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Cork spot-like physiological disorder (CSPD) is a newly identified issue in 'Kurenainoyume' apples, yet its mechanism remains unclear. To investigate CSPD, we conducted morphological observations on 'Kurenainoyume' apples with and without pre-harvest fruit-bagging treatment using light-impermeable paper bags. Non-bagged fruit developed CSPD in mid-August, while no CSPD symptoms were observed in bagged fruit. The bagging treatment significantly reduced the proportion of opened lenticels, with only 17.9% in bagged fruit compared to 52.0% in non-bagged fruits. In non-bagged fruit, CSPD spots tended to increase from the lenticels, growing in size during fruit development. The cuticular thickness and cross-sectional area of fresh cells in CSPD spots were approximately 16 µm and 1600 µm², respectively. Healthy non-bagged fruit reached these values around 100 to 115 days after full bloom from mid- to late August. Microscopic and computerized tomography scanning observations revealed that many CSPD spots developed at the tips of vascular bundles. Therefore, CSPD initiation between opened lenticels and vascular bundle tips may be influenced by water stress, which is potentially caused by water loss, leading to cell death and the formation of CSPD spots. [ABSTRACT FROM AUTHOR]

The purification of a protein inhibiting lipid peroxidation led to the discovery of the selenoperoxidase GPx4 forty years ago. Thus, the evidence of the enzymatic activity was reached after identifying the biological effect and unambiguously defined the relationship between the biological function and the enzymatic activity. In the syllogism where GPx4 inhibits lipid peroxidation and its inhibition is lethal, cell death is operated by lipid peroxidation. Based on this rationale, this form of cell death emerged as regulated iron-enforced oxygen toxicity and was named ferroptosis in 2012. In the last decades, we learned that reduction of lipid hydroperoxides is indispensable and, in cooperation with prooxidant systems, controls the critical steady state of lipid peroxidation. This concept defined the GPx4 reaction as both the target for possible anti-cancer therapy and if insufficient, as cause of degenerative diseases. We know the reaction mechanism, but the details of the interaction at the membrane cytosol interface are still poorly defined. We know the gene structure, but the knowledge about expression control is still limited. The same holds true for post-transcriptional modifications. Reverse genetics indicate that GPx4 has a role in inflammation, immunity, and differentiation, but the observations emerging from these studies need a more specifically addressed biochemical evidence. Finally, the role of GPx4 in spermatogenesis disclosed an area unconnected to lipid peroxidation. In its mitochondrial and nuclear form, the peroxidase catalyzes the oxidation of protein thiols in two specific aspects of sperm maturation: stabilization of the mid-piece and chromatin compaction. Thus, although available evidence converges to the notion that GPx4 activity is vital due to the inhibition of lipid peroxidation, it is reasonable to foresee other unknown aspects of the GPx4 reaction to be disclosed. [Display omitted] • GPx4 is the vital selenoperoxidase active on membrane lipid hydroperoxides. • The redox center is flanked by a site for binding the phospholipid polar head. • GPx4 prevents regulated cell death routines operated by peroxidation. • Survival controlled by GPx4 impacts on immunity inflammation and differentiation. • Protein oxidation by distinct GPx4 isoforms is indispensable to sperm maturation. [ABSTRACT FROM AUTHOR]

The common phenomenon expected from any anti-cancer drug in use is to kill the cancer cells without any side effects to non-malignant cells. Doxorubicin is an anthracycline derivative anti-cancer drug active over different types of cancers with anti-cancer activity but attributed to unintended cytotoxicity and genotoxicity triggering mitogenic signals inducing apoptosis. Administration of doxorubicin tends to both acute and chronic toxicity resulting in cardiomyopathy (left ventricular dysfunction) and congestive heart failure (CHF). Cardiotoxicity is prevented through administration of different cardioprotectants along with the drug. This review elaborates on mechanism of drug-mediated cardiotoxicity and attenuation principle by different cardioprotectants, with a focus on Hsp27 as cardioprotectant by prevention of drug-induced oxidative stress, cell survival pathways with suppression of intrinsic cell death. In conclusion, Hsp27 may offer an exciting/alternating cardioprotectant, with a wider study being need of the hour, specifically on primary cell line and animal models in conforming its cardioprotectant behaviour.

Cell death occurs when a pathogen invades a host organism or the organism is subjected to sterile injury. Thus, cell death is often closely associated with the induction of an immune response. Furthermore, cell death can occur as a consequence of the immune response and precedes the tissue renewal and repair responses that are initiated by innate immune cells during resolution of an immune response. Beyond immunity, cell death is required for development, morphogenesis and homeostasis. How can such a ubiquitous event as cell death trigger such a wide range of context-specific effector responses? Dying cells are sensed by innate immune cells using specialized receptors and phagocytosed through a process termed efferocytosis. Here, we outline a general principle whereby signals within the dead cell as well as the environment are integrated by specific efferocytes to define the appropriate effector response.

Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions. [ABSTRACT FROM AUTHOR]

The gasdermins are a family of recently identified pore-forming effector proteins that cause membrane permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. Gasdermins contain a cytotoxic N-terminal domain and a C-terminal repressor domain connected by a flexible linker. Proteolytic cleavage between these two domains releases the intramolecular inhibition on the cytotoxic domain, allowing it to insert into cell membranes and form large oligomeric pores, which disrupts ion homeostasis and induces cell death. Gasdermin-induced pyroptosis plays a prominent role in many hereditary diseases and (auto)inflammatory disorders as well as in cancer. In this Review, we discuss recent developments in gasdermin research with a focus on mechanisms that control gasdermin activation, pore formation and functional consequences of gasdermin-induced membrane permeabilization.

We have known for decades that many viruses kill their host cells, and the discovery of programmed cell death, such as apoptosis, provided distinction from regular necrotic cell death. To highlight the various types of virus-induced cell death, and to frame these in the context of how they affect the immune response against various viruses, Viral Immunology is organizing a Special Issue on Virus-Induced Programmed Cell Death. [Extracted from the article]

We have known for decades that many viruses kill their host cells, and the discovery of programmed cell death, such as apoptosis, provided distinction from regular necrotic cell death. To highlight the various types of virus-induced cell death, and to frame these in the context of how they affect the immune response against various viruses, Viral Immunology is organizing a Special Issue on Virus-Induced Programmed Cell Death. [Extracted from the article]

In this study, a bibliometric analysis was carried out to identify the most influential clinical studies and research trends on anti-programmed cell death 1/programmed cell death 1 ligand 1 (anti-PD1/PDL1) immunotherapy. On January 1, 2022, we used Web of Science to identify the 100 most frequently cited papers on clinical studies investigating anti-PD1/PDL1 immunotherapy, and extracted the following data: publication year, source title, country/region, institution, and the total number of citations. The research design and area were classified independently by the authors. Subsequently, we carried out a bibliometric analysis to determine the trends and identify the major journals on anti-PD1/PDL1 immunotherapy. The authors analyzed the current research hotspots based on papers published in major journals from 2020 to 2021. These 100 papers were cited a total of 138,840 times, and the median number of citations was 899.5 (range: 341–7,983). "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer" by Topalian et al. had the highest number of citations (7,983 times). New England Journal of Medicine had the highest number of top-cited papers (40 papers), average citations per paper (1,558.3 citations), and rate of top-cited papers (65.6%). Authors from the USA contributed most of the papers (76 papers). Lung cancer (30 papers, 46,422 citations) and melanoma (20 papers, 30,881 citations) were the most cited research areas. In summary, anti-PD1/PDL1 has become standard treatment for various cancer, while adjuvant anti-PD1/PDL1 therapy is currently a research hotspot. New England Journal of Medicine was identified as the most influential journal in this area. Non-small cell lung cancer and melanoma are the most well-studied cancers, while nivolumab and pembrolizumab are the most commonly investigated anti-PD1/PDL1 antibodies. Further studies are warranted to identify effective predictive biomarkers or models, clarify the molecular mechanism of combined therapy, and establish optimal therapeutic strategies. This study may assist researchers in obtaining a comprehensive impression of the landscape and current trends in anti-PD1/PDL1 immunotherapy and gain inspiration to conduct further studies. [ABSTRACT FROM AUTHOR]

Ferroptosis is a newly characterized form of regulated cell death. This bibliometric analysis identified the scientific output, leading institutions and research teams, current research hotspots and trends in research on ferroptosis since the origin of the concept. We searched the Science Citation Index Expanded of Web of Science Core Collection for papers on ferroptosis up to 3 June 2022. The acquired data were analysed and visualized by Bibliometrix package and VOSviewer. The study ultimately included 3511 relevant papers, and annual production in this field has grown rapidly in recent years. Institutions and scholars from China contributed the most work, but the impact of their research was much less than that of the United States. Prof. Brent R. Stockwell's team from Columbia University in the United States has a very strong academic influence in the field. Front Cell Dev Biol published the most papers in the field of ferroptosis. As the keywords of the papers in this field changed from the most numerous 'oxidative stress', 'cell‐death', 'iron', 'expression', and 'lipid‐peroxidation', to 'prognosis', 'immunotherapy', 'progression', 'tumour microenvironment', and 'colorectal cancer', the hotspot of ferroptosis research is gradually shifting from basic research to clinical translational research. The mechanism of tumour formation and treatment will become the frontier in the field of ferroptosis research in the future. [ABSTRACT FROM AUTHOR]

