Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
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.

2.
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.

3.
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.

4.
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
5.
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
6.
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.

7.
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
8.
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.

9.
J Immunol ; 2018 Nov 26.
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.

10.
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.

11.
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.

12.
J Diabetes Investig ; 2018 Sep 06.
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.

13.
PLoS One ; 13(6): e0199721, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29928043

RESUMO

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

14.
Lipids ; 53(3): 301-311, 2018 Mar.
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.

15.
Biol Trace Elem Res ; 186(1): 21-30, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29502251

RESUMO

Helicobacter pylori (H. pylori) infection can interfere with the absorption of most elements, and the variations of some element levels are related to the incidence of gastric cancer. However, there have been conflicting results concerning the influence of H. pylori infection on serum element levels. The present study aimed to compare the serum element concentrations of H. pylori-infected local residents with uninfected residents from Lujiang County with high gastric cancer risk in Eastern China. We used data and serum samples from the H. pylori screening-survey program which was a cross-sectional study. We took 155 samples randomly from the screening survey, identified 74 H. pylori-positive residents and 81 H. pylori-negative residents by a serological test. The serum concentrations of 15 elements (calcium, magnesium, iron, zinc, selenium, copper, molybdenum, chromium, cobalt, nickel, lead, cadmium, mercury, arsenic, and aluminum) were determined using inductively coupled plasma mass spectrometry. Serum cobalt was found at higher levels in the H. pylori-infected residents than the H. pylori-uninfected residents (0.246 vs 0.205 µg/L, P = 0.022), but no statistically significant differences in the serum levels of other elements were found. This is the first study to report the serum concentrations of 15 elements and their relationships with the infection status of H. pylori among local residents from Lujiang County with high gastric cancer risk. Although the International Agency for Research on Cancer has classified cobalt and other soluble cobalt salts as possibly carcinogenic to human beings, our results may provide a clue to the relationships between cobalt, H. pylori, and gastric cancer.

16.
Mucosal Immunol ; 11(3): 752-762, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29411774

RESUMO

The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and ß-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43-/- mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and ß-defensins in intestinal epithelial enteroids generated from WT but not GPR43-/- mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and ß-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.

17.
Bioorg Med Chem Lett ; 28(2): 85-93, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233651

RESUMO

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Desenho de Drogas , Propanóis/farmacologia , Receptores do Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacologia , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
18.
Asia Pac J Clin Oncol ; 14(2): e29-e36, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28374495

RESUMO

AIM: The aim of this study was to analyze the gene expression profile and biological processes enriched in gastric cancer. METHODS: We collected five human advanced gastric cancer tissues by gastroscopy and five peritumor normal tissues as controls and examined the gene expression changes by microarray. KEGG Orthology Based Annotation System annotation was used to identify pathways and biological processes regulated by the deregulated genes. Protein-protein interaction network analysis identified protein complex and functional modules. We also selected 14 genes for further verification by real-time quantitative Polymerase Chain Reaction (PCR). RESULTS: Human gene expression profile analysis showed that 2028 deregulated genes were detected in gastric cancer compared with the control group (at least a 2.0-fold change and P < 0.05), among which there were 689 upregulated and 1339 downregulated genes. Interestingly, we identified some important genes, such as CXCL17, OTX1 and CCDC125, which have not previously been reported in gastric cancer. Real-time quantitative PCR results verified that CXCL8, OTX1, CEBPB, FOSL1, FOXS1, ARFRP1 and IRF9 were upregulated in gastric cancer and CCDC125, PPP1R36, SOX2, JUN and MIA2 were downregulated. Moreover, bioinformatics analysis demonstrated that the biological processes of inflammatory response, angiogenesis, cell migration and pathways of chemokine signaling pathway, TNF signaling pathway were enriched. We also selected the top 30 significant Gene Ontology terms and select pathways for a brief summary. CONCLUSION: We performed a global analysis of the mRNA landscape in gastric cancer. Our results may stimulate a deeper understanding of the disease, and lead to the development of potential therapies and the identification of novel biomarkers.


Assuntos
Biologia Computacional/métodos , Gastroscopia/métodos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Neoplasias Gástricas/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/patologia
19.
Bioanalysis ; 9(20): 1573-1588, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29072496

RESUMO

AIM: IP-10 is a protein target for the treatment of Crohn's disease. Inhibition of IP-10 by anti-IP-10 mAbs neutralizes its various biological activities. The measurement of free IP-10 suppression as a target engagement biomarker is required for the assessment of drug effect on the target. RESULTS: The development of highly sensitive immunoaffinity-LC-MS/MS assays for quantifying free and total IP-10 in cynomolgus monkey serum is reported for the first time. This paper details strategies for maximizing assay sensitivity by selecting digestion routes, and optimizing immunocapture to achieve full recovery and minimal matrix effect. For the free IP-10 assay, bioanalytical strategies have been established to minimize drug/ligand dissociation. CONCLUSION: The assays have been implemented for target engagement measurement, pharmacokinetic-pharmacodynamic correlation, and human dose projections.


Assuntos
Biomarcadores/sangue , Quimiocina CXCL10/sangue , Cromatografia de Afinidade , Espectrometria de Massas em Tandem , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Cromatografia Líquida de Alta Pressão , Humanos , Ligantes , Macaca fascicularis , Peptídeos/química , Peptídeos/isolamento & purificação , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência
20.
PLoS One ; 12(9): e0184681, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898278

RESUMO

Phytolacca americana L. (pokeweed) has metal phytoremediation potential, but little is known about its metal accumulation-related genes. In this study, the de novo sequencing of total RNA produced 53.15 million reads covering 10.63 gigabases of transcriptome raw data in cadmium (Cd)-treated and untreated pokeweed. Of the 97,502 assembled unigenes, 42,197 had significant matches in a public database and were annotated accordingly. An expression level comparison between the samples revealed 1515 differentially expressed genes (DEGs), 923 down- and 592 up-regulated under Cd treatment. A KEGG pathway enrichment analysis of DEGs revealed that they were involved in 72 metabolism pathways, with photosynthesis, phenylalanine metabolism, ribosome, phenylpropanoid biosynthesis, flavonoid biosynthesis and carbon fixation in photosynthetic organisms containing 24, 18, 72, 14, 7 and 15 genes, respectively. Genes related to heavy metal tolerance, absorption, transport and accumulation were also identified, including 11 expansins, 8 nicotianamine synthases, 6 aquaporins, 4 ZRT/IRT-like proteins, 3 ABC transporters and 3 metallothioneins. The gene expression results of 12 randomly selected DEGs were validated using quantitative real-time PCR, and showed different response patterns to Cd in their roots, stems and leaves. These results may be helpful in increasing our understanding of heavy metal hyperaccumulators and in future phytoremediation applications.


Assuntos
Cádmio/toxicidade , Phytolacca americana/genética , Estresse Fisiológico , Transcriptoma , Phytolacca americana/efeitos dos fármacos , Phytolacca americana/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA