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1.
Cancer Sci ; 111(3): 807-816, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31908105

RESUMO

Activation-induced cell death (AICD) mediated by the Fas/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL-derived NK cell lines NK-YS and Hank1, and primary lymphoma cells expressed procaspase-8/FADD-like interleukin-1ß-converting enzyme (FLICE) modulator and cellular FLICE-inhibitory protein (c-FLIP), along with Fas and FasL. Compared with Fas-sensitive Jurkat cells, NK-YS and Hank1 showed resistance to Fas-mediated apoptosis in spite of the same expression levels of c-FLIP and the death-inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c-FLIP (c-FLIPL ) was coimmunoprecipitated with Fas predominantly in both ENKL-derived NK cell lines after Fas ligation. Indeed, c-FLIPL was more sufficiently recruited to the DISC in both ENKL-derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c-FLIPL per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK-YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c-FLIPL , which prevents their Fas-mediated apoptosis. Our results show that c-FLIPL could be a promising therapeutic target against ENKL.


Assuntos
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Células Matadoras Naturais/metabolismo , Linfoma/metabolismo , Receptor fas/metabolismo , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 8/metabolismo , Caspases/metabolismo , Morte Celular/fisiologia , Proteína Ligante Fas , Proteína de Domínio de Morte Associada a Fas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Jurkat , Isoformas de Proteínas/metabolismo , Transdução de Sinais/fisiologia
2.
J Photochem Photobiol B ; 204: 111780, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31981988

RESUMO

Photothermal therapy (PTT) is recently clinically established cancer therapy that uses near-infrared light for thermal ablation of solid tumors. The biopolymer N-dihydrogalactochitosan (GC) was shown in multiple reports to act as a very effective adjunct to tumor PTT. In the present study, mouse tumor model SCCVII (squamous cell carcinoma) was used with two protocols, in situ tumor PTT and therapeutic PTT vaccine for tumors, for investigating the effects of GC. The results reveal that GC can potentiate tumoricidal action of PTT through both direct and indirect mechanisms. In addition to previously known capacity of GC for activating immune effector cells, the indirect means is shown to include reducing the populations of immunoregulatory T cells (Tregs) in PTT-treated tumors. Testing the effects of GC on PTT-treated SCCVII tumor cells in vitro uncovered the existence of a direct mechanism evident by reduced colony survival of these cells. Fluorescence microscopy demonstrated increased binding of fluorescein-labeled GC to PTT-treated compared to untreated SCCVII cells that can be blocked by pre-exposure to annexin V. The results of additional in vitro testing with specific inhibitors demonstrate that these direct mechanisms do not involve the engagement of death surface receptors that trigger extrinsic apoptosis pathway signaling but may be linked to pro-survival activity of caspase-1. Based on the latter, it can be suggested that GC-promoted killing of PTT-treated cells stems from interference of GC bound to damaged membrane components with the repair of these structures that consequently hinders cell survival.


Assuntos
Quitosana/química , Lasers Semicondutores , Fototerapia/métodos , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Caspase 1/química , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quitosana/farmacologia , Modelos Animais de Doenças , Proteína Ligante Fas/metabolismo , Fluoresceína/química , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Camundongos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Receptor fas/metabolismo
3.
Life Sci ; 241: 117086, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31756344

