Mechanism Of Cell Death Research Articles

Studying the Role of Novel Carbon Nano Tubes as a Therapeutic Agent to Treat Triple Negative Breast Cancer (TNBC) - an In Vitro and In Vivo Study

Triple Negative Breast Cancer (TNBC) is a malignant cancer with a very high mortality rate around the world. African American(AA) women are 28% more likely to die from triple-negative breast cancer (TNBC) than white women with the same diagnosis. AA patients are also more likely to be diagnosed at a later stage of the disease and have the lowest survival rates for any stage of diagnosis; There are very few existing anti TNBC drugs with therapeutic efficacy hence newer anti TNBC drug design and investigation is needed. Carbon Nano Tubes(CNT) in recent years have shown effective anti-cancer properties in various types of cancers as reported in peer reviewed journals. Henceforth, we did an investigation to study the anticancer properties of a novel CNT in both in vitro and in vivo models of TNBC. We tested the CNT drug in vitro cytotoxicity studies on TNBC model MDA-MB-231 VIM RFP cell lines and Spheroid forming assays on the same cancer cells; we also did an in vivo study on TNBC model mice to study the therapeutic efficacy of this CNT drug in reducing the tumor load. Our initial studies showed increased cell death and reduction in spheroid numbers in the CNT treated cancer cells in comparison to control and a significant reduction in the tumor volume in the TNBC model mice than in untreated animals. Thus our initial studies have shown significant therapeutic efficacy of the novel CNT as an anti TNBC agent. Additional mechanistic studies need to be done to find out the cell death mechanisms, core canonical pathways involved, pharmacokinetic studies before translational research for this novel nanoparticle as a therapeutic agent from bench to bedside.

DDDR-27. BMP SIGNALING MODULATES APOPTOTIC AND NON-APOPTOTIC CELL DEATH IN GLIOBLASTOMA

Abstract Recurrence occurs in approximately 90% of glioblastoma (GBM) patients, in part due to the tumors becoming resistant to cell death in response to existing therapies. These therapies often trigger apoptosis; however, apoptosis is only one of several different forms of cell death. We hypothesize that activating non-canonical death mechanisms could provide a back door to killing treatment-resistant GBM cells. To test this hypothesis, we first developed a new imaging-based high-throughput method to directly quantify cell death in 3D models. Using this method, we find patient-derived GBM spheroids to be resistant to the induction of cell death in response to various standard-of-care and experimental therapeutic compounds. To further investigate mechanisms underlying this resistance, we screened a panel of extracellular protein ligands for the modulation of cell death response. We find that bone morphogenic protein (BMP) signaling increases resistance to several apoptosis-inducing compounds, including temozolomide and tyrosine kinase inhibitors. Intriguingly, BMP signaling simultaneously enhanced sensitivity to a novel non-apoptotic cell death pathway triggered by the small molecule CIL56. Efforts are ongoing to further understand how BMP signaling governs apoptotic and non-apoptotic cell death mechanisms. Nevertheless, our results suggest a novel approach to treating GBM, centered upon the modulation of BMP signaling combined with the use of agents that induce non-apoptotic cell death.

Mechanistic Insights into Influenza A Virus-Induced Cell Death and Emerging Treatment Strategies

Influenza A virus (IAV) infection initiates a complex interplay of cell death modalities, including apoptosis, necroptosis, pyroptosis, and their integration, known as PANoptosis, which significantly impacts host immune responses and tissue integrity. These pathways are intricately regulated by viral proteins and host factors, contributing to both viral clearance and pathogenesis-related tissue damage. This review comprehensively explores the molecular mechanisms underlying these cell death processes in influenza infection. We highlight the roles of key regulatory proteins, such as ZBP1 (Z-DNA binding protein 1) and RIPK3 (receptor-interacting protein kinase 3), in orchestrating these responses, emphasizing the dual roles of cell death in both antiviral defense and tissue injury. Furthermore, we discuss emerging therapeutic strategies targeting these pathways, aiming to enhance antiviral efficacy while minimizing collateral tissue damage. Future research should focus on targeted approaches to modulate cell death mechanisms, aiming to reduce tissue damage and improve clinical outcomes for patients with severe influenza.

