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1.
Int J Mol Sci ; 24(24)2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38139118

RESUMO

The hematological effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important in COVID-19 pathophysiology. However, the interactions of SARS-CoV-2 with platelets and red blood cells are still poorly understood. There are conflicting data regarding the mechanisms and significance of these interactions. The aim of this review is to put together available data and discuss hypotheses, the known and suspected effects of the virus on these blood cells, their pathophysiological and diagnostic significance, and the potential role of platelets and red blood cells in the virus's transport, propagation, and clearance by the immune system. We pay particular attention to the mutual activation of platelets, the immune system, the endothelium, and blood coagulation and how this changes with the evolution of SARS-CoV-2. There is now convincing evidence that platelets, along with platelet and erythroid precursors (but not mature erythrocytes), are frequently infected by SARS-CoV-2 and functionally changed. The mechanisms of infection of these cells and their role are not yet entirely clear. Still, the changes in platelets and red blood cells in COVID-19 are significantly associated with disease severity and are likely to have prognostic and pathophysiological significance in the development of thrombotic and pulmonary complications.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Plaquetas , Coagulação Sanguínea , Eritrócitos
2.
Int J Mol Sci ; 23(7)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35409093

RESUMO

Mitotic catastrophe is a defensive mechanism that promotes elimination of cells with aberrant mitosis by triggering the cell-death pathways and/or cellular senescence. Nowadays, it is known that apoptosis, autophagic cell death, and necrosis could be consequences of mitotic catastrophe. Here, we demonstrate the ability of a DNA-damaging agent, doxorubicin, at 600 nM concentration to stimulate mitotic catastrophe. We observe that the inhibition of caspase activity leads to accumulation of cells with mitotic catastrophe hallmarks in which RIP1-dependent necroptotic cell death is triggered. The suppression of autophagy by a chemical inhibitor or ATG13 knockout upregulates RIP1 phosphorylation and promotes necroptotic cell death. Thus, in certain conditions mitotic catastrophe, in addition to apoptosis and autophagy, can precede necroptosis.


Assuntos
Mitose , Necroptose , Apoptose/fisiologia , Morte Celular , Humanos , Necrose
3.
Biochim Biophys Acta Gen Subj ; 1862(3): 557-566, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29203282

RESUMO

BACKGROUND: The development of approaches that increase therapeutic effects of anti-cancer drugs is one of the most important tasks of oncology. Caloric restriction in vivo or serum deprivation (SD) in vitro has been shown to be an effective tool for sensitizing cancer cells to chemotherapeutic drugs. However, the detailed mechanisms underlying the enhancement of apoptosis in cancer cells by SD remain to be elucidated. METHODS: Flow cytometry, caspase activity assay and western blotting were used for cell death rate evaluation. Western blotting, gel-filtration, siRNA approach and qRT-PCR were used to elucidate the mechanism underlying cell death potentiation upon SD. RESULTS: We demonstrated that SD sensitizes cancer cells to treatment with chemotherapeutic agent cisplatin. This effect is independent on activation of caspases-2 and -8, apical caspases triggering apoptosis in response to genotoxic stress. SD potentiates cell death via downregulation of the anti-apoptotic protein Mcl-1. In fact, SD reduces the Mcl-1 mRNA level, which consequently decreases the Mcl-1 protein level and renders cells more susceptible to apoptosis induction via the formation of apoptosome. CONCLUSIONS: Mcl-1 protein is an important regulator of sensitivity of cancer cells to apoptotic stimuli upon SD. GENERAL SIGNIFICANCE: This study identifies Mcl-1 as a new target for the sensitization of human cancer cells to cell death by SD, which is of great significance for the development of efficient anti-cancer therapies.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Meios de Cultura Livres de Soro/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Proteínas de Neoplasias/biossíntese , Apoptose/fisiologia , Apoptossomas/fisiologia , Caspase 2/fisiologia , Caspase 8/fisiologia , Linhagem Celular Tumoral , Cisteína Endopeptidases/fisiologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Células HeLa , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/fisiologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética
4.
Cell Mol Life Sci ; 72(3): 505-517, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25323133

RESUMO

Programmed cell death plays a central role in the regulation of homeostasis and development of multicellular organisms. Deregulation of programmed cell death is connected to a number of disorders, including cancer and autoimmune diseases. Initiation of cell death occurs in the multiprotein complexes or high molecular weight platforms. Composition, structure, and molecular interactions within these platforms influence the cellular decision toward life or death and, therefore, define the induction of a particular cell death program. Here, we discuss in detail the key cell-death complexes-including DISC, complex II, and TNFRI complex I/II, and the necrosome, RIPoptosome, apoptosome, and PIDDosome-that control apoptosis or necroptosis pathways as well as their regulation. The possibility of their pharmacological targeting leading to the development of new strategies of interference with cell death programs via control of the high molecular weight platforms will be discussed.