RESUMO

BACKGROUND/AIMS: Recent studies have found vitamin D deficiency promotes fat deposition into the hepatocytes, thus contributing to the development of nonalcoholic fatty liver disease (NAFLD), which is a hepatic manifestation of metabolic syndrome. This study aimed to investigate the potential effects of vitamin D on NAFLD with the involvement of the p53 pathway. METHODS: Initially, an in vivo high-fat diet (HFD)-induced NAFLD mouse model was established. Then the HFD-induced NAFLD mice were treated with vitamin D. Next, the serum levels of TNF-α, GSH-px and malondialdehyde (MDA) were assessed using ELISA and ROS content was evaluated by flow cytometry, followed by the measurement of expression of Duox1, Duox2, SOD1, SOD2, PRDX1 I, ACC, SREBP1c, MTTP, PPARα, p53, p21 and p16 using RT-qPCR and Western blot analysis. Positive expression of FAS and FASL proteins was measured using immunohistochemistry. TUNEL and Senescence-associated ß-galactosidase (SA-ß-Gal) staining were subsequently conducted to assess the senescence and apoptosis of hepatocytes. RESULTS: HFD-induced mice treated with vitamin D presented with significantly increased GSH-px levels, as well as protein expression of SOD1, SOD2, PRDX1, MTTP and PPARα, but decreased MDA and ROS levels, expression of Duox1, Duox2, ACC, SREBP1c, p53, p21 and p16, positive expression of FAS and FASL proteins as well as impaired senescence and apoptosis of hepatocytes. CONCLUSION: Active vitamin D supplementation could potentially impede hepatocyte senescence and apoptosis via suppression of the p53 pathway, thus preventing the progression of NAFLD. Our study provides available evidence on the potential clinical utility of vitamin D supplementation in NAFLD.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Vitamina D/farmacologia , Animais , Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Proteína Ligante Fas/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas/metabolismo , Esteroide Hidroxilases/genética , Proteína Supressora de Tumor p53/genética , Receptor fas/metabolismo
4.
BMC Genomics ; 20(Suppl 3): 293, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31815628

RESUMO

BACKGROUND: Structural homology modeling supported by bioinformatics analysis plays a key role in uncovering new molecular interactions within gene regulatory networks. Here, we have applied this powerful approach to analyze the molecular interactions orchestrating death receptor signaling networks. In particular, we focused on the molecular mechanisms of CD95-mediated NF-κB activation and the role of c-FLIP/NEMO interaction in the induction of this pathway. RESULTS: To this end, we have created the homology model of the c-FLIP/NEMO complex using the reported structure of the v-FLIP/NEMO complex, and rationally designed peptides targeting this complex. The designed peptides were based on the NEMO structure. Strikingly, the experimental in vitro validation demonstrated that the best inhibitory effects on CD95-mediated NF-κB activation are exhibited by the NEMO-derived peptides with the substitution D242Y of NEMO. Furthermore, we have assumed that the c-FLIP/NEMO complex is recruited to the DED filaments formed upon CD95 activation and validated this assumption in silico. Further insight into the function of c-FLIP/NEMO complex was provided by the analysis of evolutionary conservation of interacting regions which demonstrated that this interaction is common in distinct mammalian species. CONCLUSIONS: Taken together, using a combination of bioinformatics and experimental approaches we obtained new insights into CD95-mediated NF-κB activation, providing manifold possibilities for targeting the death receptor network.


Assuntos
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Quinase I-kappa B/metabolismo , Sondas Moleculares , NF-kappa B/metabolismo , Receptor fas/metabolismo , Sequência de Aminoácidos , Biologia Computacional , Humanos , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Alinhamento de Sequência , Transdução de Sinais
5.
Anticancer Res ; 39(11): 5911-5918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704815

RESUMO

BACKGROUND/AIM: Double-negative T (DNT) cells are phenotypically CD3+CD4-CD8-T cells. This study aimed to investigate the anti-cancer activity of DNT cells against pancreatic cancer cells. MATERIALS AND METHODS: DNT cells were isolated from human peripheral blood. The effect of DNT cells on proliferation and invasion of the human pancreatic cell line Panc-1 was assessed. Expression of Nrf2 and Fas in Panc-1 cells co-cultured with DNT cells was analyzed with RT-PCR. The supernatants of Panc-1 and DNT co-cultures were analyzed with ELISA for IFN-r and FasL levels. RESULTS: The isolated DNT cell phenotype was CD4-CD8-CD56- CD3+TCR (T cell receptor) α/ß+ T cells with more than 90% purity. Panc-1 cell proliferation was significantly inhibited by co-culture with DNT cells. Panc-1 cells co-cultured with DNT cells showed significantly reduced cell invasion. Panc-1 cells co-cultured with DNT cells showed increased Nrf2 and Fas mRNA expression. Increased INF-r and FasL levels were detected in the supernatants of co-cultures of DNT and pancreatic cells. CONCLUSION: DNT cells inhibited proliferation and invasion of human pancreatic cancer cells. The INF-r, Fas/FasL pathway and Nrf2 may be involved in the anti-cancer effect of DNT cells against human pancreatic cancer.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cocultura/métodos , Ativação Linfocitária/imunologia , Neoplasias Pancreáticas/prevenção & controle , Apoptose , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Proteína Ligante Fas/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Interferon/metabolismo , Células Tumorais Cultivadas , Receptor fas/metabolismo
6.
Genes Dev ; 33(23-24): 1657-1672, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727774