Development of a novel disulfidptosis-correlated m6A/m1A/m5C/m7G gene signature to predict prognosis and therapeutic response for lung adenocarcinoma patients by integrated machine-learning

BackgroundLung adenocarcinoma (LUAD) represents a significant global health burden, necessitating advanced prognostic tools for improved patient management. RNA modifications (m6A, m1A, m5C, m7G), and disulfidptosis, a novel cell death mechanism, have emerged as promising biomarkers and therapeutic targets in cancer.MethodsWe systematically compiled disulfidptosis-correlated genes and RNA modification-related genes from existing literature. A novel disulfidptosis-correlated m6A/m1A/m5C/m7G riskscore was computed using integrated machine-learning algorithms. Transcriptomic data from TCGA and GEO databases were downloaded analyzed. Single-cell RNA-sequencing data from the TISCH database was processed using the Seurat package. Genes’ protein–protein interaction network was constructed using the String database. Functional phenotype analysis was performed using GSVA, ClusterProfiler, and IOBR packages. Consensus clustering divided patients into two distinct groups. Drug sensitivity predictions were obtained from the GDSC1 database and predicted using the Oncopredict package.ResultsThe disulfidptosis-correlated m6A/m1A/m5C/m7G risk score effectively stratified LUAD patients into prognostically distinct groups, demonstrating superior predictive accuracy compared to conventional clinical parameters. Patients in different risk groups exhibited significant molecular and clinical differences. Subsequent analyses identified two molecular subtypes associated with RNA modification and disulfidptosis, revealing differences in immune infiltration and prognosis. Functional enrichment analyses highlighted pathways involving RNA modification and disulfidptosis, underscoring their roles in LUAD pathogenesis. Single-cell analysis revealed distinct features between high- and low-risk status cells.ConclusionThis study introduces a novel disulfidptosis-correlated m6A/m1A/m5C/m7G risk score as a robust prognostic tool for LUAD, integrating insights from RNA modifications and cell death mechanisms. The risk score enhances prognostic stratification and identifies potential targets for personalized therapeutic strategies in LUAD. This comprehensive approach emphasizes the critical roles of RNA modifications and disulfidptosis in LUAD biology, paving the way for future research and clinical applications aimed at improving patient outcomes.

Recent Advances in Nanomaterial-Mediated Cell Death for Cancer Therapy.

Nanomedicine has shown great anticancer potential by disrupting redox homeostasis and increasing the levels of oxidative stress, but the therapeutic effect is limited by factors including the intrinsic self-protection mechanism of tumors. Cancer cell death can be induced by the exploration of different cell death mechanisms, such as apoptosis, pyroptosis, necroptosis, cuproptosis, and ferroptosis. The merging of nanotechnology with biomedicine has provided tremendous opportunities to construct cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only used for the targeted delivery of cell death inducers, but also as therapeutic components to induce cell death to achieve efficient tumor treatment. This review focuses on seven cell death modalities mediated by nanomaterials, such as apoptosis, pyroptosis, necroptosis, ferroptosis, cuprotosis, immunogenic cell death, and autophagy. The mechanisms of these seven cell death modalities are described in detail, as well as the preparation of nanomaterials that induce them and the mechanisms, they used to exert their effects. Finally, this work describes the potential future development based on the current knowledge related to cell death induced by nanomaterials.