Sepsis, a disease caused by severe infection, has a high mortality rate. At present, there is a lack of reliable algorithmic models for biomarker mining and diagnostic model construction for sepsis. Programmed cell death (PCD) has been shown to play a vital role in disease occurrence and progression, and different PCD-related genes have the potential to be targeted for the treatment of sepsis. In this paper, we analyzed PCD-related genes in sepsis. Implicated PCD processes include apoptosis, necroptosis, ferroptosis, pyroptosis, netotic cell death, entotic cell death, lysosome-dependent cell death, parthanatos, autophagy-dependent cell death, oxeiptosis, and alkaliptosis. We screened for diagnostic-related genes and constructed models for diagnosing sepsis using multiple machine-learning models. In addition, the immune landscape of sepsis was analyzed based on the diagnosis-related genes that were obtained. In this paper, 10 diagnosis-related genes were screened for using machine learning algorithms, and diagnostic models were constructed. The diagnostic model was validated in the internal and external test sets, and the Area Under Curve (AUC) reached 0.7951 in the internal test set and 0.9627 in the external test set. Furthermore, we verified the diagnostic gene via a qPCR experiment. The diagnostic-related genes and diagnostic genes obtained in this paper can be utilized as a reference for clinical sepsis diagnosis. The results of this study can act as a reference for the clinical diagnosis of sepsis and for target discovery for potential therapeutic drugs. [ABSTRACT FROM AUTHOR]

Background: Ferroptosis is a recently discovered type of cell death. It is genetically, morphologically, and biochemically distinct from other types of programmed cell death, such as necrosis, apoptosis, and autophagy. The level of intracellular free iron and reactive oxygen species formation are important for ferroptosis activation, which can occur through either of two key inhibitory processes. The first one involves inhibition of cystine transfer into cells by the cystine/glutamate antiporter system (Xc-). Cystine serves as a precursor for the synthesis of glutathione, a major cellular antioxidant. The second one involves the inhibition of glutathione peroxidase 4, which protects cells from lipid peroxidation. Ferroptosis is associated with many metabolic disorders, including neurological diseases and cancer. Molecules involved in the activation of ferroptotic pathways are involved in protecting cells against stress conditions, and in the maintenance of nicotinamide adenine dinucleotide phosphate and glutathione levels, as well as iron homeostasis. Also important is the connection with autophagy, so called ferritinophagy, in which iron is released from lysosomes into the cytosol. Cascade reactions of free unstable iron atoms with other molecules result in the production of reactive oxygen species that initiate the cellular stress that triggers ferroptosis. In diseases such as cancer where cell death inducing mechanisms, including apoptosis, are usually suppressed by genetic changes, the induction of alternative pathways leading to cell death could provide an attractive treatment strategy., Conclusion: In recent years, research into new antimetastatic drugs has focused on the activation of alternative cell death pathways that might overcome disturbed metabolic processes inside cancer cells or the chemotherapy resistance acquired in the course of routine treatment. A number of molecules have been found to induce ferroptosis in tumor cells, suggesting that they may offer new alternatives for anticancer treatment. Key words: cell death - cancer - autophagy - ferroptosis - ferritinophagy - cellular stress - ROS This work was supported by the projects GAČR 17-05838S, MEYS - NPS I - LO1413 and MH CZ- -DRO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 31. 8. 2018.

A response from A. Mairani and colleagues to a letter to the editor about their article "Modelling of Cell Killing Due to Sparsely Ionizing Radiation in Normoxic and Hypoxic Conditions and an Extension to High LET Radiation" in a 2013 issue is presented.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies. Highlights: Colorectal cancer (CRC) is one of the leading causes of death among patients. CRC has been characterized with changes at the genetic and epigenetic factors. The molecular factors can be used as diagnostic and prognostic factors in CRC. The cell death mechanisms demonstrate dysregulation in CRC. Autophagy has aberrant activation in CRC and exerts dual function. [ABSTRACT FROM AUTHOR]

Background: Quercetin, a widespread polyphenolic flavonoid, is known for its extensive health benefits and is commonly found in the plant kingdom. The natural occurrence and extraction methods of quercetin are crucial due to its bioactive potential. Purpose: This review aims to comprehensively cover the natural sources of quercetin, its extraction methods, bioavailability, pharmacokinetics, and its role in various cell death pathways and liver fibrosis. Methods: A comprehensive literature search was performed across several electronic databases, including PubMed, Embase, CNKI, Wanfang database, and ClinicalTrials.gov, up to 10 February 2024. The search terms employedwere "quercetin", "natural sources of quercetin", "quercetin extraction methods", "bioavailability of quercetin", "pharmacokinetics of quercetin", "cell death pathways", "apoptosis", "autophagy", "pyroptosis", "necroptosis", "ferroptosis", "cuproptosis", "liver fibrosis", and "hepatic stellate cells". These keywords were interconnected using AND/OR as necessary. The search focused on studies that detailed the bioavailability and pharmacokinetics of quercetin, its role in different cell death pathways, and its effects on liver fibrosis. Results: This review details quercetin's involvement in various cell death pathways, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis, with particular attention to its regulatory influence on apoptosis and autophagy. It dissects the mechanisms through which quercetin affects these pathways across different cell types and dosages. Moreover, the paper delves into quercetin's effectson liver fibrosis, its interactions with hepatic stellate cells, and its modulation of pertinent signaling cascades. Additionally, it articulates from a physical organic chemistry standpoint the uniqueness of quercetin's structure and its potential for specific actions in the liver. Conclusion: The paper provides a detailed analysis of quercetin, suggesting its significant role in modulating cell death mechanisms and mitigating liver fibrosis, underscoring its therapeutic potential. [ABSTRACT FROM AUTHOR]

