Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 71
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Free Radic Biol Med ; 220: 222-235, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38735540

RESUMO

Studies have highlighted oxidative damage in the inner ear as a critical pathological basis for sensorineural hearing loss, especially the presbycusis. Poly(ADP-ribose) polymerase-1 (PARP1) activation responds to oxidative stress-induced DNA damage with pro-repair and pro-death effects resembling two sides of the same coin. PARP1-related cell death, known as parthanatos, whose underlying mechanisms are attractive research hotspots but remain to be clarified. In this study, we observed that aged rats showed stria vascularis degeneration and oxidative damage, and PARP1-dependent cell death was prominent in age-related cochlear disorganization and dysfunction. Based on oxidative stress model of primary cultured stria marginal cells (MCs), we revealed that upregulated PARP1 and PAR (Poly(ADP-ribose)) polymers are responsible for MCs oxidative death with high mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane potential (MMP) collapse, while inhibition of PARP1 ameliorated the adverse outcomes. Importantly, the PARylation of apoptosis-inducing factor (AIF) is essential for its conformational change and translocation, which subsequently causes DNA break and cell death. Concretely, the interaction of PAR and truncated AIF (tAIF) is the mainstream in the parthanatos pathway. We also found that the effects of AIF cleavage and release were achieved through calpain activity and mPTP opening, both of which could be regulated by PARP1 via mediation of mitochondria Ca2+ concentration. In conclusion, the PAR-Ca2+-tAIF signaling pathway in parthanatos contributes to the oxidative stress damage observed in MCs. Targeting PAR-Ca2+-tAIF might be a potential therapeutic strategy for the early intervention of presbycusis and other oxidative stress-associated sensorineural deafness.


Assuntos
Fator de Indução de Apoptose , Cálcio , Estresse Oxidativo , Poli(ADP-Ribose) Polimerase-1 , Presbiacusia , Animais , Fator de Indução de Apoptose/metabolismo , Fator de Indução de Apoptose/genética , Ratos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Cálcio/metabolismo , Presbiacusia/metabolismo , Presbiacusia/patologia , Presbiacusia/genética , Parthanatos/genética , Potencial da Membrana Mitocondrial , Estria Vascular/metabolismo , Estria Vascular/patologia , Apoptose , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Ratos Sprague-Dawley , Dano ao DNA , Envelhecimento/metabolismo , Envelhecimento/patologia , Cóclea/metabolismo , Cóclea/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Masculino , Humanos , Células Cultivadas
2.
Burns ; 50(6): 1562-1577, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38570249

RESUMO

The cellular mechanisms of burn conversion of heat damaged tissue are center of many studies. Even if the molecular mechanisms of heat-induced cell death are controversially discussed in the current literature, it is widely accepted that caspase-mediated apoptosis plays a central role. In the current study we wanted to develop further information on the nature of the mechanism of heat-induced cell death of fibroblasts in vitro. We found that heating of human fibroblast cultures (a 10 s rise from 37 °C to 67 °C followed by a 13 s cool down to 37 °C) resulted in the death of about 50% of the cells. However, the increase in cell death started with a delay, about one hour after exposure to heat, and reached the maximum after about five hours. The lack of clear evidence for an active involvement of effector caspase in the observed cell death mechanism and the lack of observation of the occurrence of hypodiploid nuclei contradict heat-induced cell death by caspase-mediated apoptosis. Moreover, a dominant heat-induced increase in PARP1 protein expression, which correlated with a time-delayed ATP synthesis inhibition, appearance of double-strand breaks and secondary necrosis, indicate a different type of cell death than apoptosis. Indeed, increased translocation of Apoptosis Inducing Factor (AIF) and Macrophage Migration Inhibitory Factor (MIF) into cell nuclei, which correlates with the mentioned enhanced PARP1 protein expression, indicate PARP1-induced, AIF-mediated and MIF-activated cell death. With regard to the molecular actors involved, the cellular processes and temporal sequences, the mode of cell death observed in our model is very similar to the cell death mechanism via Parthanatos described in the literature.


Assuntos
Apoptose , Queimaduras , Fibroblastos , Temperatura Alta , Poli(ADP-Ribose) Polimerase-1 , Humanos , Fibroblastos/patologia , Fibroblastos/metabolismo , Queimaduras/patologia , Temperatura Alta/efeitos adversos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Parthanatos , Necrose , Células Cultivadas , Morte Celular , Pele/patologia , Pele/citologia , Pele/lesões , Poli(ADP-Ribose) Polimerases/metabolismo , Fator de Indução de Apoptose/metabolismo , Caspases/metabolismo , Quebras de DNA de Cadeia Dupla , Trifosfato de Adenosina/metabolismo
3.
Eur J Pharmacol ; 972: 176557, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38574839

RESUMO

Cerebral ischemia-reperfusion injury (CIRI) can induce massive death of ischemic penumbra neurons via oxygen burst, exacerbating brain damage. Parthanatos is a form of caspase-independent cell death involving excessive activation of PARP-1, closely associated with intense oxidative stress following CIRI. 4'-O-methylbavachalcone (MeBavaC), an isoprenylated chalcone component in Fructus Psoraleae, has potential neuroprotective effects. This study primarily investigates whether MeBavaC can act on SIRT3 to alleviate parthanatos of ischemic penumbra neurons induced by CIRI. MeBavaC was oral gavaged to the middle cerebral artery occlusion-reperfusion (MCAO/R) rats after occlusion. The effects of MeBavaC on cerebral injury were detected by the neurological deficit score and cerebral infarct volume. In vitro, PC-12 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R), and assessed cell viability and cell injury. Also, the levels of ROS, mitochondrial membrane potential (MMP), and intracellular Ca2+ levels were detected to reflect mitochondrial function. We conducted western blotting analyses of proteins involved in parthanatos and related signaling pathways. Finally, the exact mechanism between the neuroprotection of MeBavaC and parthanatos was explored. Our results indicate that MeBavaC reduces the cerebral infarct volume and neurological deficit scores in MCAO/R rats, and inhibits the decreased viability of PC-12 cells induced by OGD/R. MeBavaC also downregulates the expression of parthanatos-related death proteins PARP-1, PAR, and AIF. However, this inhibitory effect is weakened after the use of a SIRT3 inhibitor. In conclusion, the protective effect of MeBavaC against CIRI may be achieved by inhibiting parthanatos of ischemic penumbra neurons through the SIRT3-PARP-1 axis.


Assuntos
Chalconas , Fármacos Neuroprotetores , Parthanatos , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Sirtuínas , Animais , Ratos , Masculino , Chalconas/farmacologia , Chalconas/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/metabolismo , Parthanatos/efeitos dos fármacos , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/patologia , AVC Isquêmico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células PC12 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Cálcio/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/complicações , Sobrevivência Celular/efeitos dos fármacos , Sirtuína 3/metabolismo , Sirtuína 3/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
4.
Aging (Albany NY) ; 16(6): 5471-5500, 2024 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499384

RESUMO

BACKGROUND: Parthanatos is a novel programmatic form of cell death based on DNA damage and PARP-1 dependency. Nevertheless, its specific role in the context of gastric cancer (GC) remains uncertain. METHODS: In this study, we integrated multi-omics algorithms to investigate the molecular characteristics of parthanatos in GC. A series of bioinformatics algorithms were utilized to explore clinical heterogeneity of GC and further predict the clinical outcomes. RESULTS: Firstly, we conducted a comprehensive analysis of the omics features of parthanatos in various human tumors, including genomic mutations, transcriptome expression, and prognostic relevance. We successfully identified 7 cell types within the GC microenvironment: myeloid cell, epithelial cell, T cell, stromal cell, proliferative cell, B cell, and NK cell. When compared to adjacent non-tumor tissues, single-cell sequencing results from GC tissues revealed elevated scores for the parthanatos pathway across multiple cell types. Spatial transcriptomics, for the first time, unveiled the spatial distribution characteristics of parthanatos signaling. GC patients with different parthanatos signals often exhibited distinct immune microenvironment and metabolic reprogramming features, leading to different clinical outcomes. The integration of parthanatos signaling and clinical indicators enabled the creation of novel survival curves that accurately assess patients' survival times and statuses. CONCLUSIONS: In this study, the molecular characteristics of parthanatos' unicellular and spatial transcriptomics in GC were revealed for the first time. Our model based on parthanatos signals can be used to distinguish individual heterogeneity and predict clinical outcomes in patients with GC.