A Novel Single Base Mutation in OsSPL42 Leads to the Formation of Leaf Lesions in Rice

Rice spotted-leaf mutants serve as valuable resources for studying plant programmed cell death (PCD) and disease resistance mechanisms, making them crucial for research on disease resistance in rice. Map-based cloning was used to identify and clone the spotted-leaf gene OsSPL42. Then, functional complementation and CRISPR/Cas9 techniques were also employed to further validate the function of this gene. By applying leaf clippings for bacterial blight (BB) inoculation, the BB resistance of different rice lines was assessed. The results in this study were as follows: The OsSPL42 behaved as a recessive nuclear gene and was narrowed down to a 111 kb region on chromosome 8. All T0 transgenic rice plants in the complementation experiments exhibited a wild-type phenotype, without any lesion spots on the rice leaves. This suggests that the LOC_Os08g06100 encoding O-methyltransferase is the candidate gene for the mutant spl42. The OsSpl42 is widely expressed and the OsSPL42-GFP protein is mainly localized in the cytoplasm. OsSPL42 overexpression lines are more susceptible to BBs, which indicates that OsSPL42 may act as a negative regulator of rice resistance to BB. In summary, we speculate that OsSPL42 plays an important role in the regulation of pathogen response, providing new insights into plant defense mechanisms.

Cell Death Mechanisms

Cells and their building blocks ensure the maintenance of life by performing complex tasks such as taking in nutrients, excreting waste materials, producing energy, growth, division and reproduction. The form of intercellular communication and coordination is critical for the organism to grow, develop, and adapt to its environment optimally. The numerical balance of the cells that make up the organism is very important for it to survive in a healthy way. While new cells are being created in the living being, some of the existing cells are also eliminated through cell death, thus ensuring a stable balance. As new cells are generated within the organism, a portion of the existing cells undergoes elimination through the process of cell death, thereby maintaining a stable balance. To uphold this mechanism, various forms of cell death mechanisms are activated. Cell death occurs spontaneously, genetically or by other factors that are a part of the life of living things. It basically exists in two main forms. These are programmed and unprogrammed cell death. Cell death mechanisms are critical for the development, survival and health of living organisms. This process, which is basically divided into two main categories, is called programmed cell death (apoptosis) and unprogrammed cell death (necrosis). Programmed and unprogrammed cell death mechanisms are very important for the proper functioning of biological systems and the continuation of life. While programmed cell death (apoptosis) plays very important roles in the regulation and development of tissues, homeostasis, immune response and prevention of diseases, unprogrammed cell death (necrosis) is important in the rapid repair of tissue by clearing damaged cells and the clearance of pathogens. Understanding the way death mechanisms work is very important in terms of understanding the effects that may occur on a healthy continuation of life and in developing more effective methods in the treatment of diseases that may arise as a result. For these reasons, what death mechanisms are, their types, differences and working principles have been tried to be summarized in this study.

Activation of autophagy, paraptosis, and ferroptosis by micheliolide through modulation of the MAPK signaling pathway in pancreatic and colon tumor cells

Micheliolide (MCL), a naturally occurring sesquiterpene lactone, has demonstrated significant anticancer properties through the induction of various programmed cell death mechanisms. This study aimed to explore MCL's effects on autophagy, paraptosis, and ferroptosis in pancreatic and colon cancer cells, along with its modulation of the MAPK signaling pathway. MCL was found to substantially suppress cell viability in these cancer cells, particularly in MIA PaCa-2 and HT-29 cell lines. The study identified that MCL induced autophagy by enhancing the levels of autophagy markers such as Atg7, p-Beclin-1, and Beclin-1, which was attenuated by the autophagy inhibitor 3-MA. Furthermore, MCL was found to facilitate paraptosis, indicated by decreased Alix and in-creased ATF4 and CHOP levels. It also promoted ferroptosis, as demonstrated by the reduced expression of SLC7A11, elevated TFRC levels, and increased intracellular iron. Additionally, MCL activated the MAPK signaling pathway, marked by the phosphorylation of JNK, p38, and ERK, linked with an increase in ROS production that is vital in regulating these cell death mechanisms. These findings propose that MCL is a versatile anticancer agent, capable of activating various cell death pathways by modulating MAPK signaling and ROS levels. These results emphasize the therapeutic promise of MCL in treating cancer, pointing to the necessity of further in vivo investigations to confirm these effects and determine its potential clinical uses.

