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1.
PLoS One ; 14(8): e0221473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437207

RESUMO

OsMADS16, a class B floral organ identity gene, plays a pivotal role in stamen formation in rice. To date, little is known about the interacting partners of OsMADS16 except for several MADS-box proteins. In this study, we constructed a high-quality cDNA library of young panicles (< 5 cm in length) and performed yeast two-hybrid (Y2H) screening using OsMADS16 as bait. Eleven candidate proteins interacting with OsMADS16 were identified by Y2H and validated by BiFC and Co-IP assays. Subcellular localization results further confirmed the possibility of the interactions of OsMADS16 with 10 of the candidate proteins in natural rice cells. Bioinformatics analysis indicated that these partners exerted various molecular, cellular and physiological functions. Some of them were known or likely to be related to reproductive events, such as stamen primordium initiation, differentiation and development (OsMADS2, OsMADS4 and OsCOP9) and pollen development (OsbHLH40 and Os6PGDH). Our results provide an important reference for further research on OsMADS16-mediated regulation mechanism on floral organ development and pollen formation.

2.
J Exp Med ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467036

RESUMO

The NLRP3 inflammasome is critical for EAE pathogenesis; however, the role of gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome, in EAE has not been well defined. Here, we observed that the levels of GSDMD protein were greatly enhanced in the CNS of EAE mice, especially near the areas surrounding blood vessels. GSDMD was required for the pathogenesis of EAE, and GSDMD deficiency in peripheral myeloid cells impaired the infiltration of immune cells into the CNS, leading to the suppression of neuroinflammation and demyelination. Furthermore, the loss of GSDMD reduced the activation and differentiation of T cell in the secondary lymphoid organs and prevented T cell infiltration into CNS of EAE. The administration of inflammasome-related cytokines partially rescued the impairment of pathogenesis of EAE in GSDMD KO mice. Collectively, these findings provide the first demonstration of GSDMD in peripheral myeloid cells driving neuroinflammation during EAE pathogenesis.

3.
Biomed Pharmacother ; 117: 109185, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387179

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is the first-line treatment in non-resectable non-small lung cancer (NSCLC) with EGFR mutation. However, EGFR-TIKs resistance would inevitably develop within 9-14 months after treatment. And, chemotherapy is the main treatment for EGFR-TKIs resistant patients. WEE1 kinase, a G2/M checkpoint regulator, was recently considered as a putative biomarker for the platinum-based chemo-response. The aim of this study is to clarify the relationship between WEE1 kinase and chemosensitivity in EGFR-TKIs resistant NSCLC. WEE1 expression was tested in EGFR-TKIs resistant cell lines (H1299, PC9/G2) and patients' specimens by western blot, qPCR and immunohistochemistry (IHC). In in vitro experiment, WEE1 expression was higher in EGFR-TKIs resistant than EGFR-TKIs sensitive cell lines and was gradually increased following cisplatin or gemcitabine treatment with the enrichment of G2/M cell cycle phase. And, for patients with acquired Icotinib/Gefitinib resistance, 58.4% (7/12) had increased WEE1 expression compared to its initial expression level. In order to explore the impact of WEE1 on chemo-response, WEE1 knockdown was conducted in EGFR-TKIs resistant H1299 and PC9/G2 cells. MTT and colony formation assay showed that the efficacy of cisplatin and gemcitabine was enhanced in the two cell lines after WEE1 knockdown. And, the IC50 value of cisplatin decreased from 8.64 µg/ml to 3.10 µg/ml or 2.38 µg/ml in H1299 and from 3.66 µg/ml to 0.97 µg/ml or 1.18 µg/ml in PC9/G2 after WEE1 knockdown with two specific shRNAs. This study revealed that WEE1 expression was increased after EGFR-TKIs resistance, and WEE1 knockdown could enhance chemosensitivity in EGFR-TKIs resistant NSCLC. It is suggested the combination of WEE1 inhibitor and chemotherapy might improve the clinical outcome of NSCLC patients with acquired EGFR-TKIs resistance.

4.
Med Sci Monit ; 25: 5942-5952, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31398183

RESUMO

BACKGROUND The incidence of Gitelman syndrome (GS) has been increasing in our hospital. The aim of this study was to explore the diagnostic accuracy and features of SLC12A3 gene in Chinese patients with GS. MATERIAL AND METHODS We searched the literature about Chinese patients with GS in the PubMed database up to July 2018 and also included 8 GS Chinese patients from our hospital in our analysis that explored the features of SLC12A3 gene. We divided all the patients into 3 groups according to diagnostic consensus. Complete compliance was defined to mean containing 2 allelic mutations, partial compliance to mean one allelic mutation, and clinical compliance to mean no mutations. RESULTS Totally, 137 patients were enrolled in this study and 90 mutations were counted. Missense mutations accounted for over 72% in Chinese GS patients and the most common one was Thr60Met. According to the consensus, there were 102 patients (74.5%) in the complete compliance group, 31 patients (22.6%) in the partial compliance group, and only 4 patients (2.9%) in the clinical compliance group. CONCLUSIONS The SLC12A3 gene analysis in Chinese GS patients revealed that the most common mutation was Thr60Met, one of the missense mutations. Most of the patients were in the complete compliance group (i.e., 2 allelic mutations); the other cases might be explained by gene rearrangement.

5.
Am J Clin Pathol ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31305894

RESUMO

OBJECTIVES: We prospectively investigate the accuracy of frozen sections for diagnosing visceral pleural invasion (VPI) by autofluorescence and evaluated its usefulness in sublobar resection. METHODS: We included patients with lung adenocarcinoma 2 cm or less to evaluate the diagnostic performance of autofluorescence for VPI in frozen sections via a fluorescence microscope. Furthermore, the impact of VPI on patients treated with sublobar resection was assessed in another cohort. RESULTS: A total of 112 patients were enrolled. The accuracy, sensitivity, and specificity of autofluorescence for VPI diagnosis was 95.5%, 86.8%, and 100%, respectively. Sublobar resection was an independent risk factor for recurrence in patients with lung adenocarcinomas 2 cm or less with VPI positivity (hazard ratio, 3.30; P = .023), whereas it was not in those with VPI negativity. CONCLUSIONS: Using autofluorescence in frozen sections appears to be an accurate method for diagnosing VPI, which is helpful for surgical decision making.

6.
J Hematol Oncol ; 12(1): 75, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299995

RESUMO

INTRODUCTION: To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates. METHODS: Whole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8+ tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database. RESULTS: The median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8+ TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P < 0.001, P = 0.005, respectively). Low TMB and high CD8+ TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8+ TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8+ TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors. CONCLUSION: The combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.

7.
Sci Data ; 6(1): 128, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332220

RESUMO

The London Planetree (Platanus acerifolia) are present throughout the world. The tree is considered a greening plant and is commonly planted in streets, parks, and courtyards. The Sycamore lace bug (Corythucha ciliata) is a serious pest of this tree. To determine the molecular mechanism behind the interaction between the London Planetree and the Sycamore lace bug, we generated a comprehensive RNA-seq dataset (630,835,762 clean reads) for P. acerifolia by sequencing both infected and non-infected leaves of C. ciliata using the Illumina Hiseq 4000 system. We assembled the transcriptomes using the Trinity De Novo assembly followed by annotation. In total, 121,136 unigenes were obtained, and 80,559 unigenes were successfully annotated. From the 121,136 unigenes, we identified 3,010,256 SNPs, 39,097 microsatellites locus, and 1,916 transcription factors. The transcriptomic dataset we present are the first reports of transcriptome information in Platanus species and will be incredibly useful in future studies with P. acerifolia and other Platanus species, especially in the areas of genomics, molecular biology, physiology, and population genetics.

8.
J Virol Methods ; 272: 113710, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351984

RESUMO

With its ever-increasing viral genetic diversity, accurate diagnosis of porcine reproductive and respiratory syndrome virus (PRRSV) infection is indispensable for PRRSV control. Here, a sensitive graphene oxide (GO)-based FRET method was developed to detect PRRSV-2 based on the ability of GO to quench fluorophore by fluorescence resonance energy transfer (FRET). Using primers and a fluorophore-labeled ssDNA probe targeting a conserved region between the PRRSV M gene and 3'UTR, asymmetric PCR specifically amplified viral ssDNA that could anneal with probe to generate dsDNA only in the presence of virus. Upon exonuclease III treatment to release the probe fluorophore, which degrades dsDNA with blunt ends or recessed 3´-termini, the ssDNA annealed with other probe to generate enhanced fluorescence. This GO-based FRET assay specifically detected both classical and highly pathogenic PRRSV, with analytical sensitivity approaching 10 copies/µL, similar to that of real-time PCR but greater than that of conventional reverse transcription PCR (RT-PCR). Consistent with real-time RT-PCR detection, the assay developed here exhibited high diagnostic sensitivity for virus detection of sera from experimentally and naturally infected pigs. Thus, this novel GO-based FRET assay combined with asymmetric PCR detection is sensitive and specific and will be valuable for future PRRSV diagnosis.

9.
Int J Mol Sci ; 20(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311085

RESUMO

The sycamore lace bug, Corythucha ciliata (Say) is a highly invasive pest insect that feeds on sycamore trees (Platanus spp.) worldwide. The interaction between Platanus species and this insect pest has not yet been studied at the molecular level. Therefore, a recent study was conducted to compare the gene expression and metabolite profiles of Platanus acerifolia leaves in response to C. ciliata feeding damage after 24 and 48 h. We employed high throughput RNA sequencing (RNA- seq) to identify a total of 2,828 significantly differentially expressed genes (DEGs) after C. ciliata feeding. In addition, 303 unigenes were found to be up-regulated at both time points. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that monoterpenoid biosynthesis, the linoleic acid metabolism pathway, and alpha- linolenic acid metabolism were the most prominent pathways among the DEGs. Further analysis of the metabolite profiles showed that nine metabolites were significantly different before and after C. ciliata damage. In addition, we analyzed DEGs detected in the P. acerifolia and C. ciliata interaction using Mapman. The terpene synthase gene family was also identified. We suggest that the results obtained from DEGs and metabolite analysis can provide important information for the identification of genes involved in the P. acerifolia-C. ciliata interaction, which might be necessary for controlling C. ciliata efficiently.

10.
Redox Biol ; 26: 101264, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31279222

RESUMO

The association between airborne fine particulate matter (PM2.5) concentration and the risk of respiratory diseases has been well documented by epidemiological studies. However, the mechanism underlying the harmful effect of PM2.5 has not been fully understood. In this study, we exposed the C57BL/6J mice to airborne PM2.5 for 3 months (mean daily concentration ~50 or ~110 µg/m3, defined as PM2.5-3L or PM2.5-3H) or 6 months (mean daily concentration ~50 µg/m3, defined as PM2.5-6L) through a whole-body exposure system. Histological and biochemical analysis revealed that PM2.5-3H exposure caused more severe lung injury than did PM2.5-3L, and the difference was greater than that of PM2.5-6L vs PM2.5-3L exposure. With RNA-sequencing technique, we found that the lungs exposed with different concentration of PM2.5 have distinct transcriptional profiles. PM2.5-3H exposure caused more differentially expressed genes (DEGs) in lungs than did PM2.5-3L or PM2.5-6L. The DEGs induced by PM2.5-3L or PM2.5-6L exposure were mainly enriched in immune pathways, including Hematopoietic cell lineage and Cytokine-cytokine receptor interaction, while the DEGs induced by PM2.5-3H exposure were mainly enriched in cardiovascular disease pathways, including Hypertrophic cardiomyopathy and Dilated cardiomyopathy. In addition, we found that upregulation of Cd5l and reduction of Hspa1 and peroxiredoxin-4 was associated with PM2.5-induced pulmonary inflammation and oxidative stress. These results may provide new insight into the cytotoxicity mechanism of PM2.5 and help to development of new strategies to attenuate air pollution associated respiratory disease.