RESUMO

In obesity, adipose tissue undergoes dynamic remodeling processes such as adipocyte hypertrophy, hypoxia, immune responses, and adipocyte death. However, whether and how invariant natural killer T (iNKT) cells contribute to adipose tissue remodeling are elusive. In this study, we demonstrate that iNKT cells remove unhealthy adipocytes and stimulate the differentiation of healthy adipocytes. In obese adipose tissue, iNKT cells were abundantly found nearby dead adipocytes. FasL-positive adipose iNKT cells exerted cytotoxic effects to eliminate hypertrophic and pro-inflammatory Fas-positive adipocytes. Furthermore, in vivo adipocyte-lineage tracing mice model showed that activation of iNKT cells by alpha-galactosylceramide promoted adipocyte turnover, eventually leading to potentiation of the insulin-dependent glucose uptake ability in adipose tissue. Collectively, our data propose a novel role of adipose iNKT cells in the regulation of adipocyte turnover in obesity.


Assuntos
Adipócitos/citologia , Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Morte Celular/fisiologia , Ativação Linfocitária/fisiologia , Células T Matadoras Naturais/fisiologia , Obesidade/fisiopatologia , Células 3T3 , Adipócitos/imunologia , Adipócitos/metabolismo , Animais , Proliferação de Células , Proteína Ligante Fas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor fas/metabolismo
7.
Environ Toxicol ; 34(12): 1320-1328, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31486215

RESUMO

Carthamus tinctorius L. (Compositae) is used in Chinese medicine to treat heart disease and inflammation. In our previous study, we found that C. tinctorius L. inhibited lipopolysaccharides (LPS)-induced tumor necrosis factor-alpha (TNF-α) activation, JNK expression, and apoptosis in H9c2 cardiomyoblast cells. The present study was performed to investigate the protective effect of C. tinctorius extract (CTF) on LPS-challenged H9c2 myocardioblast cell and to explore the possible underlying mechanism. Cell viability assay showed that LPS treatment decreased the cell viability of H9c2 cell, whereas CTF treatment reversed LPS cytotoxicity in a dose-dependent manner, especially in the LPS + CTF 25 (µg/mL) group. LPS treatment-induced apoptosis was determined by transferase-mediated dUTP nick end labeling assay, and by Western blot. LPS-induced apoptotic bodies were decreased following CTF treatment. Expression of TNF-α, FAS-L, FAS, FADD, caspase-8, BID, and t-BID was significantly increased in LPS-treated H9c2 cells. In contrast, it was significantly suppressed by the administration of CTF extract. In addition, CTF treatment activates antiapoptotic proteins, Bcl-2 and p-Bad, and downregulates Bax, cytochrome-c, caspase-9, caspase-3, and apoptosis-inducing factor expression. Furthermore, CTF exerted cytoprotective effects by activating insulin-like growth factor-I (IGF-I) signaling pathway leading to downregulation of the apoptotic proteins involved in FAS death receptor pathway. In addition, AG1024 and IGF-I receptor (IGF-IR) inhibitor and siRNA silencing reverses the effect of CTF implying that CTF functions through the IGF-IR pathway to inhibit LPS-induced H9c2 apoptosis. These results suggest that treatment with CTF extract prevented the LPS-induced apoptotic response through IGF-I pathway.