New vatalanib analogs: Design, synthesis, in silico study and biological evaluation for anticancer activity

In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs. Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT‐116) using vatalanib as a positive control. The new candidates showed promising anticancer activity against two tested cancer cell lines with IC50 values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 µM, in particular compounds 11b and 11c which were more potent than vatalanib. The most potent was the 4-benzoylquinoxaline derivative 11b (IC50 = 6.04 ± 0.19 µM and 15.58 ± 0.58 µM) compared to vatalanib (IC50 of 25.27 ± 0.84 µM and 43.91 ± 1.64 µM) against HepG2 and HCT116, respectively. The selectivity indices of 11b were found to be approximately 14 and 5 towards HepG2 and HCT116, respectively. While vatalanib showed selectivity indices of about 5 and 3 towards HepG2 and HCT116, respectively. The most promising compound 11b was further investigated in HepG‐2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death. It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC50 of 0.918 ± 0.033 µM compared to vatalanib (IC50 of 0.265 ± 0.009 µM). Deep computational studies were created for the designed compounds including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates. The results of the docking study were consistent with biological testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib. So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead molecules for development of new effective anticancer drugs.

Emerging Therapeutic Approaches Targeting Ferroptosis in Cancer: Focus on Immunotherapy and Nanotechnology.

Ferroptosis is a newly discovered form of programmed cell death characterized by iron overload, ROS accumulation, and lipid peroxidation. It is distinguished by unique morphological, biochemical, and genetic features and stands apart from other known regulated cell death mechanisms. Studies have demonstrated a close association between ferroptosis and various cancers, including liver cancer, lung cancer, renal cell carcinoma, colorectal cancer, pancreatic cancer, and ovarian cancer. Inducing ferroptosis has shown promising results in inhibiting tumor growth and reversing tumor progression. However, the challenge lies in regulating ferroptosis in vivo due to the scarcity of potent compounds that can activate it. Integrating emerging biomedical discoveries and technological innovations with conventional therapies is imperative. Notably, considerable progress has been made in cancer treatment by leveraging immunotherapy and nanotechnology to trigger ferroptosis. This review explores the relationship between ferroptosis and emerging immunotherapies and nanotechnologies, along with their potential underlying mechanisms, offering valuable insights for developing novel cancer treatment strategies.

Structural characterization and potential antitumor and immunostimulatory activities of mycelial polysaccharides from Ophiocordyceps gracilis

Ophiocordyceps gracilis (O. gracilis), the same genus as Ophiocordyceps sinensis, has been used as an edible medicinal fungus for many years. However, the active ingredients of O. gracilis polysaccharides remain relatively unknown. To address this, a 310.1kDa novel polysaccharide (PDP-1a) was isolated from O. gracilis. The structural characteristics of PDP-1a were determined by different spectroscopy analyses, revealing that PDP-1a was α-glucan homologs with →4)-α-Glcp(1→ as the main chain. Furthermore, PDP-1a inhibited tumor cell proliferation, particularly in the A549 cell line, with a cell death mechanism involving cell cycle blockage, mitochondrial membrane potential reduction, and increased reactive oxygen species, thereby leading to apoptosis. Importantly, PDP-1a promotes antitumor cytokine secretion and enhances macrophage phagocytosis concentration-dependently. These findings provide a theoretical foundation for the use of O. gracilis and emphasize the potential application of PDP-1a in antitumor immunomodulatory therapy.

High TNF and NF-κB Pathway Dependency Are Associated with AZD5582 Sensitivity in OSCC via CASP8-Dependent Apoptosis.

Mechanistically guided drug repurposing has been made possible by systematically integrating pharmacologic and CRISPR-Cas9 screen data. Our study discovers the biomarker and cell death mechanisms underpinning sensitivity toward AZD5582, an antagonist of the inhibitor of apoptosis family protein. Our findings have important implications for improving future trial design for patients with OSCC using this emerging drug class.

