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1.
Sci Total Environ ; 713: 136620, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-32019017

RESUMO

Human activities have distinctly enhanced the deposition levels of atmospheric nitrogen (N) pollutants into terrestrial ecosystems, but whether and to what extents soil carbon (C) and N status have been influenced by elevated N inputs remain poorly understood in the 'real' world given related knowledge has largely based on N-addition experiments. Here we reported soil organic C (OC) and total N (TN) for twenty-seven forests along a gradient of N deposition (22.4-112.9 kg N/ha/yr) in the Beijing-Tianjin-Hebei (BTH) region of northern China, a global hotspot of high N pollution. Levels of soil TN in forests of the BTH region have been elevated compared with investigations in past decades, suggesting that long-term N deposition might cause soil TN increases. Combining with major geographical and environmental factors among the study forests, we found unexpectedly that soil moisture and pH values rather than N deposition levels were major regulators of the observed spatial variations of soil OC and TN contents. As soil moisture and pH values increased with mean annual precipitation and temperature, respectively, soil C and N status in forests of the BTH region might be more responsive to climate change than to N pollution. These evidence suggests that both N deposition and climate differences should be considered into managing ecosystem functions of forest resources in regions with high N pollution.

2.
Chemosphere ; 248: 126103, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32041074

RESUMO

BACKGROUND: Excessive daytime sleepiness is associated with many adverse consequences, including cardiovascular diseases and mortality. Although exposure to air pollution has been suggested in connection with excessive daytime sleepiness, evidence in China is scarce. The study aimed to explore the association between long-term exposure to air pollution and excessive daytime sleepiness in rural China. METHODS: A lot of 27935 participants (60% females) from the Henan Rural Cohort Study were included in this analysis. A satellite-based spatiotemporal model estimated a 3-year average air pollution exposure to NO2 (nitrogen dioxide), PM1 (particulate matter with aerodynamic diameters not more than 1 µm) and PM2.5 (particulate matter with aerodynamic diameters not more than 2.5 µm) at the home address of participants before the baseline survey. Logistic regression was used to evaluate the odds ratio and 95% confidence interval between long-term air pollution and excessive daytime sleepiness. RESULTS: The average concentrations of NO2, PM1 and PM2.5 during three years preceding baseline survey were 38.22 µg/m³, 56.29 µg/m³ and 72.30 µg/m³. Exposure to NO2, PM1 and PM2.5 were all associated with excessive daytime sleepiness. Each 1 µg/m³ increment of NO2, PM1 and PM2.5 were related to a 20% (OR: 1.20, 95% CI: 1.13-1.27), 10% (OR: 1.10, 95% CI: 1.05-1.16) and 17% (OR: 1.17, 95% CI: 1.10-1.23) increase of the prevalence of excessive daytime sleepiness. CONCLUSION: The study demonstrated that long-term exposure to NO2, PM1 and PM2.5 were all associated with excessive daytime sleepiness. The impact of air pollution should be considered when treating individuals with excessive daytime sleepiness.

3.
Theranostics ; 10(4): 1798-1813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042337

RESUMO

Background: Cancer genomic studies have identified Zinc Finger Protein 750 (ZNF750) was a novel significantly mutated gene in esophageal squamous cell carcinoma (ESCC). This study was designed to determine the clinical value and molecular mechanisms of ZNF750 in the development of ESCC. Methods: Genomic data from 4 reported ESCC cohorts were used to analyze the mutation profile of ZNF750. Tissue microarrays were used to detect its expression in 308 ESCC samples. Furtherly, the effects of ZNF750 on proliferation, colony formation, migration and invasion were tested in ESCC cells. PCR-array, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay were used to explore the mechanism of ZNF750. Correlation of ZNF750 with its target genes was analyzed in TCGA data from various SCC types. Results: ZNF750 was frequently mutated in ESCC and the most common type was nonsense mutation. Its nucleus/cytoplasm ratio in ESCC was significantly lower than that in paired non-tumor tissues; it was an independent and potential predictor for survival in ESCC patients. Furtherly, ZNF750 knockdown significantly promoted proliferation, colony formation, migration and invasion in ESCC cells. PCR-array showed epithelial-to-mesenchymal transition (EMT) was the main biologic process affected by ZNF750. Moreover, ZNF750 directly bound to the promoter region of SNAI1 and depressed its activity. Decreased ZNF750 up-regulated SNAI1 expression and promoted EMT phenotype. SNAI1 knockdown partially reversed the malignant phenotype induced by ZNF750 knockdown. Further TCGA data analyses showed ZNF750 expression was positively correlated with E-cadherin and negatively correlated with SNAI1, N-cadherin and Vimentin in ESCC and other SCC samples. Conclusion: Our results suggest that ZNF750 may act as a tumor suppressor by directly repressing SNAI1 and inhibiting EMT process in ESCC and other types of SCC.

