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1.
Toxicol Lett ; 318: 57-64, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31585160

RESUMO

3-Bromopyruvate (3-BrPA) is a promising agent that has been widely studied in the treatment of cancer and pulmonary hypertension. Rotenone is a pesticide commonly used on farms and was shown to have anti-cancer activity and delay fibrosis progression in chronic kidney disease in a recent study. However, there are few studies showing the toxicity of rotenone and 3-BrPA in the myocardium. To support further medical exploration, it is necessary to clarify the side effects of these compounds on the heart. This study was designed to examine the cardiotoxicity of 3-BrPA and rotenone by investigating electrical and structural cardiac remodeling in rats. Forty male rats were divided into 4 groups (n = 10 in each group) and injected intraperitoneally with 3-BrPA, rotenone or a combination of 3-BrPA and rotenone. The ventricular effective refractory period (VERP), corrected QT interval (QTc), and ventricular tachycardia/ventricular fibrillation (VT/VF) inducibility were measured. The expression of Cx43, Kir2.1, Kir6.2, DHPRα1, KCNH2, caspase3, caspase9, Bax, Bcl2, and P53 was detected. Masson's trichrome, TUNEL, HE, and PAS staining and transmission electron microscopy were used to detect pathological and ultrastructural changes. Our results showed that rotenone alone and rotenone combined with 3-BrPA significantly increased the risk of ventricular arrhythmias. Rotenone combined with 3-BrPA caused myocardial apoptosis, and rotenone alone and rotenone combined with 3-BrPA caused electrical and structural cardiac remodeling in rats.


Assuntos
Antineoplásicos/toxicidade , Ventrículos do Coração/efeitos dos fármacos , Inseticidas/toxicidade , Piruvatos/toxicidade , Rotenona/toxicidade , Taquicardia Ventricular/induzido quimicamente , Fibrilação Ventricular/induzido quimicamente , Remodelação Ventricular/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade , Conexina 43/genética , Conexina 43/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/ultraestrutura , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos Wistar , Período Refratário Eletrofisiológico/efeitos dos fármacos , Medição de Risco , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/patologia , Fibrilação Ventricular/fisiopatologia
2.
Bratisl Lek Listy ; 120(10): 769-776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31663353

RESUMO

OBJECTIVE AND BACKGROUND: Methamphetamine (Meth) is one of the most important central nervous system (CNS) stimulant abuse drugs that cause long-term or permanent damage to different regions of the brain, particularly hippocampus, by neuronal apoptosis and inflammation. In this study, we evaluated Nod-like Receptor Protein 3(NLRP3) and Nod-like Receptor Protein1 (NLRP1) Inflammasome Activation in the Hippocampal Region of postmortem Meth Chronic User. METHODS: Molecular and histological analyses were conducted on the brain of 14 non-addicted and 11 Meth users separately. The expression level of NLRP1, NLRP3 was measured using western blotting and immunohistochemistry (IHC) techniques. Histopathological assessment was performed with stereological Cell Counting of hippocampal cells stained with hematoxylin and eosin (H et E). Moreover, Tunel staining was carried out in order to detect any kind of DNA damage. RESULTS: Based on our findings using western blotting and immunohistochemistry assay, overexpression of NLRP1 and NLRP3 proteins in the hippocampal region of Meth addicts was observed. The stereological analysis in the hippocampus of the human brain revealed increased neurodegeneration. Furthermore, the increased rate of apoptosis and cell death were significant and confirmed by Tunel assay in the hippocampus of Meth groups. CONCLUSION: Chronic Meth abuse could result in increases of NLRP1 and NLRP3 and induction of inflammation and apoptosis in the hippocampus in Meth groups (Tab. 1, Fig. 9, Ref. 40).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Hipocampo/metabolismo , Inflamassomos/metabolismo , Metanfetamina , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/mortalidade , Apoptose , Cadáver , Humanos , Imuno-Histoquímica
3.
Zhonghua Zhong Liu Za Zhi ; 41(9): 675-680, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550857

