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As a significant biomarker during the apoptosis process, cytochrome c (Cyt c) is considered as a critical component in the inherent apoptotic pathway, but the simple and portable detection still remains challengeable. In this work, a portable and visual sensing platform for Cyt c was developed based upon the fluorescence quenching of graphene quantum dots (GQDs), which could be finished within a few seconds. Herein, the absorption spectrum of Cyt c matched the emission spectrum of GQDs well, which could cause the fluorescence quenching of GQDs via the inner filter effect (IFE) in the range of 1–50 μg/mL with the limit of detection as low as 0.1 μg/mL. Furthermore, the intracellular Cyt c was imaged to observe the apoptosis process of cancer cells induced by staurosporine. To achieve the portable and visual detection of Cyt c, GQDs were deposited on the filter paper to form the solid platform, which displayed a gradual fluorescence quenching when different concentrations of Cyt c were present. Compared to the conventional methods, the proposed assay is low-cost, fast, portable, and visual, which will be useful for the investigation of mitochondrial dysfunction and apoptotic cell death. [ABSTRACT FROM AUTHOR]

The concomitant activation of both the YAP1 co-transcription factor and RAS GTPases is a hallmark of several aggressive cancers, though the intricacies of their relationship and implications for oncogenesis are still poorly understood. This review has presented a cooperative model where YAP1 and RAS are not independently acting oncogenes but rather interdependently acting ones, with each fulfilling an essential role within the oncogenic process. YAP1 is responsible for initiating the expression of key proteins that contribute to various cancer traits. However, these proteins must often be transported into the cytoplasm to exert their effects. We suggest that oncogenic RAS actually facilitates this transport, enabling the phosphorylation and subsequent activation of the nuclear transporter XPO1 (aka Exportin1). This mechanism is particularly crucial for anti-apoptotic proteins. Instead of being sequestered within the nucleus in an ineffective state, these proteins are rather shuttled into the cytoplasm. Within the cytoplasm, they can effectively inhibit apoptosis, undermining by these means the efficacy of chemotherapeutic agents designed to induce cell death in cancer cells. Therefore, a clearer understanding of the oncogenic partnership between RAS and YAP1 will likely provide new insights into the molecular underpinnings of cancer and highlight as well potential targets for therapeutic interventions designed to disrupt this pernicious interaction. I. YAP1 triggers expression of its target genes, some of which encode cargoes with a nuclear export signal. In response to physiological signals, some cargoes are shuttled into the cytoplasm. Exportin1 serves as the transfer vehicle from the nucleus into the cytoplasm (not shown). For functional nuclear proteins, this shuttling terminates their function, whereas for cytoplasmic proteins, it does initiate their function. In this drawing, the topology within the nucleus is not depicted. II. Oncogenic RAS leads to Exportin1 activation and subsequent unwarranted nuclear-cytoplasmic shuttling of cargoes [17, 35]. The cascade from RAS to Exportin1 is not depicted for the sake of clarity. Some of the cargoes are oncoproteins, cytoplasmic GTPases regulators, or antiapoptotic proteins (example shown: BIRC5 aka Survivin). These latter proteins are now empowered to hinder apoptosis, as expected upon anti-cancer therapies. Of course, the BIRC5 is not the only aberrantly shuttled protein. Another example is Beclin1 (BECN1), which is subjected to the same fate; once in the cytoplasm, it does initiate autophagy in the absence of any autophagic clue [35]. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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.

