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1.
Ecotoxicol Environ Saf ; : 109977, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31759747

RESUMO

1-Nitropyrene (1-NP), a key component of fine particulate matter (PM2.5), is a representative of nitrated polycyclic aromatic hydrocarbons (NPAHs). The aim of this research is to investigate proinflammatory effects of acute 1-NP exposure in mouse lungs and human A549 cells. All mice except controls were intratracheally instilled with 1-NP (20 µg/mouse). A549 cell, a human lung cancer cell line, was cultured with or without 1-NP (5 µM). Acute 1-NP exposure elevated lung weight and caused infiltration of inflammatory cells, especially neutrophils in mouse lungs. Although it had little effect on serum TNF-α and KC, acute 1-NP exposure elevated the levels of TNF-α and KC in BALF. Correspondingly, acute 1-NP exposure upregulated pulmonary Il-1ß, Il-6, Tnf-α and Kc. Mechanistically, acute 1-NP exposure activated nuclear factor kappa B (NF-κB) in mouse lungs and human A549 cells. Additionally, acute 1-NP exposure induced Akt phosphorylation in mouse lungs and human A549 cells. Moreover, acute 1-NP exposure induced phosphorylation of pulmonary JNK and ERK1/2, molecules of the mitogen-activated protein kinase (MAPK) pathway. This study provides evidence that acute 1-NP exposure induces inflammatory responses through activating various inflammatory signaling pathways in mouse lungs and human A549 cells.

2.
Cell Biol Toxicol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31768838

RESUMO

Inflammation reaction mediated by NLRP3 inflammasome and Nrf2-related oxidative stress are vital participants in the development of diabetic nephropathy (DN) and closely associated to kidney fibrosis. Nrf2, a known antioxidative transcription factor, has been reported to activate NLRP3 inflammasome through its downstream factors (HO-1, NQO1, etc.) recently. AB38b is a newly synthesized biphenyl diester derivative with a Nrf2 activation property. This research aims to evaluate the renal protective effects of AB-38b and to elucidate the anti-inflammation mechanisms involved. Type 2 diabetic mice induced by high fat diet with streptozocin (STZ) and high glucose-cultured mouse glomerular mesangial cells (GMCs) were used in current study. Results showed that administration of AB-38b improved the kidney function while attenuated renal fibrosis progression in diabetic mice together with reducing the extracellular matrix (ECM) accumulation of GMCs cultured in high glucose. Mechanistically, treatment with AB-38b significantly decreased the high level of NLRP3 inflammasome in diabetic condition by inhibiting the ROS/TXNIP/NLRP3 signaling pathway. And meanwhile, AB-38b treatment effectively improved Nrf2 signaling during diabetic condition. Furthermore, knocking down the gene expression of Nrf2 by siRNA in GMCs abolished the inhibition effect of AB-38b on NLRP3 inflammasome activation and ECM accumulation. Taken together, our data suggest that AB-38b was able to improve the renal function of diabetic mice, and the NLRP3 inflammasome inhibition effect of AB-38b was responsible for the renal protective effect. Further exploration indicate that Nrf2 plays pivotal role in AB-38b's attenuation of DN progression through inhibiting NLRP3 inflammasome activation.

3.
Chemosphere ; 243: 125356, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743867

RESUMO

1-nitropyrene (1-NP) is widespread in the environment, as a typical nitrated polycyclic aromatic hydrocarbon. The purpose of this research was to explore the effects of gestational 1-NP exposure on susceptibility of allergic asthma in offspring. Maternal mice were exposed to 1-NP (100 µg kg-1) by gavage throughout the whole pregnancy. Pups were sensitized by injecting with ovalbumin (OVA) on postnatal day (PND)23, 29, and 36, respectively. At 7 days following the last injection, sensitized mice were exposed to aerosol OVA. As expected, there were quite a few inflammatory cells in the lungs of OVA-sensitized pups, accompanied by bronchial wall thickening and hyperemia. Elevated goblet cells and overproduced mucus were observed in the airways of OVA-sensitized pups. Interestingly, gestational 1-NP exposure aggravated infiltration of inflammatory cells, mainly eosinophils, in OVA-sensitized offspring. Although it had little effect on airway smooth muscle layer thickening and basement membrane fibrosis, gestational 1-NP exposure aggravated goblet cell hyperplasia, Muc5ac mRNA upregulation, and mucus secretion in the airways of OVA-sensitized and challenged offspring. Mechanistically, gestational 1-NP exposure aggravated elevation of pulmonary IL-5 in OVA-sensitized pups. These findings suggest that gestational 1-NP exposure increases susceptibility of allergic asthma in offspring.