Assuntos
Parthanatos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Transcriptoma , Análise de Sequência de RNA , Algoritmos , Microambiente Tumoral/genética
5.
Br J Cancer ; 130(9): 1529-1541, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38461169

RESUMO

BACKGROUND: Several studies have described a potential anti-tumour effect of cannabinoids (CNB). CNB receptor 2 (CB2) is mostly present in hematopoietic stem cells (HSC). The present study evaluates the anti-leukaemic effect of CNB. METHODS: Cell lines and primary cells from acute myeloid leukaemia (AML) patients were used and the effect of the CNB derivative WIN-55 was evaluated in vitro, ex vivo and in vivo. RESULTS: We demonstrate a potent antileukemic effect of WIN-55 which is abolished with CB antagonists. WIN-treated mice, xenografted with AML cells, had better survival as compared to vehicle or cytarabine. DNA damage-related genes were affected upon exposure to WIN. Co-incubation with the PARP inhibitor Olaparib prevented WIN-induced cell death, suggesting PARP-mediated apoptosis which was further confirmed with the translocation of AIF to the nucleus observed in WIN-treated cells. Nicotinamide prevented WIN-related apoptosis, indicating NAD+ depletion. Finally, WIN altered glycolytic enzymes levels as well as the activity of G6PDH. These effects are reversed through PARP1 inhibition. CONCLUSIONS: WIN-55 exerts an antileukemic effect through Parthanatos, leading to translocation of AIF to the nucleus and depletion of NAD+, which are reversed through PARP1 inhibition. It also induces metabolic disruptions. These effects are not observed in normal HSC.


Assuntos
Leucemia Mieloide Aguda , Parthanatos , Humanos , Animais , Camundongos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Parthanatos/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Apoptose/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Canabinoides/farmacologia , Ftalazinas/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Dano ao DNA/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Antineoplásicos/farmacologia
6.
Biochem Biophys Res Commun ; 705: 149733, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38442446

RESUMO

Osteoarthritis (OA) is a common chronic inflammatory degenerative disease. Since chondrocytes are the only type of cells in cartilage, their survival is critical for maintaining cartilage morphology. This review offers a comprehensive analysis of how reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide, hydroxyl radicals, nitric oxide, and their derivatives, affect cartilage homeostasis and trigger several novel modes of regulated cell death, including ferroptosis, parthanatos, and oxeiptosis, which may play roles in chondrocyte death and OA development. Moreover, we discuss potential therapeutic strategies to alleviate OA by scavenging ROS and provide new insight into the research and treatment of the role of regulated cell death in OA.


Assuntos
Ferroptose , Osteoartrite , Parthanatos , Humanos , Condrócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Osteoartrite/metabolismo
7.
Mov Disord ; 39(4): 644-650, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38396375

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing its potential implications for parthanatos-directed treatment. © 2024 International Parkinson and Movement Disorder Society.


Assuntos
Neurônios Dopaminérgicos , Fatores Inibidores da Migração de Macrófagos , Doença de Parkinson , Humanos , Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/metabolismo , Animais , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Parthanatos/efeitos dos fármacos
8.
J Neurochem ; 168(3): 205-223, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38225203

RESUMO

Post-operative progression and chemotherapy resistance are the main causes of treatment failure in glioma patients. There is a lack of ideal prediction models for post-operative glioma patient progression and drug sensitivity. We aimed to develop a prognostic model of parthanatos mRNA biomarkers for glioma outcomes. A total of 11 parthanatos genes were obtained from ParthanatosCluster database. ConsensusClusterPlus and R "Limma" package were used to cluster The Cancer Genome Atlas (TCGA)-glioma cohort and analyze the differential mRNAs. Univariate Cox regression analysis, random survival forest model, and least absolute shrinkage and selection operator (LASSO) regression analysis were used to determine the nine ParthanatosScore prognostic genes combination. ParthanatosScore was verified by 656 patients and 979 patients in TCGA and CGCA-LGG/GBM datasets. Differences in genomic mutations, tumor microenvironments, and functional pathways were assessed. Drug response prediction was performed using pRRophetic. Kaplan-Meier survival analysis was analyzed. Finally, COL8A1 was selected to evaluate its potential biological function and drug sensitivity of temozolomide and AZD3759 in glioma cells. ParthanatosScore obtained a combination of nine glioma prognostic genes, including CD58, H19, TNFAIP6, FTLP3, TNFRSF11B, SFRP2, LOXL1, COL8A1, and FABP5P7. In the TCGA-LGG/GBM dataset, glioma prognosis was poor in high ParthanatosScore. Low-score glioma patients were sensitive to AZD3759_1915, AZD5582_1617, AZD8186_1918, Dasatinib_1079, and Temozolomide_1375, while high-score patients were less sensitive to these drugs. Compared with HA cells, COL8A1 was significantly over-expressed in LN229 and U251 cells. Silencing COL8A1 inhibited the malignant characterization of LN229 and U251 cells. Temozolomide and AZD3759 also promoted parthanatos gene expression in glioma cells. Temozolomide and AZD3759 inhibited COL8A1 expression and cell viability and promoted apoptosis in glioma cells and PGM cells. ParthanatosScore can accurately predict clinical prognosis and drug sensitivity after glioma surgery. Silencing COL8A1 inhibited the malignant characterization. Temozolomide and AZD3759 inhibited COL8A1 expression and cell viability and promoted apoptosis and parthanatos gene expression, which is a target to improve glioma.