4.
Mol Cell ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32035036

RESUMO

The functional relevance and mechanistic basis of the effects of the neurotransmitter dopamine (DA) on inflammation remain unclear. Here we reveal that DA inhibited TLR2-induced NF-κB activation and inflammation via the DRD5 receptor in macrophages. We found that the DRD5 receptor, via the EFD and IYX(X)I/L motifs in its CT and IC3 loop, respectively, can directly recruit TRAF6 and its negative regulator ARRB2 to form a multi-protein complex also containing downstream signaling proteins, such as TAK1, IKKs, and PP2A, that impairs TRAF6-mediated activation of NF-κB and expression of pro-inflammatory genes. Furthermore, the DA-DRD5-ARRB2-PP2A signaling axis can prevent S. aureus-induced inflammation and protect mice against S. aureus-induced sepsis and meningitis after DA treatment. Collectively, these findings provide the first demonstration of DA-DRD5 signaling acting to control inflammation and a detailed delineation of the underlying mechanism and identify the DRD5-ARRB2-PP2A axis as a potential target for future therapy of inflammation-associated diseases such as meningitis and sepsis.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32056461

RESUMO

Background: The combination of BEZ235 with sorafenib (SFB) enhances anti-hepatocellular carcinoma (HCC) efficacy of the two agents. However, pharmacokinetic profiles in vivo and different endocytosis abilities of these two drugs hinder their therapeutic application.Research design and methods: In this work, we developed d-α-tocopheryl polyethylene glycol 1000 succinate - polycaprolactone polymer nanoparticles (NPs) for co-delivery of SFB and BEZ235 (SFB/BEZ235-NPs). Explored the anti-proliferative and pro-apoptotic effects of SFB/BEZ235-NPs through in vitro and in vivo experiments.Results: Stabilized SFB/BEZ235-NPs were prepared with optimized drug ratio, yielding high encapsulation efficiency, low polydispersity, and enhanced cellular internalization in HepG2 cells. Synergistic cytotoxicity and pro-apoptotic ability were documented. In vivo pharmacokinetic results revealed extended circulation and bioavailability of SFB/BEZ235-NPs compared with those of free drugs. SFB/BEZ235-NPs enhanced antitumor effectiveness in SFB-resistant HCC xenograft mouse models.Conclusion: Taken together, the results of this study describe a promising strategy using SFB and BEZ235 in a nanoparticle formulation for treatment of SFB-resistant HCC.

