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1.
Proc Natl Acad Sci U S A ; 121(25): e2405468121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38861601

RESUMO

Pannexin1 hemichannels (Panx1 HCs) are found in the membrane of most mammalian cells and communicate the intracellular and extracellular spaces, enabling the passive transfer of ions and small molecules. They are involved in physiological and pathophysiological conditions. During apoptosis, the C-terminal tail of Panx1 is proteolytically cleaved, but the permeability features of hemichannels and their role in cell death remain elusive. To address these topics, HeLa cells transfected with full-length human Panx1 (fl-hPanx1) or C-terminal truncated hPanx1 (Δ371hPanx1) were exposed to alkaline extracellular saline solution, increasing the activity of Panx1 HCs. The Δ371hPanx1 HC was permeable to DAPI and Etd+, but not to propidium iodide, whereas fl-hPanx1 HC was only permeable to DAPI. Furthermore, the cytoplasmic Ca2+ signal increased only in Δ371hPanx1 cells, which was supported by bioinformatics approaches. The influx of Ca2+ through Δ371hPanx1 HCs was necessary to promote cell death up to about 95% of cells, whereas the exposure to alkaline saline solution without Ca2+ failed to induce cell death, and the Ca2+ ionophore A23187 promoted more than 80% cell death even in fl-hPanx1 transfectants. Moreover, cell death was prevented with carbenoxolone or 10Panx1 in Δ371hPanx1 cells, whereas it was undetectable in HeLa Panx1-/- cells. Pretreatment with Ferrostatin-1 and necrostatin-1 did not prevent cell death, suggesting that ferroptosis or necroptosis was not involved. In comparison, zVAD-FMK, a pancaspase inhibitor, reduced death by ~60%, suggesting the involvement of apoptosis. Therefore, alkaline pH increases the activity of Δ371hPanx1HCs, leading to a critical intracellular free-Ca2+ overload that promotes cell death.


Assuntos
Cálcio , Conexinas , Proteínas do Tecido Nervoso , Humanos , Conexinas/metabolismo , Conexinas/genética , Células HeLa , Cálcio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Apoptose , Morte Celular , Sinalização do Cálcio
2.
Sci Rep ; 14(1): 13116, 2024 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849435

RESUMO

Stearoyl-CoA desaturase 1 (SCD1) is an attractive target for cancer therapy. However, the clinical efficacy of SCD1 inhibitor monotherapy is limited. There is thus a need to elucidate the mechanisms of resistance to SCD1 inhibition and develop new therapeutic strategies for combination therapy. In this study, we investigated the molecular mechanisms by which cancer cells acquire resistance to endoplasmic reticulum (ER) stress-dependent cancer cell death induced by SCD1 inhibition. SCD1 inhibitor-sensitive and -resistant cancer cells were treated with SCD1 inhibitors in vitro, and SCD1 inhibitor-sensitive cancer cells accumulated palmitic acid and underwent ER stress response-induced cell death. Conversely, SCD1-resistant cancer cells did not undergo ER stress response-induced cell death because fatty acid desaturase 2 (FADS2) eliminated the accumulation of palmitic acid. Furthermore, genetic depletion using siRNA showed that FADS2 is a key determinant of sensitivity/resistance of cancer cells to SCD1 inhibitor. A549 cells, an SCD1 inhibitor-resistant cancer cell line, underwent ER stress-dependent cancer cell death upon dual inhibition of SCD1 and FADS2. Thus, combination therapy with SCD1 inhibition and FADS2 inhibition is potentially a new cancer therapeutic strategy targeting fatty acid metabolism.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático , Ácidos Graxos Dessaturases , Estearoil-CoA Dessaturase , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/antagonistas & inibidores , Humanos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Linhagem Celular Tumoral , Células A549 , Ácido Palmítico/farmacologia , Morte Celular/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Neoplasias/tratamento farmacológico
3.
BMC Plant Biol ; 24(1): 558, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38877396