Assuntos
Glioma , Parthanatos , Humanos , Apoptose , Glioma/genética , Prognóstico , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Microambiente Tumoral
9.
Acta Neuropathol Commun ; 12(1): 5, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172953

RESUMO

BACKGROUND: Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2 ought to be a therapeutic target for the disease, regrettably, it is deemed undruggable due to its non-enzymatic nature and predominant localization within the tRNA synthetase multi-complex. Instead, AIMP2 possesses an antagonistic splice variant, designated DX2, which counteracts AIMP2-induced apoptosis in the p53 or inflammatory pathway. Consequently, we examined whether DX2 competes with AIMP2 for PARP-1 activation and is therapeutically effective in Parkinson's disease. METHODS: The binding affinity of AIMP2 and DX2 to PARP-1 was contrasted through immunoprecipitation. The efficacy of DX2 in neuronal cell death was assessed under 6-OHDA and H2O2 in vitro conditions. Additionally, endosomal and exosomal activity of synaptic vesicles was gauged in AIMP2 or DX2 overexpressed hippocampal primary neurons utilizing optical live imaging with VAMP-vGlut1 probes. To ascertain the role of DX2 in vivo, rotenone-induced behavioral alterations were compared between wild-type and DX2 transgenic animals. A DX2-encoding self-complementary adeno-associated virus (scAAV) was intracranially injected into 6-OHDA induced in vivo animal models, and their mobility was examined. Subsequently, the isolated brain tissues were analyzed. RESULTS: DX2 translocates into the nucleus upon ROS stress more rapidly than AIMP2. The binding affinity of DX2 to PARP-1 appeared to be more robust compared to that of AIMP2, resulting in the inhibition of PARP-1 induced neuronal cell death. DX2 transgenic animals exhibited neuroprotective behavior in rotenone-induced neuronal damage conditions. Following a single intracranial injection of AAV-DX2, both behavior and mobility were consistently ameliorated in neurodegenerative animal models induced by 6-OHDA. CONCLUSION: AIMP2 and DX2 are proposed to engage in bidirectional regulation of parthanatos. They physically interact with PARP-1. Notably, DX2's cell survival properties manifest exclusively in the context of abnormal AIMP2 accumulation, devoid of any tumorigenic effects. This suggests that DX2 could represent a distinctive therapeutic target for addressing Parkinson's disease in patients.


Assuntos
Doença de Parkinson , Parthanatos , Animais , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases , Proteínas Nucleares/metabolismo , Peróxido de Hidrogênio , Oxidopamina , Doença de Parkinson/genética , Doença de Parkinson/terapia , Rotenona , Linhagem Celular Tumoral
10.
Neurobiol Dis ; 187: 106314, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37783233

RESUMO

Poly (ADP-ribose) polymerase-1 (PARP-1) is the most extensively studied member of the PARP superfamily, with its primary function being the facilitation of DNA damage repair processes. Parthanatos is a type of regulated cell death cascade initiated by PARP-1 hyperactivation, which involves multiple subroutines, including the accumulation of ADP-ribose polymers (PAR), binding of PAR and apoptosis-inducing factor (AIF), release of AIF from the mitochondria, the translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and massive MIF-mediated DNA fragmentation. Over the past few decades, the role of PARP-1 in central nervous system health and disease has received increasing attention. In this review, we discuss the biological functions of PARP-1 in neural cell proliferation and differentiation, memory formation, brain ageing, and epigenetic regulation. We then elaborate on the involvement of PARP-1 and PARP-1-dependant parthanatos in various neuropathological processes, such as oxidative stress, neuroinflammation, mitochondrial dysfunction, excitotoxicity, autophagy damage, and endoplasmic reticulum (ER) stress. Additional highlight contains PARP-1's implications in the initiation, progression, and therapeutic opportunities for different neurological illnesses, including neurodegenerative diseases, stroke, autism spectrum disorder (ASD), multiple sclerosis (MS), epilepsy, and neuropathic pain (NP). Finally, emerging insights into the repurposing of PARP inhibitors for the management of neurological diseases are provided. This review aims to summarize the exciting advancements in the critical role of PARP-1 in neurological disorders, which may open new avenues for therapeutic options targeting PARP-1 or parthanatos.