11.
Viruses ; 11(7)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288481

RESUMO

Peste des petits ruminants virus (PPRV) is associated with global peste des petits ruminants resulting in severe economic loss. Peste des petits ruminants virus dampens host interferon-based signaling pathways through multiple mechanisms. Previous studies deciphered the role of V and C in abrogating IFN-ß production. Moreover, V protein directly interacted with signal transducers and activators of transcription 1 (STAT1) and STAT2 resulting in the impairment of host IFN responses. In our present study, PPRV infection inhibited both IFN-ß- and IFN-γ-induced activation of IFN-stimulated response element (ISRE) and IFN-γ-activated site (GAS) element, respectively. Both N and P proteins, functioning as novel IFN response antagonists, markedly suppressed IFN-ß-induced ISRE and IFN-γ-induced GAS promoter activation to impair downstream upregulation of various interferon-stimulated genes (ISGs) and prevent STAT1 nuclear translocation. Specifically, P protein interacted with STAT1 and subsequently inhibited STAT1 phosphorylation, whereas N protein neither interacted with STAT1 nor inhibited STAT1 phosphorylation as well as dimerization, suggesting that the N and P protein antagonistic effects were different. Though they differed in their relationship to STAT1, both proteins blocked JAK-STAT signaling, severely negating the host antiviral immune response. Our study revealed a new mechanism employed by PPRV to evade host innate immune response, providing a platform to study the interaction of paramyxoviruses and host response.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31245300

RESUMO

To investigate the parameters associated with post-treatment recurrence of bacterial vaginosis (BV), clinical factors and vaginal microbiota were examined and analyzed for BV patients who received standard metronidazole therapy. The variables associated with BV recurrence included clinical factors of past BV history, use of intravaginal device, and D7 Nugent score as well as many microbial genera, with Lactobacillus, Enterococcus, Ureaplasma, and Aerococcus being the top contributors. Co-occurrence network analysis showed that whereas overwhelming majority of interbacterial interactions were positive, negative interactions were present and connected mostly to Lactobacillus, Enterococcus, and to a less extent Ureaplasma, suggesting the importance of interbacterial antagonism for treatment outcome. The patients who were cured and recurrent also exhibited clear differences in the species composition of Lactobacillus: although L. iners remained the dominant species at all time points, L. crispatus, L. gasseri, and L. jensenii displayed apparent differences in relative abundance between the cure and recurrent groups. Based on these results, we developed a 5-component panel comprising Enterococcus, L. crispatus, Ureaplasma, Aerococcus, and L. jensenii for predicting recurrence using D7 data and showed that it generated the specificity, sensitivity, and AUC values of 0.80, 0.66, and 0.73 for the discovery cohort and 0.80, 0.67, and 0.69 for the validation cohort. Our findings highlighted key microbial components for BV recurrence and suggested that they could be used to monitor the treatment outcome.

13.
Org Lett ; 21(13): 5035-5039, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31247784

RESUMO

A rhodium/sulfur-olefin complex catalyzed asymmetric 1,2-addition of arylboronic acids to six-membered 1,2,6-thiadiazinane 1,1-dioxide-type cyclic imines to access highly optically active sulfamides (95-99% ee) has been developed. By taking advantage of the simple functional group transformations, an interesting array of valuable chiral 1,3-diamines with different substitution patterns can be readily obtained in a highly enantioenriched manner.

14.
iScience ; 16: 468-484, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31229895

RESUMO

Although mitochondria are known to be involved in host defense against viral infection, the physiological role of mitophagy, a crucial mechanism for maintaining mitochondrial homeostasis, in antiviral immunity remains poorly defined. Here, we show that Parkin, a central player in mitophagy, has a vital function in regulating host antiviral responses. Parkin-knockout mice exhibit improved viral clearance and survival after viral infection. However, Parkin deficiency does not affect antiviral signaling and interferon production. Instead, Parkin deficiency augments innate antiviral inflammation by enhancing mitochondrial ROS (mtROS)-mediated NLRP3 inflammasome activation and promoting viral clearance. Loss of NLRP3 can reverse the enhanced antiviral responses in Parkin knockout mice. Furthermore, we find that Parkin expression is downregulated in peripheral blood mononuclear cells of patients infected with virus. Collectively, our results suggest that Parkin plays an important role in antiviral immunity by controlling mtROS-NLRP3 axis-mediated inflammation. These findings provide physiological insight of the importance of mitophagy in regulating host antiviral response.