Background: Spinal cord injury (SCI) is a severe central nervous trauma that can cause serious consequences. Cell death is emerging as a common pathogenesis after SCI. In the last two decades, numerous studies have been published in the field of cell death after SCI. However, it is still rare to find relevant bibliometric analyses. This bibliometric study aims to visually represent global research trends in the field of cell death after SCI. Methods: Bibliometric data were sourced from the Web of Science Core Collection (WoSCC) database. VOSviewer, CiteSpace, and R software ("bibliometrix" package) were used to analyze and visualize bibliometric data. Annual scientific production, countries/regions, institutions, authors, journals, highly cited papers, keywords, and literature co-citation were evaluated to determine research performance. Results: An analysis of 5,078 publications extracted from the WoSCC database revealed a fluctuating yet persistent growth in the field of cell death after SCI over the past 23 years. China and the United States, contributing 69% of the total publications, were the main driving force in this field. The Wenzhou Medical University from China contributed to the most papers. In terms of authors, Salvatore Cuzzocrea from the University of Messina had the highest number of publications. The "Journal of Neurotrauma" was the top journal in terms of the number of publications, however, the "Journal of Neuroscience" was the top journal in terms of the number of citations. The theme of the highly cited articles mainly focused on the mechanism of cell death after SCI. The keyword and literature co-citation analysis mainly focused on the mode of cell death, mechanism research of cell death, and functional recovery after SCI. Conclusion: This study analyzes the research hotspots, frontiers, and development trends in the field of cell death after SCI, which is important for future studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Photodynamic therapy (PDT) is a cancer treatment that uses photogenerated reactive oxygen species (ROS) to damage target cells. The unique mechanism of action of PDT involves the systemic or local administration of a photosensitizing compound (photosensitizer), which is then activated by light of a specific energy. PDT induces a very strong local inflammatory response. A number of adaptive mechanisms are induced within the tumor, related to increased amino acid metabolism and damage to lymphatic vessels. In this review, we are describing the adaptive immune response induced by ROS and generated by PDT. Cancer is one of the most significant causes of death worldwide. Despite the rapid development of modern forms of therapy, results are still unsatisfactory. The prognosis is further worsened by the ability of cancer cells to metastasize. Thus, more effective forms of therapy, such as photodynamic therapy, are constantly being developed. The photodynamic therapeutic regimen involves administering a photosensitizer that selectively accumulates in tumor cells or is present in tumor vasculature prior to irradiation with light at a wavelength corresponding to the photosensitizer absorbance, leading to the generation of reactive oxygen species. Reactive oxygen species are responsible for the direct and indirect destruction of cancer cells. Photodynamically induced local inflammation has been shown to have the ability to activate an adaptive immune system response resulting in the destruction of tumor lesions and the creation of an immune memory. This paper focuses on presenting the latest scientific reports on the specific immune response activated by photodynamic therapy. We present newly discovered mechanisms for the induction of the adaptive response by analyzing its various stages, and the possible difficulties in generating it. We also present the results of research over the past 10 years that have focused on improving the immunological efficacy of photodynamic therapy for improved cancer therapy. [ABSTRACT FROM AUTHOR]

Cell death maintains cell morphology and homeostasis during development by removing damaged or obsolete cells. The concentration of metal ions whithin cells is regulated by various intracellular transporters and repositories to maintain dynamic balance. External or internal stimuli might increase the concentration of metal ions, which results in ions overloading. Abnormal accumulation of large amounts of metal ions can lead to disruption of various signaling in the cell, which in turn can produce toxic effects and lead to the occurrence of different types of cell deaths. In order to further study the occurrence and development of metal ions overloading induced cell death, this paper reviewed the regulation of Ca 2+ , Fe 3+ , Cu 2+ and Zn 2+ metal ions, and the internal mechanism of cell death induced by overloading. Furthermore, we found that different metal ions possess a synergistic and competitive relationship in the regulation of cell death. And the enhanced level of oxidative stress was present in all the processes of cell death due to metal ions overloading, which possibly due to the combination of factors. Therefore, this review offers a theoretical foundation for the investigation of the toxic effects of metal ions, and presents innovative insights for targeted regulation and therapeutic intervention. HIGHLIGHTS: • Metal ions overloading disrupts homeostasis, which in turn affects the regulation of cell death. • Metal ions overloading can cause cell death via reactive oxygen species (ROS). • Different metal ions have synergistic and competitive relationships for regulating cell death., (© 2024. The Author(s).)