RESUMO

Objective: To investigate the inhibitory effect of programmed cell death factor 4 (PDCD4) on arsenic trioxide (As(2)O(3))-induced cell growth and nuclear factor kappa B (NF-κB) signaling pathway in neuroblastoma. Methods: The PDCD4 overexpression vector was transfected into neuroblastoma cells and detected by fluorescence quantitative PCR and Western blot. As(2)O(3) was used to treat PDCD4 overexpressing neuroblastoma cells. MTT assay was used to measure the proliferation. Colony formation assay was used to determine the cell clone forming ability. Apoptosis was measured by flow cytometry. Western blot was used to detect the expression of NF-κB p65 and cleaved caspase-3 protein in cells. Results: The transfection of PDCD4 overexpression vector significantly increased the expression level of PDCD4 in neuroblastoma cells. The cell survival rates of the control group, PDCD4 group, As(2)O(3) group and As(2)O(3)+ PDCD4 group were 100%, (72.14±5.20)%, (62.58±3.14)% and (40.87±2.47)%, respectively. The colony formation rates in these four groups were (91.25±8.36)%, (65.32±7.14)%, (57.23±5.28)% and (37.14±3.64)%, respectively. In addition, the cell apoptotic rates of these four groups were (3.57±0.24)%, (28.64±3.20)%, (36.41±4.58)% and (49.65±5.27)%, respectively. Therefore, overexpression of PDCD4 in the absence or presence of As(2)O(3) inhibited cell proliferation and clone formation ability, while promoted apoptosis. Furthermore, the expression levels of cleaved caspase-3 in the control group, PDCD4 group, As(2)O(3) group and As(2)O(3)+ PDCD4 group were 0.21±0.03, 0.30±0.02, 0.43±0.05 and 0.57±0.06, respectively. And the expression levels of NF-κB p65 protein were 0.68±0.04, 0.52±0.03, 0.43±0.04, and 0.32±0.02, respectively. Compared with the control group, the expression levels of NF-κB p65 protein in PDCD4 group, As(2)O(3) group and As(2)O(3)+ PDCD4 group were significantly decreased (P<0.05), whereas the expression level of cleaved Caspase-3 protein was significantly increased (P<0.05). The changes in As(2)O(3)+ PDCD4 group were more significant than those in PDCD4 group and As(2)O(3) groups (both P<0.05). Conclusion: PDCD4 enhances the inhibitory effect of As(2)O(3) on the growth and NF-κB signaling pathway in neuroblastoma cells.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Apoptose/efeitos dos fármacos , Trióxido de Arsênio/farmacologia , NF-kappa B/fisiologia , Neuroblastoma/tratamento farmacológico , Proteínas de Ligação a RNA/genética , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos , Proteínas Reguladoras de Apoptose/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Gene ; 721: 144107, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31499127

RESUMO

BACKGROUND: Gene environment interactions leading to epigenetic alterations play pivotal role in the pathogenesis of Coronary Artery Disease (CAD). Altered DNA methylation is one such epigenetic factor that could lead to altered disease etiology. In this study, we comprehensively identified methylation sites in several genes that have been previously associated with young CAD patients. METHODS: The study population consisted of 42 healthy controls and 33 young CAD patients (age group <50 years). We performed targeted bisulfite sequencing of promoter as well as gene body regions of several genes in various pathways like cholesterol synthesis and metabolism, endothelial dysfunction, apoptosis, which are implicated in the development of CAD. RESULTS: We observed that the genes like GALNT2, HMGCR were hypermethylated in the promoter whereas LDLR gene promoter was hypomethylated indicating that intracellular LDL uptake was higher in CAD patients. Although APOA1 did not show significant change in methylation but APOC3 and APOA5 showed variation in methylation in promoter and exonic regions. Glucokinase (GCK) and endothelial nitric oxide synthase 3 (NOS3) were hyper methylated in the promoter. Genes involved in apoptosis (BAX/BCL2/AKT2) and inflammation (PHACTR1/LCK) also showed differential methylation between controls and CAD patients. A combined analysis of the methylated CpG sites using machine learning tool revealed 14 CpGs in 11 genes that could discriminate CAD cases from controls with over 93% accuracy. CONCLUSIONS: This study is unique because it highlights important gene methylation alterations which might predict the risk of young CAD in Indian population. Large scale studies in different populations would be important for validating our findings and understanding the epigenetic events associated with CAD.