RESUMO

BACKGROUND: Wheat is one of the important grain crops in the world. The formation of lesion spots related to cell death is involved in disease resistance, whereas the regulatory pathway of lesion spot production and resistance mechanism to pathogens in wheat is largely unknown. RESULTS: In this study, a pair of NILs (NIL-Lm5W and NIL-Lm5M) was constructed from the BC1F4 population by the wheat lesion mimic mutant MC21 and its wild genotype Chuannong 16. The formation of lesion spots in NIL-Lm5M significantly increased its resistance to stripe rust, and NIL-Lm5M showed superiour agronomic traits than NIL-Lm5W under stripe rust infection.Whereafter, the NILs were subjected to transcriptomic (stage N: no spots; stage S, only a few spots; and stage M, numerous spots), metabolomic (stage N and S), and hormone analysis (stage S), with samples taken from normal plants in the field. Transcriptomic analysis showed that the differentially expressed genes were enriched in plant-pathogen interaction, and defense-related genes were significantly upregulated following the formation of lesion spots. Metabolomic analysis showed that the differentially accumulated metabolites were enriched in energy metabolism, including amino acid metabolism, carbohydrate metabolism, and lipid metabolism. Correlation network diagrams of transcriptomic and metabolomic showed that they were both enriched in energy metabolism. Additionally, the contents of gibberellin A7, cis-Zeatin, and abscisic acid were decreased in leaves upon lesion spot formation, whereas the lesion spots in NIL-Lm5M leaves were restrained by spaying GA and cytokinin (CTK, trans-zeatin) in the field. CONCLUSION: The formation of lesion spots can result in cell death and enhance strip rust resistance by protein degradation pathway and defense-related genes overexpression in wheat. Besides, the formation of lesion spots was significantly affected by GA and CTK. Altogether, these results may contribute to the understanding of lesion spot formation in wheat and laid a foundation for regulating the resistance mechanism to stripe rust.


Assuntos
Morte Celular , Resistência à Doença , Doenças das Plantas , Reguladores de Crescimento de Plantas , Transcriptoma , Triticum , Triticum/genética , Triticum/microbiologia , Triticum/metabolismo , Resistência à Doença/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/genética , Reguladores de Crescimento de Plantas/metabolismo , Giberelinas/metabolismo , Citocininas/metabolismo , Perfilação da Expressão Gênica , Metabolômica , Regulação da Expressão Gênica de Plantas
4.
Wiley Interdiscip Rev RNA ; 15(3): e1862, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38837618

RESUMO

Cell death plays a crucial role in various physiological and pathological processes. Until recently, programmed cell death was mainly attributed to caspase-dependent apoptosis. However, emerging evidence suggests that caspase-independent cell death (CICD) mechanisms also contribute significantly to cellular demise. We and others have reported and functionally characterized numerous long noncoding RNAs (lncRNAs) that modulate caspase-dependent apoptotic pathways potentially in a pathway-dependent manner. However, the interplay between lncRNAs and CICD pathways has not been comprehensively documented. One major reason for this is that most CICD pathways have been recently discovered with some being partially characterized at the molecular level. In this review, we discuss the emerging evidence that implicates specific lncRNAs in the regulation and execution of CICD. We summarize the diverse mechanisms through which lncRNAs modulate different forms of CICD, including ferroptosis, necroptosis, cuproptosis, and others. Furthermore, we highlight the intricate regulatory networks involving lncRNAs, protein-coding genes, and signaling pathways that orchestrate CICD in health and disease. Understanding the molecular mechanisms and functional implications of lncRNAs in CICD may unravel novel therapeutic targets and diagnostic tools for various diseases, paving the way for innovative strategies in disease management and personalized medicine. This article is categorized under: RNA in Disease and Development > RNA in Disease.


Assuntos
Morte Celular , RNA Longo não Codificante , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Humanos , Animais , Morte Celular/genética , Caspases/metabolismo , Caspases/genética , Transdução de Sinais , Apoptose/genética
5.
J Cell Mol Med ; 28(11): e18463, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38847472

