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1.
Acta Pharmacol Sin ; 45(6): 1237-1251, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38472317

RESUMO

Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4 mg·kg-1·d-1, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFß signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.


Assuntos
Barreira Hematotesticular , Dexametasona , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais , Animais , Masculino , Feminino , Gravidez , Dexametasona/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Barreira Hematotesticular/efeitos dos fármacos , Barreira Hematotesticular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ratos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ratos Sprague-Dawley , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia
3.
Sci Total Environ ; 827: 154396, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35259391

RESUMO

A variety of adverse environmental factors during pregnancy cause maternal chronic stress. Caffeine is a common stressor, and its consumption during pregnancy is widespread. Our previous study showed that prenatal caffeine exposure (PCE) increased maternal blood glucocorticoid levels and caused abnormal development of offspring. However, the placental mechanism for fetal development inhibition caused by PCE-induced high maternal glucocorticoid has not been reported. This study investigated the effects of PCE-induced high maternal glucocorticoid level on placental and fetal development by regulating placental 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) expression and its underlying mechanism. First, human placenta and umbilical cord blood samples were collected from women without prenatal use of synthetic glucocorticoids. We found that placental 11ß-HSD2 expression was significantly correlated with umbilical cord blood cortisol level and birth weight in male newborns but not in females. Furthermore, we established a rat model of high maternal glucocorticoids induced by PCE (caffeine, 60 mg/kg·d, ig), and found that the expression of 11ß-HSD2 in male PCE placenta was decreased and negatively correlated with the maternal/fetal/placental corticosterone levels. Meanwhile, we found abnormal placental structure and nutrient transporter expression. In vitro, BeWo cells were used and confirm that 11ß-HSD2 mediated inhibition of placental nutrient transporter expression induced by high levels of glucocorticoid. Finally, combined with the animal and cell experiments, we further confirmed that high maternal glucocorticoid could activate the GR-C/EBPα-Egr1 signaling pathway, leading to decreased expression of 11ß-HSD2 in males. However, there was no significant inhibition of placental 11ß-HSD2 expression, placental and fetal development in females. In summary, we confirmed that high maternal glucocorticoids could regulate placental 11ß-HSD2 expression in a sex-specific manner, leading to differences in placental and fetal development. This study provides the theoretical and experimental basis for analyzing the inhibition of fetoplacental development and its sex difference caused by maternal stress.


Assuntos
Glucocorticoides , Placenta , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Cafeína/metabolismo , Feminino , Desenvolvimento Fetal , Glucocorticoides/toxicidade , Humanos , Recém-Nascido , Masculino , Gravidez , Ratos , Caracteres Sexuais
4.
Toxicol Lett ; 359: 65-72, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35143883

RESUMO

This study aimed to investigate the correlation between prenatal dexamethasone exposure (PDE) and susceptibility to pulmonary fibrosis in offspring. Healthy female Wistar rats were given dexamethasone (0.2 mg/kg.d) or an equal volume of normal saline subcutaneously from 9 to 20 days after conception. Some of their female offspring underwent ovariectomy (OV) at 22 weeks after birth. All animals were euthanized at 28 weeks after birth. The morphological changes related to pulmonary fibrosis and extracellular matrix-related gene expression were detected, and Two-way ANOVA analyzed the interaction between PDE and OV. The results showed that adult offspring rats in FD group (female rats with PDE treatment) had early pulmonary fibrosis changes, such as pulmonary interstitial thickening, and increased expression of type IV collagen (COL4), α -smooth muscle actin (α-SMA) and fibronectin (FN) in lung tissues compared with those in FC group (female rats with saline treatment). In addition, adult offspring rats in FDO group (female rats with PDE and OV treatment) showed signs of pulmonary fibrosis, including apparent extracellular matrix deposition, increased lung injury scores (P<0.01, P<0.05), and extracellular matrix related gene expression (P<0.01, P<0.05), compared with rats in FDS (female rats with PDE treatment alone) or rats in FCO group (female rats with OV treatment alone). Moreover, PDE and OV had an interactive effect on the development of pulmonary fibrosis in female adult offspring. This study first reported the correlation between PDE and susceptibility to pulmonary fibrosis in female offspring rats, as well as the synergistic effect of PDE and OV in this pathological event, which provided a basis for further understanding of the pathogenesis of fetal originated pulmonary fibrosis.


Assuntos
Dexametasona/toxicidade , Suscetibilidade a Doenças/induzido quimicamente , Desenvolvimento Fetal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal/genética , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Wistar , Fatores Sexuais
5.
BMC Med ; 19(1): 311, 2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34876109

RESUMO

BACKGROUND: Prenatal adverse environments can cause fetal intrauterine growth retardation (IUGR) and higher susceptibility to multiple diseases after birth, related to multi-organ development programming changes mediated by intrauterine overexposure to maternal glucocorticoids. As a glucocorticoid barrier, P-glycoprotein (P-gp) is highly expressed in placental syncytiotrophoblasts; however, the effect of P-gp on the occurrence of IUGR remains unclear. METHODS: Human placenta and fetal cord blood samples of IUGR fetuses were collected, and the related indexes were detected. Pregnant Wistar rats were administered with 30 mg/kg·d (low dose) and 120 mg/kg·d (high dose) caffeine from gestational day (GD) 9 to 20 to construct the rat IUGR model. Pregnant mice were administered with caffeine (120 mg/kg·d) separately or combined with sodium ferulate (50 mg/kg·d) from gestational day GD 9 to 18 to confirm the intervention target on fetal weight loss caused by prenatal caffeine exposure (PCE). The fetal serum/placental corticosterone level, placental P-gp expression, and related indicator changes were analyzed. In vitro, primary human trophoblasts and BeWo cells were used to confirm the effect of caffeine on P-gp and its mechanism. RESULTS: The placental P-gp expression was significantly reduced, but the umbilical cord blood cortisol level was increased in clinical samples of the IUGR neonates, which were positively and negatively correlated with the neonatal birth weight, respectively. Meanwhile, in the PCE-induced IUGR rat model, the placental P-gp expression of IUGR rats was decreased while the corticosterone levels of the placentas/fetal blood were increased, which were positively and negatively correlated with the decreased placental/fetal weights, respectively. Combined with the PCE-induced IUGR rat model, in vitro caffeine-treated placental trophoblasts, we confirmed that caffeine decreased the histone acetylation and expression of P-gp via RYR/JNK/YB-1/P300 pathway, which inhibited placental and fetal development. We further demonstrated that P-gp inducer sodium ferulate could reverse the inhibitory effect of caffeine on the fetal body/placental weight. Finally, clinical specimens and other animal models of IUGR also confirmed that the JNK/YB-1 pathway is a co-regulatory mechanism of P-gp expression inhibition, among which the expression of YB-1 is the most stable. Therefore, we proposed that YB-1 could be used as the potential early warning target for the opening of the placental glucocorticoid barrier, the occurrence of IUGR, and the susceptibility of a variety of diseases. CONCLUSIONS: This study, for the first time, clarified the critical role and epigenetic regulation mechanism of P-gp in mediating the opening mechanism of the placental glucocorticoid barrier, providing a novel idea for exploring the early warning, prevention, and treatment strategies of IUGR.


Assuntos
Peso Fetal , Glucocorticoides , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Epigênese Genética , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Camundongos , Placenta , Gravidez , Ratos , Ratos Wistar
6.
Crit Rev Toxicol ; 51(6): 555-570, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34666604

RESUMO

According to the Developmental Origin of Health and Disease (DOHaD), intrauterine exposure to adverse environments can affect fetus and birth outcomes and lead to long-term disease susceptibility. Evidence has shown that neonatal outcomes and the timing and severity of adult diseases are sexually dimorphic. As the link between mother and fetus, the placenta is an essential regulator of fetal development programming. It is found that the physiological development trajectory of the placenta has sexual dimorphism. Furthermore, under pathological conditions, the placental function undergoes sex-specific adaptation to ensure fetal survival. Therefore, the placenta may be an important mediator of sexual dimorphism in neonatal outcomes and adult disease susceptibility. Few systematic reviews have been conducted on sexual dimorphism in placental development and its underlying mechanisms. In this review, sex chromosomes and sex hormones, as the main reasons for sexual differentiation of the placenta, will be discussed. Besides, in the etiology of fetal-originated adult diseases, overexposure to glucocorticoids is closely related to adverse neonatal outcomes and long-term disease susceptibility. Studies have found that prenatal glucocorticoid overexposure leads to sexually dimorphic expression of placental glucocorticoid receptor isoforms, resulting in different sensitivity of the placenta to glucocorticoids, and may further affect fetal development. The present review examines what is currently known about sex differences in placental development and the underlying regulatory mechanisms of this sex bias. This review highlights the importance of placental contributions to the origins of sexual dimorphism in health and diseases. It may help develop personalized diagnosis and treatment strategies for fetal development in pathological pregnancies.