4.
Respir Res ; 20(1): 266, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775746

RESUMO

BACKGROUND: Our earlier report indicated that active vitamin D3 inhibited epithelial-mesenchymal transition (EMT) in bleomycin (BLM)-induced pulmonary fibrosis. The objective of this study was to further investigate whether vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis. METHODS: This study consists of two independent experiments. Experiment 1, male mice were fed with vitamin D deficient (VDD) fodder. Experiment 2, Cyp27b1+/+, Cyp27b1+/- and Cyp27b1-/- mice were fed with standard diet. For pulmonary fibrosis, mice were intratracheally instilled with a single dose of BLM (1.5 mg/kg). Serum 25(OH) D level was measured. Pulmonary collagen deposition was assessed by Sirius red staining. EMT was measured and transforming growth factor-beta (TGF-ß)/Smad3 signaling was evaluated in the lungs of BLM-treated mice. RESULTS: The relative weight of lungs was elevated in BLM-treated mice. Col1α1 and Col1α2, two collagen protein genes, were upregulated, and collagen deposition, as determined by Sirius red staining, was observed in the lungs of BLM-treated mice. E-cadherin, an epithelial marker, was downregulated. By contrast, vimentin and α-SMA, two EMT markers, were upregulated in the lungs of BLM-treated mice. Pulmonary TGF-ß/Smad3 signaling was activated in BLM-induced lung fibrosis. Further analysis showed that feeding VDD diet, leading to vitamin D deficiency, aggravated elevation of BLM-induced relative lung weight. Moreover, feeding VDD diet aggravated BLM-induced TGF-ß/Smad3 activation and subsequent EMT in the lungs. In addition, feeding VDD diet exacerbated BLM-induced pulmonary fibrosis. Additional experiment showed that Cyp27b1 gene knockout, leading to active vitamin D3 deficiency, exacerbated BLM-induced pulmonary fibrosis. Moreover, Cyp27b1 gene knockout aggravated pulmonary TGF-ß/Smad2/3 activation and subsequent EMT in BLM-induced lung fibrosis. CONCLUSION: Vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis partially through aggravating TGF-ß/Smad2/3-mediated EMT in the lungs.

6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1440-1448, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607296

RESUMO

OBJECTIVE: To explore the coexisting mutations in IDH-mutated acute myeloid leukemia(AML) and its relation with partial clinical parametrs. METHODS: The exon 4 mutation of IDH1/2 gene was screened by using genome DNA-PCR combined with sanger sequencing, 51 targeted gene mutations in the patients with IDH1/2 mutation were detected by using high throughput DNA sequencing combined with sanger sequencing. RESULTS: Among 358 patients, the IDH1/2 mutation was found in 46 cases including IDH1 mutation in 35 cases and IDH2 mutation in 11 cases, 97.87%(45/46) patients with IDH1/2 mutation simultaneously carried other gene mutations including 8(17.8%) cases with mutation of double gene, 17(37.8%) cases with mutation of 3 genes and 20(44.4%) cases with mutation of ≥ 4 genes. The mutation frequency of each patient averaged 3.52 times. In mutation of accompanied genes, the common genes were NPM1(n=29, 63.0%), next DNMT3A(n=25, 54.3%), FLT3-ITD(n=7, 15.2%), TET2(n=5, 10.9%) and NRAS(n=5, 10.9%). The average WBC level of patients with NPM1 mutation in IDH1 mutation group was higher than that of patients in wild type group(P<0.05). The complete remission (CR) rate of patients with DNMT3A mutation was significant lower than that of patients with wild type (30% vs 80%, P<0.01). The presence of ≥ 4 mutations was found to be significantly associated with higher white blood level than that in the patients with double mutations(P<0.05). CONCLUSION: More than 95% AML patients with IDH1/2 mutation commonly show additional mutations. The number and the type of IDH coexisting mutations have certain effect on the clinical features and CR rate.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda , Éxons , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Indução de Remissão
7.
World J Gastroenterol ; 25(38): 5850-5861, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636477