RESUMO

Accumulating evidence suggests that a wide variety of cell deaths are deeply involved in cancer immunity. However, their roles in glioma have not been explored. We employed a logistic regression model with the shrinkage regularization operator (LASSO) Cox combined with seven machine learning algorithms to analyse the patterns of cell death (including cuproptosis, ferroptosis, pyroptosis, apoptosis and necrosis) in The Cancer Genome Atlas (TCGA) cohort. The performance of the nomogram was assessed through the use of receiver operating characteristic (ROC) curves and calibration curves. Cell-type identification was estimated by using the cell-type identification by estimating relative subsets of known RNA transcripts (CIBERSORT) and single sample gene set enrichment analysis methods. Hub genes associated with the prognostic model were screened through machine learning techniques. The expression pattern and clinical significance of MYD88 were investigated via immunohistochemistry (IHC). The cell death score represents an independent prognostic factor for poor outcomes in glioma patients and has a distinctly superior accuracy to that of 10 published signatures. The nomogram performed well in predicting outcomes according to time-dependent ROC and calibration plots. In addition, a high-risk score was significantly related to high expression of immune checkpoint molecules and dense infiltration of protumor cells, these findings were associated with a cell death-based prognostic model. Upregulated MYD88 expression was associated with malignant phenotypes and undesirable prognoses according to the IHC. Furthermore, high MYD88 expression was associated with poor clinical outcomes and was positively related to CD163, PD-L1 and vimentin expression in the in-horse cohort. The cell death score provides a precise stratification and immune status for glioma. MYD88 was found to be an outstanding representative that might play an important role in glioma.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Glioma , Aprendizado de Máquina , Nomogramas , Humanos , Glioma/genética , Glioma/imunologia , Glioma/patologia , Prognóstico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Morte Celular/genética , Masculino , Feminino , Curva ROC , Perfilação da Expressão Gênica , Pessoa de Meia-Idade , Transcriptoma , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo
6.
Neoplasia ; 54: 101009, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38850836

RESUMO

BACKGROUND: Lipid metabolism and regulated cell death (RCD) play a role in the remodeling of tumor immune microenvironment and regulation of cancer progression. Since the underlying immune mechanisms of colon cancer remain elusive, this study aims to identify potential therapeutic target genes. METHODS: Differential genes related to lipid metabolism and RCD in COAD patients were identified using R language and online tools. Based on the expression of genes, two groups were classified using consensus clustering. CIBERSORT and ssGSEA were used to detect immune infiltration in both groups. Prognostic signature genes for colon cancer were screened using machine learning algorithms. KEGG, GO and GSEA for gene pathway enrichment. In addition, interacting genes in the immune module were obtained using a weighted gene co-expression network (WGCNA). Finally, expression and mutation of key in colon cancer genes were detected using TIMER, HPR, cBioPortal website and qPCR. RESULTS: The consensus clustering analysis revealed that 231 relevant differential genes were highly associated with immune infiltration. A series of machine learning and website analyses identified AGT as a hub gene linked to lipid metabolism and regulated cell death, which is overexpressed in colon cancer. CONCLUSION: AGT, as a signature gene of lipid metabolism and regulated cell death, plays a critical role in the development of COAD and is associated with tumor immune infiltration.


Assuntos
Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos , Microambiente Tumoral , Humanos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Metabolismo dos Lipídeos/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Prognóstico , Morte Celular/genética , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Transcriptoma
7.
Biochem Biophys Res Commun ; 723: 150178, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-38823363

RESUMO

Cell models of mitochondrial complex Ⅰ (CⅠ) deficiency display significant elevations in reactive oxygen species (ROS) levels and an increase in cellular apoptosis. However, the underlying mechanisms governing anti-apoptotic processes in CⅠ-deficient cells remain elusive. Here, we introduced a mutation in NDUFS7, a crucial subunit of CI, in HEK293T cells and found that the absence of NDUFS7 resulted in reduced cell proliferation, elevated cell death, and increased susceptibility to oxidative stress. Mechanismly, we revealed that the upregulation of SLC7A11 played a crucial role in mitigating cell death resulting from NDUFS7 deficiency. Specifically, the increased expression of SLC7A11 enhanced cystine import, which subsequently reduced cell death by promoting the biosynthesis of reduced glutathione (GSH). Collectively, our findings suggest that SLC7A11-mediated cystine import, representing a novel pathway independent of NADPH production, plays a vital role in protection against NDUFS7 deficiency-induced cell death. This novel pathway provides potential insights into the understanding of pathogenic mechanisms and the therapeutic management of mitochondrial disorders associated with CⅠ deficiency.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Cistina , Complexo I de Transporte de Elétrons , Humanos , Células HEK293 , Cistina/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/deficiência , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Estresse Oxidativo , Morte Celular , Glutationa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose
8.
Sensors (Basel) ; 24(11)2024 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-38894226

RESUMO

This study presents a novel label-free approach for characterizing cell death states, eliminating the need for complex molecular labeling that may yield artificial or ambiguous results due to technical limitations in microscope resolution. The proposed holographic tomography technique offers a label-free avenue for capturing precise three-dimensional (3D) refractive index morphologies of cells and directly analyzing cellular parameters like area, height, volume, and nucleus/cytoplasm ratio within the 3D cellular model. We showcase holographic tomography results illustrating various cell death types and elucidate distinctive refractive index correlations with specific cell morphologies complemented by biochemical assays to verify cell death states. These findings hold promise for advancing in situ single cell state identification and diagnosis applications.


Assuntos
Morte Celular , Holografia , Imageamento Tridimensional , Tomografia , Holografia/métodos , Tomografia/métodos , Imageamento Tridimensional/métodos , Humanos , Refratometria/métodos
9.
Nat Commun ; 15(1): 4920, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858353

RESUMO

The differentiation of the stroma is a hallmark event during postnatal uterine development. However, the spatiotemporal changes that occur during this process and the underlying regulatory mechanisms remain elusive. Here, we comprehensively delineated the dynamic development of the neonatal uterus at single-cell resolution and characterized two distinct stromal subpopulations, inner and outer stroma. Furthermore, single-cell RNA sequencing revealed that uterine ablation of Pr-set7, the sole methyltransferase catalyzing H4K20me1, led to a reduced proportion of the inner stroma due to massive cell death, thus impeding uterine development. By combining RNA sequencing and epigenetic profiling of H4K20me1, we demonstrated that PR-SET7-H4K20me1 either directly repressed the transcription of interferon stimulated genes or indirectly restricted the interferon response via silencing endogenous retroviruses. Declined H4K20me1 level caused viral mimicry responses and ZBP1-mediated apoptosis and necroptosis in stromal cells. Collectively, our study provides insight into the epigenetic machinery governing postnatal uterine stromal development mediated by PR-SET7.


Assuntos
Epigênese Genética , Histona-Lisina N-Metiltransferase , Células Estromais , Útero , Feminino , Animais , Útero/metabolismo , Células Estromais/metabolismo , Camundongos , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Interferons/metabolismo , Interferons/genética , Retrovirus Endógenos/genética , Apoptose/genética , Camundongos Endogâmicos C57BL , Morte Celular/genética , Necroptose/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Histonas/metabolismo , Análise de Célula Única , Camundongos Knockout , Diferenciação Celular/genética
10.
Int J Mol Sci ; 25(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892443

RESUMO

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose/patologia , Animais , Morte Celular/imunologia , Interações Hospedeiro-Patógeno/imunologia , Apoptose , Imunidade Inata , Autofagia/imunologia , Transdução de Sinais , Macrófagos/imunologia , Macrófagos/microbiologia
11.
Int J Mol Sci ; 25(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892448

RESUMO

Canonical transient receptor potential channel 3 (TRPC3) is the most abundant TRPC channel in the brain and is highly expressed in all subfields of the hippocampus. Previous studies have suggested that TRPC3 channels may be involved in the hyperexcitability of hippocampal pyramidal neurons and seizures. Genetic ablation of TRPC3 channel expression reduced the intensity of pilocarpine-induced status epilepticus (SE). However, the underlying cellular mechanisms remain unexplored and the contribution of TRPC3 channels to SE-induced neurodegeneration is not determined. In this study, we investigated the contribution of TRPC3 channels to the electrophysiological properties of hippocampal pyramidal neurons and hippocampal synaptic plasticity, and the contribution of TRPC3 channels to seizure-induced neuronal cell death. We found that genetic ablation of TRPC3 expression did not alter basic electrophysiological properties of hippocampal pyramidal neurons and had a complex impact on epileptiform bursting in CA3. However, TRPC3 channels contribute significantly to long-term potentiation in CA1 and SE-induced neurodegeneration. Our results provided further support for therapeutic potential of TRPC3 inhibitors and raised new questions that need to be answered by future studies.