Assuntos
Transtorno do Espectro Autista , Doenças Neurodegenerativas , Parthanatos , Humanos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ribose , Inibidores de Poli(ADP-Ribose) Polimerases , Epigênese Genética , Doenças Neurodegenerativas/patologia
11.
Cell Mol Life Sci ; 80(9): 258, 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37594630

RESUMO

HtrA2/Omi is a mitochondrial serine protease with ascribed pro-apoptotic as well as pro-necroptotic functions. Here, we establish that HtrA2/Omi also controls parthanatos, a third modality of regulated cell death. Deletion of HtrA2/Omi protects cells from parthanatos while reconstitution with the protease restores the parthanatic death response. The effects of HtrA2/Omi on parthanatos are specific and cannot be recapitulated by manipulating other mitochondrial proteases such as PARL, LONP1 or PMPCA. HtrA2/Omi controls parthanatos in a manner mechanistically distinct from its action in apoptosis or necroptosis, i.e., not by cleaving cytosolic IAP proteins but rather exerting its effects without exiting mitochondria, and downstream of PARP-1, the first component of the parthanatic signaling cascade. Also, previously identified or candidate substrates of HtrA2/Omi such as PDXDC1, VPS4B or moesin are not cleaved and dispensable for parthanatos, whereas DBC-1 and stathmin are cleaved, and thus represent potential parthanatic downstream mediators of HtrA2/Omi. Moreover, mass-spectrometric screening for novel parthanatic substrates of HtrA2/Omi revealed that the induction of parthanatos does not cause a substantial proteolytic cleavage or major alterations in the abundance of mitochondrial proteins. Resolving these findings, reconstitution of HtrA2/Omi-deficient cells with a catalytically inactive HtrA2/Omi mutant restored their sensitivity against parthanatos to the same level as the protease-active HtrA2/Omi protein. Additionally, an inhibitor of HtrA2/Omi's protease activity did not confer protection against parthanatic cell death. Our results demonstrate that HtrA2/Omi controls parthanatos in a protease-independent manner, likely via novel, unanticipated functions as a scaffolding protein and an interaction with so far unknown mitochondrial proteins.


Assuntos
Parthanatos , Serina Proteases/genética , Necroptose , Serina Endopeptidases/genética , Proteínas Mitocondriais/genética
12.
Eur J Pharmacol ; 956: 175980, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37567459

RESUMO

The use of cisplatin and its derivatives in cancer treatment triggered the interest in metal-containing complexes as potential novel anticancer agents. Palladium (II)-based complexes have been synthesized in recent years with promising antitumor activity. Previously, we described the synthesis and cytotoxicity of palladium (II) complexes containing halogen-substituted Schiff bases and 2-picolylamine. Here, we selected two palladium (II) complexes with double chlorine-substitution or double iodine-substitution that displayed the best cytotoxicity in drug-sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells for further biological investigation. Surprisingly, these compounds did not significantly induce apoptotic cell death. This study aims to reveal the major mode of cell death of these two palladium (II) complexes. We performed annexin V-FITC/PI staining and flow cytometric mitochondrial membrane potential measurement followed by western blotting, immunofluorescence microscopy, and alkaline single cell electrophoresis (comet assay). J4 and J6 still induced neither apoptosis nor necrosis in both leukemia cell lines. They also insufficiently induced autophagy as evidenced by Beclin and p62 detection in western blotting. Interestingly, J4 and J6 induced a novel mode of cell death (parthanatos) as mainly demonstrated in CCRF-CEM cells by hyper-activation of poly(ADP-ribose) polymerase 1 (PARP) and poly(ADP-ribose) (PAR) using western blotting, flow cytometric measurement of mitochondrial membrane potential collapse, nuclear translocation of apoptosis-inducing factor (AIF) by immunofluorescence microscopy, and DNA damage by alkaline single cell electrophoresis (comet assay). AIF translocation was also observed in CEM/ADR5000 cells. Thus, parthanatos was the predominant mode of cell death induced by J4 and J6, which explains the high cytotoxicity in CCRF-CEM and CEM/ADR5000 cells. J4 and J6 may be interesting drug candidates and deserve further investigations to overcome resistance of tumors against apoptosis. This study will promote the design of further novel palladium (II)-based complexes as chemotherapeutic agents.