RESUMO

BACKGROUND: Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes? AIM: To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes. METHODS: Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured. RESULTS: A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. CONCLUSION: The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

8.
Pain ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31651582

RESUMO

Chronic pain and anxiety symptoms are frequently encountered clinically, but the neural circuit mechanisms underlying the comorbid anxiety symptoms in pain (CASP) in context of chronic pain remain unclear. Using viral neuronal tracing in mice, we identified a previously unknown pathway whereby glutamatergic neurons from layer 5 of the hindlimb primary somatosensory cortex (S1) (Glu), a well-known brain region involved in pain processing, project to GABAergic neurons in the caudal dorsolateral striatum (GABA). In a persistent inflammatory pain model induced by complete Freund's adjuvant injection, enhanced excitation of the Glu→GABA pathway was found in mice exhibiting CASP. Reversing this pathway using chemogenetic or optogenetic approaches alleviated CASP. In addition, the optical activation of Glu terminals in the cDLS produced anxiety-like behaviors in naive mice. Overall, the current study demonstrates the putative importance of a novel Glu→GABA pathway in controlling at least some aspects of CASP.

9.
Environ Sci Technol ; 53(20): 11877-11887, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525870

RESUMO

Microfibers, characterized as small fibers shed from textiles that are less than 5 mm in size, are a prominent contaminant in the environment. Thus, it is important that we have methods to accurately quantify and characterize them, including in water, sediment, wildlife, seafood, and drinking water samples. Unfortunately, their small size and the presence of different dyes on the microfibers themselves cause difficulties in identification via conventional spectroscopic methods of total attenuated resonance-Fourier transform infrared and Raman. To help solve some of these methodological challenges, we developed a new method employing polymer-dye binding chemistry, density tests, unique surface morphological traits, and fluorescent staining to identify microfibers in environmental samples. The identification method introduced here was tested in our laboratory via trials using microfibers shed from new textiles and environmental samples. We found that the method can be successfully applied to identify the different polymer types of microfibers, which can ultimately help source apportion microfiber contamination in the environment.

10.
Nat Neurosci ; 22(10): 1649-1658, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451801

RESUMO

Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.


Assuntos
Dor Crônica/patologia , Depressão/patologia , Vias Neurais/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Dor Crônica/complicações , Dor Crônica/diagnóstico por imagem , Depressão/complicações , Depressão/diagnóstico por imagem , Núcleo Dorsal da Rafe/diagnóstico por imagem , Núcleo Dorsal da Rafe/patologia , Feminino , Habenula/diagnóstico por imagem , Habenula/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/diagnóstico por imagem , Neuralgia/diagnóstico por imagem , Neuralgia/patologia , Optogenética , Serotonina/metabolismo , Somatostatina/metabolismo
12.
Mediators Inflamm ; 2019: 6212934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210750

RESUMO

Background: Systemic inflammation impairs cognitive performance, yet the brain networks mediating this process remain to be elucidated. The purpose of the current study was to use resting-state functional magnetic resonance imaging (fMRI) to explore changes in the functional connectivity in a lipopolysaccharide- (LPS-) induced systemic inflammation animal model. Materials and Methods: We used the regional homogeneity (ReHo) method to examine abnormal brain regions between the control and LPS groups and then considered them as seeds of functional connectivity analysis. Results: Compared with the control group, our study showed that (1) LPS impaired mood function, as reflected by a depression-like behavior in the forced swim test; (2) LPS induced significantly increased ReHo values in the anterior cingulate cortex (ACC) and caudate putamen (CPu); (3) the ACC seed showed increased functional connectivity with the retrosplenial cortex, superior colliculus, and inferior colliculus; and (4) the right CPu seed showed increased functional connectivity with the left CPu. Linear regression analysis showed a LPS-induced depression-like behavior which was associated with increased ReHo values in the ACC and right CPu. Moreover, the LPS-induced depression-like behavior was related to increased functional connectivity between the right CPu and left CPu. Conclusion: This is the first study to show that systemic inflammation impairs mood function that is associated with an altered resting-state functional network based on ReHo analysis, providing evidence of the abnormal regional brain spontaneous activity which might be involved in inflammation-related neurobehavioral abnormalities.