Cytotoxic effects of ivermectin on Giardia lamblia: induction of apoptosis and cell cycle arrest

IntroductionGiardia lamblia is a flagellated protozoan parasite causing giardiasis, a common intestinal infection characterized by diarrhea, abdominal cramps, and nausea. Treatments employed to combat this parasitic infection have remained unchanged for the past 40 years, leading to the emergence of resistant strains and prompting the search for new therapeutic agents.MethodsThis study investigated the cytotoxic effects of ivermectin (IVM) on G. lamblia trophozoites. We conducted dose-response experiments to assess IVM-induced cytotoxicity. We utilized various biochemical and ultrastructural analyses to explore the underlying mechanisms of cell death, including reactive oxygen species (ROS) production, DNA fragmentation, cell cycle arrest, and apoptosis markers.ResultsOur findings demonstrate that IVM induces dose-dependent cytotoxicity and triggers cell death pathways. We found that IVM treatment generates elevated levels of reactive oxygen species (ROS), DNA fragmentation, and arrests of trophozoites in the cell cycle’s S phase. Additionally, ultrastructural analysis reveals morphological alterations consistent with apoptosis, such as cytoplasmic vacuolization, chromatin condensation, and tubulin distribution.DiscussionThe insights gained from this study may contribute to developing new therapeutic strategies against giardiasis, addressing the challenge posed by drug-resistant strains.

Antioxidants as adjuvant in cancer therapy: A systematic review

While cancer therapies can effectively remove malignant cells from the body, their efficacy is mostly limited to a number of harmful side effects. Antioxidant treatment is therefore frequently necessary to lessen these negative effects by lowering reactive species levels and minimizing chronic oxidative damage. Antioxidants have a crucial role in inhibiting the production of reactive nitrogen and oxygen species as well as their activities. Reviewing the role of antioxidants in the development or prevention of cancer was the goal of this study. It is thought that antioxidants can both prevent and treat different kinds of cancer. As of right now, cancer prevention and treatment have primarily involved consuming natural antioxidant substances. These are unquestionably cell-type- and Reactive Oxygen Species (ROS)-specific, as evidenced by alterations in gene expression, cellular activities, and mechanisms of cell death. By decreasing hydrogen donors or quenching singlet oxygen and postponing oxidative reactions in cancer cells that are actively developing, natural antioxidants eliminate an overabundance of free radical intermediates. The primary topics covered in this study are antioxidant categorization, metabolic regulation, and antioxidant involvement in cancer treatment.

Mechanisms Underlying Sensory Nerve-Predominant Damage by Methylmercury in the Peripheral Nervous System

Sensory disturbances and central nervous system symptoms are important in patients with Minamata disease. In the peripheral nervous system of these patients, motor nerves are not strongly injured, whereas sensory nerves are predominantly affected. In this study, we investigated the mechanisms underlying the sensory-predominant impairment of the peripheral nervous system caused by methylmercury. We found that the types of cell death in rat dorsal root ganglion (DRG) neurons caused by methylmercury included apoptosis, necrosis, and necroptosis. Methylmercury induced apoptosis in cultured rat DRG neurons but not in anterior horn neurons or Schwann cells. Additionally, methylmercury activated both caspase 8 and caspase 3 in DRG neurons. It increased the expression of tumor necrosis factor (TNF) receptor-1 and the phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL). The expression of TNF-α was increased in macrophage-like RAW264.7 cells by methylmercury. The increase was suggested to be mediated by the NF-κB pathway. Moreover, methylmercury induced neurological symptoms, evaluated by a hindlimb extension response, were significantly less severe in TNF-α knockout mice. Based on these results and our previous studies, we propose the following hypothesis regarding the pathogenesis of sensory nerve-predominant damage by methylmercury: First, methylmercury accumulates within sensory nerve neurons and initiates cell death mechanisms, such as apoptosis, on a small scale. Second, cell death triggers the infiltration of macrophages into the sensory fibers. Third, the macrophages are stimulated by methylmercury and secrete TNF-α through the NF-κB pathway. Fourth, TNF-α induces cell death mechanisms, including necrosis, apoptosis through the caspase 8/3 pathway, and necroptosis through the TNFR1-RIP1-RIP3-MLKL pathway, activated by methylmercury in sensory neurons. Consequently, methylmercury exhibits potent cytotoxicity specific to the DRG/sensory nerve cells in the peripheral nervous system. This chain of events caused by methylmercury may contribute to sensory disturbances in patients with Minamata disease.

