. Furthermore, serum levels of LDH and inflammatory factors IL-1β and IL-18 decrease with PKM2 inhibition. Based on these findings, we can conclude that PKM2 plays a crucial role in regulating hippocampal neuronal pyroptosis of HIBD rats via NLRP3/Caspase-1/GSDMD pathway. Therefore, inhibiting PKM2 could be a promising therapeutic strategy for the treatment of neonatal ischemic-hypoxic encephalopathy.

Exploring Anticancer Potential of Lactobacillus Strains: Insights into Cytotoxicity and Apoptotic Mechanisms on HCT 115 Cancer Cells.

This study aims to systematically assess the anticancer potential of distinct Lactobacillus strains on Human Colorectal Tumor (HCT) 115 cancer cells, with a primary focus on the apoptotic mechanisms involved. Lactobacillus strains were isolated from sheep milk and underwent a meticulous microbial isolation process. Previous research indicates that certain probiotic bacteria, including Lactobacillus species, may exhibit anticancer properties through mechanisms such as apoptosis induction. However, there is limited understanding of how different Lactobacillus strains exert these effects on cancer cells and the underlying molecular pathways involved. Cytotoxicity was evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and exposure durations of Lactobacillus cell-free lyophilized filtrates. Additional apoptotic features were characterized using 4.6-diamidino-2-phenylindole (DAPI) analysis for nuclear fragmentation and Annexin V/PI analysis for apoptosis quantification. Genetic analysis explored the modulation of apoptotic proteins (Bax and Bcl2) in response to Lactobacillus treatment. Whole-genome sequencing (WGS) was performed to understand the genetic makeup of the Lactobacillus strains used in the study. The study demonstrated a significant reduction in HCT 115 cell viability, particularly with L. plantarum, as evidenced by Sulforhodamine B (SRB) and MTT assays. DAPI analysis revealed nuclear fragmentation, emphasizing an apoptotic cell death mechanism. Annexin V/PI analysis supported this, showing a higher percentage of early and late apoptosis in L. plantarum-treated cells. Genetic analysis uncovered up-regulation of pro-apoptotic protein Bax and down-regulation of anti-apoptotic protein Bcl2 in response to Lactobacillus treatment. WGS study revealed a strain reported to NCBI PRJNA439183. L. plantarum emerged as a potent antiproliferative agent against HCT 115 cancer cells, inducing apoptosis through intricate molecular mechanisms. This study underscores the scientific basis for L. plantarum's potential role in cancer therapeutics, highlighting its impact on antiproliferation, adhesion, and gene-protein regulation. Further research is warranted to elucidate the specific molecular pathways involved and to evaluate the therapeutic potential of L. plantarum in preclinical and clinical settings.

Molecular Mechanisms of HT-29 Colorectal Cancer Cell Death Induced by Artemisia annua Methanolic Extract

Background: Although chemotherapy and targeted therapies have improved survival outcomes, there is growing interest in incorporating herbal medicines, such as Artemisia annua, into cancer treatment. Objectives: This study aims to investigate the mechanisms underlying the effects of A. annua methanolic extract on HT-29 colorectal cancer cells, particularly focusing on cell viability and the modulation of p53 and BAX/Bcl2 ratio expression. Methods: The half-maximal inhibitory concentration (IC50) of A. annua methanolic extract in HT-29 cells was determined via the MTT viability assay, while apoptosis was assessed using the propidium iodide (PI) staining method. Reverse transcription (RT)-PCR was performed to evaluate gene expression in the HT-29 cell line. Values are presented as the average of three separate determinations and expressed as mean ± SD. Results: The results showed that the viability of HT-29 cells significantly decreased in a dose- and time-dependent manner (IC50 for 48 h: 1358.1 μg.mL-1). Propidium iodide staining results confirmed the findings of the MTT assay. Gene expression analysis revealed a decrease in p53 expression and a two-fold increase in the BAX/Bcl2 ratio following exposure to 1000 μg.mL-1 of A. annua extract. Conclusions: The findings from the MTT and PI assays confirm the cytotoxic effects of A. annua extract on HT-29 cells. However, the gene expression analysis of BAX, Bcl2, and p53 suggests that the observed cell death is not primarily due to apoptosis.

Characterization of regulated cancer cell death pathways induced by the different modalities of non-thermal plasma treatment

Non-thermal plasma (NTP) has shown promising anti-cancer effects, but there is still limited knowledge about the underlying cell death mechanisms induced by NTP and inherent differences between NTP treatment modalities. This study aimed to investigate four major regulated cell death (RCD) pathways, namely apoptosis, pyroptosis, necroptosis, and ferroptosis, in melanoma cancer cells following NTP treatment, and to provide an overview of molecular mechanistic differences between direct and indirect NTP treatment modalities. To discriminate which cell death pathways were triggered after treatment, specific inhibitors of apoptosis, pyroptosis, necroptosis, and ferroptosis were evaluated. RCD-specific molecular pathways were further investigated to validate the findings with inhibitors. Both direct and indirect NTP treatment increased caspase 3/7 and annexin V expression, indicative of apoptosis, as well as lipid peroxidation, characteristic of ferroptosis. Pyroptosis, on the other hand, was only induced by direct NTP treatment, evidenced by increased caspase 1 activity, whereas necroptosis was stimulated in a cell line-dependent manner. These findings highlight the molecular differences and implications of direct and indirect NTP treatment for cancer therapy. Altogether, activation of multiple cell death pathways offers advantages in minimizing treatment resistance and enhancing therapeutic efficacy, particularly in a combination setting. Understanding the mechanisms underlying NTP-induced RCD will enable the development of strategic combination therapies targeting multiple pathways to achieve cancer lethality.