Assuntos
Antineoplásicos Fitogênicos , Leucemia , Parthanatos , Humanos , Paládio/farmacologia , Halogênios/farmacologia , Bases de Schiff/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Resistência a Múltiplos Medicamentos , Antineoplásicos Fitogênicos/farmacologia , Morte Celular , Apoptose , Leucemia/tratamento farmacológico
13.
Am J Pathol ; 193(11): 1833-1844, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37423550

RESUMO

Retinal detachment (RD) refers to the separation between the neuroepithelium and the pigment epithelium layer. It is an important disease leading to irreversible vision damage worldwide, in which photoreceptor cell death plays a major role. α-Synuclein (α-syn) is reportedly involved in numerous mechanisms of neurodegenerative diseases, but the association with photoreceptor damage in RD has not been studied. In this study, elevated transcription levels of α-syn and parthanatos proteins were observed in the vitreous of patients with RD. The expression of α-syn- and parthanatos-related proteins was increased in experimental rat RD, and was involved in the mechanism of photoreceptor damage, which was related to the decreased expression of miR-7a-5p (miR-7). Interestingly, subretinal injection of miR-7 mimic in rats with RD inhibited the expression of retinal α-syn and down-regulated the parthanatos pathway, thereby protecting retinal structure and function. In addition, interference with α-syn in 661W cells decreased the expression of parthanatos death pathway in oxygen and glucose deprivation model. In conclusion, this study demonstrates the presence of parthanatos-related proteins in patients with RD and the role of the miR-7/α-syn/parthanatos pathway in photoreceptor damage in RD.


Assuntos
MicroRNAs , Parthanatos , Descolamento Retiniano , Ratos , Humanos , Animais , Descolamento Retiniano/genética , Descolamento Retiniano/metabolismo , Apoptose , Células Fotorreceptoras de Vertebrados/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Células Fotorreceptoras/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Animais de Doenças
14.
Cell Biol Toxicol ; 39(6): 2971-2997, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37322258

RESUMO

Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking in silico and binding to recombinant MEK by microscale thermophoresis in vitro. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer. A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest.


Assuntos
Glicosídeos Cardíacos , Leucemia , Parthanatos , Humanos , Apoptose , Fosforilação , Linhagem Celular Tumoral , Glicosídeos Cardíacos/farmacologia , Glicosídeos Cardíacos/uso terapêutico , Regulação para Baixo , Simulação de Acoplamento Molecular , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Pontos de Checagem da Fase G2 do Ciclo Celular , Proteínas de Neoplasias , Leucemia/tratamento farmacológico , Cardenolídeos/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/uso terapêutico , Resistencia a Medicamentos Antineoplásicos
15.
Med Intensiva (Engl Ed) ; 47(12): 691-696, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37268496

RESUMO

OBJECTIVE: Parthanatos is a form of programmed cell death mediated by apoptosis-inducing factor (AIF). However, there are not data on parthanatos in septic patients. The objective of the current study was to explore whether parthanatos is associated with mortality of septic patients. DESIGN: Observational and prospective study. SETTING: Three Spanish Intensive Care Units during 2017. PATIENTS: Patients with sepsis according to Sepsis-3 Consensus criteria. INTERVENTIONS: Serum AIF concentrations were determined at moment of sepsis diagnosis. MAIN VARIABLE OF INTEREST: Mortality at 30 days. RESULTS: There were included 195 septic patients, and non-surviving (n=72) had serum AIF levels (p<0.001), lactic acid (p<0.001) and APACHE-II (p<0.001) that surviving (n=123). Multiple logistic regression analysis showed that patients with serum AIF levels>55.6ng/mL had higher mortality risk (OR=3.290; 95% CI=1.551-6.979; p=0.002) controlling for age, SOFA and lactic acid. CONCLUSIONS: Parthanatos is associated with mortality of septic patients.