Cetylpyridinium chloride (CPC) is a quaternary ammonium compound used widely in health and personal care products. Meanwhile, due to its increasing use, its potential adverse health effects are emerging as a topic of public concern. In this study, we first administered CPC by pharyngeal aspiration to determine the survival level (the maximum concentration at which no death is observed) and then administered CPC to mice repeatedly for 28 days using the survival level as the highest concentration. CPC increased the total number of pulmonary cells secreting pro- and anti-inflammatory cytokines and chemokines. Infiltration of inflammatory cells, production of foamy alveolar macrophages, and chronic inflammatory lesions were found in the lung tissue of male and female mice exposed to the highest dose of CPC. We also investigated the toxicity mechanism using BEAS-2B cells isolated from normal human bronchial epithelium. At 6 h after exposure to CPC, the cells underwent non-apoptotic cell death, especially at concentrations greater than 2 μg/mL. The expression of the transferrin receptor was remarkably enhanced, and the expression of proteins that contribute to intracellular iron storage was inhibited. The expression of both mitochondrial SOD and catalase increased with CPC concentration, and PARP protein was cleaved, suggesting possible DNA damage. In addition, the internal structure of mitochondria was disrupted, and fusion between damaged organelles was observed in the cytoplasm. Most importantly, lamellar body-like structures and autophagosome-like vacuoles were found in CPC-treated cells, with enhanced expression of ABCA3 protein, a marker for lamellar body, and a docking score between ABCA3 protein and CPC was considered to be approximately -6.8969 kcal/mol. From these results, we propose that mitochondrial damage and iron depletion may contribute to CPC-induced non-apoptotic cell death and that pulmonary accumulation of cell debris may be closely associated with the inflammatory response. Furthermore, we hypothesize that the formation of lamellar body-like structures may be a trigger for CPC-induced cell death., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we designed an in vitro administration device based on compartment model theory and utilized it to construct an in vitro simulated one compartment extravascular administration model of copper chloride. Within the C max range of 3.91-1000.00 μM, the measured concentration-time curves of the simulated one compartment extravascular administration model almost coincide with the corresponding theoretical curves. The measured values of toxicokinetic parameters, including k e , T 1/2 , k a , T 1/2a , T max , C max , CL, and AUC 0-∞ are close to the corresponding theoretical values. The fitting coefficients are >0.9990. In simulated one compartment extravascular administration and classic in vitro administration, copper chloride dose-dependently induced HepG2 cell death. When C max /administration concentration is equal, classic in vitro administration induces a higher cell death rate than simulated one compartment extravascular administration. However, there is no significant difference in inducing cell death between the two administration models when area under the curve is equal. In conclusion, the device designed in this study can be used to in vitro simulate one compartment extravascular administration, making in vitro toxicity testing more similar to in vivo scenarios. There are differences in copper chloride induced HepG2 cell death between simulated one compartment extravascular administration and classic in vitro administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic neurons and neuroinflammation. Recent studies have identified a role of T cells in the pathogenesis of PD. Additionally, these studies suggested that α-synuclein (α-Syn) is related to abnormal T-cell responses and may act as an epitope and trigger autoimmune T-cell responses. However, it is unclear whether the α-Syn-mediated autoimmune response occurs and whether it is related to neuronal cell death and glial cell activation. In this study, we investigated the autoimmune T-cell response induced by α-Syn peptides and evaluated the neurotoxic effect of the α-Syn peptide-mediated autoimmune response. The immunization of mice with α-Syn peptides resulted in enhanced autoimmune responses, such as the peptide recall response, polarization toward Th1/Th17 cells, and regulatory T cell imbalance. Furthermore, the α-Syn autoimmune response led to the death of primary neurons cocultured with splenocytes. Treatment with conditioned media from α-Syn peptide-immunized splenocytes induced microglia and toxic A1-type astrocyte activation. Taken together, our results provide evidence of the potential role of the α-Syn-initiated autoimmune response and its contribution to neuronal cell death and glial cell activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Programmed cell death is intricately linked to various physiological phenomena such as growth, development, and metabolism, as well as the proper function of the pancreatic β cell and the migration and invasion of trophoblast cells in the placenta during pregnancy. Traditional and recently identified programmed cell death include apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. In addition to cancer and degenerative diseases, abnormal activation of cell death has also been implicated in pregnancy related diseases like preeclampsia, gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, fetal growth restriction, and recurrent miscarriage. Excessive or insufficient cell death and pregnancy related diseases may be mutually determined, ultimately resulting in adverse pregnancy outcomes. In this review, we systematically describe the characteristics and mechanisms