Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 57
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Eur J Cancer Prev ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32032154

RESUMO

We aimed to detect the expression of specific LncRNAs in exosomes isolated from the serum of patients with precancerous lesions and to study the effect of these serum exosomes on the activity of GES-1 cells in patients with precancerous lesions, as well as the activity of all-trans retinoic acid on GES-1 cells with or without the exosomes. Exosomes were extracted from the serum of patients with precancerous lesions and normal controls. Based on our previous sequencing results, quantitative real time-PCR was used to detect differentially expressed LncRNAs. Exosomes from the serum of patients with precancerous lesions were cocultured with GES-1 cells, and 5 µM all-trans retinoic acid was added as an intervention. Changes in cell viability and expression of LncHOXA10 were observed. Compared with the blank group, the proliferation activity of GES-1 cells cocultured with exosomes derived from the serum of patients with precancerous lesions was increased (P < 0.01), the proportion of cells in S phase was increased (P < 0.05). After adding 5 µM all-trans retinoic acid, the viability of cells decreased significantly (P < 0.01), the proportion of cells in S phase decreased significantly (P < 0.05). The expression of LncHOXA10 was decreased (P < 0.05). All-trans retinoic acid can conduct its chemopreventive effects by inhibiting the expression of LncHOXA10, thereby reducing the activity of LncHOXA10 in GES-1 cells cocultured with serum exosomes from patients with precancerous lesions.

2.
J Med Chem ; 62(21): 9931-9946, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

3.
Oncol Lett ; 18(2): 1607-1616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31423228

RESUMO

Chemotherapy resistance is a major obstacle to the effective treatment of patients with gastric cancer (GC). Mounting evidence has indicated that the dysregulation of microRNAs (miRNAs) is associated with the sensitivity of cancer cells to chemotherapy. However, the mechanisms underlying miRNA-mediated chemoresistance in GC cells remain to be elucidated. The present study aimed to identify functional miRNAs that may regulate the sensitivity of human GC cells to cisplatin (DDP) treatment. miRNA microarray analysis was used to identify differentially expressed miRNAs between the human cisplatin-sensitive GC cell line SGC7901 and the corresponding cisplatin-resistant cell line SGC7901/DDP. miRNA (miR)-362-5p, which is associated with numerous types of tumors, was identified to be downregulated in the SGC7901/DDP cell line. However, the biological role of miR-362-5p in SGC7901/DDP cells remains to be explored. The expression level of miR-362-5p was demonstrated to be reduced in SGC7901/DDP cells compared with SGC7901 cells by reverse transcription-quantitative PCR. Upregulation of miR-362-5p significantly increased cisplatin sensitivity and cisplatin-induced apoptosis, whereas downregulation of miR-362-5p attenuated these effects. Databases predicted that suppressor of zeste 12 protein (SUZ12) may function as a target of miR-362-5p. In addition, the mRNA and protein expression levels of SUZ12 in SGC7901/DDP cells were significantly higher compared with SGC7901 cells and negatively associated with miR-362-5p expression. MTT and western blot analysis assays confirmed that knockdown of SUZ12 enhanced cisplatin sensitivity and decreased NF-κB/p65 protein levels in SGC7901/DDP cells. In addition, upregulation of miR-362-5p in SGC7901/DDP cells decreased the protein expression level of SUZ12, whereas downregulation of miR-362-5p increased the SUZ12 expression level. The results of the present study suggested that dysregulated miR-362-5p may target SUZ12 to promote the development of cisplatin resistance and attenuate cisplatin-induced apoptosis. Therefore, miR-362-5p upregulation combined with cisplatin treatment may serve as a promising therapeutic strategy for patients with cisplatin-resistant GC.

4.
Sci Transl Med ; 11(502)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

5.
Bioorg Med Chem Lett ; 29(16): 2265-2269, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257087

RESUMO

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.