Assuntos
Parthanatos , Sepse , Humanos , Estudos Prospectivos , Prognóstico , Ácido Láctico , Apoptose
16.
J Med Chem ; 66(13): 8767-8781, 2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37352470

RESUMO

Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and essential signaling protein associated with inflammation and cancers. One of the newly described roles of MIF is binding to apoptosis-inducing factor (AIF) that "brings" cells to death in pathological conditions. The interaction between MIF and AIF and their nuclear translocation stands as a central event in parthanatos. However, classical competitive MIF tautomerase inhibitors do not interfere with MIF functions in parthanatos. In this study, we employed a pharmacophore-switch to provide allosteric MIF tautomerase inhibitors that interfere with the MIF/AIF co-localization. Synthesis and screening of a focused compound collection around the 1,2,3-triazole core enabled identification of the allosteric tautomerase MIF inhibitor 6y with low micromolar potency (IC50 = 1.7 ± 0.1 µM). This inhibitor prevented MIF/AIF nuclear translocation and protects cells from parthanatos. These findings indicate that alternative modes to target MIF hold promise to investigate MIF function in parthanatos-mediated diseases.


Assuntos
Fatores Inibidores da Migração de Macrófagos , Parthanatos , Humanos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fator de Indução de Apoptose , Inflamação/metabolismo , Oxirredutases Intramoleculares/metabolismo
17.
Acta Pharmacol Sin ; 44(11): 2265-2281, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37344563

RESUMO

The majority of blood malignancies is incurable and has unforeseeable remitting-relapsing paths in response to different treatments. Cynaropicrin, a natural sesquiterpene lactone from the edible parts of the artichoke plant, has gained increased attention as a chemotherapeutic agent. In this study, we investigated the effects of cynaropicrin against multiple myeloma (MM) cells in vitro and assessed its in vivo effectiveness in a xenograft tumor zebrafish model. We showed that cynaropicrin exerted potent cytotoxicity against a panel of nine MM cell lines and two leukemia cell lines with AMO1 being the most sensitive cell line (IC50 = 1.8 ± 0.3 µM). Cynaropicrin (0.8, 1.9, 3.6 µM) dose-dependently reduced c-Myc expression and transcriptional activity in AMO1 cells that was associated with significant downregulation of STAT3, AKT, and ERK1/2. Cell cycle analysis showed that cynaropicrin treatment arrested AMO1 cells in the G2M phase along with an increase in the sub-G0G1 phase after 24 h. With prolonged treatment times, cells accumulated more in the sub-G0G1 phase, implying cell death. Using confocal microscopy, we revealed that cynaropicrin disrupted the microtubule network in U2OS cells stably expressing α-tubulin-GFP. Furthermore, we revealed that cynaropicrin promoted DNA damage in AMO1 cells leading to PAR polymer production by PARP1 hyperactivation, resulting in AIF translocation from the mitochondria to the nucleus and subsequently to a novel form of cell death, parthanatos. Finally, we demonstrated that cynaropicrin (5, 10 µM) significantly reduced tumor growth in a T-cell acute lymphoblastic leukemia (T-ALL) xenograft zebrafish model. Taken together, these results demonstrate that cynaropicrin causes potent inhibition of hematopoietic tumor cells in vitro and in vivo.


Assuntos
Mieloma Múltiplo , Parthanatos , Sesquiterpenos , Animais , Humanos , Tubulina (Proteína) , Peixe-Zebra/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Lactonas/farmacologia , Lactonas/uso terapêutico , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Linhagem Celular Tumoral
18.
Acta Pharmacol Sin ; 44(10): 2125-2138, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37277492

RESUMO

Parthanatos is a type of programmed cell death dependent on hyper-activation of poly (ADP-ribose) polymerase 1 (PARP-1). SIRT1 is a highly conserved nuclear deacetylase and often acts as an inhibitor of parthanatos by deacetylation of PARP1. Our previous study showed that deoxypodophyllotoxin (DPT), a natural compound isolated from the traditional herb Anthriscus sylvestris, triggered glioma cell death via parthanatos. In this study, we investigated the role of SIRT1 in DPT-induced human glioma cell parthanatos. We showed that DPT (450 nmol/L) activated both PARP1 and SIRT1, and induced parthanatos in U87 and U251 glioma cells. Activation of SIRT1 with SRT2183 (10 µmol/L) enhanced, while inhibition of SIRT1 with EX527 (200 µmol/L) or knockdown of SIRT1 attenuated DPT-induced PARP1 activation and glioma cell death. We demonstrated that DPT (450 nmol/L) significantly decreased intracellular NAD+ levels in U87 and U251 cells. Further decrease of NAD+ levels with FK866 (100 µmol/L) aggravated, but supplement of NAD+ (0.5, 2 mmol/L) attenuated DPT-induced PARP1 activation. We found that NAD+ depletion enhanced PARP1 activation via two ways: one was aggravating ROS-dependent DNA DSBs by upregulation of NADPH oxidase 2 (NOX2); the other was reinforcing PARP1 acetylation via increase of N-acetyltransferase 10 (NAT10) expression. We found that SIRT1 activity was improved when being phosphorylated by JNK at Ser27, the activated SIRT1 in reverse aggravated JNK activation via upregulating ROS-related ASK1 signaling, thus forming a positive feedback between JNK and SIRT1. Taken together, SIRT1 activated by JNK contributed to DPT-induced human glioma cell parthanatos via initiation of NAD+ depletion-dependent upregulation of NOX2 and NAT10.