Assuntos
Morte Celular , Hipocampo , Células Piramidais , Convulsões , Canais de Cátion TRPC , Animais , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPC/genética , Camundongos , Células Piramidais/metabolismo , Células Piramidais/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Convulsões/metabolismo , Convulsões/patologia , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Estado Epiléptico/induzido quimicamente , Masculino , Neurônios/metabolismo , Pilocarpina , Potenciação de Longa Duração , Camundongos Knockout , Camundongos Endogâmicos C57BL , Plasticidade Neuronal
12.
PLoS Comput Biol ; 20(6): e1012129, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38848426

RESUMO

Understanding the dynamics of acute HIV infection can offer valuable insights into the early stages of viral behavior, potentially helping uncover various aspects of HIV pathogenesis. The standard viral dynamics model explains HIV viral dynamics during acute infection reasonably well. However, the model makes simplifying assumptions, neglecting some aspects of HIV infection. For instance, in the standard model, target cells are infected by a single HIV virion. Yet, cellular multiplicity of infection (MOI) may have considerable effects in pathogenesis and viral evolution. Further, when using the standard model, we take constant infected cell death rates, simplifying the dynamic immune responses. Here, we use four models-1) the standard viral dynamics model, 2) an alternate model incorporating cellular MOI, 3) a model assuming density-dependent death rate of infected cells and 4) a model combining (2) and (3)-to investigate acute infection dynamics in 43 people living with HIV very early after HIV exposure. We find that all models qualitatively describe the data, but none of the tested models is by itself the best to capture different kinds of heterogeneity. Instead, different models describe differing features of the dynamics more accurately. For example, while the standard viral dynamics model may be the most parsimonious across study participants by the corrected Akaike Information Criterion (AICc), we find that viral peaks are better explained by a model allowing for cellular MOI, using a linear regression analysis as analyzed by R2. These results suggest that heterogeneity in within-host viral dynamics cannot be captured by a single model. Depending on the specific aspect of interest, a corresponding model should be employed.


Assuntos
Morte Celular , Infecções por HIV , Modelos Biológicos , Infecções por HIV/virologia , Infecções por HIV/fisiopatologia , Humanos , Morte Celular/fisiologia , HIV-1/fisiologia , HIV-1/patogenicidade , Biologia Computacional , Carga Viral , Masculino , Adulto , Doença Aguda , Feminino
13.
J Exp Clin Cancer Res ; 43(1): 168, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38877579

RESUMO

PANoptosis represents a novel type of programmed cell death (PCD) with distinctive features that incorporate elements of pyroptosis, apoptosis, and necroptosis. PANoptosis is governed by a newly discovered cytoplasmic multimeric protein complex known as the PANoptosome. Unlike each of these PCD types individually, PANoptosis is still in the early stages of research and warrants further exploration of its specific regulatory mechanisms and primary targets. In this review, we provide a brief overview of the conceptual framework and molecular components of PANoptosis. In addition, we highlight recent advances in the understanding of the molecular mechanisms and therapeutic applications of PANoptosis. By elucidating the complex crosstalk between pyroptosis, apoptosis and necroptosis and summarizing the functional consequences of PANoptosis with a special focus on the tumor immune microenvironment, this review aims to provide a theoretical basis for the potential application of PANoptosis in cancer therapy.


Assuntos
Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Morte Celular , Necroptose , Microambiente Tumoral/imunologia , Animais , Piroptose , Apoptose
14.
Front Endocrinol (Lausanne) ; 15: 1344729, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38904034

RESUMO

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


Assuntos
Cobre , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Cobre/metabolismo , Animais , Mitocôndrias/metabolismo , Morte Celular
15.
Sci Rep ; 14(1): 12749, 2024 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-38830963

RESUMO

Keratoconus is corneal disease in which the progression of conical dilation of cornea leads to reduced visual acuity and even corneal perforation. However, the etiology mechanism of keratoconus is still unclear. This study aims to identify the signature genes related to cell death in keratoconus and examine the function of these genes. A dataset of keratoconus from the GEO database was analysed to identify the differentially expressed genes (DEGs). A total of 3558 DEGs were screened from GSE151631. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that they mainly involved in response to hypoxia, cell-cell adhesion, and IL-17 signaling pathway. Then, the cell death-related genes datasets were intersected with the above 3558 DEGs to obtain 70 ferroptosis-related DEGs (FDEGs), 32 autophagy-related DEGs (ADEGs), six pyroptosis-related DEGs (PDEGs), four disulfidptosis-related DEGs (DDEGs), and one cuproptosis-related DEGs (CDEGs). After using Least absolute shrinkage and selection operator (LASSO), Random Forest analysis, and receiver operating characteristic (ROC) curve analysis, one ferroptosis-related gene (TNFAIP3) and five autophagy-related genes (CDKN1A, HSPA5, MAPK8IP1, PPP1R15A, and VEGFA) were screened out. The expressions of the above six genes were significantly decreased in keratoconus and the area under the curve (AUC) values of these genes was 0.944, 0.893, 0.797, 0.726, 0.882 and 0.779 respectively. GSEA analysis showed that the above six genes mainly play an important role in allograft rejection, asthma, and circadian rhythm etc. In conclusion, the results of this study suggested that focusing on these genes and autoimmune diseases will be a beneficial perspective for the keratoconus etiology research.


Assuntos
Biologia Computacional , Perfilação da Expressão Gênica , Ceratocone , Ceratocone/genética , Ceratocone/patologia , Humanos , Biologia Computacional/métodos , Ontologia Genética , Morte Celular/genética , Redes Reguladoras de Genes , Ferroptose/genética , Bases de Dados Genéticas , Transcriptoma , Mapas de Interação de Proteínas/genética
16.
J Transl Med ; 22(1): 532, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831284

RESUMO

BACKGROUND: The Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule. METHODS: A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). RESULTS: In total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. CONCLUSIONS: AccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications.


Assuntos
Sinergismo Farmacológico , Inibidores de Checkpoint Imunológico , Espécies Reativas de Oxigênio , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linhagem Celular Tumoral , Humanos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/imunologia , Camundongos Endogâmicos C57BL , Feminino , Morte Celular/efeitos dos fármacos
17.
Cell Death Dis ; 15(5): 374, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811543

RESUMO

High workload-induced cellular stress can cause pancreatic islet ß cell death and dysfunction, or ß cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents ß cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1+ pancreatic progenitor cells led to pancreas hypoplasia and reduced ß cell mass during pancreas development in mice. Here, we show that GRP94 was involved in ß cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for ß cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in ß cell failure related to diabetes.


Assuntos
Células Secretoras de Insulina , Receptor IGF Tipo 1 , Animais , Camundongos , Morte Celular , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Receptores para Leptina/metabolismo , Receptores para Leptina/genética
18.
J Mater Chem B ; 12(23): 5645-5660, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38747306

RESUMO

The increasing frequency of drug-resistant pathogens poses serious health issues to humans around the globe, leading to the development of new antibacterial agents to conquer drug resistance and bacterial infections. In view of this, we have synthesized a series of bis-naphthalimides to respond to awful drug resistance. Bioactivity assay and structure-activity relationship disclosed that compounds 5d and 5o exhibit potent antibacterial activity against E. faecalis, outperforming the marketed antibiotics. These drug candidates not only inhibit the biofilm formation of E. faecalis but also display rapid bactericidal properties, thus delaying the development of drug resistance within 20 passages. To explore the mechanism of antibacterial activity against E. faecalis, biofunctional examination was carried out which unveiled that 5d and 5o effectively disrupt bacterial cell membranes, causing the leakage of cytoplasmic contents and metabolic activity loss. Concurrently, 5d and 5o effectively intercalate with DNA to block DNA replication, causing the build-up of excessive reactive oxygen species and inhibiting the glutathione activity, ultimately leading to oxidative damage of E. faecalis and cell death. In addition, these compounds readily bind with HSA with a high binding constant, indicating that these drug candidates could be easily delivered to the target site. The above finding manifested that these newly synthesized bis-naphthalimides with multitargeting antibacterial properties offer a new prospect to overcome drug resistance.


Assuntos
Antibacterianos , Enterococcus faecalis , Testes de Sensibilidade Microbiana , Naftalimidas , Enterococcus faecalis/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Naftalimidas/química , Naftalimidas/farmacologia , Humanos , Relação Estrutura-Atividade , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Estrutura Molecular , Morte Celular/efeitos dos fármacos
19.
Biomolecules ; 14(5)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38785921

RESUMO

Musculoskeletal diseases (MSDs), including osteoarthritis (OA), osteosarcoma (OS), multiple myeloma (MM), intervertebral disc degeneration (IDD), osteoporosis (OP), and rheumatoid arthritis (RA), present noteworthy obstacles associated with pain, disability, and impaired quality of life on a global scale. In recent years, it has become increasingly apparent that N6-methyladenosine (m6A) is a key regulator in the expression of genes in a multitude of biological processes. m6A is composed of 0.1-0.4% adenylate residues, especially at the beginning of 3'-UTR near the translation stop codon. The m6A regulator can be classified into three types, namely the "writer", "reader", and "eraser". Studies have shown that the epigenetic modulation of m6A influences mRNA processing, nuclear export, translation, and splicing. Regulated cell death (RCD) is the autonomous and orderly death of cells under genetic control to maintain the stability of the internal environment. Moreover, distorted RCDs are widely used to influence the course of various diseases and receiving increasing attention from researchers. In the past few years, increasing evidence has indicated that m6A can regulate gene expression and thus influence different RCD processes, which has a central role in the etiology and evolution of MSDs. The RCDs currently confirmed to be associated with m6A are autophagy-dependent cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, immunogenic cell death, NETotic cell death and oxeiptosis. The m6A-RCD axis can regulate the inflammatory response in chondrocytes and the invasive and migratory of MM cells to bone remodeling capacity, thereby influencing the development of MSDs. This review gives a complete overview of the regulatory functions on the m6A-RCD axis across muscle, bone, and cartilage. In addition, we also discuss recent advances in the control of RCD by m6A-targeted factors and explore the clinical application prospects of therapies targeting the m6A-RCD in MSD prevention and treatment. These may provide new ideas and directions for understanding the pathophysiological mechanism of MSDs and the clinical prevention and treatment of these diseases.


Assuntos
Adenosina , Doenças Musculoesqueléticas , Humanos , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/patologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Morte Celular/genética , Animais , Epigênese Genética
20.
J Control Release ; 370: 501-515, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38703950

RESUMO

Although nanomaterial-based nanomedicine provides many powerful tools to treat cancer, most focus on the "immunosilent" apoptosis process. In contrast, ferroptosis and immunogenic cell death, two non-apoptotic forms of programmed cell death (PCD), have been shown to enhance or alter the activity of the immune system. Therefore, there is a need to design and develop nanoplatforms that can induce multiple modes of cell death other than apoptosis to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment for cancer therapy. In this study, a new type of multifunctional nanocomposite mainly consisting of HMME, Fe3+ and Tannic acid, denoted HFT NPs, was designed and synthesized to induce multiple modes of cell death and prime the tumor microenvironment (TME). The HFT NPs consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O2 upon ultrasound irradiation, and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS ·OH through inorganic catalytic reactions. The administration of HFT NPs and subsequent ultrasound treatment caused cell death through the consumption of GSH, the generation of ROS, ultimately inducing apoptosis, ferroptosis, and immunogenic cell death (ICD). More importantly, the combination of HFT NPs and ultrasound irradiation could reshape the TME and recruit more T cell infiltration, and its combination with immune checkpoint blockade anti-PD-1 antibody could eradicate tumors with low immunogenicity and a cold TME. This new nano-system integrates sonodynamic and chemodynamic properties to achieve outstanding therapeutic outcomes when combined with immunotherapy. Collectively, this study demonstrates that it is possible to potentiate cancer immunotherapy through the rational and innovative design of relatively simple materials.


Assuntos
Ferroptose , Imunoterapia , Espécies Reativas de Oxigênio , Microambiente Tumoral , Microambiente Tumoral/efeitos dos fármacos , Animais , Imunoterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Ferroptose/efeitos dos fármacos , Humanos , Morte Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Taninos/química , Taninos/farmacologia , Camundongos , Feminino , Nanocompostos/química , Nanocompostos/administração & dosagem , Ondas Ultrassônicas , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Morte Celular Imunogênica/efeitos dos fármacos
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