Regulated cell death joins in atherosclerotic plaque silent progression

Non-apoptotic regulated cell death (ferroptosis and necroptosis) leads to the release of damage-associated molecular patterns (DAMPs), which initiate and perpetuate a non-infectious inflammatory response. We hypothesize that DAMPs and non-apoptotic regulated cell death are critical players of atherosclerotic plaque progression with inadequate response to lipid-lowering treatment. We aimed to uncover the silent mechanisms that govern the existing residual risk of cardiovascular-related mortality in experimental atherosclerosis. Proteomic and genomic approaches were applied on the ascending aorta of hyperlipidemic rabbits and controls with and without lipid-lowering treatment. The hyperlipidemic animals, which presented numerous heterogeneous atherosclerotic lesions, exhibited high concentrations of serum lipids and increased lipid peroxidation oxidative stress markers. The analyses revealed the significant upregulation of DAMPs and proteins implicated in ferroptosis and necroptosis by hyperlipidemia. Some of them did not respond to lipid-lowering treatment. Dysregulation of five proteins involved in non-apoptotic regulated cell death proteins (VDAC1, VDAC3, FTL, TF and PCBP1) and nine associated DAMPs (HSP90AA1, HSP90AB1, ANXA1, LGALS3, HSP90B1, S100A11, FN, CALR, H3-3A) was not corrected by the treatment. These proteins could play a key role in the atherosclerotic silent evolution and may possess an unexplored therapeutic potential. Mass spectrometry data are available via ProteomeXchange with identifier PXD026379.publishedVersio

Impact of ethanol on regulated cell death Crithidia Fasciculata

Given the early divergence of trypanosomatids in evolution and absence of genes central to “classical” cell death pathways, induction, and mechanisms of regulated cell death in these species will shed light on origin of these processes. The early divergence of eukaryotic cells can be observed with the Trypanosomatids taxa (Green, 2015) Crithidia fasciculata is a trypanosomatid, mosquito parasite. We explored sensitivity of Crithidia to ethanol (≤20%) on cell death and externalization of phosphatidylserine (PS) using propidium iodide (PI) and annexin V-FITC (AV). While 20% ethanol killed cells necrotically (PI+ /AV+), 9% ethanol resulted elicited nonlethal, PS externalization in a subset (2%) of the population (PI- /AV+). To elucidate the mechanism of this cell death-like phenotype, alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH) were inhibited. I hypothesized inhibition of (ALDH) with disulfiram will increase proportion of stressed, alive cells (PI-/AV+) because of (ALDH) is used to process acetaldehyde with the enzyme (ALDH) that produces acetate that is used in many metabolic processes. While disulfiram yielded an increase in this subset of cells, effects of inhibition were ethanol independent. In contrast, the (ADH) inhibitor 4- methyl pyrazole caused necrosis. The different patterns of cellular death can be observed by the different staining. These results suggest cell death pathways are sensitive to fermentation products produced by trypanosomatids and that early evolution of “classical,” cell death pathways could have been driven by responses to sublethal stress

Artemisinin-Type Drugs in Tumor Cell Death:Mechanisms, Combination Treatment with Biologics and Nanoparticle Delivery

Artemisinin, the most famous anti-malaria drug initially extracted from Artemisia annua L., also exhibits anti-tumor properties in vivo and in vitro. To improve its solubility and bioavailability, multiple derivatives have been synthesized. However, to reveal the anti-tumor mechanism and improve the efficacy of these artemisinin-type drugs, studies have been conducted in recent years. In this review, we first provide an overview of the effect of artemisinin-type drugs on the regulated cell death pathways, which may uncover novel therapeutic approaches. Then, to overcome the shortcomings of artemisinin-type drugs, we summarize the recent advances in two different therapeutic approaches, namely the combination therapy with biologics influencing regulated cell death, and the use of nanocarriers as drug delivery systems. For the former approach, we discuss the superiority of combination treatments compared to monotherapy in tumor cells based on their effects on regulated cell death. For the latter approach, we give a systematic overview of nanocarrier design principles used to deliver artemisinin-type drugs, including inorganic-based nanoparticles, liposomes, micelles, polymer-based nanoparticles, carbon-based nanoparticles, nanostructured lipid carriers and niosomes. Both approaches have yielded promising findings in vitro and in vivo, providing a strong scientific basis for further study and upcoming clinical trials

Ferroptosis Holds Novel Promise in Treatment of Cancer Mediated by Non-coding RNAs