Aphthous stomatitis - computational biology suggests external biotic stimulus and immunogenic cell death involved

BackgroundThe exact cause of recurrent aphthous stomatitis is still unknown, making it a challenge to develop effective treatments. This study employs computational biology to investigate the molecular basis of recurrent aphthous stomatitis, aiming to identify the nature of the stimuli triggering these ulcers and the type of cell death involved.MethodsTo understand the molecular underpinnings of recurrent aphthous stomatitis, we used the Génie tool for gene identification, targeting those associated with cell death in recurrent aphthous stomatitis. The ToppGene Suite was employed for functional enrichment analysis. We also used Reactome and InteractiVenn for protein integration and prioritization against a PANoptosis gene list, enabling the construction of a protein-protein interaction network to pinpoint key proteins in recurrent aphthous stomatitis pathogenesis.ResultsThe study’s computational approach identified 1,375 protein-coding genes linked to recurrent aphthous stomatitis. Critical among these were proteins responsive to bacterial stimuli, especially high mobility group protein B1 (HMGB1), toll-like receptor 2 (TLR2), and toll-like receptor 4 (TLR4). The enrichment analysis suggested an external biotic factor, likely bacterial, as a triggering agent in recurrent aphthous stomatitis. The protein interaction network highlighted the roles of tumor necrosis factor (TNF), NF-kappa-B essential modulator (IKBKG), and tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), indicating an immunogenic cell death mechanism, potentially PANoptosis, in recurrent aphthous stomatitis.ConclusionThe findings propose that bacterial stimuli could trigger recurrent aphthous stomatitis through a PANoptosis-related cell death pathway. This new understanding of recurrent aphthous stomatitis pathogenesis underscores the significance of oral microbiota in the condition. Future experimental validation and therapeutic strategy development based on these findings are necessary.

Research Progress on Mechanism of Chinese Medicine Intervention on Cuprotosis Induced Apoptosis of Tumor Cells

In the current field of cancer treatment, the search for new therapeutic targets and methods remains a focal area of research. Traditional Chinese medicine contains a variety of pharmacologically active components that interact with multiple targets and signaling pathways in the human body, demonstrating potential anti-tumor effects. Copper plays a crucial role in various physiological processes; its homeostasis is tightly regulated to limit the production of oxidative stress and toxicity, and it intervenes in the processes of tumor development, metastasis, and recurrence. Cuproptosis represents a novel form of copper-dependent cell death that differs from previously known regulatory cell death mechanisms, offering a fresh perspective on the link between copper homeostasis and mitochondrial metabolism. Targeting copper has emerged as a new anti-cancer strategy. Current research on the intervention of cuproptosis by TCM is limited; leveraging the advantages of TCM's multi-target, multi-pathway approach could further elucidate the mechanisms of cuproptosis, bringing more possibilities to cancer treatment modalities.

Intracellular biliverdin dynamics during ferroptosis.

Ferroptosis is a cell death mechanism mediated by iron-dependent lipid peroxidation. Although ferroptosis has garnered attention as a cancer-suppressing mechanism, there are still limited markers available for identifying ferroptotic cells or assessing their sensitivity to ferroptosis. The study focused on biliverdin, an endogenous reducing substance in cells, and examined the dynamics of intracellular biliverdin during ferroptosis using a biliverdin-binding cyanobacteriochrome. It was found that intracellular biliverdin decreases during ferroptosis and that this decrease is specific to ferroptosis among different forms of cell death. Furthermore, the feasibility of predicting sensitivity to ferroptosis by measuring intracellular biliverdin was demonstrated using a ferroptosis model induced by the re-expression of the transcription factor BACH1. These findings provide further insight into ferroptosis research and are expected to contribute to the development of cancer therapies that exploit ferroptosis.

Considerations for Exploring Nanosecond Pulsed Electric Fields (nsPEFs) for Treatments of Cancer, Benign Skin Diseases, Atrial Fibrillation, and for New Mechanistic Understandings

Pulsed power includes acquiring electrical energy, compressing it, and releasing it in instantaneous bursts that are low in energy but very high in power. When the pulse duration is near the plasma membrane charging time constant, which is the time during which the cell interior is exposed to the applied pulsed electric field, it affects intracellular structures and functions. The technology is called nanosecond Pulsed Electric Fields (nsPEFs), nanosecond electric pulses (nsEP), or Nanopulse Stimulation (NPSTM) according to Pulse Biosciences, Inc., a company taking the technology to the market. Initial studies showed the elimination of tumor cells in vitro by apoptosis, and other regulated cell death mechanisms, elimination of rodent and canine osteosarcoma, and a basal cell carcinoma clinical trial. In the rat liver and mouse breast cancers, tumor-free animals were in situ vaccinated (ISV), preventing the recurrence of the treated cancers. The technology has also focused on treating benign skin diseases, with some advantages over cryoablation. More recently, the same technology called nanosecond pulsed-field ablation (nsPFA) has been used to treat cardiac arrhythmias like Atrial Fabulation (AFib) with catheters in humans. In pre-clinical studies and now in humans, this technology is showing advantages over radiofrequency ablation and cryoablation. On a new mechanistic landscape, nonlethal nsPEFs modulation of electron transport in the plasma membrane and the mitochondria show potential for controlling redox homeostasis and metabolism. Furthermore, different nsPEF waveforms have different effects on cells; waveforms can differ by pulse duration, rise time, electric field, and/or post-pulse features. So, for nsPEFs, there is a lethal side used for ablation as with NPS and nsPFA and a more recently recognized nonlethal side indicating new possibilities to differentially modify cell physiology depending on the different nsPEF waveforms.