Assuntos
Doença da Artéria Coronariana/metabolismo , Ilhas de CpG , Metilação de DNA , Análise de Sequência de DNA , Adulto , Apolipoproteínas/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Sulfitos/química
5.
Life Sci ; 235: 116828, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31479679

RESUMO

AIMS: The renal tubule cells require a large number of mitochondria to supply ATP due to their high-energy demand during reabsorption and secretion against chemical gradients and result in mitochondria susceptible to disorder and injury during stress conditions. Injured mitochondria are eventually degraded by mitophagy, and disturbances in mitophagy are associated with the pathogenesis of acute kidney injury (AKI) such as diabetic nephropathy and glomerulosclerosis. However, whether a disturbance in mitophagy has occurred and the role it plays in (SAKI) is still unclear. Therefore, the aim of this study was to investigate the key features of mitophagy and mitochondrial dynamics in sepsis-induced acute kidney injury (SAKI). MAIN METHODS: In this study, a murine septic AKI model induced by cecal ligation and puncture (CLP) was built; mitophagy and mitochondrial dynamics were measured in mice kidney in different time point. KEY FINDINGS: The results showed that mitochondrial dynamics were characterized by fission/fusion aberrant, however more inclined to fission, and mitochondrial associated apoptosis was elevated over-time during SAKI. Furthermore, mitophagy was impaired in the later phase of SAKI, although elevated in early stage of SAKI. The results indicate that the underlying mechanisms of impaired mitophagy may associate with the cleavage of Parkin via caspases activated by NLRP3, at least partly. SIGNIFICANCE: It is conceivable that this selective autophagic process and quality control machinery was impaired, leading to the accumulation of damaged mitochondria, oxidative stress, and cell death. Therefore, a targeted approach, by enhancing mitophagy during SAKI, may be a promising therapeutic strategy.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/fisiopatologia , Degradação Mitocondrial/fisiologia , Dinâmica Mitocondrial/fisiologia , Sepse/complicações , Sepse/fisiopatologia , Lesão Renal Aguda/metabolismo , Animais , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sepse/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
6.
Life Sci ; 235: 116842, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494170

RESUMO

MicroRNAs plays important role in the development of myocardial infarction (MI). The aim of this study was to analyze whether miR-429 has effect on the process of autophagy in myocardial anoxia/reoxygenation (AR) or ischemia/reperfusion (IR) injury and explore the underlying mechanism. The results showed that miR-429 was significantly decreased in MI mouse hearts and AR treated cardiomyocytes. Dual luciferase activity assay proved that MO25 was the direct target of miR-429. MO25 was dramatically decreased in AR treated cardiomyocytes. Overexpression of miR-429 dramatically decreased the expression of MO25, whereas inhibition of miR-429 noticeably increased the expression of MO25. In addition, overexpression of miR-429 reduced GFP-LC3B labelled cells, decreased the number of vesicle and autophagosome in each cardiomyocyte, and induced cell apoptosis in AR treated cardiomyocytes. In contrast, inhibition of miR-429 had the opposite effect. The further in vivo study showed that when mouse in IR group were injected with antagomiR-429, the weight of left ventricular was increased and infarct size was significantly decreased. Finally, both the in vitro and in vivo study showed that the expression of MO25, LKB1, pAMPKa, ATG13, p62 and LC3BI/II was noticeably increased by antagomiR-429. In conclusion, our results suggested that antagonism of miR-429 ameliorates anoxia/reoxygenation injury in cardiomyocytes by enhancing MO25/LKB1/AMPK mediated autophagy.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Hipóxia/metabolismo , MicroRNAs/antagonistas & inibidores , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Autofagossomos/efeitos dos fármacos , Contagem de Células , Vesículas Citoplasmáticas/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Camundongos , MicroRNAs/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Traumatismo por Reperfusão Miocárdica , Miocárdio/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
7.
Life Sci ; 235: 116858, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31505195