Assuntos
Morte Celular/fisiologia , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Necrose/fisiopatologia , Transdução de Sinais/fisiologia , Apoptossomas/metabolismo , Caspase 2/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo
5.
Cell Mol Life Sci ; 72(23): 4593-612, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26346492

RESUMO

Since their establishment in the early 1970s, the nuclear changes upon apoptosis induction, such as the condensation of chromatin, disassembly of nuclear scaffold proteins and degradation of DNA, were, and still are, considered as the essential steps and hallmarks of apoptosis. These are the characteristics of the execution phase of apoptotic cell death. In addition, accumulating data clearly show that some nuclear events can lead to the induction of apoptosis. In particular, if DNA lesions resulting from deregulation during the cell cycle or DNA damage induced by chemotherapeutic drugs or viral infection cannot be efficiently eliminated, apoptotic mechanisms, which enable cellular transformation to be avoided, are activated in the nucleus. The functional heterogeneity of the nuclear organization allows the tight regulation of these signaling events that involve the movement of various nuclear proteins to other intracellular compartments (and vice versa) to initiate and govern apoptosis. Here, we discuss how these events are coordinated to execute apoptotic cell death.


Assuntos
Apoptose/fisiologia , Caspases/metabolismo , Núcleo Celular/metabolismo , Animais , Caspases/genética , Núcleo Celular/genética , Núcleo Celular/fisiologia , Cromatina/genética , Cromatina/metabolismo , Dano ao DNA , Fragmentação do DNA , Genes p53 , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/metabolismo , Leucemia Promielocítica Aguda/genética , Ribossomos/genética , Ribossomos/metabolismo , Transdução de Sinais
6.
Biol Direct ; 19(1): 58, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39075541

RESUMO

Cluster of Differentiation 1 (CD1) proteins are widely expressed throughout jawed vertebrates and present lipid antigens to specific CD1-restricted T lymphocytes. CD1 molecules play an important role in immune defense with the presence or absence of particular CD1 proteins frequently associated with the functional characteristics of the immune system. Here, we show the evolution of CD1 proteins in the Rodentia family and the diversity among its members. Based on the analysis of CD1 protein-coding regions in rodent genomes and the reconstruction of protein structures, we found that Heterocephalus glaber represents a unique member of the suborder Hystricomorpha with significant changes in protein sequences and structures of the CD1 family. Multiple lines of evidence point to the absence of CD1d and CD1e and probably a dysfunctional CD1b protein in Heterocephalus glaber. In addition, the impact of CD1d loss on the CD1d/Natural killer T (NKT) cell axis in the naked mole-rat and its potential implications for immune system function are discussed in detail.


Assuntos
Antígenos CD1 , Ratos-Toupeira , Animais , Ratos-Toupeira/genética , Ratos-Toupeira/imunologia , Antígenos CD1/genética , Antígenos CD1/imunologia , Evolução Molecular , Filogenia , Sistema Imunitário , Família Multigênica , Células T Matadoras Naturais/imunologia , Roedores/genética , Roedores/imunologia
7.
Trends Mol Med ; 29(12): 996-1013, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37716905

RESUMO

The PIDDosome is a multiprotein complex that includes p53-induced protein with a death domain 1 (PIDD1), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and caspase-2, the activation of which is driven by PIDDosome assembly. In addition to the key role of the PIDDosome in the regulation of cell differentiation, tissue homeostasis, and organogenesis and regeneration, caspase-2, RAIDD and PIDD1 engagement in neuronal development was shown. Here, we focus on the involvement of PIDDosome components in neurodegenerative disorders, including retinal neuropathies, different types of brain damage, and Alzheimer's disease (AD), Huntington's disease (HD), and Lewy body disease. We also discuss pathogenic variants of PIDD1, RAIDD, and caspase-2 that are associated with intellectual, behavioral, and psychological abnormalities, together with prospective PIDDosome inhibition strategies and their potential clinical application.


Assuntos
Proteína Adaptadora de Sinalização CRADD , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte , Humanos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Proteína Adaptadora de Sinalização CRADD/metabolismo , Caspase 2/genética , Caspase 2/metabolismo , Estudos Prospectivos , Apoptose/fisiologia
8.
Cell Death Discov ; 9(1): 352, 2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37749074

RESUMO

Lung cancer is the leading cause of cancer mortality worldwide. In recent years, the incidence of lung cancer subtype lung adenocarcinoma (LUAD) has steadily increased. Mitochondria, as a pivotal site of cell bioenergetics, metabolism, cell signaling, and cell death, are often dysregulated in lung cancer cells. Mitochondria maintenance and integrity depend on mitochondrial quality control proteins (MQCPs). During lung cancer progression, the levels of MQCPs could change and promote cancer cell adaptation to the microenvironment and stresses. Here, univariate and multivariate proportional Cox regression analyses were applied to develop a signature based on the level of MQCPs (dimeric form of BNIP3, DRP1, and SIRT3) in tumorous and non-tumorous samples of 80 patients with LUAD. The MQCP signature could be used to separate the patients with LUAD into high- and low-risk groups. Survival analysis indicated that patients in the high-risk group had dramatically shorter overall survival compared with the low-risk patients. Moreover, a nomogram combining clinicopathologic features and the MQCP signature was constructed and validated to predict 1-, 3-, and 5-year overall survival of the patients. Thus, this study presents a novel signature based on MQCPs as a reliable prognostic tool to predict overall survival for patients with LUAD.

9.
J Vis Exp ; (188)2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36314804

RESUMO

Apoptosis is a type of programmed cell death that eliminates damaged cells and controls the development and tissue homeostasis of multicellular organisms. Caspases, a family of cysteine proteases, play a key role in apoptosis initiation and execution. The maturation of caspases and their activity is fine-tuned by post-translational modifications in a highly dynamic fashion. To assess the effect of post-translational changes, potential sites are routinely mutated with residues persistent to any modifications. For example, the serine residue is replaced with alanine or aspartic acid. However, such substitutions could alter the caspase active site's conformation, leading to disturbances in catalytic activity and cellular functions. Moreover, mutations of other amino acid residues located in critical positions could also break the structure and functions of caspases and lead to apoptosis perturbation. To avoid the difficulties of employing mutated residues, molecular modeling approaches can be readily applied to estimate the potential effect of amino acid substitutions on caspase structure. The present protocol allows the modeling of both the wild-type caspase and its mutant forms with the biomolecular simulation package (Amber) and supercomputer facilities to test the effect of mutations on the protein structure and function.


Assuntos
Apoptose , Caspases , Caspases/genética , Caspases/metabolismo , Modelos Moleculares , Processamento de Proteína Pós-Traducional , Mutação , Caspase 3/metabolismo
10.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188584, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34157315

RESUMO

An emerging role of long non-coding RNAs (lncRNAs) in tumor progression has been revealed in the last decade. Through interactions with nucleic acids and proteins, lncRNAs could act as enhancers, scaffolds or decoys for a number of oncoproteins and tumor suppressors. The aberrant lncRNA expression or mutations are often associated with changes in a variety of cellular processes, including proliferation, stress response and cell death. Here, we will focus on the tumor-associated lncRNAs in ovarian cancer according to their contribution to cancer hallmarks, such as intense proliferation, cell death resistance, altered energy metabolism, invasion and metastasis, and immune evasion. Moreover, the potential clinical implications of lncRNAs and their significance for the diagnosis, prognosis and therapy of ovarian cancer will be discussed.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ovarianas/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas , Resistencia a Medicamentos Antineoplásicos , Feminino , Edição de Genes , Regulação Neoplásica da Expressão Gênica , Terapia Genética , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , RNA Longo não Codificante/genética , Transdução de Sinais
11.
Cancers (Basel) ; 14(1)2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-35008345

RESUMO

BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependent mechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance to Mcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissues from patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increased Bak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrated dramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL and Mcl-1 might lead to a release of Bak, which cannot be neutralized by other anti-apoptotic proteins. Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition.