Ferroptosis is a newly identified form of regulated cell death that is associated with iron metabolism and oxidative stress. As a physiological mechanism, ferroptosis selectively removes cancer cells by regulating the expression of vital chemical molecules. Current findings on regulation of ferroptosis have largely focused on the function of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), in mediating ferroptotic cell death, while the sponging effect of circular RNAs (circRNAs) has not been widely studied. In this review, we discuss the molecular regulation of ferroptosis and highlight the value of circRNAs in controlling ferroptosis and carcinogenesis. Herein, we deliberate future role of this emerging form of regulated cell death in cancer therapeutics and predict the progression and prognosis of oncogenesis in future clinical therapy.publishedVersio

Transcriptional networks orchestrating programmed cell death during plant development

Transcriptional gene regulation is a fundamental biological principle in the development of eukaryotes. It does control not only cell proliferation, specification, and differentiation, but also cell death processes as an integral feature of an organism's developmental program. As in animals, developmentally regulated cell death in plants occurs in numerous contexts and is of vital importance for plant vegetative and reproductive development. In comparison with the information available on the molecular regulation of programmed cell death (PCD) in animals, however, our knowledge on plant PCD still remains scarce. Here, we discuss the functions of different classes of transcription factors that have been implicated in the control of developmentally regulated cell death. Though doubtlessly representing but a first layer of PCD regulation, information on PCD-regulating transcription factors and their targets represents a promising strategy to understand the complex machinery that ensures the precise and failsafe execution of PCD processes in plant development

Bcl-2-regulated cell death signalling in the prevention of autoimmunity

Cell death mediated through the intrinsic, Bcl-2-regulated mitochondrial apoptosis signalling pathway is critical for lymphocyte development and the establishment of central and maintenance of peripheral tolerance. Defects in Bcl-2-regulated cell death signalling have been reported to cause or correlate with autoimmunity in mice and men. This review focuses on the role of Bcl-2 family proteins implicated in the development of autoimmune disorders and their potential as targets for therapeutic intervention

Emerging opportunities to target gene transcription and DNA repair in drug discovery

After the completion of the Human Genome Project, biological research in the post-genomic era has focused on interpreting the biological functions of genes and their products. This includes investigating the regulation of DNA transcription as well as DNA replication and damage repair. These aspects are intricately connected to regulated cell death and diseases associated with it, such as drug-resistant cancers and neurodegenerative diseases. The discovery of novel DNA processing mechanisms that modulate cell death, whether by inducing or inhibiting it, could unveil promising therapeutic strategies for treating diseases related to cell death. DNA processing has several aspects, including DNA transcription, DNA replication, and DNA damage repair. This thesis mainly focuses on the modulation of DNA transcription by histone lysine acetylation and on DNA damage repair mechanisms. The aim of this thesis is to elucidate the regulatory mechanisms of DNA processing involved in regulated cell death and their role in disease pathogenesis, meanwhile developing novel small molecular entities to treat cell-death-related diseases based on the mechanisms identified in this thesis

Regulation of cell death induced by acetic acid in yeasts

Acetic acid has long been considered a molecule of great interest in the yeast research field. It is mostly recognized as a by-product of alcoholic fermentation or as a product of the metabolism of acetic and lactic acid bacteria, as well as of lignocellulosic biomass pretreatment. High acetic acid levels are commonly associated with arrested fermentations or with utilization as vinegar in the food industry. Due to its obvious interest to industrial processes, research on the mechanisms underlying the impact of acetic acid in yeast cells has been increasing. In the past twenty years, a plethora of studies have addressed the intricate cascade of molecular events involved in cell death induced by acetic acid, which is now considered a model in the yeast regulated cell death field. As such, understanding how acetic acid modulates cellular functions brought about important knowledge on modulable targets not only in biotechnology but also in biomedicine. Here, we performed a comprehensive literature review to compile information from published studies performed with lethal concentrations of acetic acid, which shed light on regulated cell death mechanisms. We present an historical retrospective of research on this topic, first providing an overview of the cell death process induced by acetic acid, including functional and structural alterations, followed by an in-depth description of its pharmacological and genetic regulation. As the mechanistic understanding of regulated cell death is crucial both to design improved biomedical strategies and to develop more robust and resilient yeast strains for industrial applications, acetic acid-induced cell death remains a fruitful and open field of study. © 2021 Chaves, Rego, Martins, Santos-Pereira, Sousa and Côrte-Real.This work was supported by the "Contrato-Programa" UIDB/04050/2020 funded by national funds through the FCT I.P.info:eu-repo/semantics/publishedVersio