6.
Methods Protoc ; 2(2)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164624

RESUMO

Th17 cells are a subset of effector T helper cells that produce interleukin (IL)-17A, IL-17F, IL-22, and IL-26, which can promote tissue inflammation and contribute to the pathogenesis of rheumatic, fibrosing, and other diseases. Research into these diseases is often limited by a lack of an animal model that closely mimics human disease and the paucity of patient clinical tissues. Therefore, the development of relevant experimental models is crucial. Three media formulations of Th17-skewing cocktail (CT) were evaluated for the ability to induce a Th17 signature in an ex vivo human skin model: CT9 contained αCD3, αCD28, IL-23, IL-1ß, IFNγ, IL-4, IL-6, IL-21, and TGFß; CT8 lacked IL-1ß; and CT4 only contained αCD3, αCD28, IL-23, and IL-1ß. Healthy donor skin was defatted, distributed as 3 mm punch biopsies, and incubated with one of the cocktail formulations or vehicle for 48 h. All of the cocktail formulations independently significantly stimulated the expression of each gene examined. CT4 induced IL-17A expression 1024-fold, significantly higher than CT9 and CT8. IL-17F was robustly stimulated by CT4 (1557-fold), CT9 (622-fold), and CT8 (111-fold), with significant differences between the CT groups. All of the formulations significantly induced IL-22 (16-42-fold). CT9 stimulated the highest IL-26 response (41-fold), which was significantly higher than CT4 and CT8. IL-10 was stimulated significantly higher with CT8 (10-fold) than CT4 or CT9. The secretion of IL-17A was significantly elevated with all cocktail formulations. Robust IL-17A/IL-17F cytokine induction was preferentially mediated by CT4, which suggested that its components are the minimal constituents necessary for the full induction of these genes in this human skin explant model, while the downstream cytokines were preferentially upregulated by CT4 (IL-22), CT9 (IL-26), or CT8 (IL-10). In summary, our findings suggest that the induction of a Th17 phenotype in human skin is feasible and can be used as a model for rheumatic and fibrosing diseases where Th17 skewing is observed.

7.
Appl Biochem Biotechnol ; 189(2): 485-497, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31049884

RESUMO

Effective pretreatment process to improve enzymatic saccharification and decrease inhibitors generation is a key operation involved in the lignocellulosic bioconversion. The pretreatment of steam explosion associated with ammonium sulfite (SEAS) process was carried out to investigate the effect on enzymatic hydrolysis and fermentation production as a combinatorial pretreatment. Results showed that after pretreatment (1.0 MPa, 30 min, 20%w/w ammonium sulfite added), the phenolic inhibitors derived from lignin significantly removed (37.8%), which transformed to chemical humic acid (humic acid and fulvic acid) mostly. Sugar conversion (glucan (77.8%) and xylan (73.3%)) and ethanol concentration (40.8 g/L) of combinatorial pretreated samples were increased by 24.7% and 33.8%, respectively, compared with steam explosion (SE) pretreated samples. FT-IR and elemental analysis results indicated that the lignin structure changed and aromatization degree increased after SEAS pretreatment. In addition, the ratio of C/N decreased and compost maturity degree increased with the holding time. The effect on the growth of wheat seedlings of soluble fulvic acid solution from combinatorial pretreatment was investigated, where below 1% (w/w) concentration did contribute to growth. Therefore, one-step chemical pretreatment process could be provided for inhibitors removal, enzymatic saccharification increase, and chemical humic acid formation as well.


Assuntos
Celulase/química , Compostos de Amônio Quaternário/química , Vapor , Sulfitos/química , Zea mays/química , Glucanos/química , Hidrólise , Xilanos/química
8.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(5): 579-585, 2019 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-31140423