Assuntos
Apoptose/efeitos dos fármacos , Carthamus tinctorius/química , Extratos Vegetais/farmacologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor fas/metabolismo , Animais , Carthamus tinctorius/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Mol Sci ; 20(16)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394726

RESUMO

Matrix metalloproteinases (MMPs) have been studied in the context of cancer due to their ability to increase cell invasion, and were initially thought to facilitate metastasis solely through the degradation of the extracellular matrix (ECM). MMPs have also been investigated in the context of their ECM remodeling activity in several acute and chronic inflammatory diseases. However, after several MMP inhibitors failed in phase III clinical trials, a global reassessment of their biological functions was undertaken, which has revealed multiple unanticipated functions including the processing of chemokines, cytokines, and cell surface receptors. Despite what their name suggests, the matrix aspect of MMPs could contribute to a lesser part of their physiological functions in inflammatory diseases, as originally anticipated. Here, we present examples of MMP substrates implicated in cell signaling, independent of their ECM functions, and discuss the impact for the use of MMP inhibitors.


Assuntos
Fenômenos Fisiológicos Celulares , Metaloproteinases da Matriz/metabolismo , Animais , Adesão Celular , Comunicação Celular , Morte Celular , Movimento Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , Matriz Extracelular/metabolismo , Humanos , Transdução de Sinais , Receptor fas/metabolismo
9.
Anticancer Res ; 39(7): 3641-3649, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262890

RESUMO

BACKGROUND/AIM: Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer. MATERIALS AND METHODS: Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro. RESULTS: Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 µM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone. CONCLUSION: Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/fisiopatologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/fisiopatologia , Receptor fas/metabolismo
10.
Nat Commun ; 10(1): 3105, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308371

RESUMO

Fas plays a major role in regulating ligand-induced apoptosis in many cell types. It is well known that several cancers demonstrate reduced cell surface levels of Fas and thus escape a potential control system via ligand-induced apoptosis, although underlying mechanisms are unclear. Here we report that the endosome associated trafficking regulator 1 (ENTR1), controls cell surface levels of Fas and Fas-mediated apoptotic signalling. ENTR1 regulates, via binding to the coiled coil domain protein Dysbindin, the delivery of Fas from endosomes to lysosomes thereby controlling termination of Fas signal transduction. We demonstrate that ENTR1 is cleaved during Fas-induced apoptosis in a caspase-dependent manner revealing an unexpected interplay of apoptotic signalling and regulation of endolysosomal trafficking resulting in a positive feedback signalling-loop. Our data provide insights into the molecular mechanism of Fas post-endocytic trafficking and signalling, opening possible explanations on how cancer cells regulate cell surface levels of death receptors.


Assuntos
Antígenos de Neoplasias/fisiologia , Endocitose/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas de Transporte Vesicular/fisiologia , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/metabolismo , Apoptose , Disbindina/metabolismo , Proteína Ligante Fas/análise , Proteína Ligante Fas/metabolismo , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 13/análise , Proteína Tirosina Fosfatase não Receptora Tipo 13/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 13/fisiologia , Transdução de Sinais , Proteínas de Transporte Vesicular/análise , Proteínas de Transporte Vesicular/metabolismo , Receptor fas/análise , Receptor fas/metabolismo
11.
Am J Chin Med ; 47(4): 879-893, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179723

RESUMO

Yang-Yin-Qing-Fei-Tang (YYQFT) is a well-known traditional Chinese medicine used in the treatment of chronic obstructive pulmonary emphysema, bronchitis, cytomegaloviral pneumonia, but the mechanisms of the medicine are not clear. This study aimed to identify the active components of YYQFT and elucidate the underlying mechanism on non-small cell lung cancer. First, YYQFT was extracted with different solvents, and then the most effective extract was determined by assessing their effects on non-small cell lung cancer cell growth. Second, several active compounds from YYQFT were identified, and quercetin was the one of the important active ingredients. Subsequently, the in vivo antitumor activity of quercetin was confirmed in a lung cancer xenograft model in mice. 200 µ g/mL quercetin significantly reduced tumor volume without affecting body weight of the mice. Furthermore, induction of apoptosis by quercetin was detected in tumor tissues treated with quercetin. Multiple apoptosis related genes including p53, Bax and Fas were upregulated by quercetin in tumor tissue and the ratio of Bax/Bcl-2 was increased accordingly. Our results demonstrated that quercetin, as the main effective component of the YYQFT, has potent inhibitory activity on non-small cell lung cancer by regulating the ratio of Bax/Bcl-2.


Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Medicamentos de Ervas Chinesas/química , Neoplasias Pulmonares/patologia , Quercetina/farmacologia , Animais , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quercetina/isolamento & purificação , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
12.
J Immunol Res ; 2019: 1242979, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198791

RESUMO

Cervical cancer is the second most frequent cancer in women in Mexico, and its development depends on the presence of human papillomaviruses in the uterine cervix. These oncogenic viruses transform cells where the control over cell cycle disappears, and the capacity to induce apoptosis is absent. On the other hand, some mutations confer to the transformed cells the ability to evade recognition by the immune system. The expression of markers of the immune system such as CD95, MICA/B, CD39, CD73, NKp30, NKp46, CD44, CD24, NKG2A, and CTLA-4 was analysed by flow cytometry on cervical cancer cells INBL (HPV 18, stage IVB), HeLa (HPV 18), CaSki (HPV 16), and C33A (HPV-). Our results showed the presence of atypical markers on cervical cancer cells; some of them are molecules involved in tumour cell recognition such as MICA/B and CD95. Other markers associated with immune system escape, such as CD39, CD73, and CTLA-4, were also present. Furthermore, we found that some cervical cancer cells expressed typical markers of NK cells like NKp30, NKp46, NKG2A, and KIR3DL1. It is not clear whether these molecules confer any gain to the tumour cells or if they represent a disadvantage, but we hypothesise that these molecules that are present in cervical cancer cells allow them to mimic in front of the immune system.


Assuntos
Papillomavirus Humano 16/fisiologia , Papillomavirus Humano 18/fisiologia , Células Matadoras Naturais/imunologia , Infecções por Papillomavirus/metabolismo , Neoplasias do Colo do Útero/metabolismo , 5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Antígeno CTLA-4/metabolismo , Feminino , Células HeLa , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vigilância Imunológica , Receptores de Células Matadoras Naturais/metabolismo , Evasão Tumoral , Receptor fas/metabolismo
13.
J Pineal Res ; 67(2): e12589, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31155748

RESUMO

It has been found that remote organ/limb temporary ischemia, known as remote ischemic conditioning, can provide protection against the formation of lethal ischemic outcome. Current evidence suggests that aging and age-releated comorbidities impair the cardioprotective effects of conditionings. In conjuction with aging, decrease in melatonin synthesis from pineal gland can have role in the pathogenesis of aging and age-related cardiovascular diseases. In this study, we investigated the effects of remote ischemic perconditioning (RIPerC) and physiological and pharmacological concentrations of melatonin on the infarct size, Fas gene, cytochrome b-245 beta chain (Cybb) gene, nuclear factor-kappa B (NfκB), and irisin using an in vivo model of myocardial ischemia/reperfusion (I/R) injury. Sprague-Dawley rats that were divided into two groups first as non-pinealectomized (Non-Px) and pinealectomized (Px), and then (a) Control; (b) I/R (30-minute ischemia, 120-minute reperfusion caused by left coronary artery ligation); (c) I/R + RIPerC (when myocardial ischemia initiated, three cycles of 5-minute occlusion followed by 5-minute reperfusion); (d) I/R + Mel; (e) Px; (f) Px + I/R; (g) Px + I/R + RIPerC; (h) Px + I/R + RIPerC + Mel groups. The infarct size was determined by TTC staining and analyzed by the ImageJ program. Molecular parameters were evaluated by qRT-PCR and Western blot. Results showed that increased infarct size in Non-Px groups decreased with RIPerC and melatonin. However, increased infarct size in Px groups was decreased minimally with RIPerC and significantly decreased with RIPerC + Melatonin. Fold change in Fas gene was associated with the infarct size. RIPerC and melatonin reduced expressions of Cybb, NfκB, and irisin genes. The physiological release and pharmacological concentration of melatonin may improve protective effect of RIPerC against I/R-induced infarct size by modulating Cybb, Fas, NfκB, Irisin signaling pathways.


