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1.
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
2.
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
3.
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
4.
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
5.
Artif Cells Nanomed Biotechnol ; 47(1): 3517-3523, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31452399

RESUMO

In this study, sevoflurane (SF) loaded, Fas ligand conjugated reduced graphene oxide (rGO) system is fabricated as a therapeutic agent to target brain ischaemic region. The fluorescence investigation of mice brain denoted that the encapsulated SF in rGOs adsorbed with Fas ligand antibody could be significantly distributed to the ipsilateral side of the ischaemic brain. In addition, the immune-histochemical assay presented that the specific nanoparticles especially deposited in the ischaemic part of the tested mice model. Furthermore, SF encapsulated rGO system exhibited noticeable progress in the brain damage along with neurological deficit post ischaemia with limited dosages in contrast to regular SF. Additionally, Rhodamine labelled nanoparticles were used to find whether Fas ligand antibody has the ability to lead the SF-encapsulated nano rGO to enter the ischaemic part of brain as well as carry out neuro-protection. Overall, these experimental findings suggested that rGOs conjugated Fas ligand system could be treated as an ideal brain targeting drug for cerebral ischemia.


Assuntos
Isquemia Encefálica/prevenção & controle , Grafite/química , Precondicionamento Isquêmico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Sevoflurano/química , Sevoflurano/farmacologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Técnicas de Química Sintética , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Proteína Ligante Fas/metabolismo , Grafite/síntese química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanotecnologia
6.
Anticancer Res ; 39(7): 3499-3506, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262874

RESUMO

BACKGROUND/AIM: The present study aimed to investigate the apoptotic effects of phenformin, a therapeutic agent for diabetes, on head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Cytotoxicity was measured by the MTT and live/dead cell assay. Phenformin-induced apoptotic FaDu cell death and its associated cellular signaling pathways were investigated by hematoxylin and eosin staining, 4',6-diamidino-2-phenylindole staining, caspase-3 activity assay, fluorescence-activated cell sorting analysis, and western blotting. RESULTS: Phenformin promoted death of and apoptotic processes in FaDu cells, including morphological alterations and nuclear condensation. Furthermore, treatment with phenformin increased caspase-3 activity and apoptotic populations via the caspase cascade through cleavage of capspase-8, -9, and -3 and poly(ADP-ribose) polymerase in FaDu cells. Moreover, phosphorylation levels of mitogen-activated protein kinases, nuclear factor-κB, and AKT were down-regulated in FaDu cells by phenformin. CONCLUSION: Phenformin induced death of FaDu cells via caspase-dependent extrinsic and intrinsic apoptosis pathways and is a promising novel therapeutic agent for HNSCC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fenformin/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Humanos
7.
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
8.
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
9.
Phytomedicine ; 63: 153005, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302316

RESUMO

BACKGROUND: 8-Hydroxyquinoline derivatives have highly sensitive fluorescent chemosensors for metal ions, which are associated with anti-oxidant, anti-tumor and anti-HIV-1 properties. Head and neck squamous cell carcinoma (HNSCC) is associated with a high rate of mortality and novel anti-HNSCC drugs must be developed. Therefore, effective chemotherapy agents are required to address this public health issue. HYPOTHESIS/PURPOSE: The aim of this study was to investigate the inhibitory effect of tris(8-hydroxyquinoline)iron (Feq3) on the HNSCC and the underlying mechanism. STUDY DESIGN/METHODS: A novel 8-hydroxyquinoline derivative, Feq3, was synthesized. The cell viabilities were analyzed using MTT reagent. Apoptosis and the cell cycle distributions were determined by flow cytometer. Reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, western blot, MitoSOX and CellROX stain assay were used to study the mechanism of Feq3. Feq3 combined with antioxidants NAC (N-acetylcysteine) and BSO (buthionine sulfoximine) measured the cell viability and intracellular ROS. RESULTS: Feq3 induced the death of HNSCC cells and caused them to exhibit the morphological features of apoptosis. Feq3 also induced apoptosis of SCC9 cells by cell cycle arrest during the G2/M phase and the induced arrest of SCC25 cells in the G0/G1 and G2/M phases, which was associated with decreased cyclin B1/cdc2 and cyclin D/cdk4 expressions. Feq3 increases reactive oxygen species (ROS) and reduces glutathione (GSH) levels, and responds to increased p53 and p21 expressions. Feq3 induced apoptosis by mitochondria-mediated Bax and cytochrome c up-expression and down-expression Bcl-2. Feq3 also up-regulated tBid, which interacts with the mitochondrial pathway and tumor necrosis factor-α (TNF-α)/TNF-Rs, FasL/Fas, and TNF-related apoptosis inducing ligand receptors (TRAIL-Rs)/TRAIL-dependent caspases apoptotic signaling pathway in HNSCC cells. However, Feq3 activates Fas but not FasL in SCC25 cells. Feq3 arrests the growth of HNSCC cells and is involved in the mitochondria- and death receptor (DR)-mediated caspases apoptotic pathway. CONCLUSION: This study is the first to suggest that apoptosis mediates the anti-HNSCC of Feq3. Feq3 has potential as a cancer therapeutic agent against HNSCC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Hidroxiquinolinas/farmacologia , Compostos de Ferro/farmacologia , Ferro/química , Estresse Oxidativo/efeitos dos fármacos , Quinolinas/farmacologia , Apoptose/fisiologia , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Proteína Ligante Fas/metabolismo , Glutationa/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Compostos de Ferro/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Receptores de Morte Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
DNA Cell Biol ; 38(8): 865-873, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31225740

RESUMO

Accumulating evidence has suggested that microRNAs play important roles in the development of hepatocellular carcinoma (HCC) and are involved in drug resistance. miR-21-5p was overexpressed in a variety of cancers and promoted the tumorigenesis; however, the function of miR-21-5p in HCC still remains unknown. In this study, our results showed that miR-21-5p was highly expressed in HCC tissues and cell lines. Notably, the level of miR-21-5p was relatively higher in cisplatin (DDP)-resistant HCC patients. Overexpression of miR-21-5p attenuated the inhibitory effect of DDP on the proliferation and apoptosis of HCC cells. Mechanistically, the luciferase report assay-identified FAS ligand (FASLG) was a direct target of miR-21-5p. Overexpression of miR-21-5p decreased both the mRNA and protein levels of FASLG in HCC cells. FASLG was downregulated in HCC tissues and was significantly negatively correlated with the expression of miR-21-5p. Restoring the expression of FASLG upregulated the chemosensitivity of HCC cells expressing miR-21-5p. In conclusion, our results demonstrated that miR-21-5p targeted FASLG and suppressed the sensitivity of HCC cells to DDP treatment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/farmacologia , Proteína Ligante Fas/genética , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/genética , Idoso , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Ligante Fas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto
11.
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
12.
Biomed Pharmacother ; 115: 108818, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102912

RESUMO

Spinal cord injury (SCI) represents a relatively common type of motor system trauma. While the SCI patient will experience varying degrees of paraplegia and quadriplegia, which severely affects their quality of life, a heavy burden is also placed on the family and society as a whole. The exact pathogenic mechanisms underlying this condition remain unknown and no specific treatments are currently available. Findings from recent studies have shown that mesenchymal stem cells (MSCs), derived from extracellular vesicles (EVs) can reduce apoptosis, inflammation and promote angiogenesis after SCI. However, the mechanisms through which EVs exert these effects have yet to be identified, indicating the necessity for further investigation. In the present study, we report that treatment with MSCs-EVs significantly improved functional recovery and attenuated lesion size and apoptosis in a rat model of SCI. These MSCs-EVs were found to be directed to the spinal injury site and mainly incorporated into neurons within the lesioned site of the spinal cord. Tandem Mass Tags quantitative proteomics was applied to compare protein changes after SCI and MSCs-EVs treatment. A total of 883 differential proteins were identified, many of which being associated with apoptosis and inflammation. Subsequently, miRNA contents of MSCs-EVs were determined using qRT-PCR, with the result that miR-21-5p was one of the most highly expressed miRNA in these MSCs-EVs. Moreover, inhibition of miR-21-5p in MSCs-EVs significantly reversed the beneficial effects of MSCs-EVs on motor function and apoptosis, an effect which was associated with modulating FasL expression. The data suggest that modulation of the MSCs-EVs miR-21-5p/FasL gene axis may serve as a promising strategy for clinical treatment of SCI and other neurological diseases.