12.
Cell Death Dis ; 11(10): 825, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011746

RESUMO

Caspase-2 is a unique and conservative cysteine protease which plays an important role in several cellular processes including apoptotic cell death. Although the molecular mechanisms of its activation remain largely unclear, a major role belongs to the architecture of the caspase-2 active center. We demonstrate that the substitution of the putative phosphorylation site of caspase-2, Serine-384 to Alanine, blocks caspase-2 processing and decreases its enzymatic activity. Strikingly, in silico analysis using molecular dynamics simulations has shown that Serine-384 is crucially involved in interactions within the caspase-2 active center. It stabilizes Arginine-378, which forms a crucial hydrogen bond with the aspartate residue of a substrate. Hence, Serine-384 is essential for supporting a proper architecture of the active center of caspase-2. Moreover, molecular modeling strongly proved steric inaccessibility of Ser-384 to be phosphorylated. Importantly, a multiple alignment has demonstrated that both Serine-384 and Arg-378 residues are highly conservative across all members of caspase family, which allows us to suggest that this diade is indispensable for caspase processing and activity. Spontaneous mutations in this diade might influence oncosuppressive function of caspases, in particular of caspase-2. Likewise, the mutation of Ser-384 is associated with the development of lung squamous cell carcinoma and adenocarcinoma. Taken together, we have uncovered a central feature of the caspase-2 activation mechanism which is crucial for the regulation of its signaling network.


Assuntos
Apoptose/genética , Caspase 2/genética , Cisteína Endopeptidases/genética , Serina/metabolismo , Adenocarcinoma/genética , Sítios de Ligação , Caspase 2/metabolismo , Caspase 9/metabolismo , Cisteína Endopeptidases/metabolismo , Humanos , Mutação de Sentido Incorreto/genética , Serina/genética
13.
Antioxidants (Basel) ; 9(9)2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32942578

RESUMO

To counteract oxidative stress, antioxidants including carotenoids are highly promising, yet their exploitation is drastically limited by the poor bioavailability and fast photodestruction, whereas current delivery systems are far from being efficient. Here we demonstrate that the recently discovered nanometer-sized water-soluble carotenoprotein from Anabaena sp. PCC 7120 (termed AnaCTDH) transiently interacts with liposomes to efficiently extract carotenoids via carotenoid-mediated homodimerization, yielding violet-purple protein samples. We characterize the spectroscopic properties of the obtained pigment-protein complexes and the thermodynamics of liposome-protein carotenoid transfer and demonstrate the delivery of carotenoid echinenone from AnaCTDH into liposomes with an efficiency of up to 70 ± 3%. Most importantly, we show efficient carotenoid delivery to membranes of mammalian cells, which provides protection from reactive oxygen species (ROS). Incubation of neuroblastoma cell line Tet21N in the presence of 1 µM AnaCTDH binding echinenone decreased antimycin A ROS production by 25% (p < 0.05). The described carotenoprotein may be considered as part of modular systems for the targeted antioxidant delivery.

14.
Int J Biochem Cell Biol ; 102: 101-108, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30025878

RESUMO

The role of caspase-2 in cell death regulation remains largely unknown. In this study we have analyzed the involvement of caspase-2 in RIPK1-regulated necrosis (necroptosis) in human ovarian carcinoma cells. We show that these cells undergo necroptosis upon treatment with the DNA damaging drug cisplatin in combination with the pan-caspase inhibitor zVAD-fmk. Downregulation of caspase-2 leads to an increase of necroptosis in CAOV-4 cells. Interestingly, an association of caspase-2 to the necrosome complex was not detected. Importantly, downregulation of caspase-2 with shRNA or CRISPR/Cas9 system led to an enhanced phosphorylation of RIPK1 and MLKL. Taken together, our data strongly indicate that caspase-2 negatively regulates necroptotic cell death, which might play an important role in further therapeutic applications.


Assuntos
Caspase 2/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Terapia de Alvo Molecular , Necrose/enzimologia , Transporte Proteico
15.
Trends Cell Biol ; 27(5): 322-339, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28188028

RESUMO

Apoptosis is a crucial program of cell death that controls development and homeostasis of multicellular organisms. The main initiators and executors of this process are the Cysteine-dependent ASPartate proteASES - caspases. A number of regulatory circuits tightly control caspase processing and activity. One of the most important, yet, at the same time still poorly understood control mechanisms of activation of caspases involves their post-translational modifications. The addition and/or removal of chemical groups drastically alters the catalytic activity of caspases or stimulates their nonapoptotic functions. In this review, we will describe and discuss the roles of key caspase modifications such as phosphorylation, ubiquitination, nitrosylation, glutathionylation, SUMOylation, and acetylation in the regulation of apoptotic cell death and cell survival.


Assuntos
Apoptose , Caspases/metabolismo , Processamento de Proteína Pós-Traducional , Sequência de Aminoácidos , Animais , Ativação Enzimática , Humanos , Fosforilação , Ubiquitinação
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