Assuntos
Fibronectinas/metabolismo , Precondicionamento Isquêmico , Melatonina/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor fas/metabolismo , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-Dawley
14.
Food Funct ; 10(7): 4153-4165, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241065

RESUMO

This study aimed to explore a novel strategy for the simultaneous consumption of soluble soybean polysaccharides (SSPS) and insoluble genistein to improve the bioavailability of genistein and its prevention against obesity and metabolic syndrome in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed a normal diet and HFD supplemented or not (n = 8) with SSPS (2.5%), genistein (0.5%) and their mixture (S + G) for 12 weeks. The UPLC-qTOP/MS assay showed that SSPS observably enhanced the urinary concentration of genistein and its metabolites compared to that of single genistein in mice. Supplementation of SSPS, genistein or their combination prevented HFD-induced gain weight, dyslipidemia, oxidative stress and inflammation in obese mice. Interestingly, the combined S + G ingestion exhibited more effective alleviation of dyslipidemia by modulating hepatic FAS, ACC, SREBP-1C and ADRP expressions relative to that of individual SSPS or genistein. Furthermore, S + G activated the energy metabolism pathway AMPK in the liver, and the hepatic PPAR-α/PPAR-γ pathways were doubly activated to alleviate lipogenesis, inflammation, obesity and metabolic syndrome. Moreover, S + G supplementation dramatically modified the gut microbial species at the phylum level with a decrease in Firmicutes and increase in Bacteroidetes. These findings support that the combined supplementation of SSPS and genistein is a novel couple to prevent obesity and metabolic syndrome.


Assuntos
Disponibilidade Biológica , Genisteína/farmacologia , Síndrome Metabólica/prevenção & controle , Obesidade/prevenção & controle , Polissacarídeos/farmacologia , Soja/química , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Dislipidemias/metabolismo , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Genisteína/uso terapêutico , Inflamação , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Estresse Oxidativo , PPAR alfa/metabolismo , PPAR gama/metabolismo , Perilipina-2/metabolismo , Extratos Vegetais/farmacologia , Polissacarídeos/uso terapêutico , RNA Ribossômico 16S/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Ganho de Peso/efeitos dos fármacos , Receptor fas/metabolismo
15.
Oncol Rep ; 42(2): 866-879, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233203

RESUMO

A satisfactory cure rate for renal cell carcinoma (RCC) is difficult to achieve through traditional immunotherapy. RCC has a relatively high spontaneous regression rate due to tumor immune escape. However, tumor­derived exosomes (TEXs), which effectively carry tumor­associated antigens (TAAs) and trigger stronger antigen­specific tumor immunity against autologous tumors than against other tumors, have been widely viewed as attractive potential vaccines for tumor treatment, although improvements are needed. Therefore, in our study, we determined whether RenCa cell­derived exosome (RDE)­stimulated CD8+ T cells exert a stronger specific cytotoxic effect on autologous tumor cells than on other types of tumor cells through the Fas ligand (FasL)/Fas signaling pathway, and whether the combination of RDE­stimulated CD8+ T cells with GM­CSF and IL­12 enhances the anticancer effect. The results showed that RDEs were isolated, as expected, and promoted an increased percentage of CD8+/CD4+ T cells. RDE­stimulated CD8+ T cells also more effectively facilitated cytotoxicity against RenCa cells when combined with GM­CSF and IL­12 in vitro. Furthermore, immunization with RDEs restrained the growth of RenCa tumors in mouse models, and facilitated the stimulation of a stronger specific cytotoxic CD8+ T cell response via the FasL/Fas signaling pathway in vitro. However, these results were observed less frequently for other types of tumor cells after treatment with RDEs, suggesting that RDEs depend on their antigen specificity to trigger antitumor immune responses. These findings revealed that RDE­stimulated CD8+ T cells combined with GM­CSF and IL­12 can more effectively exert a stronger cytotoxic effect than RDEs alone and that RDEs can induce immunization more effectively against renal cortical adenocarcinoma than against other types of cancer. Therefore, according to our study, exosomes are promising potential vaccines, and the combination of exosome­stimulated CD8+ T cells with GM­CSF and IL­12 may be a novel strategy for the treatment of RCC.


Assuntos
Carcinoma Adrenocortical/terapia , Linfócitos T CD8-Positivos/imunologia , Exossomos/imunologia , Proteína Ligante Fas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Interleucina-12/administração & dosagem , Receptor fas/metabolismo , Neoplasias do Córtex Suprarrenal/imunologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/imunologia , Carcinoma Adrenocortical/patologia , Animais , Apoptose , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Proliferação de Células , Terapia Combinada , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia , Células Tumorais Cultivadas
16.
Cancer Sci ; 110(7): 2145-2155, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087525

RESUMO

Gastric cancer (GC) is a common cause of cancer-related death worldwide. As a result of the lack of reliable diagnostic or prognostic biomarkers for GC, patient prognosis is still poor. Therefore, there is an urgent need for studies examining the underlying pathogenesis of GC in order to find effective biomarkers. LRRN1 (leucine-rich repeat neuronal protein-1) is a type I transmembrane protein that plays an important role in the process of nerve development and regeneration. However, its role in cancer, especially in GC, remains unclear. In the present study, we found that LRRN1 expression is upregulated in GC tissues and that high LRRN1 expression is associated with poor prognosis. siRNA and shRNA-mediated knockdowns of LRRN1 expression promoted GC cell apoptosis and activation of the Fas/FasL pathway. LRRN1 knockdown also resulted in upregulation of JUN, a subunit of the transcription factor AP-1 (activator protein-1). This suggests that LRRN1 suppresses GC cell apoptosis by downregulating AP-1, resulting in inhibition of the Fas/FasL pathway. These results confirm that LRRN1 plays a significant role in GC pathogenesis. Moreover, LRRN1 may be a potential prognostic biomarker and therapeutic target for GC.


Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Regulação para Cima , Animais , Apoptose , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de Sobrevida , Fator de Transcrição AP-1/metabolismo , Receptor fas/metabolismo
17.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142011

RESUMO

Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride levels. Various physiological activities of omega-3 fatty acids are due to their agonistic actions on G-protein-coupled receptor 40 (GPR40) and GPR120. Lipid droplets (LD) accumulation in hepatocytes confirmed that DHA treatment reduced the number of larger ( >10 µm2) LDs, as well as the total area of LDs. Moreover, DHA lowered protein and mRNA expression levels of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase and stearoyl-CoA desaturase-1 (SCD-1) in primary hepatocytes incubated with liver X receptor (LXR) agonist T0901317 or high glucose and insulin. DHA also decreased protein expression of nuclear and precursor sterol response-element binding protein (SREBP)-1, a key lipogenesis transcription factor. We further found that exposure of murine primary hepatocytes to DHA for 12 h increased GPR40 and GPR120 mRNA levels. Specific agonists (Compound A for GPR120 and AMG-1638 for GPR40), hepatocytes from GPR120 knock-out mice and GPR40 selective antagonist (GW1100) were used to assess whether DHA's antilipogenic effects are mediated through GPR120 or GPR40. Compound A did not decrease SREBP-1 and FAS protein expression in hepatocytes exposed to T0901317 or high glucose with insulin. Moreover, DHA downregulated lipogenesis enzyme expression in GPR120-null hepatocytes. In contrast, AMG-1638 lowered SREBP-1 and SCD-1 protein levels. Additionally, GW1100, a GPR40 antagonist, reversed the antilipogenic effects of DHA. Collectively, our data demonstrate that DHA downregulates the expression SREBP-1-mediated lipogenic enzymes via GPR40 in primary hepatocytes.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Hepatócitos/metabolismo , Lipogênese , Receptores Acoplados a Proteínas-G/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Células Cultivadas , Ácidos Graxos Ômega-3/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
18.
J Therm Biol ; 82: 63-69, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31128660