RESUMO

AIMS: The current study was conducted to investigate the potential protective effects of hesperidin and its possible mechanisms of action on pancreatic ß-cells in diabetes. MAIN METHODS: Male Sprague Dawley rats were made diabetic using 65 mg/kg intraperitoneal injection of streptozotocin, and then administered daily with 100 mg/kg of hesperidin over 4 weeks. On conclusion of the experiment, blood and pancreatic tissue were collected to determine the function of ß-cells, apoptosis, oxidative stress, ER stress, and inflammation. KEY FINDINGS: Treatment of diabetic rats with hesperidin, significantly decreased fasting blood glucose and food intake, along with increased body weight, serum and pancreatic insulin levels, and pancreatic-duodenal homeobox-1 (PDX-1) protein expression. The beneficial roles of hesperidin on diabetic pancreatic ß-cells exhibited an increment in antioxidant SOD and GPx activities, and a decrement in nitrotyrosine as well as malondialdehyde (MDA) levels. Additionally, the elevated concentration of TNF-α and expressions of ER stress maker GRP78 and CHOP proteins in the pancreas of diabetic rats were significantly diminished by hesperidin treatment. Furthermore, hesperidin effectively modulated expressions of apoptosis-regulatory proteins in diabetic rat pancreas, as revealed by upregulating anti-apoptotic Bcl-xL; with a concomitant downregulating pro-apoptotic Bax, cleaved caspase-3, and inhibiting the activation of DNA repair protein poly (ADP-ribose) polymerase (PARP). SIGNIFICANCE: Collectively, these findings suggest that hesperidin may have the potential to protect pancreatic ß-cells and improve their function by suppressing oxidative and ER stress, along with activating its antioxidant, anti-inflammatory, and anti-apoptotic effects.


Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hesperidina/farmacologia , Células Secretoras de Insulina/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Homeodomínio/biossíntese , Inflamação , Insulina/sangue , Insulina/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Superóxido Dismutase/metabolismo , Transativadores/biossíntese , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
8.
Physiol Rev ; 99(4): 1765-1817, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364924

RESUMO

Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.


Assuntos
Morte Celular , Citotoxicidade Imunológica , Cardiopatias/patologia , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Humanos , Mitocôndrias Cardíacas/imunologia , Mitocôndrias Cardíacas/metabolismo , Miocárdio/imunologia , Miocárdio/metabolismo , Necrose , Piroptose , Transdução de Sinais
9.
Cancer Immunol Immunother ; 68(9): 1479-1492, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31463653

RESUMO

RIG-I is a cytosolic RNA sensor that recognizes short 5' triphosphate RNA, commonly generated during virus infection. Upon activation, RIG-I initiates antiviral immunity, and in some circumstances, induces cell death. Because of this dual capacity, RIG-I has emerged as a promising target for cancer immunotherapy. Previously, a sequence-optimized RIG-I agonist (termed M8) was generated and shown to stimulate a robust immune response capable of blocking viral infection and to function as an adjuvant in vaccination strategies. Here, we investigated the potential of M8 as an anti-cancer agent by analyzing its ability to induce cell death and activate the immune response. In multiple cancer cell lines, M8 treatment strongly activated caspase 3-dependent apoptosis, that relied on an intrinsic NOXA and PUMA-driven pathway that was dependent on IFN-I signaling. Additionally, cell death induced by M8 was characterized by the expression of markers of immunogenic cell death-related damage-associated molecular patterns (ICD-DAMP)-calreticulin, HMGB1 and ATP-and high levels of ICD-related cytokines CXCL10, IFNß, CCL2 and CXCL1. Moreover, M8 increased the levels of HLA-ABC expression on the tumor cell surface, as well as up-regulation of genes involved in antigen processing and presentation. M8 induction of the RIG-I pathway in cancer cells favored dendritic cell phagocytosis and induction of co-stimulatory molecules CD80 and CD86, together with increased expression of IL12 and CXCL10. Altogether, these results highlight the potential of M8 in cancer immunotherapy, with the capacity to induce ICD-DAMP on tumor cells and activate immunostimulatory signals that synergize with current therapies.