13.
Cell Death Dis ; 10(7): 489, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222000

RESUMO

Adrenomedullin (ADM) exerts anti-oxidant, anti-inflammatory and anti-apoptotic effects in Leydig cells. However, the role and mechanism of ADM in the pyroptosis of Leydig cells are poorly understood. This study first showed the protective effects of ADM on the pyroptosis and biological functions of Leydig cells exposed to lipopolysaccharide (LPS) by promoting autophagy. Primary rat Leydig cells were treated with various concentrations of LPS and ADM, together with or without N-acetyl-L-cysteine (NAC) or 3-methyladenine (3-MA). Cell proliferation was detected through CCK-8 and BrdU incorporation assays, and ROS level was measured with the DCFDA assay. Real-time PCR, western blot, immunofluorescence, transmission electron microscopy, TUNEL and flow cytometry were performed to examine ADM's effect on the pyroptosis, autophagy and steroidogenic enzymes of Leydig cells and AMPK/mTOR signalling. Like NAC, ADM dose-dependently reduced LPS-induced cytotoxicity and ROS overproduction. ADM also dose-dependently ameliorated LPS-induced pyroptosis by reversing the increased expression of NLRP3, ASC, caspase-1, IL-1ß, IL-18, GSDMD, caspase-3, caspase-7, TUNEL-positive and PI and active caspase-1 double-stained positive rate, DNA fragmentation and LDH concentration, which could be rescued via co-incubation with 3-MA. ADM dose-dependently increased autophagy in LPS-induced Leydig cells, as confirmed by the increased expression of LC3-I/II, Beclin-1 and ATG-5; decreased expression of p62 and autophagosomes formation; and increased LC3-II/LC3-I ratio. However, co-treatment with 3-MA evidently decreased autophagy. Furthermore, ADM dose-dependently rescued the expression of steroidogenic enzymes, including StAR, P450scc, 3ß-HSD and CYP17, and testosterone production in LPS-induced Leydig cells. Like rapamycin, ADM dose-dependently enhanced AMPK phosphorylation but reduced mTOR phosphorylation in LPS-induced Leydig cells, which could be rescued via co-incubation with 3-MA. In addition, pyroptosis was further decreased, and autophagy was further promoted in LPS-induced Leydig cells upon co-treatment with ADM and rapamycin. ADM may protect the steroidogenic functions of Leydig cells against pyroptosis by activating autophagy via the ROS-AMPK-mTOR axis.

14.
Environ Int ; 130: 104875, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31200159

RESUMO

The robustness of in vitro bioaccessibility assays to predict oral relative bioavailability (RBA) of multiple metals in contaminated soils requires validation using additional soil samples. In this study, 11 contaminated soils from mining/smelting areas were analyzed for As-, Cd-, and Pb-RBA using a mouse bioassay and metal bioaccessibility via the UBM gastric phase assay. Metal-RBA varied considerably among soils, with As-RBA (2.5-23%, mean 12%) being generally lower than Cd-and Pb-RBA (3.4-88 and 3.3-59%, mean 42 and 28%), due to higher proportions of As in the residual fractions. Metal-RBA generally decreased with increasing metal concentrations probably due to reduced labile metal fractions. In addition, strong negative correlations were observed between total Fe with As-, Cd-, and Pb-RBA (R2 = 0.46-0.77), suggesting the role of Fe in controlling metal-RBA in soils. Like RBA, metal bioaccessibility by the UBM assay also varied among samples. However, strong in vivo-in vitro correlations (IVIVCs) were observed between metal-RBA and bioaccessibility (R2 = 0.52-0.81). Further, there were little differences when As-, Cd-, and Pb-IVIVCs established using soils from this study and soils pooled from literature were compared, suggesting the robustness of the UBM assay to predict metal-RBA in contaminated soils.