6.
Biofabrication ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059197

RESUMO

Three-dimensional (3D) biofabrication techniques enable the production of multicellular tissue models as assay platforms for drug screening. The increased cellular and physiological complexity in these 3D tissue models should recapitulate the relevant biological environment found in the body. Here we describe the use of 3D bioprinting techniques to fabricate skin equivalent tissues of varying physiological complexity, including human epidermis, non-vascularized and vascularized full-thickness skin tissue equivalents, in a multi-well platform to enable drug screening. Human keratinocytes, fibroblasts, and pericytes, and induced pluripotent stem cell (iPSC)-derived endothelial cells were used in the biofabrication process to produce the varying complexity. The skin equivalents exhibit the correct structural markers of dermis and epidermis stratification, with physiological functions of the skin barrier. The robustness, versatility and reproducibility of the biofabrication techniques are further highlighted by the generation of atopic dermatitis (AD)-disease like tissues. These AD models demonstrate several clinical hallmarks of the disease, including: (i) spongiosis and hyperplasia; (ii) early and terminal expression of differentiation proteins; and (iii) increases in levels of pro-inflammatory cytokines. We show the pre-clinical relevance of the biofabricated AD tissue models to correct disease phenotype by testing the effects of dexamethasone, an anti-inflammatory corticosteroid, and three Janus Kinase inhibitors from clinical trials for AD. This study demonstrates the development of a versatile and reproducible bioprinting approach to create human skin equivalents with a range of cellular complexity for disease modelling. In addition, we establish several assay readouts that are quantifiable, robust, AD relevant, and can be scaled up for compound screening. The results show that the cellular complexity of the tissues develops a more physiologically relevant AD disease model. Thus, the skin models in this study offer an in vitro approach for the rapid understanding of pathological mechanisms, and testing for efficacy of action and toxic effects of drugs.

7.
Cell Death Dis ; 11(2): 97, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029701

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

8.
Surg Endosc ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016520

RESUMO

BACKGROUND: Laparoscopic splenectomy (LS) has been proven to be a safe and advantageous procedure. To ensure that resections of appropriate difficulty are selected, an objective preoperative grading of difficulty is required. We aimed to develop a predictive difficulty grading of LS based on intraoperative complications. METHODS: A total of 272 non-traumatic patients who underwent LS were identified from a regional medical center. Patients were randomized into a training cohort (n = 222) and a validation cohort (n = 50). Data on demographics, medical and surgical history, operative and pathological characteristics, and postoperative outcome details were collected. Univariate and multivariate analyses of risk factors for intraoperative complications were performed to develop a difficulty scoring system. The Spearman correlation coefficient was used to evaluate the relationship between the difficulty grading score and intraoperative outcomes. Receiver operating characteristic (ROC) curve was used to evaluate the discriminatory power of this scoring system. RESULTS: Three preoperative factors (spleen weight, esophagogastric varices, and INR) had a significant effect on operative time, bleeding, and conversion to open surgery. We created a difficulty grading score with three levels of difficulty: low (≤ 4 points), medium (5-6 points), and high (≥ 7 points), based on the three preoperative parameters. The correlation was highly significant (P < 0.01) according to Spearman's correlation. The area under the ROC curve was 0.695 (95% CI 0.630-0.755). The external validation showed significant correlations with the present model, with an AUC of 0.725 (95% CI 0.580-0.842). The comparison between our difficulty score and the previous grading system in the 272-patient cohort presented a significant difference in the AUC (0.701, 95% CI 0.643-0.755 vs. 0.644, 95% CI 0.584-0.701, P = 0.0452). CONCLUSION: The present difficulty scoring system, based on preoperative factors, has good performance in predicting the risk of intraoperative complications of LS and could be helpful for enabling appropriate case selection with respect to the current experience of a surgeon.

9.
Environ Pollut ; 261: 114007, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-32036198

RESUMO

Zearalenone (ZEA), an estrogen-like mycotoxin, is commonly detected in animal feeds including improperly stored grains. It has been well demonstrated that ovarian granulosa cells (GCs) perform vital roles during follicular development, however, the competing endogenous RNA (ceRNA) network in GCs after ZEA exposure remains to be well described. Here, for the first time, we adopted whole-transcriptome sequence technology to explore the molecular mechanism of ZEA toxicology on porcine GCs. The results provide evidence that the cell cycle of porcine GCs is arrested in the G2/M phase after exposure to ZEA. Furthermore, bioinformation analysis found that cell cycle arrest related genes were perturbed, including CDK1, CCNB1, CDC25A, and CDC25C, which was consistent with the results of RT-qPCR, immunofluorescence, and Western Blotting. Based on the whole-transcriptome sequence data, by constructing ceRNA networks related to cell cycle arrest, we observed that ZEA exposure arrested cell cycle progression at the G2/M phase in porcine GCs, and non-coding RNAs (ncRNAs) played an important role in this process via regulating the expressions of cell cycle arrest related genes. Taken together, our data here provides strong data to support that the toxicological mechanism regarding the widely distributed toxicant ZEA acts through ceRNA networks in porcine granulosa cells.

10.
Int J Cancer ; 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32064600

RESUMO

Although early detection and systemic therapies have improved the diagnosis and clinical cure rate of breast cancer, breast cancer remains the most frequently occurring malignant cancer in women due to a lack of sufficiently effective treatments. Thus, to develop potential targeted therapies and thus benefit more patients, it is helpful to understand how cancer cells work. ZIC family members have been shown to play important roles in neural development and carcinogenesis. In this study, we found that ZIC2 is downregulated in breast cancer tissues at both the mRNA and protein levels. Low expression of ZIC2 was correlated with poor outcome in breast cancer patients and serves as an independent prognostic marker. Furthermore, overexpression of ZIC2 repressed, whereas knockdown of ZIC2 promoted, cell proliferation and colony formation ability in vitro and tumor growth in vivo. Using ChIP-seq and RNA-seq analysis, we screened and identified STAT3 as a potential target for ZIC2. ZIC2 bound to the STAT3 promoter and repressed the promoter activities of STAT3. ZIC2 knockdown induced the expression of STAT3, increasing the level of phosphorylated STAT3. These results suggest that ZIC2 regulates the transcription of STAT3 by directly binding to the STAT3 promoter. Additionally, interfering STAT3 with siRNAs or inhibitors abrogated the oncogenic effects induced by decreased ZIC2. Taken together, our results indicate that ZIC2 serves as a useful prognostic marker in breast cancer and acts as a tumor suppressor by regulating STAT3, implying that STAT3 inhibitors might provide an alternative treatment option for breast cancer patients with ZIC2 downregulation. This article is protected by copyright. All rights reserved.

11.
Carbohydr Polym ; 232: 115787, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952595

RESUMO

Although the clinical usage of drugs administration was raising, the application of nanoparticles encapsulating the hydrophobic drugs with plummy efficiency was very scarce for atherosclerosis (AS) treatment. In this work, a novel dual ROS-sensitive and CD44 receptors targeting amphiphilic carrier material, oligomeric hyaluronic acid-2'-[propane-2,2-diyllbls (thio)] diacetic acl-hydroxymethylferrocene (oHA-TKL-Fc), named HASF, was synthesized and characterized by 1H-NMR spectra. Then, we combined curcumin (Cur) with HASF into nano-micelles (HASF@Cur micelles) by self-assembling method. The resulting HASF@Cur micelles had the average size of 150.8 nm and zeta potential of -35.04 mV to maintain the will-defined spheroidal structure and stability. Importantly, the HASF@Cur micelles had ultrahigh entrapment efficiency (about 51.41 %). Moreover, in vitro release study, Cur release from HASF@Cur micelles was effective in the reactive oxygen species (ROS) condition, and the release rate was interrelated with the concentration of hydrogen peroxide (H2O2). Further, fluorescence imaging showed that the HASF@Cur micelles could more selective access to Raw 264.7 cells than free Cur via oHA-receptor mediated endocytosis. The MTT assay attested the safety of amphiphilic carrier material HASF. Additionally, the results of in vivo Oil red O lipid staining studies showed that the lesion area of the aorta was reduced to 47.3±3.4 % with HASF@Cur micelles, compared with the lesion area of Cur group (63.2±2.7 %), HASF@Cur micelles had the more remarkable effect in reducing lesion area (*P < 0.05). Consequently, the novel dual ROS-sensitive and CD44 receptors targeting drug delivery system would become a promising strategy for atherosclerosis.