Assuntos
Placentação , Caracteres Sexuais , Adulto , Feminino , Desenvolvimento Fetal , Feto , Humanos , Recém-Nascido , Masculino , Placenta , Gravidez
7.
Mol Cell Biochem ; 476(7): 2613-2622, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33660185

RESUMO

The selection of suitable reference genes (RGs), especially the identification of the proper combination of RGs is the key to obtain reliable results of gene expression for quantitative real-time polymerase chain reaction (qRT-PCR). To date, there is no relevant study dealing with the stability of RGs in rat placenta. In this study, the geNorm, NormFinder, and BestKeeper software were used to analyze the expression stability of the candidate RGs in placenta under physiological and prenatal caffeine exposure (PCE) conditions. The expression of Tbp, Gapdh and Ywhaz in female and Polr2a, Gapdh and Ywhaz in male placenta were highly stable under physiological conditions, and there was no obvious gender difference. We further found that two RGs were sufficient for reliable normalization in female and male placenta and the combination of Ywhaz and Gapdh was the most suitable compound RGs under physiological conditions. Under PCE conditions, Ywhaz, Gapdh and Polr2a were the most stable genes in both female and male placenta. Among them, Ywhaz and Gapdh were chosen as the best paring. Finally, selected RGs were employed for normalization of the expression of a clear target gene and the results of standardization supported our choice. In conclusion, our study confirmed that Ywhaz/Gapdh combination was the most suitable RGs in rat placenta under physiological and PCE pathological conditions and provided a theoretical and experimental basis for physiological and pathological research of the rat placenta.


Assuntos
Regulação da Expressão Gênica , Placenta/metabolismo , Proteínas da Gravidez/biossíntese , Reação em Cadeia da Polimerase em Tempo Real/normas , Animais , Feminino , Gravidez , Proteínas da Gravidez/genética , Ratos , Ratos Wistar , Padrões de Referência
8.
Toxicol Lett ; 332: 97-106, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32599024

RESUMO

As important members in steroids related signal pathways, bile acids are very important in regulating substance metabolism and immune homeostasis. However, bile acids are highly cytotoxic, and the excessive accumulation can induce several abnormalities such as cholestatic liver injury. It is known that the bile acid metabolism alters during pregnancy and mostly will not result in pathologies. However, the effect of dexamethasone exposure during pregnancy on bile acid metabolism is still unknown. In this study, pregnant Wistar rats were subcutaneously administered dexamethasone (0.2 mg/kg.d) or saline from gestation day 9-21, while virgin rats were given the same treatment for 13 days. We found that, physiological pregnancy or dexamethasone exposure during non-pregnancy did not affect maternal serum TBA level and liver function. Nevertheless, dexamethasone exposure during pregnancy increased serum TBA level and accompanied with liver injury. Furthermore, we discovered that the conservation of bile acid homeostasis under pregnancy or dexamethasone exposure was maintained through compensatory pathways. However, dexamethasone exposure during pregnancy tipped the balance of liver bile acid homeostasis by increasing classical synthesis and decreasing efflux and uptake. In addition, dexamethasone exposure during pregnancy also increased serum estrogen level and nuclear receptors mRNA expression levels. Finally, two-way ANOVA analysis showed that dexamethasone exposure during pregnancy could induce or facilitate maternal cholestasis and liver injury by up-regulating ERα and CYP7A1 expression. This study confirmed that dexamethasone exposure during pregnancy was related to maternal intrahepatic cholestasis of pregnancy and should be carefully monitored in clinical settings.


Assuntos
Ácidos e Sais Biliares/metabolismo , Dexametasona/toxicidade , Animais , Colestase Intra-Hepática , Colesterol 7-alfa-Hidroxilase/biossíntese , Estrogênios/sangue , Feminino , Hormônios Esteroides Gonadais/sangue , Homeostase/efeitos dos fármacos , Infusões Subcutâneas , Testes de Função Hepática , Gravidez , Ratos , Ratos Wistar , Receptores de Estrogênio/biossíntese
9.
Int Immunopharmacol ; 66: 236-241, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30481683

RESUMO

Many studies confirmed that the over-activation of RAF-MEK-ERK signaling pathway plays a central role in human cancers. To avoid drug resistance during cancer treatment, many researchers focused on the study of the downstream therapeutic target of RAF-MEK-ERK signaling pathway. Therefore, ERK1/2 became a hot anticancer target. It has been shown that ERK phosphorylation could activate Th17 cells and therefore induce inflammatory diseases. Due to these results, inhibition of ERK, as a potential drug target, could provide a solution for autoimmune diseases, especially T cell mediated diseases. In this study, a small synthetic molecule JSI287 was found with the function of alleviating IMQ-induced mice skin lesions through ERK/IL-17 signaling pathway during the screening of small molecule databases targeting ERK. The results showed that JS1287 small molecule alleviated epidermal thickness, epidermis congestion, edema and inflammatory cell infiltration, decreased release of inflammatory cytokines of IL-6, IL-12 and IL-17A, and further regulated the mRNA expression of ATF1 and protein expression of ERK1/2 in IMQ-induced skin lesions. Our study suggested that ERK inhibitor JSI287 could be a promising candidate for psoriasis treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Interleucina-17/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Psoríase/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Células Th17/imunologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Imiquimode/toxicidade , Interleucina-12/metabolismo , Interleucina-6/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Psoríase/induzido quimicamente , Pele/patologia , Bibliotecas de Moléculas Pequenas , Quinases raf/metabolismo
10.
Chin J Nat Med ; 16(8): 572-579, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30197122

RESUMO

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.


Assuntos
Artemisia/química , Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Coelhos , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
11.
Biomed Pharmacother ; 98: 399-405, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29276968

RESUMO

To investigate the effects of icotinib hydrochloride and a derivative cream on epidermal growth factor receptor (EGFR) signaling and within animal psoriasis models, respectively. The effect of icotinib on EGFR signaling was examined in HaCaT cells, while its effect on angiogenesis was tested in chick embryo chorioallantoic membranes (CAM). The effectiveness of icotinib in treating psoriasis was tested in three psoriasis models, including diethylstilbestrol-treated mouse vaginal epithelial cells, mouse tail granular cell layer formation, and propranolol-induced psoriasis-like features in guinea pig ear skin. Icotinib treatment blocked EGFR signaling and reduced HaCaT cell viability as well as suppressed CAM angiogenesis. Topical application of icotinib ameliorated psoriasis-like histological characteristics in mouse and guinea pig psoriasis models. Icotinib also significantly inhibited mouse vaginal epithelium mitosis, promoted mouse tail squamous epidermal granular layer formation, and reduced the thickness of the horny layer in propranolol treated auricular dorsal surface of guinea pig. We conclude that icotinib can effectively inhibit psoriasis in animal models. Future clinical studies should be conducted to explore the therapeutic effects of icotinb in humans.


Assuntos
Éteres de Coroa/farmacologia , Receptores ErbB/metabolismo , Psoríase/tratamento farmacológico , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Cobaias , Humanos , Camundongos , Camundongos Endogâmicos ICR , Mitose/efeitos dos fármacos , Modelos Animais , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Psoríase/metabolismo
12.
Zhongguo Zhong Yao Za Zhi ; 37(17): 2618-21, 2012 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-23236763

RESUMO

OBJECTIVE: To study and compare the anti-inflammatory effect and molecular mechanism of artemisinin and dihydroartemisinin. METHOD: Mouse mononuclear macrophage RAW264.7 cells were stimulated to release inflammatory mediators such as TNF-alpha, IL-6 and NO, in order to assess the drugs' inhibitory effect on macrophage's release of above inflammatory mediators. The levels of TNF-alpha and IL-6 were determined by ELISA and the cytotoxicity was determined by MTT method. The protein expression of iNOS, COX-2 and beta-actin were tested by Western blot. The enzymatic activity of COX-2 was determined by colorimetric method. RESULT: Dihydroartemisinin significantly inhibited LPS-induced release of TNF-alpha, IL-6 and NO from RAW264.7 in mice with the concentration range of 12.5 - 100 micromol x L(-1), and showed good dose dependence. Artemisinin only inhibited the IL-6 release to a certain extent. CONCLUSION: Dihydroartemisinin inhibits macrophages from releasing inflammatory factors TNF-alpha and IL-6 and inflammatory mediators NO by down-regulating iNOS protein. Artemisinin may help dihydroartemisinin to show its anti-inflammatory effect through metabolism.


Assuntos
Anti-Inflamatórios/farmacologia , Artemisininas/farmacologia , Animais , Linhagem Celular , Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Óxido Nítrico/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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