RESUMO
The theory of "Developmental Origins of Health and Disease (DOHaD)" espouses that environmental exposures to toxicants during critical developmental stages can affect health outcomes in adulthood. Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that can be transferred to developing organisms via the placenta and breast milk as an environmental endocrine disruptor. We herein implemented a cross-fostering model to decipher the contributions of prenatal vs. postnatal exposure to low or high dose DEHP (30 or 500 mg/kg-bwâ¢d) on reproductive outcomes in male offspring and the underlying mechanism of action. Unexpectedly, we observed that postnatal DEHP exposure programmed weight gain in a dose-dependent manner, in-utero exposure to high dose DEHP appeared to constitute a significant factor in the weight loss of male offspring. Moreover, in the low dose group, offspring of control that were suckled by DEHP dams (CC-DE) generated a considerable number of adverse reproductive outcomes compared with the offspring of DEHP that were suckled by control dams (DE-CC), based on histopathologic alterations in the testis, blockage of sex hormone secretion, and transcriptional inhibition of steroid-hormone-related factors in the hypothalamic-pituitary-testicular (HPT) axis. However, DE-CC group affected reproductive dysfunction in male offspring more so than CC-DE in the high dose group. Mechanistically, DEHP contributed to the inhibition of steroidogenesis by perturbing the Wnt/ß-catenin-signaling pathway. These studies confirm the sensitivity window in which future reproductive outcomes in offspring are influenced following developmental exposure to DEHP at two different dosages, and reveals a critical role for the Wnt/ß-catenin signaling pathway in DEHP-induced male reproductive disorders.
Assuntos
Dietilexilftalato , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Masculino , Dietilexilftalato/toxicidade , Dietilexilftalato/metabolismo , Via de Sinalização Wnt , Testículo/metabolismo , Reprodução , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
BACKGROUND: Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome (PI-IBS). γδ T cells play a crucial role in innate and adaptive immunity. Adenosine receptors expressed on the surface of γδ T cells participate in intestinal inflammation and immunity regulation. AIM: To investigate the role of γδ T cell regulated by adenosine 2A receptor (A2AR) in PI-IBS. METHODS: The PI-IBS mouse model has been established with Trichinella spiralis (T. spiralis) infection. The intestinal A2AR and A2AR in γδ T cells were detected by immunohistochemistry, and the inflammatory cytokines were measured by western blot. The role of A2AR on the isolated γδ T cells, including proliferation, apoptosis, and cytokine production, were evaluated in vitro. Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction (RT-PCR). The animals were administered with A2AR agonist, or A2AR antagonist. Besides, γδ T cells were also injected back into the animals, and the parameters described above were examined, as well as the clinical features. Furthermore, the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR. RESULTS: PI-IBS mice exhibited elevated ATP content and A2AR expression (P < 0.05), and suppression of A2AR enhanced PI-IBS clinical characteristics, indicated by the abdominal withdrawal reflex and colon transportation test. PI-IBS was associated with an increase in intestinal T cells, and cytokine levels of interleukin-1 (IL-1), IL-6, IL-17A, and interferon-α (IFN-α). Also, γδ T cells expressed A2AR in vitro and generated IL-1, IL-6, IL-17A, and IFN-α, which can be controlled by A2AR agonist and antagonist. Mechanistic studies demonstrated that the A2AR antagonist improved the function of γδ T cells through the PKA/CREB/NF-κB signaling pathway. CONCLUSION: Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function of γδ T cells via the PKA/CREB/NF-κB signaling pathway.
Assuntos
Síndrome do Intestino Irritável , Triquinelose , Camundongos , Animais , NF-kappa B/metabolismo , Interleucina-17/metabolismo , Interleucina-6 , Citocinas/metabolismo , Transdução de Sinais , Triquinelose/complicações , Inflamação/complicações , Interleucina-1RESUMO
Long noncoding RNA taurine upregulated gene 1 (lncRNA TUG1) and microRNA196a (miR196a) have been reported to serve important roles in the development of renal cell carcinoma (RCC). However, their potential mechanisms have not been completely elucidated. The aim of the present study was to clarify the biological functions of lncRNATUG1 and miR196a, in addition to investigating the interaction between lncRNATUG1 and microRNA196a, providing a novel insight into RCC tumorigenesis. The present study comprised two parts. In the first part, lncRNATUG1 was confirmed as an oncogene, via reverse transcriptionquantitative polymerase chain reaction (RTqPCR) analysis, MTT assay, flow cytometry analysis, and migration and invasion assays. In the second part, the association between lncRNATUG1 and miR196a, and the molecular mechanism, was illustrated via RTqPCR analysis, MTT assay, dual luciferase reporter assay and western blotting. The results of the present study demonstrated that lncRNATUG1 was able to promote RCC cell proliferation, migration and invasion in vitro by suppressing miR196a. Additionally, lncRNATUG1 achieved its biological functions by regulating the expression levels of RACα serine/threonineprotein kinase, mitogenactivated protein kinase and extracellular signalregulated kinase via inhibition of miR196a. In conclusion, the present findings proposed a novel potential therapeutic target, the lncRNATUG1miR196a axis, which may be applicable to the treatment of RCC.
Assuntos
Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , Apoptose/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Although laboratory fish are increasingly used in genetics and other life science research fields, standard quality control and supervision are needed. In China, laboratory animals are all put into a strict licensing and quality management system by the government. The standardization of genetic quality control is crucial to a laboratory fish quality control management system. The goal of Laboratory Animal Regulation is to control genetic quality, avoid hereditary degeneration and genetic drift, and circumvent experimental errors. To achieve this goal, Laboratory Animal Regulations are being developed by consulting experimental data and research findings throughout the world, combining the best known practices in laboratory fish production, and consulting specialists. A new set of laboratory fish genetic quality standards focusing on zebrafish and swordtail fish has been established as a reference for scientific researchers. The new standards define inbred and outbred zebrafish and swordtail fish hereditary classifications, naming principles, breeding methods, and hereditary quality surveying. The new standards provide a frame of reference for laboratory fish users and managers.
Assuntos
Experimentação Animal/normas , Animais de Laboratório/genética , Peixes/genética , Modelos Animais , Experimentação Animal/legislação & jurisprudência , Animais , Controle de QualidadeRESUMO
Brain and eye tissues are subject to a reduced version of immune surveillance, which has evolved to protect the particularly sensitive tissues from accidental bystander damage created by regular inflammatory responses. Yet, there are autoimmune diseases in both organs. This review discusses the nature of immune reactivity in the healthy eye and brain tissues, and mechanisms that can overcome the protective barriers to create tissue specific disease.