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]

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]

The Ribosomal S6 Kinase (RSK) family of serine/threonine kinases function as key downstream effectors of the MAPK signaling cascade. In the nervous system, RSK signaling plays crucial roles in neuronal development and contributes to activity-dependent neuronal plasticity. This study examined the role of RSK signaling in cell viability during neuronal development and in neuroprotection in the mature nervous system. Using neuronal cell-culture-based profiling, we found that suppressing RSK signaling led to significant cell death in developing primary neuronal cultures. To this end, treatment with the RSK inhibitors BiD1870 or SL0101 on the first day of culturing resulted in over 80% cell death. In contrast, more mature cultures showed attenuated cell death upon RSK inhibition. Inhibition of RSK signaling during early neuronal development also disrupted neurite outgrowth and cell growth. In maturing hippocampal explant cultures, treatment with BiD1870 had minimal effects on cell viability, but led to a striking augmentation of NMDA-induced cell death. Finally, we used the endothelin 1 (ET-1) model of ischemia to examine the neuroprotective effects of RSK signaling in the mature hippocampus in vivo. Notably, in the absence of RSK inhibition, the granule cell layer (GCL) was resistant to the effects of ET-1; However, disruption of RSK signaling (via the microinjection of BiD1870) prior to ET-1 injection triggered cell death within the GCL, thus indicating a neuroprotective role for RSK signaling in the mature nervous system. Together these data reveal distinct, developmentally-defined, roles for RSK signaling in the nervous system., 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 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer lacks estrogen, progesterone, and HER2 receptors and hence, is therapeutically challenging. Towards this, we studied an alternate therapy by repurposing metformin (FDA-approved type-2 diabetic drug with anticancer properties) in a 3D-scaffold culture, with electrical pulses. 3D cell culture was used to simulate the tumor microenvironment more closely and MDA-MB-231, human TNBC cells, treated with both 5 mM metformin (Met) and 8 electrical pulses at 2500 V/cm, 10 µs (EP1) and 800 V/cm, 100 µs (EP2) at 1 Hz were studied in 3D and 2D. They were characterized using cell viability, reactive oxygen species (ROS), glucose uptake, and lactate production assays at 24 h. Cell viability, as low as 20 % was obtained with EP1 + 5 mM Met. They exhibited 1.65-fold lower cell viability than 2D with EP1 + 5 mM Met. ROS levels indicated a 2-fold increase in oxidative stress for EP1 + 5 mM Met, while the glucose uptake was limited to only 9 %. No significant change in the lactate production indicated glycolytic arrest and a non-conducive environment for MDA-MB-231 growth. Our results indicate that 3D cell culture, with a more realistic tumor environment that enhances cell death using metformin and electrical pulses could be a promising approach for TNBC therapeutic intervention studies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Dettin, A. Zamuner, E. Sieni, F. Dughiero has patent # “IN VITRO MODELS FOR ELECTROPORATION”, application for PCT PCT/EP2019/070209 27 07.2017 concessione 26 07.2019 licensed to Licensee. M. Dettin, A. Zamuner, E. Sieni, F. Dughiero has patent #“Modelli in vitro per l’elettroporazione”, patent number 102018000007589, 27.07.20 licensed to Licensee. any If there are other authors, they 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration, destruction, and excessive ossification of articular cartilage. The prevalence of OA is rising annually, concomitant with the aging global population and increasing rates of obesity. This condition imposes a substantial and escalating burden on individual health, healthcare systems, and broader social and economic frameworks. The etiology of OA is multifaceted and not fully understood. Current research suggests that the death of chondrocytes, encompassing mechanisms such as cellular apoptosis, pyroptosis, autophagy, ferroptosis and cuproptosis, contributes to both the initiation and progression of the disease. These cell death pathways not only diminish the population of chondrocytes but also exacerbate joint damage through the induction of inflammation and other deleterious processes. This paper delineates the morphological characteristics associated with various modes of cell death and summarizes current research results on the molecular mechanisms of different cell death patterns in OA. The objective is to review the advancements in understanding chondrocyte cell death in OA, thereby offering novel insights for potential clinical interventions., (© 2024. The Author(s).)