A Potential Role for Oridonin in Cancer Control: Mechanisms of Autophagy and Apoptosis.

Cancer is one of the leading causes of mortality and morbidity worldwide. It is characterized by unmanaged cell proliferation and growth, leading to tumour formation with the potential to metastasize to various organs of the human body. Currently, several common therapeutic approaches exist to treat malignancies, including chemotherapy, surgery, and radi-otherapy, which can be used to prevent the progression of malignancies. However, these ther-apeutic approaches often face challenges due to their cytotoxic impacts and various side ef-fects. Ergo is currently researching a new treatment that effectively reduces cancer progression with minimal side effects. Emerging evidence suggests that harnessing herbal sources, which are both accessible and safe, can be useful in improving various disorders, including cancer. Oridonin, a diterpenoid isolated from the traditional Chinese medicinal herb Rabdosia ru-bescens, has shown significant potential in cancer therapy. Moreover, numerous pharmacolog-ical and biological capacities have been attributed to this naturally active compound, such as anti-oxidative, anti-inflammatory, anti-bacterial, and anti-viral influences. This review sum-marizes the current knowledge on oridonin's mechanisms of action, particularly its effects on autophagy and apoptosis. While apoptosis is a well-established pathway for eliminating cancer cells through DNA fragmentation, autophagy plays a complex role, acting as both a cytopro-tective and cell death mechanism depending on the context. We provide a comprehensive evaluation of the relevant studies, highlighting oridonin's potential in cancer control and iden-tifying areas for further research.

Nanoplatforms for Magnetic-Photo-Heating of Thermo-Resistant Tumor Cells: Singular Synergic Therapeutic Effects at Mild Temperature.

A self-assemble amphiphilic diblock copolymer that can incorporate iron oxide nanocubes (IONCs) in chain-like assemblies as heat mediators for magnetic hyperthermia (MHT) and tuneable amounts of IR780 dye as agent for photothermal therapy (PTT) is developed. MHT-heating performance of photobeads in viscous media have the same heat performances in water at magnetic field conditions of clinical use. Thanks to IR780, the photobeads are activated by infrared laser light within the first biological window (808nm) with a significant enhancement of photo-stability of IR780 enabling the raise of the temperature at therapeutic values during multiple PTT cycles and showing unchanged optical features up to 8 days. Moreover, the photobeads fluorescent signal is preserved once internalized by glioblastoma multiforme (GBM) cells. Peculiarly, the photobeads are used as toxic agents to eradicate thermo-resistant GBM cells at mild heat, as low as 41°C, with MHT and PTT both of clinical use. Indeed, a high U87 GBM cell mortality percentage is obtained only with dual MHT/PTT while each single treatment dose not provide the same cytotoxic effects. Only for the combined treatment, the cell death mechanism is assigned to clear sign of apoptosis as observed by structural/morphological cell studies and enhanced lysosome permeability.

Mature cardiac tissues modeling Duchenne muscular dystrophy related cardiomyopathy