RESUMO

OBJECTIVE: To investigate the changes in the expression of voltage-gated potassium channel subunit KCNA2 in the dorsal root ganglion (DRG) neurons of rats with osteoarthritis (OA) pain induced by sodium monoiodoacetate and explore the mechanism. METHODS: A total of 156 adult male Sprague-Dawley rats were randomly divided into blank control group, saline group and intra-articular monoiodoacetate injection-induced OA group. The paw withdrawal mechanical threshold (PWMT) was measured before and at 1, 2, 4, and 6 weeks after monoiodoacetate injection. At 4 weeks after the injection, the pathological changes in the knee joints were analyzed using HE staining and Safranin O-Fast Green staining, and the expression of activating transcription factor 3 (ATF-3) and inducible nitric oxide synthase (iNOS) in the DRG neurons were detected by immunofluorescence staining. The expression of Kcna2 mRNA in the DRG neurons was detected by RT-qPCR at 1, 2, 4 and 6 weeks after the injection. The expression of KCNA2 in the DRG was measured by Western blotting, and the methylation level of Kcna2 promoter region was measured by MSPCR at 4 weeks after the injection. RESULTS: The PWMT of the rats in OA group was significantly decreased at 2, 4, and 6 weeks after the injection as compared with the baseline (P < 0.05 or P < 0.001) as well as the control group (P < 0.05 or P < 0.001). Four weeks after the intra-articular injection, fractures and defects on the surface of the articular cartilage, bone hyperplasia, and blurred tidal line were observed in the rats in OA group, but no obvious pathological changes were detected in the control or saline groups. Compared with those in the control group, the expressions of ATF-3 and iNOS were significantly increased (P < 0.01) at 4 weeks after injection; the expression of Kcna2 mRNA at 2, 4 and 6 weeks and the expression of KCNA2 protein at 4 weeks were all significantly decreased (P < 0.05 or P < 0.01), and the methylation level of Kcna2 gene was significantly increased at 4 weeks after the injection in OA group (P < 0.01). CONCLUSIONS: The expression of KCNA2 is decreased in the DRG neurons of rats with OA pain likely as a result of enhanced methylation of Kcna2 promoter region.


Assuntos
Gânglios Espinais , Canal de Potássio Kv1.2/metabolismo , Osteoartrite , Dor , Animais , Modelos Animais de Doenças , Articulação do Joelho , Masculino , Osteoartrite/complicações , Osteoartrite/metabolismo , Dor/etiologia , Dor/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley
9.
J Immunol ; 203(1): 282-292, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076530

RESUMO

The gut microbiota has been shown critical for mucosal adjuvant activity of cholera toxin (CT), a potent mucosal adjuvant. However, the mechanisms involved remain largely unknown. In this study, we report that depletion of gut bacteria significantly decreased mucosal and systemic Ab responses in mice orally immunized with OVA and CT. Feeding mice short-chain fatty acids (SCFAs) promoted Ab responses elicited by CT, and, more importantly, rescued Ab responses in antibiotic-treated mice. In addition, mice deficient in GPR43, a receptor for SCFAs, showed impaired adjuvant activity of CT. Administering CT did not promote SCFA production in the intestines; thus, SCFAs facilitated but did not directly mediate the adjuvant activity of CT. SCFAs promoted B cell Ab production by promoting dendritic cell production of BAFF and ALDH1a2, which induced B cell expression of IFN regulatory factor 4, Blimp1, and XBP1, the plasma B cell differentiation-related genes. Furthermore, when infected with Citrobacter rodentium, GPR43-/- mice exhibited decreased Ab responses and were more susceptible to infection, whereas the administration of SCFAs promoted intestinal Ab responses in wild-type mice. Our study thereby demonstrated a critical role of gut microbiota and their metabolite SCFAs in promoting mucosal adjuvant activity of CT through GPR43.

10.
ACS Med Chem Lett ; 10(3): 300-305, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891130

RESUMO

We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.

11.
ACS Med Chem Lett ; 10(3): 367-373, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891142

RESUMO

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRß. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

12.
J Cancer ; 10(4): 1039-1051, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854110

RESUMO

Cisplatin chemoresistance is a clinical obstacle in the treatment of gastric cancer (GC). Enhanced DNA repair capacity may lead to cisplatin resistance. However, the detailed molecular mechanism of GC cisplatin resistance specifically involving nucleotide excision repair (NER) is not clear. However, the mechanism through which the NER pathway contributes to cisplatin resistance in GC is still unclear. In light of the crucial role of microRNAs (miRNAs) in regulating protein expression and biological behavior, we aimed to analyze the expression and function of miR-192-5p in the NER pathway and its role in cisplatin resistance in GC. Comet assays were performed to measure the amount of DNA damage and repair in the SGC7901 and SGC7901/DDP GC cell lines by observing the tail length. MiRNA expression levels in SGC7901/DDP and SGC7901 cells were detected by microarray. Quantitative real-time PCR (qRT-PCR) was carried out to confirm the expression level of miR-192-5p. Lentiviral vector transfection modifies miR-192-5p levels in SGC7901/DDP and SGC7901 cells. The IC50 values of cisplatin-treated cells were assessed by MTT assays. The protein level was determined by Western blot and immunohistochemistry. With enhanced DNA repair, the expression levels of ERCC3 and ERCC4 in SGC 7901DDP cells increased, while miR-192-5p was significantly downregulated in SGC7901/DDP compared with SGC7901 cells. ERCC3 and ERCC4 were identified as the main targets of miR-192-5p. Forced expression of miR-192-5p in SGC7901/DDP cells significantly inhibited the expression of ERCC3 and ERCC4, making GC cells more sensitive to cisplatin in vitro and in vivo. In contrast, knockdown of miR-192-5p expression in SGC7901 cells increased the expression of ERCC3 and ERCC4, resulting in cisplatin resistance in vitro and in vivo. MiR-192-5p partially reversed GC cisplatin resistance by targeting ERCC3 and ERCC4, which participate in the NER pathway, suggesting that miR-192-5p may be a potential biomarker and therapeutic target for GC cisplatin resistance.