Lead (Pb) is harmful to almost all organs, particularly the developmental neural system, and previous studies revealed oxidative stress played an important role in Pb neurotoxicity. Rutin, a type of flavonoid glycoside found in various plants and fruits, is widely used as a dietary supplement due to its antioxidant and anti-inflammatory properties, but whether rutin could protect against Pb neurotoxicity is unclear. In this study, we found rutin treatment significantly alleviated Pb-induced cell death, oxidative stress, and inflammation, resulting in cell survival. Moreover, rutin treatment promoted nuclear factor erythroid 2-related factor 2 (Nrf2) translocation from cytoplasm to nucleus and subsequently activated antioxidant and detoxifying enzymes expression including HO-1. Knocking down Nrf2 by siRNA transfection abolished this protection of rutin against Pb. Overall, rutin could alleviate Pb-induced oxidative stress, inflammation, and cell death by activating the Nrf2/antioxidant response elements (ARE) system., 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.)

Plants have developed intricate immune mechanisms to impede Phytophthora colonization. In response, Phytophthora secretes RxLR effector proteins that disrupt plant defense and promote infection. The specific molecular interactions through which Phytophthora RxLR effectors undermine plant immunity, however, remain inadequately defined. In this study, we delineate the role of the nuclear-localized RxLR effector PcAvh87, which is pivotal for the full virulence of Phytophthora cinnamomi. Gene expression analysis indicates that PcAvh87 expression is significantly upregulated during the initial infection stages, interacting with the immune responses triggered by the elicitin protein INF1 and pro-apoptotic protein BAX. Utilizing PEG/CaCl 2 -mediated protoplast transformation and CRISPR/Cas9-mediated gene editing, we generated PcAvh87 knockout mutants, which demonstrated compromised hyphal growth, sporangium development, and zoospore release, along with a marked reduction in pathogenicity. This underscores PcAvh87's crucial role as a virulence determinant. Notably, PcAvh87, conserved across the Phytophthora genus, was found to modulate the activity of plant immune protein 113, thereby attenuating plant immune responses. This implies that the PcAvh87-mediated regulatory mechanism could be a common strategy in Phytophthora species to manipulate plant immunity. Our findings highlight the multifaceted roles of PcAvh87 in promoting P. cinnamomi infection, including its involvement in sporangia production, mycelial growth, and the targeting of plant immune proteins to enhance pathogen virulence., 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 GmbH.. All rights reserved.)

GABA modulators such as phenobarbital (PB) and sodium channel blockers such as phenytoin (PHT) have long been the mainstay of pharmacotherapy for the epilepsies. In the context of neonatal seizures, both PB and PHT display incomplete clinical efficacy. Moreover, in animal models, neonatal exposure to these medications result in neurodegeneration raising concerns about safety. Cenobamate, a more recently approved medication, displays unique pharmacology as it is both a positive allosteric modulator of GABA-A receptors, and a voltage-gated sodium channel blocker. While cenobamate is approved for adult use, its efficacy and safety profile against neonatal seizures is poorly understood. To address this gap, we assessed the efficacy and safety of cenobamate in immature rodents. Postnatal day (P)7 rat pups were pretreated with cenobamate and challenged with the chemoconvulsant pentylenetetrazole (PTZ) to screen for anti-seizure effects. In a separate experiment, P7 rats were treated with cenobamate, and brains were processed to assess induction of cell death. Cenobamate displays dose-dependent anti-seizure efficacy in neonatal rats. Unlike PHB and PHT, it does not induce neurotoxicity in P7 rats. Thus, cenobamate may be effective at treating neonatal seizures while avoiding unwanted neurotoxic side effects such as 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 Inc. All rights reserved.)

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.)

Hypoxia can regulate oxygen-sensitive pathways that could be neuroprotective to compensate for the detrimental effects of low oxygen. However, prolonged hypoxia can activate neurodegenerative pathways. HIF-1α is upregulated/stabilized in hypoxic conditions, promoting alteration of gene expression, and ultimately leading to cell-death. Therefore, regulation of HIF-1α expression pharmacologically is a vital approach to mitigate cell death. In this review, we provide information showing the role of HIF-1α and its associated pathways in ocular retinopathies. We also discuss the beneficial roles of HIF-1α inhibitor, KC7F2, in ocular pathologies. Finally, we provided our own data demonstrating RGC neuroprotection by KC7F2 in glaucomatous animals., 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.)