Abstract Background The major cause of mortality in patients with Duchenne muscular dystrophy (DMD) is cardiomyopathy. This disease is caused by dystrophin gene mutations that result in the loss of dystrophin protein. Gene replacement therapies have been approved for skeletal muscle symptoms of DMD. However, these therapeutic modalities are not indicated for cardiomyopathy due to their low efficiency of delivery to the heart. Despite the significant unmet needs, a limitation in this area of research is the divergence of cardiomyopathy symptoms in model animals from those in patients. Alternatively, cardiomyocytes differentiated from patient-derived iPS cells have recently been analyzed. However, existing results are based on a single time point analysis and do not model disease progression or non-cardiomyocyte involvement. Purpose Our research aims to establish an in vitro model that can reproduce the pathological progression of DMD cardiomyopathy. Methods We have generated cardiac organoids and engineered heart tissues (EHTs) from patient-derived iPS cells, consisting of cardiomyocytes and epicardial-derived non-cardiomyocytes. An iPS cell line in which the dystrophin mutation was repaired by genome editing was used as a control. The cardiac organoids or EHTs were subjected to transient activation of fatty acid metabolism to promote the maturation of iPS-derived cardiomyocytes. Pathological conditions were then induced in these 3D-models by applying loads that mimicked the DMD-disease environment. Results The mature cardiac organoids displayed adult-like gene expression profiles in the components of dystrophin-associated-protein-complex and calcium handling. After continuous mechanical loading, cell death appeared in DMD-EHTs, although there was only a slight decrease in contractility and fibrosis. Elevated mitochondrial ROS production and DNA damage were observed as a part of the cell death mechanism. Furthermore, pathological stimuli in addition to mechanical loading reproduced progressive contractile dysfunction and further increase in fibrosis in DMD-EHTs. Conclusions From these observations, we concluded that our DMD-EHT model recapitulate the pathological development of DMD-cardiomyopathy. These results suggest that the key factors involved in the progression of DMD cardiomyopathy are (i) the fragility of cardiomyocytes to stress in early stages and (ii) the involvement of non-cardiomyocytes such as fibrosis. Our model provides insight into the molecular mechanisms underlying disease progression and novel therapeutic targets.

A potential role of gut microbiota in stroke: mechanisms, therapeutic strategies and future prospective.

Neurological conditions like Stroke and Alzheimer's disease (AD) often include inflammatory responses in the nervous system. Stroke, linked to high disability and mortality rates, poses challenges related to organ-related complications. Recent focus on understanding the pathophysiology of ischemic stroke includes aspects like cellular excitotoxicity, oxidative stress, cell death mechanisms, and neuroinflammation. The objective of this paper is to summarize and explore the pathophysiology of ischemic stroke, elucidates the gut-brain axis mechanism, and discusses recent clinical trials, shedding light on novel treatments and future possibilities. Changes in gut architecture and microbiota contribute to dementia by enhancing intestinal permeability, activating the immune system, elevating proinflammatory mediators, altering blood-brain barrier (BBB) permeability, and ultimately leading to neurodegenerative diseases (NDDs). The gut-brain axis's potential role in disease pathophysiology offers new avenues for cell-based regenerative medicine in treating neurological conditions. In conclusion, the gut microbiome significantly impacts stroke prognosis by highlighting the role of the gut-brain axis in ischemic stroke mechanisms. This insight suggests potential therapeutic strategies for improving outcomes.

Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy

Excessive DNA damage triggers various types of programmed cell death (PCD), yet the regulatory mechanism of DNA damage-induced cell death is not fully understood. Here, we report that PANoptosis, a coordinated PCD pathway, including pyroptosis, apoptosis and necroptosis, is activated by DNA damage. The Z-DNA binding protein 1 (ZBP1) is the apical sensor of PANoptosis and essential for PANoptosome assembly in response to DNA damage. We find endogenous retroviruses (ERVs) are activated by DNA damage and act as ligands for ZBP1 to trigger PANoptosis. By using ZBP1 knock-out and knock-in mice disrupting ZBP1 nucleic acid-binding activity, we demonstrate that ZBP1-mediated PANoptosis contributes to the toxic effects of chemotherapeutic drugs, which is dependent on ZBP1 nucleic acid-binding activity. We found that ZBP1 expression is downregulated in tumor tissue. Furthermore, in colorectal cancer patients, dsRNA is induced by chemotherapy and sensed by ZBP1 in normal colonic tissues, suggesting ZBP1-mediated PANoptosis is activated by chemotherapy in normal tissues. Our findings indicate that ZBP1-mediated PANoptosis is activated by DNA damage and contributes to the toxic side effects of DNA-damage-based chemotherapy. These data suggest that ZBP1 could be a promising therapeutic target to alleviate chemotherapy-related side effects.