13.
J Immunol ; 202(1): 79-92, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30478092

RESUMO

The role of retinoid-related orphan receptor γ t (RORγt) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, RORγt inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with RORγt-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. RORγt inhibitor-treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the RORγt inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1-/- T cells produced significantly fewer IL-10 when treated with RORγt inhibitor compared with wild-type T cells. Furthermore, RORγt inhibitor-treated Prdm1-/- Th17 cells induce more severe colitis compared with RORγt inhibitor-treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which RORγt drives and maintains pathogenic Th17 cell development by inhibiting IL-10 production.


Assuntos
Colite/imunologia , Interleucina-10/metabolismo , Intestinos/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Th17/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Repressão Epigenética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-30364840

RESUMO

Background & Aims: Crohn's disease is an inflammatory bowel disease that affects the ileum and is associated with increased cytokines. Although interleukin (IL)6, IL17, IL21, and IL22 are increased in Crohn's disease and are associated with disrupted epithelial regeneration, little is known about their effects on the intestinal stem cells (ISCs) that mediate tissue repair. We hypothesized that ILs may target ISCs and reduce ISC-driven epithelial renewal. Methods: A screen of IL6, IL17, IL21, or IL22 was performed on ileal mouse organoids. Computational modeling was used to predict microenvironment cytokine concentrations. Organoid size, survival, proliferation, and differentiation were characterized by morphometrics, quantitative reverse-transcription polymerase chain reaction, and immunostaining on whole organoids or isolated ISCs. ISC function was assayed using serial passaging to single cells followed by organoid quantification. Single-cell RNA sequencing was used to assess Il22ra1 expression patterns in ISCs and transit-amplifying (TA) progenitors. An IL22-transgenic mouse was used to confirm the impact of increased IL22 on proliferative cells in vivo. Results: High IL22 levels caused decreased ileal organoid survival, however, resistant organoids grew larger and showed increased proliferation over controls. Il22ra1 was expressed on only a subset of ISCs and TA progenitors. IL22-treated ISCs did not show appreciable differentiation defects, but ISC biomarker expression and self-renewal-associated pathway activity was reduced and accompanied by an inhibition of ISC expansion. In vivo, chronically increased IL22 levels, similar to predicted microenvironment levels, showed increases in proliferative cells in the TA zone with no increase in ISCs. Conclusions: Increased IL22 limits ISC expansion in favor of increased TA progenitor cell expansion.


Assuntos
Células Epiteliais/citologia , Íleo/citologia , Interleucinas/farmacologia , Organoides/citologia , Células-Tronco/citologia , Animais , Biomarcadores/metabolismo , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Simulação por Computador , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Receptores de Interleucina/metabolismo , Soro/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
15.
J Diabetes Investig ; 10(2): 499-512, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30187673