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.)

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]

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.)

Epilepsy, a complex neurological disorder, is characterized by recurrent seizures caused by aberrant electrical activity in the brain. Central to this study is the role of lysosomal dysfunction in epilepsy, which can lead to the accumulation of toxic substrates and impaired autophagy in neurons. Our focus is on phosphodiesterase-4 (PDE4), an enzyme that plays a crucial role in regulating intracellular cyclic adenosine monophosphate (cAMP) levels by converting it into adenosine monophosphate (AMP). In pathological states, including epilepsy, increased PDE4 activity contributes to a decrease in cAMP levels, which may exacerbate neuroinflammatory responses. We hypothesized that amlexanox, an anti-inflammatory drug and non-selective PDE4 inhibitor, could offer neuroprotection by addressing lysosomal dysfunction and mitigating neuroinflammation, ultimately preventing neuronal death in epileptic conditions. Our research utilized a pilocarpine-induced epilepsy animal model to investigate amlexanox's potential benefits. Administered intraperitoneally at a dose of 100 ​mg/kg daily following the onset of a seizure, we monitored its effects on lysosomal function, inflammation, neuronal death, and cognitive performance in the brain. Tissue samples from various brain regions were collected at predetermined intervals for a comprehensive analysis. The study's results were significant. Amlexanox effectively improved lysosomal function, which we attribute to the modulation of zinc's influx into the lysosomes, subsequently enhancing autophagic processes and decreasing the release of inflammatory factors. Notably, this led to the attenuation of neuronal death in the hippocampal region. Additionally, cognitive function, assessed through the modified neurological severity score (mNSS) and the Barnes maze test, showed substantial improvements after treatment with amlexanox. These promising outcomes indicate that amlexanox has potential as a therapeutic agent in the treatment of epilepsy and related brain disorders. Its ability to combat lysosomal dysfunction and neuroinflammation positions it as a potential neuroprotective intervention. While these findings are encouraging, further research and clinical trials are essential to fully explore and validate the therapeutic efficacy of amlexanox in epilepsy management., 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 Author(s). Published by Elsevier Inc. 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.)

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.)

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.)

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.)