RESUMO

Heat stress has been documented to reduce reproductive performance of female animals through injury to germ cells, with few studies available in male animals. The objectives of this study were to evaluate protective effects of baicalin on testicular tissue damage of mice subjected to heat stress and its related mechanisms. In this experiment, A total of forty mice were divided into four groups, including control group (C), baicalin group (B), heat stressed group (H) and heat stress with baicalin treatment (H + B) group. Morphological changes, activities of antioxidant enzymes and apoptosis-related parameters in the mice testes tissue were monitored. The results showed that the process of spermatogenesis in mice testis was impaired and the cellular apoptosis increased due to acute heat stress at 41 °C. Interestingly, the tissue damage was alleviated with the significant (P < 0.05) increase in the activities of SOD, CAT and GSH-Px enzymes, decrease (P < 0.05) in MDA content and number of cellular apoptosis recorded in mice of H + B group compared with those in mice from H group. In addition, the Fas, FasL and P-JNK protein expressions were significantly (P < 0.05) increased; and apaf-1, caspase-3, -9 were slightly expressed in the H group, while there was no difference in Bcl-2 expression, compared with C, B and H + B groups. The above results clearly indicate that heat stress induces macroscopic/apoptotic and oxidative changes in the testicular tissue of mice; these changes are alleviated by Baicalin through increasing anti-oxidative enzyme activities and possibly through blocking Fas/FasL pathway.


Assuntos
Flavonoides/farmacologia , Resposta ao Choque Térmico/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Testículo/citologia , Testículo/metabolismo , Testículo/ultraestrutura , Receptor fas/metabolismo
19.
Environ Toxicol ; 34(8): 928-940, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31067004

RESUMO

Bioactive components of dietary phytochemicals have been reported to possess antitumor activities. Evidences suggested key role of stress responsive p38MAPK in the induction of nutraceuticals mediated apoptosis in hepatocellular carcinoma (HCC). Current study demonstrated detailed molecular bagatelle associated with p38 MAPK mediated effective suppression of cell growth both in HepG2 and chemically induced liver carcinoma after S-allyl cysteine (SAC) treatment. SAC promoted p38MAPK activity responsible for p53 phosphorylation, its stabilization followed by nuclear translocation leading to induction in expression and oligomerization of Fas protein. Distinctive p38MAPK-p53 axis dependent Fas-FasL-FADD mediated caspase activities along with perturbed cell cycling became normalized with continuation of SAC treatment for another month to diethylnitrosamine induced liver carcinoma. Co-treatment with SB203580, the p38MAPK inhibitor, prevented pro-apoptotic effect of SAC by altering p53 phosphorylation and death inducing signaling complex conformation in HepG2 and induced HCC. Collectively study suggested significant contribution of p38MAPK-p53-DISC-Caspase pathway in the regulation of anti-neoplastic activity of SAC against HCC.


Assuntos
Antineoplásicos/farmacologia , Cisteína/análogos & derivados , Neoplasias Hepáticas Experimentais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antineoplásicos/uso terapêutico , Caspases/metabolismo , Cisteína/farmacologia , Cisteína/uso terapêutico , Proteína Ligante Fas/metabolismo , Células Hep G2 , Humanos , Imidazóis/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Receptor fas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
20.
Cells ; 8(5)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052273

RESUMO

SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4-CD8- T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação com Ganho de Função/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Animais , Anticorpos Antinucleares/sangue , Apoptose , Linfócitos B/imunologia , Caspase 3/metabolismo , Diferenciação Celular , Células Dendríticas/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Linfonodos/patologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Fagocitose , Fenótipo , Análise de Sobrevida , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Receptor fas/metabolismo
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