12.
BMJ Open ; 10(1): e028593, 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31932385

RESUMO

OBJECTIVE: The aims of this study were to describe distributions of the prevalence of osteopenia and osteoporosis and identify the potential risk factors by gender in a Chinese rural population. DESIGN: A cross-sectional survey. SETTING AND PARTICIPANTS: A total of 8475 participants (18-79 years) were obtained from the Henan Rural Cohort Study. Bone mineral density (BMD) of the calcaneus for each individual was measured by ultrasonic bone density apparatus. Logistic regression models were used to evaluate associations of potential risk factors with prevalence of osteopenia and osteoporosis. Furthermore, a meta-analysis of prevalence of osteoporosis which included eight studies was conducted to confirm this study results. RESULTS: The mean of BMD were 0.42 and 0.32 g/cm2 for men with osteopenia and osteoporosis (p<0.001), as well as 0.40 and 0.30 g/cm2 (p<0.001) for women with osteopenia and osteoporosis, respectively. The overall age-standardised prevalence of osteopenia and osteoporosis were 42.09% and 11.76% in all participants. The age-standardised prevalence of osteopenia in men (45.98%) was significantly higher than that in women (39.73%), whereas the age-standardised prevalence of osteoporosis in men (7.82%) was lower than that in women (14.38%). Meta-analysis results displayed pooled prevalence of osteoporosis of 18.0% (10.1%-25.8%) in total sample, 7.7% (5.7%-9.7%) in men and 22.4% (17.1%-27.6%) in women. Multivariable logistic regression models showed that ageing, women, low education level or income, drinking or underweight was related to increased risk for osteopenia or osteoporosis. CONCLUSIONS: About one-sixth of the participants suffered osteoporosis in rural China, and the prevalence in women was higher than men. Although the results were lower than that of meta-analysis, osteoporosis still accounts for huge burden of disease in rural population due to limited medical service and lack of health risk awareness rather than urban area. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR-OOC-15006699; Pre-results).

13.
Clin Sci (Lond) ; 134(2): 103-122, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31898747

RESUMO

Alcohol consumption causes renal injury and compromises kidney function. The underlying mechanism of the alcoholic kidney disease remains largely unknown. In the present study, an alcoholic renal fibrosis animal model was first employed which mice received liquid diet containing alcohol for 4 to 12 weeks. The Masson's Trichrome staining analysis showed that kidney fibrosis increased at week 8 and 12 in the animal model that was further confirmed by albumin assay, Western blot, immunostaining and real-time PCR of fibrotic indexes (collagen I and α-SMA). In vitro analysis also confirmed that alcohol significantly induced fibrotic response (collagen I and α-SMA) in HK2 tubular epithelial cells. Importantly, both in vivo and in vitro studies showed alcohol treatments decreased Smad7 and activated Smad3. We further determined how the alcohol affected the balance of Smad7 (inhibitory Smad) and Smad3 (regulatory Smad). Genome-wide methylation sequencing showed an increased DNA methylation of many genes and bisulfite sequencing analysis showed an increased DNA methylation of Smad7 after alcohol ingestion. We also found DNA methylation of Smad7 was mediated by DNMT1 in ethyl alcohol (EtOH)-treated HK2 cells. Knockdown of Nox2 or Nox4 decreased DNMT1 and rebalanced Smad7/Smad3 axis, and thereby relieved EtOH-induced fibrotic response. The inhibition of reactive oxygen species by the intraperitoneal injection of apocynin attenuated renal fibrosis and restored renal function in the alcoholic mice. Collectively, we established novel in vivo and in vitro alcoholic kidney fibrosis models and found that alcohol induces renal fibrosis by activating oxidative stress-induced DNA methylation of Smad7. Suppression of Nox-mediated oxidative stress may be a potential therapy for long-term alcohol abuse-induced kidney fibrosis.