Simple Summary: Ferroptosis is a regulated form of cell death driven by iron and lipid peroxidation, showing great potential in cancer therapy, particularly for tumors that resist conventional treatments. In our review, we focus on the role of inorganic nanoparticles in inducing ferroptosis and how this can be combined with therapies such as chemotherapy, radiotherapy, immunotherapy, and phototherapy. These nanoparticles not only trigger ferroptosis to kill cancer cells but also enhance the body's immune system response against tumors. The review discusses significant progress in using nanomedicine to promote ferroptosis and highlights its potential to improve treatment outcomes. Additionally, we explore the metabolic processes involved, particularly how interactions between iron, lipid, and redox pathways regulate ferroptosis in tumor cells. Understanding these mechanisms is crucial for developing more effective cancer treatments. As research in this field advances, the opportunity to move ferroptosis-based therapies from the lab to clinical practice increases. This combination of ferroptosis with inorganic nanomedicine offers a promising strategy for creating more targeted and powerful cancer therapies, ultimately improving patient survival and expanding treatment possibilities. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has generated substantial interest in cancer therapy. Various methods have been developed to induce ferroptosis in tumor cells, including approved drugs, experimental compounds, and nanomedicine formulations. Unlike apoptosis, ferroptosis presents unique molecular and cellular features, representing a promising approach for cancers resistant to conventional treatments. Recent research indicates a strong link between ferroptosis and the tumor immune microenvironment, suggesting the potential of ferroptosis to trigger robust antitumor immune responses. Multiple cellular metabolic pathways control ferroptosis, including iron, lipid, and redox metabolism. Thus, understanding the interaction between tumor metabolism and ferroptosis is crucial for developing effective anticancer therapies. This review provides an in-depth discussion on combining inorganic nanoparticles with cancer therapies such as phototherapy, chemotherapy, radiotherapy, and immunotherapy, and the role of ferroptosis in these combination treatments. Furthermore, this paper explores the future of tumor treatment using nanomedicine, focusing on how inorganic nanoparticles can enhance ferroptosis in tumor cells and boost antitumor immunity. The goal is to advance ferroptosis-based nanomedicine from the laboratory to clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment options for patients with advanced renal cancer are limited, as one of the main methods, chemotherapy, is prone to drug resistance in the course of treatment. There have been numerous studies confirming that ferroptosis is involved in the development of renal cancer and drug resistance during treatment. In this review, we provide new insights into the resistance of classical chemotherapy drugs sorafenib and sunitinib in renal cancer and explore the mechanism of different types of ferroptosis-related drugs to treat renal cancer, such as herb extract medicine, ferroptosis inducers, natural compounds, nanomaterials, etc. We have also conducted an in-depth discussion on the application of ferroptosis-related drugs in the clinical treatment of renal cancer. Renal cancer is a common and serious malignant tumor of the urinary system. While surgery effectively treats early-stage renal cancer, advanced cases pose a significant challenge due to poor treatment outcomes and chemotherapy resistance. Therefore, there is an urgent need to develop alternative therapeutic strategies. Ferroptosis is a newly defined form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, which plays a critical role in tumor progression and drug resistance. Recent studies have shown that ferroptosis is involved in the occurrence and development of renal cancer, and ferroptosis-related genes can induce cell apoptosis and can be used as potential biomarkers for early diagnosis of renal cancer and participate in drug resistance of renal cancer chemotherapy. With the continuous improvement of the mechanism of ferroptosis, drugs targeting ferroptosis for the treatment of renal cancer are emerging in an endless stream. Based on the theoretical basis of the occurrence of ferroptosis, this paper reviewed drug-induced ferroptosis in renal cancer cells from the aspects of herbal medicine, natural compounds, drug resistance mechanisms, and nanomaterials, and delves into the clinical application potential of ferroptosis-related drugs in the treatment of renal cancer. [ABSTRACT FROM AUTHOR]

Recovery after visual loss is a key goal of neuroscience and treatments able to improve visual function are still largely lacking. Glaucoma, one of the leading causes of visual disability in the world, is usually associated with elevated intraocular pressure (IOP), but a subset of "normal tension glaucoma" patients develop damage without ever manifesting high IOP. Sometimes, even in patients with good control of IOP, retinal ganglion cell degeneration can progress to forward blindness. Moreover, usually the damage already caused by the disease remains. These considerations underline the need to find new, effective treatments and solutions to add to the standard ones. In this paper, we expose the most important data supporting the use of alternating current stimulation, including the theoretical bases of this approach, in glaucoma. [ABSTRACT FROM AUTHOR]

Synthetic lethality (SL) has shown great promise for the discovery of novel targets in cancer. CRISPR double-knockout (CDKO) technologies can only screen several hundred genes and their combinations, but not genome-wide. Therefore, good SL prediction models are highly needed for genes and gene pairs selection in CDKO experiments. However, lack of scalable SL properties prevents generalizability of SL interactions to out-of-sample data, thereby hindering modeling efforts. In this paper, we recognize that SL connectivity is a scalable and generalizable SL property. We develop a novel two-step multilayer encoder for individual sample-specific SL prediction model (MLEC-iSL), which predicts SL connectivity first and SL interactions subsequently. MLEC-iSL has three encoders, namely, gene, graph, and transformer encoders. MLEC-iSL achieves high SL prediction performance in K562 (AUPR, 0.73; AUC, 0.72) and Jurkat (AUPR, 0.73; AUC, 0.71) cells, while no existing methods exceed 0.62 AUPR and AUC. The prediction performance of MLEC-iSL is validated in a CDKO experiment in 22Rv1 cells, yielding a 46.8% SL rate among 987 selected gene pairs. The screen also reveals SL dependency between apoptosis and mitosis cell death pathways. [ABSTRACT FROM AUTHOR]

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]