Assuntos
Antineoplásicos/uso terapêutico , Células Dendríticas/imunologia , Melanoma/tratamento farmacológico , Nelfinavir/análogos & derivados , Alarminas/imunologia , Apresentação do Antígeno/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Calreticulina/metabolismo , Caspase 3/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proteína DEAD-box 58/antagonistas & inibidores , Proteína HMGB1/metabolismo , Humanos , Imunização , Interferons/metabolismo , Terapia de Alvo Molecular , Nelfinavir/farmacologia , Nelfinavir/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais
10.
Mol Immunol ; 112: 387-393, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288148

RESUMO

Programmed cell death 4 (Pdcd4) was found to be related to apoptosis upon first discovery. It was later found to play the role of tumor suppressor gene in a variety of tumors by inhibiting transcription and translation. Recently, it has been proposed that it may play an important role in some inflammatory diseases and in the immune response. In our previous study, deficiency of Pdcd4 was found to attenuate the formation of atherosclerotic plaques. This might be because deficiency of Pdcd4 may increase IL-10 expression and lipoautophagy by macrophages and attenuate the formation of foam cells. However, the effect of Pdcd4 on the subsets of T cells in hyperlipidemic mice still remained unclear. In the present study, results showed that Pdcd4 deficiency decreased the percentage of CD8+ T cells and increased that of regulatory T cells (Tregs) under hyperlipidemic conditions both in vitro and in vivo, which may be due to the reduced expression of co-stimulatory molecules CD28 and CD137, and the enhancive expression of co-inhibitory molecules CTLA-4. These results indicated that endogenous Pdcd4 promotes immune response mediated by T cells through regulation of the co-stimulatory molecules expression, which may contribute to the development of advanced atherosclerotic plaques. The current work provides new data to understand the role of Pdcd4 in different T cell subsets under hyperlipidemic microenvironment.


Assuntos
Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/metabolismo , Hiperlipidemias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Apoptose/fisiologia , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Espumosas/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
11.
Life Sci ; 232: 116623, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279781

RESUMO

AIMS: Doxorubicin, an antibiotic belonging to anthracycline family, has been used for treatment of malignancies. Cardiotoxicity is the main adverse effect of doxorubicin. Apigenin, as a flavonoid, has antioxidant, anti-inflammatory and anti-tumoral properties. The aim of this study was the assessment of any protective effect of apigenin on cardiotoxicity induced by doxorubicin. MAIN METHODS: 40 male Wistar rats were randomly divided into 4 groups: control, cardiotoxicity (DOX), apigenin treated group (DOX + Api 25) and apigenin group (Api 25). At the end of the experiment, the markers of cardiac function (%EF, %FS, LVIDs, LVIDd), cardiac and liver injury (LDH, CK-MB, cTn-I, ALT, and AST), cardiac apoptosis (Bax, Bcl-2 and Caspase3), cardiac oxidative stress (SOD, GSH, MDA) and cardiac fibrosis were measured. KEY FINDINGS: Apigenin improved cardiac functional parameters. The levels of cardiac and liver injury markers were significantly decreased in DOX + Api 25 compared to DOX. Treatment with apigenin caused significant decrease in percentage of cardiac fibrosis in comparison with DOX. Apigenin in DOX + Api 25 group led to significant decrease in apoptotic proteins (Casp3, Bax) and a significant increase in anti-apoptotic proteins (Bcl2). In apigenin treatment groups, SOD levels significantly increased while a significant decrease was observed in MDA. The amount of GSH in DOX + Api 25 had no significant change in comparison to control and Api 25 groups. SIGNIFICANCE: Apigenin reduced cardiac injuries induced by DOX through anti-fibrotic, antioxidant and anti-apoptotic properties. It seems that apigenin prevents cardiac injuries and improves cardiac function.