15.
J Pharm Biomed Anal ; 172: 364-371, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31096095

RESUMO

Gefitinib, the first approved oral epidermal growth factor receptor (EGFR) inhibitor, has been demonstrated effective in cancers with EGFR active mutations. In this study, we established and validated a method for determining gefitinib and its main metabolites, M605211, M387783, M537194 and M523595 in patients with non-small cell lung cancer (NSCLC) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The mobile phase was water: acetonitrile (35:65, v/v) with 0.1% formic acid at a flow-rate of 0.35 mL/min, within a 3 min run time. Gefitinib and its main metabolites were separated on a X-Terra RP18 column (50 × 2.1 mm, 3.5 µm) at 40 ℃ and subjected to mass analysis using positive electro-spray ionization (ESI). The calibration ranges of gefitinib and M523595 were 0.5-1000 ng/mL, and other compounds were 0.05-100 ng/mL with the correlation coefficients (r2) ≥ 0.99. Accuracies ranged from 92.60%-107.58 and the inter- and intra-assay precision were less than 15% for all analytes in quality control samples. There was no significant matrix effect. The ranges of extraction recoveries were 86-105% for all analytes and IS. Thirty plasmas were obtained from Sun Yat-sen university cancer center. The mean plasma concentration of (± SD) of gefitinib M537194, M523595, M387783 and M605211 were 247.18 (± 140.39) ng/mL, 7.78 (± 6.74) ng/mL, 101.09 (± 93.44) ng/mL, 1.6 (± 0.9) ng/mL and 11.63 (± 4.98) ng/mL, respectively. The validated LC/MS/MS method was effectively used in the determination of gefitinib and its four metabolites in NSCLC patients.

16.
J Hematol Oncol ; 12(1): 53, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142326

RESUMO

The tumor microenvironment (TME) is an essential intrinsic portion of hepatocellular carcinoma (HCC) for the regulation of its origination, development, invasion, and metastasis. As emerging components of the tumor-host interaction, exosomes are increasingly recognized as professional carriers of information in TME and as pivotal molecular entities involved in tumorigenic microenvironment setup. However, much remains unknown about the role of the exosome communication system within TME in the development and progression of HCC. In this review, we focus on the roles and probable mechanisms of TME in HCC and show the exosome-based immune regulation in TME to promote HCC. Multiple processes are involved in HCC, including tumor survival, growth, angiogenesis, invasion, and metastasis. We also discuss the specific roles of exosomes in HCC processes by molding hospitable TME for HCC, such as providing energy, transmitting protumor signals, and evading inhibitory signals. In addition, exosomes induce angiogenesis by changing the biological characteristics of endothelial cells and directly regulating proangiogenic and propermeability factors. Furthermore, exosomes may lead to HCC metastatic invasion by epithelial-mesenchymal transformation, extracellular matrix degradation, and vascular leakage. Finally, we summarize the therapeutic usage of exosomes in the HCC microenvironment and attempt to provide a theoretical reference for modern antitumor agents designed to target these mechanisms.

17.
Biosci Rep ; 39(5)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30988072

RESUMO

Background: Diabetic retinopathy (DR) is currently the leading cause of blindness and visual disability in adults with diabetes mellitus (DM). Neovascularization has been identified as an important clinical property in DR, however, the exact mechanisms in DR neovascularization are still unclear and need further elucidation.Methods: Quantitative real-time PCR (qRT-PCR) was conducted to detect the expression level of long non-coding RNA (lncRNA)-metastasis associated lung adenocarcinoma transcript 1 (MALAT1), miR-125b and vascular endothelial-cadherin (VE-cadherin) in human retina microvascular endothelial cells (hRMECs) treated with high glucose (HG). Luciferase assay was used to detect interaction of MALAT1 with miR-125b and miR-125b with VE-cadherin. MTT assay, transwell assay, tube formation assay and vascular permeability assay were conducted to detect the cell viability, migration tube formation ability and permeability of hRMECs, respectively. ELISA was used to examine the release of VE-cadherin and vascular endothelial growth factor (VEGF). Western blotting was used to access the protein expression of VE-cadherin, VEGF, ß-catenin, matrix metalloproteinase (MMP) 2 (MMP2) and MMP9.Results: MALAT1 and VE-cadherin were up-regulated while miR-125b was down-regulated in hRMECs treated with HG. MALAT1 could competitively bind to miR-125b against VE-cadherin at the site of 3'-untranslated region (3'-UTR), leading to the up-regulation of VE-cadherin. Knockdown of MALAT1 inhibited the proliferation, migration, tube formation and vascular permeability of hRMECs induced by HG through up-regulating miR-125b. Furthermore, we found the deletion of MALAT1 suppressed the VE-cadherin/ß-catenin complex and neovascularization related proteins expression, which was up-regulated by HG.Conclusion: Knockdown of MALAT1 inhibited cell proliferation, migration and angiogenesis of hRMECs via suppressing the VE-cadherin/ß-catenin complex through targeting miR-125b. Inhibition of MALAT1 may serve as a potential target for anti-angiogenic therapy for DR.

18.
Metabolism ; 96: 33-45, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028762

RESUMO

BACKGROUND: Renal fibrosis promotes the development of diabetic nephropathy (DN). A growing number of studies have reported that Yin Yang 1 (YY1), which is involved in cellular proliferation and differentiation, plays a crucial role in the pathogenesis of many diseases, such as pulmonary fibrosis, hepatic steatosis and cancer. METHODS: We detected the expression of YY1 under various glucose concentration and time gradient conditions. Rapamycin was used to verify the mTORC1/p70S6K/YY1 signaling pathway in HK-2 cells. We used db/db mice to examine the connection between renal fibrosis and YY1. A luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to identify whether YY1 directly regulated α-SMA by binding to the α-SMA promoter. RNA silencing and overexpression were performed by using a YY1 expression/knockdown plasmid to investigate the function of YY1 in renal fibrosis of DN. RESULTS: YY1 expression and subsequent nuclear translocation were upregulated in a glucose- and time-dependent manner via the mTORC1/p70S6K signaling pathway in HK-2 cells. YY1 expression and nuclear translocation was significantly upregulated in db/db mice. Furthermore, YY1 upregulated α-SMA expression and activity in high-glucose-cultured HK-2 cells. Overexpression of YY1 promoted renal fibrosis in db/m mice mainly by upregulating α-SMA expression and inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Finally, downregulation of YY1 reversed renal fibrosis by improving EMT in vivo and in vitro. CONCLUSIONS: These results reveal that upregulation of YY1 plays a critical role in HG-induced deregulation of EMT-associated protein expression, which finally results in renal fibrosis of DN. Therefore, decreasing YY1 expression might represent a new therapeutic target for diabetic nephropathy-induced renal fibrosis.

19.
Neuropharmacology ; 153: 20-31, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31026437

RESUMO

Resveratrol is a natural non-flavonoid polyphenol found in red wine, which has numerous pharmacological properties including anti-stress and antidepressant-like abilities. However, whether the antidepressant- and anxiolytic-like effects of resveratrol are related to the inhibition of phosphodiesterase 4 (PDE4) and its subtypes remains unknown. The same holds true for the subsequent cAMP-dependent pathway. The first set of studies investigated whether resveratrol exhibited neuroprotective effects against corticosterone-induced cell lesion as well as its underlying mechanism. We found that 100 µM corticosterone induced PDE2A, PDE3B, PDE4A, PDE4D, PDE10 and PDE11 expression in HT-22 cells, which results in significant cell lesion. However, treatment with resveratrol increased cell viability in a dose- and time-dependent manner. These effects seem related to the inhibition of PDE4D, as evidenced by resveratrol dose-dependently decreasing PDE4D expression. In addition, the PKA inhibitor H89 reversed resveratrol's effects on cell viability. Resveratrol prevented corticosterone-induced reduction in cAMP, pVASP(s157), pCREB, and BDNF levels, indicating that cAMP signaling is involved in resveratrol-induced neuroprotective effects. Not to mention, PDE4D knockdown by PDE4D siRNA potentiated the effect of low dose of resveratrol on cAMP, pVASP, pCREB, and BDNF expression, while PDE4D overexpression reversed the effect of high dose of resveratrol on the expression of the above proteins. Finally, the subsequent in vivo data supports the in vitro findings, suggesting that resveratrol-induced antidepressant- and anxiolytic-like effects are mediated by PDE4D. Overall, these findings support the hypothesis that PDE4D-mediated cAMP signaling plays an important role in resveratrol's protective effects on stress-induced depression- and anxiety-like behavior.

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