15.
ACS Appl Mater Interfaces ; 11(24): 21702-21710, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31120233

RESUMO

Fluorination is an effective process to open the band gap of graphene (Gr), which is beneficial to the development of optoelectronic devices working in wide wavelength. Herein, we report a dual-mode broadband photodetector (PD) by integrating fluorinated graphene (F-Gr) with silicon (Si). It is found that when working in photoconductive mode, the F-Gr/Si heterojunction exhibited a remarkable photoresponse over a wide spectral region from ultraviolet (UV), visible to near infrared (NIR) light with a high responsivity ( R) of 1.9 × 107 A W-1 and specific detectivity ( D*) of 4.4 × 1012 Jones at 650 nm. Nonetheless, both parameters will be considerably reduced when the F-Gr/Si heterojunction works in the photodiode mode. In this mode, the Ilight/ Idark ratio is as high as 2.0 × 105 and the response speed is accelerated by more than 3 orders of magnitude from about 5 ms to 6.3 µs. Notably, the responsivity of the device in the UV and NIR regions was remarkably enhanced in comparison with that of pristine Gr/Si-heterojunction-based devices. Considering the F-coverage-dependent band gap of the F-Gr revealed by the first-principle calculations, we believe that the enhancement was ascribed to the opening of the band gap in the partially fluorinated Gr, which is stabilized due to the configuration entropy as the temperature increases. The dual-mode PD enabled the simultaneous weak light detection and fast photodetection, which overcome the limitation of the traditional monomode PD.

16.
Nat Microbiol ; 4(8): 1378-1388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31110366

RESUMO

Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-ß-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C210 on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.

17.
Vet Immunol Immunopathol ; 211: 19-24, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084889

RESUMO

Porcine reproductive and respiratory syndrome (PRRS) is one of the most common diseases in the global swine industry. PRRSV infection is highly restricted to cells of the monocyte-macrophage lineage. However, the lack of antibodies to swine monocyte-macrophage lineage markers significantly hampers PRRSV research. In this study, we have developed a monoclonal antibody against the swine leukocyte antigen (SLA)-DRα chain and confirmed its reactivity with endogenous expressed SLA-DR in a variety of cell lines and primary swine antigen-presenting cells (PAMs, PBMC and BM-DCs). Moreover, the level of SLA-DR expression after PRRSV infection were evaluated by our homemade Mab and a commercial anti-SLA-DR antibody. Based on our result, the protein level of SLA-DRα expression is increased after PRRSV infection in DC, while the mRNA of both SLA-DRα and SLA-DRß were significantly inhibited by PRRSV replication. In conclusion, we successfully developed a MAb reactive with endogenous SLA-DR in western blotting, and this MAb could be a useful tool for further research and analysis. Moreover, the inconsistency of SLA-DR expression between protein and mRNA levels may suggest a novel role of DC played during the immune response after PRRSV infection.


Assuntos
Anticorpos Monoclonais/imunologia , Células Dendríticas/metabolismo , Cadeias alfa de HLA-DR/imunologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Animais , Western Blotting , Medula Óssea/imunologia , Medula Óssea/metabolismo , Linhagem Celular , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Células HEK293 , Cadeias alfa de HLA-DR/metabolismo , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Proteínas Recombinantes , Suínos/imunologia
18.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(4): 464-470, 2019 Apr 30.
Artigo em Chinês | MEDLINE | ID: mdl-31068291