RESUMO

AIMS/INTRODUCTION: Children who are exposed to gestational diabetes mellitus (GDM) in utero are at high risk of developing related illnesses, such as type 2 diabetes mellitus in young adulthood, but the underlying mechanism and related predictive biomarkers are not known. MATERIALS AND METHODS: The present study identified the related biomarkers of hyperglycemia in young adults from the relationship between fetal blood glucose and placental lipid transporters at messenger ribonucleic acid (mRNA) and protein expression levels. We recruited patients from a prospective cohort, and determined the mRNA and protein levels of placental fatty acid transporters. Diet-induced mouse models of GDM were established, and the mRNA and protein levels of the same transporters in placentas were validated. RESULTS: Only the mRNA levels of peroxisome proliferator-activated receptor gamma correlated with the levels of neonatal blood glucose in GDM patients using linear regression and Spearman's correlation analyses (r = 0.774, P = 0.001). The mRNA levels of peroxisome proliferator-activated receptor gamma, matrix metalloproteinase-2 and fatty acid transport protein-6 correlated with blood glucose levels in mouse offspring (r = 0.82, P = 0.001, r = 0.737, P = 0.006 and r = -0.891, P = 0.001, respectively) at young adulthood using the same analyses. Notably, we observed significantly higher blood glucose levels in GDM offspring at 12 weeks-of-age compared with the control and rosiglitazone-supplemented groups (P < 0.05). CONCLUSIONS: The downregulation of peroxisome proliferator-activated receptor gamma in the placenta might predict hyperglycemia in offspring at young adulthood.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Gestacional/fisiopatologia , Feto/metabolismo , Hiperglicemia/etiologia , PPAR gama/metabolismo , Placenta/metabolismo , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adulto , Animais , Biomarcadores/análise , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Seguimentos , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/metabolismo , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
16.
J Immunol Res ; 2018: 5241526, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515423

RESUMO

Liver ischemia-reperfusion injury (IRI) and regeneration deficiency are two major challenges for surgery patients with chronic liver disease. As a survival factor for hepatocytes, interleukin 22 (IL-22) plays an important role in hepatoprotection and the promotion of regeneration after hepatectomy. In this study, we aim to investigate the roles of an interleukin 22 fusion protein (IL-22-FP) in mice with a predamaged liver after a two-third partial hepatectomy (PHx). Predamaged livers in mice were induced by concanavalin A (ConA)/carbon tetrachloride (CCl4) following PHx with or without IL-22-FP treatment. A hepatic IRI mouse model was also used to determine the hepatoprotective effects of IL-22-FP. In the ConA/CCl4 model, IL-22-FP treatment alleviated liver injury and accelerated hepatocyte proliferation. Administration of IL-22-FP activated the hepatic signal transducer and activator of transcription 3 (STAT3) and upregulated the expression of many mitogenic proteins. IL-22-FP treatment prior to IRI effectively reduced liver damage through decreased aminotransferase and improved liver histology. In conclusion, IL-22-FP promotes liver regeneration in mice with predamaged livers following PHx and alleviates IRI-induced liver injury. Our study suggests that IL-22-FP may represent a promising therapeutic drug against regeneration deficiency and liver IRI in patients who have undergone PHx.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Hepatócitos/fisiologia , Interleucinas/metabolismo , Fígado/patologia , Proteínas Recombinantes de Fusão/metabolismo , Animais , Tetracloreto de Carbono , Sobrevivência Celular , Doença Hepática Induzida por Substâncias e Drogas/cirurgia , Concanavalina A , Modelos Animais de Doenças , Hepatectomia , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/genética , Regeneração , Fator de Transcrição STAT3/metabolismo
17.
Ecotoxicol Environ Saf ; 166: 336-344, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30278395

RESUMO

Cadmium (Cd) is a pervasive carcinogen and environmental endocrine disruptor. We studied the changes in learning and memory of offspring mice, whose mothers were exposed to 10 mg Cd/L via the drinking water during pregnancy and lactation period, as well as the changes of testosterone and estrogen levels, serum Cd levels, the histopathological changes and the changes in the mRNA and protein levels of different subunits of γ-aminobutyric acid receptor subtype A subunits (GABAARs) in the hippocampus at the prepuberty, puberty, young adult, and adult stages. At birth, Cd had no obvious effect on mice offspring as statistically accessed based on their body weight, body length, and tail length (all p > 0.05). After grouped, the serum Cd levels increased in the three exposed groups more than in the normal control group at stages (all p < 0.05). Only serum estradiol of female offspring at age 7 weeks was significantly decreased compared with other groups (all p < 0.05). Histopathological results showed that the arrangement of the cells in hippocampal CA1 area of mice offspring was significantly sparse in the exposed groups compared with the control group. At 5 and 7 weeks, two Cd-exposed groups showed prolonged escape latency and exploring time for the platform compared with the normal group in the Morris water maze (all p < 0.05). Only increased protein expression of GABAARα5 was found in the Cd group at these two ages. At age 12 weeks, similar impaired learning and memory of female mice, and decreased protein expression of GABAARδ was found in Cd-exposed groups. Collectively, low-dose Cd had no effect on the growth of mice offspring but affected their learning and memory, especially female offspring, at puberty, young adulthood, and adulthood through changed structure in the hippocampal CA1 area and protein expression of GABAARα5 and GABAARδ.