Assuntos
Glioma , Parthanatos , Sirtuína 1 , Humanos , Glioma/tratamento farmacológico , Acetiltransferases N-Terminal/genética , Acetiltransferases N-Terminal/metabolismo , NAD/metabolismo , NADPH Oxidase 2/metabolismo , Parthanatos/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Regulação para Cima
19.
Acta Pharmacol Sin ; 44(9): 1906-1919, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37186123

RESUMO

Parthanatos is a type of programmed cell death initiated by over-activated poly (ADP-ribose) polymerase 1 (PARP1). Nuclear translocation of apoptosis inducing factor (AIF) is a prominent feature of parthanatos. But it remains unclear how activated nuclear PARP1 induces mitochondrial AIF translocation into nuclei. Evidence has shown that deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells via induction of excessive ROS. In this study we explored the downstream signal of activated PARP1 to induce nuclear translocation of AIF in DPT-triggered glioma cell parthanatos. We showed that treatment with DPT (450 nM) induced PARP1 over-activation and Tax1 binding protein 1 (TAX1BP1) distribution to mitochondria in human U87, U251 and U118 glioma cells. PARP1 activation promoted TAX1BP1 distribution to mitochondria by depleting nicotinamide adenine dinucleotide (NAD+). Knockdown of TAX1BP1 with siRNA not only inhibited TAX1BP1 accumulation in mitochondria, but also alleviated nuclear translocation of AIF and glioma cell death. We demonstrated that TAX1BP1 enhanced the activity of respiratory chain complex I not only by upregulating the expression of ND1, ND2, NDUFS2 and NDUFS4, but also promoting their assemblies into complex I. The activated respiratory complex I generated more superoxide to cause mitochondrial depolarization and nuclear translocation of AIF, while the increased mitochondrial superoxide reversely reinforced PARP1 activation by inducing ROS-dependent DNA double strand breaks. In mice bearing human U87 tumor xenograft, administration of DPT (10 mg· kg-1 ·d-1, i.p., for 8 days) markedly inhibited the tumor growth accompanied by NAD+ depletion, TAX1BP1 distribution to mitochondria, AIF distribution to nuclei as well as DNA DSBs and PARP1 activation in tumor tissues. Taken together, these data suggest that TAX1BP1 acts as a downstream signal of activated PARP1 to trigger nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.


Assuntos
Glioma , Parthanatos , Humanos , Camundongos , Animais , Fator de Indução de Apoptose/genética , Superóxidos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , NAD/metabolismo , Transporte de Elétrons , Complexo I de Transporte de Elétrons , Glioma/metabolismo , Proteínas de Neoplasias/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
20.
CNS Neurosci Ther ; 29(10): 2857-2872, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37063066

RESUMO

INTRODUCTION: Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as motor, sensory, and autonomic dysfunction below the level of damage. Our previous studies confirmed the ability of zinc to protect mitochondria, protect neurons and promote spinal cord recovery. However, the role of zinc in Parthanatos is unknown. AIM: We investigated the effects of zinc in Parthanatos from oxidative stress and mitophagy. We elucidated the role of SIRT3 in providing new ideas for treating spinal cord injury. THE RESULTS: Zinc protected SCI mice by regulating Parthanatos. On the one hand, zinc eliminated ROS directly through SIRT3 deacetylation targeting SOD2 to alleviate Parthanatos. On the other hand, zinc eliminated ROS indirectly through SIRT3-mediated promotion of mitophagy to alleviate Parthanatos. CONCLUSION: Zinc defends against Parthanatos and promotes functional recovery after spinal cord injury through SIRT3-mediated anti-oxidative stress and mitophagy.


Assuntos
Parthanatos , Sirtuína 3 , Traumatismos da Medula Espinal , Camundongos , Animais , Sirtuína 3/metabolismo , Zinco/farmacologia , Espécies Reativas de Oxigênio , Mitofagia , Estresse Oxidativo/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...