RESUMO

OBJECTIVE: To investigate the effects of exendin-4 on hepatic lipid metabolism, fibrosis and oxidative stress in mice with streptozotocin (STZ)-induced diabetes and explore the underlying mechanisms. METHODS: C57BL/6J mice were fed with high-fat diet (HFD) for 4 weeks and received intraperitoneal injections of 120 mg/kg STZ to induce diabetes. After successful modeling, the mice were randomized into diabetic control group and exendin-4 treatment group (DM+E4), and in the latter group, the mice were given a daily dose of 1 nmol/kg of exendin-4 for 8 weeks. The changes in the body weight (BW) and random blood glucose (RBG) in the mice were recorded. The mRNA expressions of the genes related with liver lipid metabolism, fibrosis and oxidative stress were analyzed using RT-PCR, and the structural changes of the liver tissues were observed with HE, Sirius red and oil red O staining; the expressions of TGF-ß1, Nrf2 and HO-1 proteins in the liver tissues were detected using Western blotting. RESULTS: The diabetic mice showed significantly higher RBG levels and BW with obvious lipid deposition, fibrosis and oxidative stress in the liver as compared with the normal control mice (P < 0.001). Exendin-4 treatment of the diabetic mice did not significantly lessened liver lipid deposition but obviously reduced the levels of RBG and TG (P < 0.05), lowered the expression levels of liver fibrosis-related genes TGF-ß, α-SMA and Col-Ⅰ (P < 0.05), increased the expression levels of the antioxidant genes Nrf2, HO-1 and GPX4 (P < 0.01), and enhanced the protein expressions of Nrf2 and HO-1 in the liver tissues (P < 0.01). CONCLUSIONS: Exendin-4 improves liver fibrosis and oxidative stress in diabetic mice by activating Nrf2/HO-1 pathway without significantly reducing liver lipid deposition.


Assuntos
Diabetes Mellitus Experimental , Cirrose Hepática , Estresse Oxidativo , Animais , Exenatida , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Estreptozocina
19.
J Diabetes ; 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31020790

RESUMO

BACKGROUND: Brown adipose tissue (BAT) has been regarded as a potential target organ to combat obesity and related metabolic disorders. However, the effect of BAT activation on the development of diabetic kidney disease (DKD) remains unclear. METHODS: Diabetic mice were induced by streptozotocin (STZ) combined with a high-fat diet. To activate BAT, mice were administered 1 mg/kg per day, i.p., CL316,243, a ß3 -adrenergic receptor agonist, for 4 weeks. Blood glucose, serum lipids, adipokines, 24-hour urinary albumin, 8-hydroxydeoxyguanosine (8-OHdG), and circulating microRNA (miRNA) levels were analyzed, in addition to renal pathology. Histological changes (fibrosis, inflammation) were evaluated in the kidneys, as was the expression of oxidative stress-related genes. Renal signaling pathways (fibroblast growth factor [Fgf]21/ß-klotho/FGF receptor 1c and AMP-activated protein kinase[AMPK]/sirtuin 1 [Sirt1]/peroxisome proliferator-activated receptor-γ coactivator-1α [Pgc1α]) were also evaluated. RESULTS: Compared with untreated STZ-diabetic mice, CL316,243 treatment reduced blood glucose, albeit not significantly (20.58 ± 3.55 vs 23.60 ± 3.90 mM), and significantly decreased triglycerides and low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol. Simultaneously, BAT activation significantly decreased 24-hour urinary albumin (34.21 ± 6.28 vs 70.46 ± 15.81 µg/24 h; P < 0.05) and 8-OHdG, improved renal fibrosis, inflammation, and oxidative stress, and ameliorated renal morphological abnormalities. In addition to enhancing BAT activity, CL316,243 significantly increased serum adiponectin concentrations and renal Fgf21 sensitivity, and reactivated the renal AMPK/Sirt1/Pgc1α signaling pathway. Furthermore, CL316,243 treatment increased levels of some circulating miRNAs and downregulated expression of their target genes in the kidney. CONCLUSIONS: Activating BAT could improve kidney injury in diabetic mice via metabolic improvements and renal AMPK activation by beneficial adipokines and miRNAs.

20.
Bioorg Med Chem Lett ; 29(12): 1492-1496, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30981577

RESUMO

The synthesis and H3 receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H3 and H1 receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). The compound with highest affinity and greatest selectivity were further profiled, In addition, compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 11 could be a potent candidate for pain treatment.

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