Assuntos
Cádmio/toxicidade , Carcinógenos/toxicidade , Poluentes Ambientais/toxicidade , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Cádmio/metabolismo , Modelos Animais de Doenças , Estrogênios/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Gravidez , Subunidades Proteicas/efeitos dos fármacos , Receptores de GABA/metabolismo , Receptores de GABA-A/metabolismo , Maturidade Sexual/efeitos dos fármacos , Testosterona/metabolismo
18.
Nat Commun ; 9(1): 3555, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177845

RESUMO

T-cells are crucial in maintanence of intestinal homeostasis, however, it is still unclear how microbiota metabolites regulate T-effector cells. Here we show gut microbiota-derived short-chain fatty acids (SCFAs) promote microbiota antigen-specific Th1 cell IL-10 production, mediated by G-protein coupled receptors 43 (GPR43). Microbiota antigen-specific Gpr43-/- CBir1 transgenic (Tg) Th1 cells, specific for microbiota antigen CBir1 flagellin, induce more severe colitis compared with wide type (WT) CBir1 Tg Th1 cells in Rag-/- recipient mice. Treatment with SCFAs limits colitis induction by promoting IL-10 production, and administration of anti-IL-10R antibody promotes colitis development. Mechanistically, SCFAs activate Th1 cell STAT3 and mTOR, and consequently upregulate transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1), which mediates SCFA-induction of IL-10. SCFA-treated Blimp1-/- Th1 cells produce less IL-10 and induce more severe colitis compared to SCFA-treated WT Th1 cells. Our studies, thus, provide insight into how microbiota metabolites regulate Th1 cell functions to maintain intestinal homeostasis.


Assuntos
Colite/imunologia , Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/imunologia , Interleucina-10/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Células Th1/imunologia , Animais , Ácidos Graxos Voláteis/metabolismo , Flagelina/imunologia , Expressão Gênica , Técnicas de Inativação de Genes , Homeostase , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Receptores Acoplados a Proteínas-G/genética , Fator de Transcrição STAT3/imunologia , Serina-Treonina Quinases TOR/imunologia , Regulação para Cima
19.
PLoS One ; 13(6): e0199721, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29928043

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0184681.].

20.
Lipids ; 53(3): 301-311, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29701266

RESUMO

Changes in dietary composition will have a significant impact on the nutritional status of the mother and the offspring. To examine the relevant hormone level changes during lactation and the expression of fatty acid transporters in the placenta and liver under the condition of a high-fat (HF) diet, we established HF animal models and conducted a cross-fostering program to mimic the shift in diet. On gestation day (GD)18, the weight of placenta in the HF group was significantly higher than that in the control group (p < 0.05). HF-fed male pups had a significantly lower serum insulin level, but the same phenomenon was not found in females. On the contrary, serum triacylglycerol (TAG) level presented a tendency to decrease only in female offspring. Oil red O staining showed lipid accumulation in the HF diet offspring livers. The mRNA levels of FATP4 in the placenta in the HF diet group were significantly upregulated compared to the control diet group (p < 0.05). High-fat diet (HFD) consumption also altered the liver mRNA levels of FATP4, SREBP-1, and SCD-1 in the male offspring, while the changes in protein levels of FATP4 were not observed in either sex. In conclusion, maternal HF diet has a profound impact on offspring growth, metabolism, and the risk of metabolic disorders, which would depend on the exposure period of pregnancy and lactation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/administração & dosagem , Proteínas de Transporte de Ácido Graxo/genética , Fígado/efeitos dos fármacos , Placenta/efeitos dos fármacos , RNA Mensageiro/genética , Animais , Gorduras na Dieta/metabolismo , Proteínas de Transporte de Ácido Graxo/agonistas , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Regulação da Expressão Gênica , Insulina/genética , Insulina/metabolismo , Lactação/efeitos dos fármacos , Lactação/fisiologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Placenta/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Fatores Sexuais , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Tempo , Triglicerídeos/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA