RESUMO
The extensive application of Tetrabromobisphenol A (TBBPA) leads to the pollution of part of the water environment and brings great safety risks to aquatic animals. As a natural extract, tea polyphenols (TPs) have antioxidant and anti-inflammatory effects. Gills are one of the immune organs of fish and constitute the first line of defense of the immune system. However, it was unclear whether TPs could mitigate TBBPA-induced gills injury. Therefore, an animal model was established to investigate the effect of TPs on TBBPA-induced gills. The results indicated that TBBPA changed the coefficient and tissue morphology of carp gills. In addition, TBBPA induced oxidative stress and inflammation, leading to ferroptosis and apoptosis in carp gills. Dietary addition of TPs significantly improved the antioxidant capacity of carp, effectively inhibited the overexpression of TLR4/NF-κB and its mediated inflammatory response. Moreover, TPs restored iron metabolism, reduced the expression of pro-apoptotic factors thereby alleviating ferroptosis and apoptosis in carp gills. This study enriched the protective effect of TPs and provided a new way to improve the innate immunity of carp.
Assuntos
Carpas , Ferroptose , Bifenil Polibromatos , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Antioxidantes/metabolismo , Receptor 4 Toll-Like/genética , Carpas/metabolismo , Brânquias , Polifenóis/farmacologia , Polifenóis/metabolismo , Transdução de Sinais , Proteínas de Peixes , Inflamação/induzido quimicamente , Inflamação/veterinária , Inflamação/metabolismo , Apoptose , Chá/metabolismoRESUMO
Microplastics (MPs) are widely distributed pollutants in the environment and accumulate in the aquatic environment due to human activities. Carp, a common edible aquatic organism, has been found to accumulate MPs in body. MicroRNA (miRNAs) is a non-coding short RNA that regulates protein expression by binding to target genes in various physiological processes such as proliferation, differentiation and apoptosis. The ovary is a crucial role in carp reproduction. In this study, we established a model of carp exposed to polyethylene microplastics (PE-MPs) in the aquatic environment to investigate the specific mechanism of PE-MPs causing ovarian injury and the involvement of miR-132/calpain (CAPN) axis. H&E stained sections revealed that PE-PMs induced inflammation in ovarian tissues and impaired oocyte development. TUNEL analysis showed an increased rate of apoptosis in ovarian cells treated with PE-PMs. RT-PCR and Western Blot assays confirmed that exposure to PE-MPs significantly decreased miR-132 expression while increasing CAPN expression at both mRNA and protein levels. The concentration of calcium ions was significantly increased in tissues, leading to CAPN enzyme activity increase. The expression of mitochondrial damage-related genes (bax, AIF, cyt-c, caspase-7, caspase-9, and caspase-3) was higher while the expression of anti-apoptotic genes (bcl-2 and bcl-xl) was lower. Protein levels of bax, AIF, caspase-3, bcl-2 and bcl-xl changed accordingly with the genetic alterations. Additionally, we discovered that PE-MPs can activate the p65 factor through the TRAF6/NF-kB pathway resulting in elevated production of pro-inflammatory factors IL-6, IL-1ß and TNF-a which contribute to ovarian inflammation development. This study investigates the impact of PE-MPs on carp ovarian function and provides insights into miRNAs' role and their target genes.
Assuntos
Carpas , MicroRNAs , Poluentes Químicos da Água , Animais , Feminino , Humanos , Microplásticos , Polietileno , Caspase 3/genética , Plásticos , Calpaína , Proteína X Associada a bcl-2 , Ovário , Poluentes Químicos da Água/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/genética , MicroRNAs/genética , Apoptose/genética , Inflamação/induzido quimicamenteRESUMO
A new cembranolide, namely, sinupendunculide A (1), along with eight known related compounds (2-9), was isolated from the South China Sea Soft coral Sinularia pendunculata. The structure of sinupendunculide A (1) was established by extensive spectroscopic analysis and X-ray diffraction experiments. In a bioassay, anti-colorectal cancer (CRC) activity was performed, and the results showed that several compounds exhibited cytotoxicity against RKO cells, and a preliminary structure-activity relationship was analysed. Meanwhile, the most effective compound 7 was proven to increase reactive oxygen species levels, which promoted cell apoptosis and inhibited cell proliferation.
Assuntos
Antozoários , Antineoplásicos , Diterpenos , Neoplasias , Animais , Antozoários/química , China , Diterpenos/farmacologia , Diterpenos/química , Estrutura Molecular , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/prevenção & controleRESUMO
Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer.Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance.Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via ß-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model.Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612-26. ©2018 AACR.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Adulto , Idoso , Antagonistas de Androgênios/efeitos adversos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
Purpose: Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.Results: High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via ß-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. Clin Cancer Res; 24(3); 708-23. ©2017 AACR.
Assuntos
Comunicação Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células Neuroendócrinas/efeitos dos fármacos , Células Neuroendócrinas/metabolismo , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Antineoplásicos/farmacologia , Benzamidas , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Imuno-Histoquímica , Macrófagos/imunologia , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Nitrilas , Feniltioidantoína/farmacologia , Neoplasias da Próstata/imunologia , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Zinc finger protein X-linked (ZFX) is frequently upregulated in multiple human malignancies and also plays a critical role in the maintenance of self-renewal in embryonic stem cells. However, the role of ZFX in liver cancer stem cells (CSCs) remains obscure. We observed that the elevated expression of both ZFX and epithelial cell adhesion molecule (EpCAM) was associated with aggressive clinicopathological features and indicated poor prognosis in patients with hepatocellular carcinoma (HCC). ZFX was commonly enriched in liver EpCAM+ CSCs. Knockdown of ZFX decreased the proportion of EpCAM+ CSCs in HCC cells and suppressed their expression of stemness-related genes, self-renewal capacity, chemoresistance, metastatic potential, and tumorigenicity. Conversely, upregulation of ZFX in CSCs rescued these inhibitory effects and enhanced stem-like properties. Mechanistically, depletion of ZFX reduced nuclear translocation and transactivation of ß-catenin, thereby inhibiting the self-renewal capacity of EpCAM+ CSCs. Moreover, knockdown of ß-catenin attenuated the self-renewal of EpCAM+ HCC cells stably expressing ZFX, further indicating that ß-catenin is required for ZFX-mediated expansion and maintenance of EpCAM+ CSCs. Taken together, our findings indicate that ZFX activates and maintains EpCAM+ liver CSCs by promoting nuclear translocation and transactivation of ß-catenin. Furthermore, combination of ZFX and EpCAM may serve as a significant indicator for prognosis of patients with HCC.