Assuntos
Vesículas Extracelulares , Proteína Ligante Fas/metabolismo , Células-Tronco Mesenquimais/fisiologia , MicroRNAs/metabolismo , Traumatismos da Medula Espinal/terapia , Animais , Apoptose , Regulação para Baixo , Proteína Ligante Fas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , MicroRNAs/genética , Neurônios/metabolismo , Neuroproteção , Ratos
13.
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
14.
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
15.
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
16.
Int J Mol Med ; 43(6): 2376-2386, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942389

RESUMO

Macrophages can induce Fas ligand (FasL)­mediated apoptosis, and the deregulation of apoptosis is known to be associated with recurrent miscarriage (RM). The aim of the present study was to investigate the possible involvement of FasL in macrophage­mediated trophoblast apoptosis and its potential role in RM. Human decidual and placental villous tissues were collected from 81 women (21 for the RM group, 26 for the spontaneous abortion group and 34 for the control group) at 7­9 weeks of gestation. The distribution changes of macrophages and the expression of FasL on macrophages were evaluated by immunohistochemical, immunofluorescence and western blot analyses. A macrophage and trophoblast co­culture model was used to determine the effects of FasL on the apoptosis of trophoblasts. The results indicated that CD86+ macrophage populations in decidual tissues were significantly increased, accompanied by reduced CD163+ macrophages in the abortion and RM groups. Furthermore, the distribution of CD68+ macrophages was also significantly altered in specimens from the abortion and RM groups, and they were observed to have infiltrated into the trophoblast cells. In addition, elevated expression of FasL on CD68+ and CD86+ macrophages in the decidua was observed in the spontaneous abortion and RM groups of patients, and FasL was demonstrated to mediate the induction of trophoblast apoptosis by macrophages in co­culture. These results indicate that the aberration of macrophage­induced FasL­mediated apoptosis may represent one of the causes of RM.


Assuntos
Aborto Habitual/patologia , Apoptose , Decídua/patologia , Proteína Ligante Fas/análise , Macrófagos/patologia , Trofoblastos/patologia , Aborto Habitual/etiologia , Aborto Habitual/metabolismo , Adulto , Linhagem Celular , Decídua/citologia , Decídua/metabolismo , Proteína Ligante Fas/metabolismo , Feminino , Humanos , Macrófagos/metabolismo , Gravidez , Trofoblastos/citologia , Trofoblastos/metabolismo
17.
Transplant Proc ; 51(3): 942-950, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979487

RESUMO

BACKGROUND: Intrasplenic transplantation of xenogeneic hepatic oval cells (HOCs) may provide metabolic support for acute liver injury. However, xenoreactive lymphocyte-mediated immune response hinders HOCs' survival in the xeno-spleen parenchyma. Cytotoxic T-lymphocyte associated protein 4-Fas ligand (CTLA4.FasL), a fusion product integrating 2 inhibitory elements against lymphocytes into 1 molecule, effectively inhibited the proliferation of allogeneic and autoimmune lymphocytes. The purpose of this study was to explore the effect of CTLA4.FasL on the proliferation of xenoreactive lymphocytes and evaluate the therapeutic efficacy of CTLA4.FasL-modified HOC transplantation on acute liver injury in rats. METHODS: The effect of CTLA4.FasL-modified mouse liver epithelial progenitor cells (CTLA4.FasL-LEPCs) on the proliferation of rat lymphocytes in xeno-mixed lymphocyte reaction was investigated. Furthermore, CTLA4.FasL-LEPCs were intrasplenically transplanted in carbon tetrachloride- and partial hepatectomy-treated rats, and the therapeutic effect was evaluated using hematoxylin and eosin staining and alanine aminotransferase and aspartate aminotransferase assays. The hepatocytic differentiation of CTLA4.FasL-LEPCs in xenogeneic spleen was monitored by immunohistochemical staining for albumin. RESULTS: In xeno-mixed lymphocyte reaction, CTLA4.FasL-LEPCs substantially inhibited the rat lymphocytes proliferation. CTLA4.FasL-LEPC transplantation significantly ameliorated liver injury compared with mCherry-modified LEPC and LEPC transplantation, as assessed by hematoxylin and eosin staining, alanine aminotransferase, and aspartate aminotransferase assays. Albumin positive cells appeared only in CTLA4.FasL-LEPCs group, but not in the mCherry-modified LEPCs group and LEPCs group. CONCLUSIONS: Our results indicate CTLA4.FasL-LEPCs substantially improved liver function and structure in carbon tetrachloride- and partial hepatectomy-induced acute liver injury rats through long-term hepatocytic differentiation.


Assuntos
Lesão Pulmonar Aguda/cirurgia , Antígeno CTLA-4/imunologia , Proteína Ligante Fas/imunologia , Hepatócitos/transplante , Linfócitos T Citotóxicos/imunologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Antígeno CTLA-4/metabolismo , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Proteína Ligante Fas/metabolismo , Feminino , Hepatócitos/citologia , Hepatócitos/metabolismo , Injeções , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Ratos , Ratos Sprague-Dawley , Baço
18.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875739

RESUMO

Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor's individual components-scFv, spacer domain, and costimulatory domains-and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Animais , Proteína Ligante Fas/metabolismo , Granzimas/metabolismo , Humanos , Neoplasias/imunologia , Perforina/metabolismo , Transdução de Sinais , Linfócitos T/transplante , Receptor fas/metabolismo
19.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875877

RESUMO

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low µM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína Ligante Fas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , NF-kappa B/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Amidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Hidrocortisona/farmacologia , Interleucina-8/metabolismo , Éteres Fenílicos/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Tiofenos/farmacologia
20.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897723

RESUMO

Background: Cleaving ligands and receptors of the tumor necrosis factor (TNF) superfamily can critically regulate the induction of apoptosis. Matrix metalloproteinases (MMPs) such as MMP-9 and tumor necrosis factor-α-converting enzyme (TACE) have been shown to cleave CD95-Ligand (CD95L) and TNF/(TNF receptor-1) TNFR1 which induce phagocytosis induced cell death (PICD) in adult monocytes. This process is reduced in neonatal monocytes. Methods: Here we tested in vitro, whether Escherichia coli infection mounts for activation of MMP-9 and TACE in monocytes and whether this process regulates PICD. Results: The surface expression of TACE was most prominent on infected adult monocytes. In contrast, surface presentation of MMP-9 was highest on infected neonatal monocytes. Selective blocking of MMP-9 decreased CD95L secretion, while inhibition of TACE left CD95L secretion unaltered. Blocking of MMP-9 increased surface CD95L (memCD95L) expression on infected neonatal monocytes to levels comparable to infected adult monocytes. Moreover, MMP-9 inhibition raised PICD of infected neonatal monocytes to levels observed for infected adult monocytes. In contrast, TACE inhibition decreased PICD in infected monocytes. Addition of extracellular TNF effectively induced memCD95L presentation and PICD of adult monocytes and less of neonatal monocytes. Conclusion: MMP-9 activity is crucial for downregulating cell-contact dependent PICD in E. coli infected neonatal monocytes. By this mechanism, MMP-9 could contribute to reducing sustained inflammation in neonates.


Assuntos
Proteína ADAM17/metabolismo , Escherichia coli/patogenicidade , Metaloproteinase 9 da Matriz/metabolismo , Monócitos/metabolismo , Monócitos/microbiologia , Apoptose/fisiologia , Membrana Celular/metabolismo , Células Cultivadas , Proteína Ligante Fas/metabolismo , Humanos , Recém-Nascido , Inflamação/imunologia , Inflamação/metabolismo , Fagocitose/fisiologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo
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