underlying several types of cell death and their roles in pregnancy related diseases. Moreover, we discuss potential therapeutic strategies that target cell death signaling pathways for pregnancy related diseases, hoping that more meaningful treatments will be applied in clinical practice in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Innate immunity is not only the first line of host defense against microbial infections but is also crucial for the host responses against a variety of noxious stimuli. Z-DNA binding protein 1 (ZBP1) is a cytosolic nucleic acid sensor that can induce inflammatory cell death in both immune and nonimmune cells upon sensing of incursive virus-derived Z-form nucleic acids and self-nucleic acids via its Zα domain. Mechanistically, aberrantly expressed or activated ZBP1 induced by pathogens or noxious stimuli enables recruitment of TANK binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 to drive type I interferon (IFN-I) responses and activation of nuclear factor kappa B (NF-κB) signaling. Meanwhile, ZBP1 promotes the assembly of ZBP1- and absent in melanoma 2 (AIM2)-PANoptosome, which ultimately triggers PANoptosis through caspase 3-mediated apoptosis, mixed lineage kinase domain like pseudokinase (MLKL)-mediated necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis. In response to damaged mitochondrial DNA, ZBP1 can interact with cyclic GMP-AMP synthase to augment IFN-I responses but inhibits toll like receptor 9-mediated inflammatory responses. This review summarizes the structure and expression pattern of ZBP1, discusses its roles in human diseases through immune-dependent (e.g., the production of IFN-I and pro-inflammatory cytokines) and -independent (e.g., the activation of cell death) functions, and highlights the attractive prospect of manipulating ZBP1 as a promising therapeutic target in diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Patulin (PAT) is the most common mycotoxin found in moldy fruits and their derived products, and is reported to cause diverse toxic effects, including hepatotoxicity, nephrotoxicity, cardiotoxicity, neurotoxicity, immunotoxicity, gastrointestinal toxicity and dermal toxicity. The cell death induction by PAT is suggested to be a key cellular mechanism involved in PAT-induced toxicities. Accumulating evidence indicates that the multiple forms of cell death are induced in response to PAT exposure, including apoptosis, autophagic cell death, pyroptosis and ferroptosis. Mechanistically, the cell death induction by PAT is associated the oxidative stress induction via reducing the antioxidant capacity or inducing pro-oxidant NADPH oxidase, the activation of mitochondrial pathway via regulating BCL-2 family proteins, the disruption of iron metabolism through ferritinophagy-mediated ferritin degradation, and the induction of the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome/caspase-1/gasdermin D (GSDMD) pathway. In this review article, we summarize the present understanding of the cell death induction by PAT, discuss the potential signaling pathways underlying PAT-induced cell death, and propose the issues that need to be addressed to promote the development of cell death-based approach to counteract PAT-induced toxicities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Gastrointestinal (GI) cancer is one of the most severe types of cancer, with a significant impact on human health worldwide. Due to the urgent demand for more effective therapeutic strategies against GI cancers, novel research on metal ions for treating GI cancers has attracted increasing attention. Currently, with accumulating research on the relationship between metal ions and cancer therapy, several metal ions have been discovered to induce cell death. In particular, the three novel modes of cell death, including ferroptosis, cuproptosis, and calcicoptosis, have become focal points of research in the field of cancer. Meanwhile, other metal ions have also been found to trigger cell death through various mechanisms. Accordingly, this review focuses on the mechanisms of metal ion-induced cell death in GI cancers, hoping to provide theoretical support for further GI cancer therapies., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest. All the authors agree to the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cell death is one of the most important mechanisms of maintaining homeostasis in our body. Ferroptosis and pyroptosis are forms of necrosis-like cell death. These cell death modalities play key roles in the pathophysiology of cancer, cardiovascular, neurological diseases, and other pathologies. Transition metals are abundant group of elements in all living organisms. This paper presents a summary of ferroptosis and pyroptosis pathways and their connection to significant transition metals, namely zinc (Zn), copper (Cu), molybdenum (Mo), lead (Pb), cobalt (Co), iron (Fe), cadmium (Cd), nickel (Ni), mercury (Hg), uranium (U), platinum (Pt), and one crucial element, selenium (Se). Authors aim to summarize the up-to-date knowledge of this topic. In this review, there are categorized and highlighted the most common patterns in the alterations of ferroptosis and pyroptosis by transition metals. Special attention is given to zinc since collected data support its dual nature of action in both ferroptosis and pyroptosis. All findings are presented together with a brief description of major biochemical pathways involving mentioned metals and are visualized in attached comprehensive figures. This work concludes that the majority of disruptions in the studied metals' homeostasis impacts cell fate, influencing both death and survival of cells in the complex system of altered pathways. Therefore, this summary opens up the space for further research. [ABSTRACT FROM AUTHOR]

The non-natriuretic-dependent glutamate/cystine inverse transporter-system Xc- is composed of two protein subunits, SLC7A11 and SLC3A2, with SLC7A11 serving as the primary functional component responsible for cystine uptake and glutathione biosynthesis. SLC7A11 is implicated in tumor development through its regulation of redox homeostasis, amino acid metabolism, modulation of immune function, and induction of programmed cell death, among other processes relevant to tumorigenesis. In this paper, we summarize the structure and biological functions of SLC7A11, and discuss its potential role in tumor therapy, which provides a new direction for precision and personalized treatment of tumors. [ABSTRACT FROM AUTHOR]

Due to their robust migration capabilities, slow degradation, and propensity for adsorbing environmental pollutants, micro(nano)plastics (MNPs) are pervasive across diverse ecosystems. They infiltrate various organisms within different food chains through multiple pathways including inhalation and dermal contact, and pose a significant environmental challenge in the 21st century. Research indicates that MNPs pose health threats to a broad range of organisms, including humans. Currently, extensive detection data and studies using experimental animals and in vitro cell culture indicate that MNPs can trigger various forms of programmed cell death (PCD) and can induce various diseases. This review provides a comprehensive and systematic analysis of different MNP-induced PCD processes, including pyroptosis, ferroptosis, autophagy, necroptosis, and apoptosis, based on recent research findings and focuses on elucidating the links between PCD and diseases. Additionally, targeted therapeutic interventions for these diseases are described. This review provides original insights into the opportunities and challenges posed by current research findings. This review evaluates ways to mitigate various diseases resulting from cell death patterns. Moreover, this paper enhances the understanding of the biohazards associated with MNPs by providing a systematic reference for subsequent toxicological research and health risk mitigation efforts. [ABSTRACT FROM AUTHOR]

Purpose: The vocal fold tissues undergo nearly continuous and repeated cycles of injury and repair throughout the course of an individual’s lifetime. It is well established that certain individuals are at greater risk of lesion development based on personality and behavioral classification. However, these characteristics alone do not wholly predict or explain lesion development or severity. In this review, we discuss current knowledge of mechanotransduction proteins and their potential relevance to tissue homeostasis in the vocal folds. Method: A review of literature surrounding mechanotransduction and tissue homeostasis as it relates to the vocal folds was conducted. Review of the literature included searches of PubMed, Google Scholar, and other various online peer-reviewed sources. Search terms pertained to mechanosensation, mechanotransduction, mechanically activated channels, mechanical cellular regulation, and other associated concepts and terms. Additional literature was identified through the reference lists of identified papers. Findings of this literature review were then applied to known physiology and pathophysiology of the vocal folds in order to speculate on the contribution of mechanically mediated mechanisms within the vocal fold. Discussion and Conclusion: Because the vocal folds are such mechanically active structures, withstanding nearly constant external forces, there is strong support for the idea that mechanically sensitive molecular pathways within the vocal fold tissue play a major role in tissue homeostasis in the presence of these considerable forces. As such, mechanotransduction within the vocal fold should be considered and targeted in future biological studies of vocal fold physiology. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PDL1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type). [ABSTRACT FROM AUTHOR]

Cuproptosis, a recently discovered form of cell death, stems from an overabundance of copper ions infiltrating mitochondria. These ions directly engage lipoylated proteins, prompting their oligomerization and subsequent loss of iron-sulfur clusters. This sequence induces proteotoxic stress, ultimately culminating in cell death. Type 2 diabetes, a chronic metabolic disorder resulting from a complex interplay of genetic and environmental factors, has not yet been fully understood in terms of its etiology and pathogenesis. Intricately, it is linked to various modalities of cell death, including mitochondrial autophagy, apoptosis, pyroptosis, and ferroptosis. Studies have discovered impaired copper metabolism in individuals with Type 2 diabetes, hinting at a unique role for copper homeostasis in the progression of the disease. To this end, the present research aims to delineate the potential correlation between cuproptosis and Type 2 diabetes by exhaustively reviewing the existing literature. By synthesizing relevant research on cuproptosis, the paper intends to lay the groundwork for a thorough exploration of the pathogenesis of Type 2 diabetes and the development of targeted therapeutic interventions. The ultimate objective is to facilitate a deeper understanding of Type 2 diabetes and to identify novel therapeutic strategies associated with cuproptosis. [ABSTRACT FROM AUTHOR]

Background: Currently, no evidence exists on the expression of apoptosis (CASP3), autophagy (BECN1), and mitophagy (BNIP3) genes in the CA3 area after ischemia with long-term survival. Objective: The goal of the paper was to study changes in above genes expression in CA3 area after ischemia in the period of 6–24 months. Methods: In this study, using quantitative RT-PCR, we present the expression of genes associated with neuronal death in a rat ischemic model of Alzheimer's disease. Results: First time, we demonstrated overexpression of the CASP3 gene in CA3 area after ischemia with survival ranging from 0.5 to 2 years. Overexpression of the CASP3 gene was accompanied by a decrease in the activity level of the BECN1 and BNIP3 genes over a period of 0.5 year. Then, during 1-2 years, BNIP3 gene expression increased significantly and coincided with an increase in CASP3 gene expression. However, BECN1 gene expression was variable, increased significantly at 1 and 2 years and was below control values 1.5 years post-ischemia. Conclusions: Our observations suggest that ischemia with long-term survival induces neuronal death in CA3 through activation of caspase 3 in cooperation with the pro-apoptotic gene BNIP3. This study also suggests that the BNIP3 gene regulates caspase-independent pyramidal neuronal death post-ischemia. Thus, caspase-dependent and -independent death of neuronal cells occur post-ischemia in the CA3 area. Our data suggest new role of the BNIP3 gene in the regulation of post-ischemic neuronal death in CA3. This suggests the involvement of the BNIP3 together with the CASP3 in the CA3 in neuronal death post-ischemia. [ABSTRACT FROM AUTHOR]

Osteoporosis represents a systemic imbalance in bone metabolism, augmenting the susceptibility to fractures among patients and emerging as a notable mortality determinant in the elderly population. It has evolved into a worldwide concern impacting the physical well-being of the elderly, imposing a substantial burden on both human society and the economy. Presently, the precise pathogenesis of osteoporosis remains inadequately characterized and necessitates further exploration. The advancement of osteoporosis is typically linked to the initiation of an inflammatory response. Cells in an inflammatory environment can cause inflammatory death including pyroptosis. Pyroptosis is a recently identified form of programmed cell death with inflammatory properties, mediated by the caspase and gasdermin families. It is regarded as the most inflammatory form of cell death in contemporary medical research. Under the influence of diverse cytokines, macrophages, and other immune cells may undergo pyroptosis, releasing inflammatory factors, such as IL-1β and IL-18. Numerous lines of evidence highlight the pivotal role of pyroptosis in the pathogenesis of inflammatory diseases, including cancer, intestinal disorders, hepatic conditions, and cutaneous ailments. Osteoporosis progression is frequently associated with inflammation; hence, pyroptosis may also play a role in the pathogenesis of osteoporosis to a certain extent, making it a potential target for treatment. This paper has provided a comprehensive summary of pertinent research concerning pyroptosis and its impact on osteoporosis. The notion proposing that pyroptosis mediates osteoporosis via the inflammatory immune microenvironment is advanced, and we subsequently investigate potential targets for treating osteoporosis through the modulation of pyroptosis. [ABSTRACT FROM AUTHOR]

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examines how statins, which are drugs commonly used to lower cholesterol, affect the growth of liver cancer cells. Statins can be either lipophilic (lipid-soluble) or hydrophilic (water-soluble), and this characteristic influences how they enter cells. In our research, we compared the effects of lipophilic simvastatin and hydrophilic pravastatin. We found that simvastatin significantly reduces cancer cell growth and increases cell death depending on the dosage and duration of treatment. In contrast, pravastatin, due to its limited uptake, has a minimal impact on cancer cells. These findings suggest that the type of statin used could be crucial in cancer treatment, potentially offering better outcomes for patients with liver cancer. The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Modelling of Cell Killing Due to Sparsely Ionizing Radiation in Normoxic and Hypoxic Conditions and an Extension to High LET Radiation" by A. Mairani and colleagues in a 2013 issue.

Introduction: Necroptosis is an alternative, caspase-independent programmed cell death that appears when apoptosis is inhibited. A gowing number of studies have reflected the link between necroptosis and tumors. However, only some systematical bibliometric analyses were focused on this field. In this study, we aimed to identify and visualize the cooperation between countries, institutions, authors, and journals through a bibliometric analysis to help understand the hotspot trends and emerging topics regarding necroptosis and cancer research. Methods: The articles and reviews on necroptosis and cancer were obtained from the Web of Science Core Collection on 16 September 2022. Countries, institutions, authors, references, and keywords in this field were visually analyzed by CtieSpace 5.8.R3, VOSviewer 1.6.18, and R package "bibliometrix." Results: From 2006 to 2022, 2,216 qualified original articles and reviews on necroptosis in tumors were published in 685 academic journals by 13,009 authors in 789 institutions from 75 countries/regions. Publications focusing on necroptosis and cancer have increased violently in the past 16 years, while the citation number peaked around 2008-2011. Most publications were from China, while the United States maintained the dominant position as a "knowledge bridge" in necroptosis and cancer research; meanwhile, Ghent University and the Chinese Academy of Sciences were the most productive institutions. Moreover, only a tiny portion of the articles were multiplecountry publications. Peter Vandenabeele had the most significant publications, while Alexei Degterev was most often co-cited. Peter Vandenabeele also gets the highest h-index and g-index in this research field. Cell Death and Disease was the journal with the most publications on necroptosis and cancer, which was confirmed to be the top core source by Bradford's Law. At the same time, Cell was the leading co-cited journal, and the focus area of these papers was molecular, biology, and immunology. High-frequency keywords mainly contained those that are molecularly related (MLKL, NF-kB, TNF, RIPK3, RIPK1), pathological process related (necroptosis, apoptosis, cell-death, necrosis, autophagy), and mechanism related (activation, expression, mechanisms, and inhibition). Conclusion: This study comprehensively overviews necroptosis and cancer research using bibliometric and visual methods. Research related to necroptosis and cancer is flourishing. Cooperation and communication between countries and institutions must be further strengthened. The information in our paper would provide valuable references for scholars focusing on necroptosis and cancer. [ABSTRACT FROM AUTHOR]