Assuntos
Apigenina/farmacologia , Cardiotoxicidade/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Apigenina/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/metabolismo , Flavonoides/farmacologia , Testes de Função Cardíaca , Inflamação/patologia , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
12.
Life Sci ; 231: 116578, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31211996

RESUMO

AIMS: The aim of the present study is to shed light on the modulating action of selenium on two of the most crucial cellular pathways; apoptosis and autophagy and the possible interplay between them in determining the pituitary fate in the context of mercury intoxication through demonstration of the molecular, histopathological, immunohistochemical, and ultrastructural features of selenium mercury-treated adenohypophysis. METHODS: Thirty adult Sprague Dawley male albino rats were assigned into control group, mercury-treated group and mercury­selenium concomitantly-treated group. The adenohypophysis was subjected to structural, molecular and protein expression assessment of autophagy and apoptotic markers and western blotted analysis of Beclin 1 as a key cross-regulator of autophagy and apoptosis. KEY FINDINGS: Selenium treatment ameliorated the mercury-induced apoptosis detected by improvement in PCR and immunohistochemical expression of the apoptotic markers Bax, Bcl-2 and Caspase-3. Selenium also improved mercury-induced autophagic dysfunction with statistically significant improvement in western blotted levels of the autophagy markers LC3I, LC3II and Beclin1. The histopathological and ultrastructural studies strongly confirmed those findings. SIGNIFICANCE: The crosstalk between the apoptotic Bcl-2 family of proteins and the autophagic Beclin-1LC3 pathway in the context of mercury intoxication paves the way for developing novel effective treatment strategies for several mercury-induced pituitary diseases.


Assuntos
Intoxicação por Mercúrio/prevenção & controle , Mercúrio/toxicidade , Hipófise/efeitos dos fármacos , Selênio/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Caspase 3/metabolismo , Masculino , Intoxicação por Mercúrio/metabolismo , Intoxicação por Mercúrio/patologia , Hipófise/metabolismo , Hipófise/patologia , Adeno-Hipófise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
13.
Life Sci ; 232: 116606, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254586

RESUMO

AIMS: Bupivacaine, a common local anesthetic, can cause neurotoxicity and abnormal neuro-disorders. However, the precise underlying mechanisms have not been fully elucidated. In this study, we investigated the function of lncRNA MALAT1 in the bupivacaine-induced neurotoxicity process. MATERIALS AND METHODS: SH-SY5Y cells and neonatal mouse DRG neurons were cultured in vitro and treated with bupivacaine to establish a neurotoxicity model. Caspase3 activity and cell survival rates were detected to evaluate the function of lncRNA MALAT1. Western blotting was used to detect the expression levels of PDCD4 and cleaved-caspase-3. A dual-luciferase reporter assay was used to explore the potential binding target of lncRNA MALAT1. RESULTS: We found that the expression of lncRNA MALAT1 was upregulated upon exposure to bupivacaine. Knockdown of lncRNA MALAT1 significantly increased the cell death rates, and Caspase3 activity assays revealed that the apoptosis rates were manifestly increased in the MALAT1 downregulation group. In addition, we screened the possible target and found that miR-101-3p is the direct target of MALAT1 using a dual-luciferase reporter assay; these results suggest that lncRNA MALAT1 may function as a decoy to sponge miR-101-3p. Furthermore, we demonstrated that activation of the MALAT1/miR-101-3p/PDCD4 axis protected cells against bupivacaine treatment. CONCLUSION: We elucidated the function and mechanism of MALAT1 in bupivacaine-induced neurotoxicity. Targeting MALAT1 might provide new methods to prevent neurotoxicity.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Bupivacaína/toxicidade , MicroRNAs/metabolismo , Síndromes Neurotóxicas/etiologia , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Anestésicos Locais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Gânglios Espinais/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , MicroRNAs/genética , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/genética , Regulação para Cima/efeitos dos fármacos
14.
Gene ; 712: 143935, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31247220

RESUMO

As seen in other types of cancer, development of drug resistance in NSCLC treatment causes adverse effects on disease fighting process. Recent studies have shown that one of the drug resistance development mechanisms is that cancer cells may acquire the ability to escape from cell death. Therefore, development of anticancer drugs which have the strategy to redirect cancer cells to any cell death pathways may provide positive results for cancer treatments. Autophagy may be a target mechanism of alternative cancer treatment strategy in cases of blocked apoptosis. There is also a complex molecular link between autophagy and apoptosis, has not been fully understood yet. The dicyano compound which we used in our study caused cell death in NSCLC cell lines. When we analyzed the cells which were treated with dicyano compound by transmission electron microscope, we observed autophagosome structures. Upon this result, we investigated expression levels of autophagic proteins in the dicyano compound-treated cells by immunoblotting and observed that expression levels of autophagic proteins were increased significantly. The TUNEL assay and qRT-PCR for pro-apoptotic and anti-apoptotic gene expression, which we performed to assess apoptosis in the dicyano compound-treated cells, showed that the cell death does not occur through apoptotic pathway. We showed that the dicyano compound, which was developed in our laboratories, may play a role in molecular link between apoptosis and autophagy and may shed light on development of new anticancer treatment strategies.


Assuntos
Autofagia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Galactose/química , Neoplasias Pulmonares/metabolismo , Triazóis/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/metabolismo , Naftiridinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
15.
Cancer Sci ; 110(9): 2690-2699, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250942

RESUMO

Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence-associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell-mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA-MB-231 and BT-549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence-associated ß-galactosidase and promoted the production of pro-inflammatory cytokines. Importantly, DXR-treated senescent MDA-MB-231 cells showed increased sensitivity to 2 types of immune cell-mediated cytotoxicity: cytotoxicity of activated CD4+ T cells and Ab-dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor-related apoptosis-inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence-inducing cyclin-dependent kinase-4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell-mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Senescência Celular/imunologia , Células Matadoras Naturais/imunologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia
16.
Neoplasma ; 66(5): 746-755, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31169019

RESUMO

MiR-21-5p has been identified as an oncogene to enhance human tumor progression. Here, we explored the mechanism by which miR-21-5p regulated the progression and paclitaxel (PTX) resistance in drug-resistant breast cancer (BC) cell lines. qRT-PCR assays were used to assess the expression levels of miR-21-5p and PDCD4 mRNA, and western blotting was used to detect PDCD4 protein level in PTX-resistant BC cell lines. Dual-luciferase reporter assay was used to observe the interaction between miR-21-5p and PDCD4 in PTX-resistant BC cell lines. Cell proliferation ability and IC50 values of PTX were measured by CCK-8 assay, cell cycle progression and apoptosis were determined with flow cytometry analysis, and cell migration and invasion capacities were analyzed using Transwell assay. Xenograft mice assay was used to validate the important role of miR-21-5p as a regulator on PTX-resistance BC cells growth in vivo. Then, we found that miR-21-5p was upregulated and PDCD4 was downregulated in BC tissues and PTX-resistant BC cell lines. MiR-21-5p silencing or PDCD4 overexpression ameliorated PTX resistance and inhibited the progression in PTX-resistant BC cell lines. Moreover, PDCD4 was demonstrated to be a direct target of miR-21-5p. MiR-21-5p exerted its regulatory effect by PDCD4 in PTX-resistant BC cell lines. Additionally, miR-21-5p silencing inhibited tumor growth in vivo. Therefore, our study demonstrated that miR-21-5p silencing ameliorated PTX resistance and inhibited the progression in PTX-resistant BC cell lines at least partly by targeting PDCD4, providing miR-21-5p as an effective therapeutic target for PTX-resistant BC treatment.


Assuntos
Proteínas Reguladoras de Apoptose , Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , MicroRNAs , Paclitaxel , Proteínas de Ligação a RNA , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/metabolismo , Paclitaxel/farmacologia , Proteínas de Ligação a RNA/metabolismo
17.
Toxicol Lett ; 313: 42-49, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31154016

RESUMO

Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53. In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.


Assuntos
Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Cálcio/metabolismo , Mitocôndrias/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Ocratoxinas/toxicidade , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Sinalização do Cálcio/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
18.
Nat Commun ; 10(1): 2761, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235698

RESUMO

Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias do Sistema Nervoso Central/patologia , Células Endoteliais/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/patologia , Diferenciação Celular/genética , Linhagem Celular , Neoplasias do Sistema Nervoso Central/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Técnicas de Inativação de Genes , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mutação com Perda de Função , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/metabolismo
19.
Oncol Res ; 27(5): 601-611, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31053182

RESUMO

Baicalein, an active ingredient separated from Astragalus membranaceus, has shown its anticancer ability in various cancers. However, its effect on nasopharyngeal carcinoma has not been explored yet. The present study aimed to investigate the effect of baicalein on the growth, proliferation, apoptosis, and cell cycle of human nasopharyngeal carcinoma cells, as well as transplanted nude mouse xenograft. The results showed that baicalein inhibited the growth and proliferation of CNE1 and CNE2 cells in a time- and concentration-dependent manner. It also caused a significant increase in the number of cells in the G0/G1 phase and a decrease in the G2/M phase, thereby reducing the number of cells entering mitosis and inhibiting the proliferation of tumor cells. Baicalein also significantly induced apoptosis of CNE1 and CNE2 cells. Western blots showed that baicalein decreased the expression of Bcl-xl and Mcl-1 and increased the expression of Bax, Bad, and caspase 3, 8, and 9. In CNE1- and CNE2-transplanted tumors of mice, baicalein significantly inhibited tumor growth. In conclusion, baicalein could inhibit the growth and proliferation of human nasopharyngeal carcinoma cells, change their cell cycle, and induce apoptosis. Baicalein also effectively limits both CNE1- and CNE2-transplanted tumors in nude mice. Downregulation of Bcl-xl and Mcl-1 proteins and upregulation of Bax and Bad may be involved in the mechanism.


Assuntos
Antineoplásicos/uso terapêutico , Flavanonas/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Astragalus propinquus/imunologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Iran J Allergy Asthma Immunol ; 18(2): 218-224, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066258

RESUMO

The mustard lung is a late consequence of exposure to sulfur mustard (SM) in veterans who had participated in the Iraq-Iran war. Three mechanisms are contributed in the pathogenesis of mustard lung including oxidative stress, protease-antiprotease imbalance, and dysregulated immune response. In the context of the immune response, the role of the inflammasome complex and their inflammatory cytokines are important. This study aims to investigate the inflammasome pathway and their inflammatory cytokine (i.e IL-1 and IL-18) in the peripheral blood of mustard lung patients as well as chronic obstructive pulmonary disease (COPD) patients. This research was conducted as a cross-sectional analytical study on 15 SM patients and was compared with 15 COPD patients and 15 healthy controls. The real-time polymerase chain reaction was used to assess gene expression levels of inflammasome components (NLRP1, NLRP3, NLRC4, and ASC), inflammatory cytokines (IL-1ß, IL-18, and IL-1ßR), and IL-37 as an anti-inflammatory cytokine. Finally, the data were analyzed by SPSS version 21 software. The gene expression level of molecules involved in inflammasome pathway showed a slight increase in the peripheral blood of SM and COPD patients compared to the control group. However, this difference was not statistically significant. Only IL-37 and NLRP1 had a significant increase in mustard lung and COPD patients; compared to healthy controls (p<0.05). Due to the normal expression of genes involved in the inflammasome pathway, it can be stated that the inflammasome pathway is not active in the blood of mustard lung patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Substâncias para a Guerra Química/efeitos adversos , Inflamassomos/metabolismo , Interleucina-1/metabolismo , Pneumopatias/imunologia , Gás de Mostarda/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Mediadores da Inflamação/sangue , Interleucina-1/sangue , Interleucina-1/genética , Interleucina-18/sangue , Guerra do Iraque 2003-2011 , Pneumopatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/imunologia , Veteranos
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