14.
Nat Commun ; 11(1): 28, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911606

RESUMO

The mechanisms of triplet energy transfer across the inorganic nanocrystal/organic molecule interface remain poorly understood. Many seemingly contradictory results have been reported, mainly because of the complicated trap states characteristic of inorganic semiconductors and the ill-defined relative energetics between semiconductors and molecules used in these studies. Here we clarify the transfer mechanisms by performing combined transient absorption and photoluminescence measurements, both with sub-picosecond time resolution, on model systems comprising lead halide perovskite nanocrystals with very low surface trap densities as the triplet donor and polyacenes which either favour or prohibit charge transfer as the triplet acceptors. Hole transfer from nanocrystals to tetracene is energetically favoured, and hence triplet transfer proceeds via a charge separated state. In contrast, charge transfer to naphthalene is energetically unfavourable and spectroscopy shows direct triplet transfer from nanocrystals to naphthalene; nonetheless, this "direct" process could also be mediated by a high-energy, virtual charge-transfer state.

15.
Biomed Pharmacother ; 122: 109696, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918270

RESUMO

BACKGROUND: Dysregulation of miRNAs is associated with aberrant migration and invasion by suppressing relevant target genes in multiple cancers, including oral squamous cell carcinoma (OSCC). Accumulating evidence suggests that microRNA-155-5p is involved in carcinogenesis and tumor progression. However, the exact function and molecular mechanism of miR-155-5p in OSCC remain unclear. This study aimed to investigate the function of miR-155-5p and the molecular mechanisms underlying the influencing progression of OSCC. METHODS: The miR-155-5p expression level in the OSCC tissues and oral cancer cell lines were determined by the qRT-PCR. Gain-of-function and knockdown approach were used to examine the effect of miR-155-5p on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of OSCC. The luciferase reporter assay was applied to confirm the AT-rich interactive domain 2 (ARID2) as a potential target of miR-155-5p, and the rescue experiment was employed to verify the roles of the miRNA-155-5p-ARID2 axis in OSCC progression. Immunohistochemical staining was used to detect ARID2 expression in another cohort sample tissues from OSCC patients. RESULTS: MiR-155-5p was significantly upregulated in OSCC tissues and cell lines. The miR-155-5p expression level was positively correlated with tumor size, TNM stage, histological grade and lymph node metastasis of OSCC patients. Functional assays demonstrated that miR-155-5p enhanced OSCC cell proliferation, migration and invasion. Mechanistically, ARID2 was identified as a direct target and functional effector of miR-155-5p in OSCC. Furthermore, ARID2 overexpression could rescue the aberrant biological function by overexpressed miR-155-5p in OSCC cells. Notably, we showed that ARID2 could be used as an independent prognosis factor in OSCC. CONCLUSIONS: Our results suggest that miR-155-5p facilitates tumor progression of OSCC by targeting ARID2, and miR-155-5p-ARID2 axis may be a potential therapeutic target of OSCC.

16.
Eur J Nutr ; 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31927672

RESUMO

PURPOSE: Type 2 diabetes is a complex disease determined by variable genes and environmental factors. The study was designed to investigate the effect of interactions of four polymorphisms of suppressor of cytokine signaling 3 (SOCS3) with fruit and vegetable (F&V) intake on type 2 diabetes in a rural population of China. METHODS: A total of 4411 participants from the rural areas of Henan, China were included in the study. Multivariate logistic regression and restricted cubic splines were used to estimate the associations between polymorphisms and risk allele score of SOCS3 and type 2 diabetes in different groups. Haplotype analysis was conducted to examine the effects of linkage inheritance at these four loci on type 2 diabetes. RESULTS: Three of the four polymorphisms showed significant associations with type 2 diabetes in the less F&V intake group after adjusting the covariates, the odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were 1.24 (1.08-1.41) for rs4969168, 1.16 (1.02-1.32) for rs9892622, and 1.21 (1.06-1.39) for rs9914220. No significant association was detected in the more F&V intake group. The obvious dose-response relationship between the risk allele score and type 2 diabetes was also noted only in the less F&V intake group. CONCLUSIONS: Variants of SOCS3 gene were associated with type 2 diabetes and the associations could be modified by the F&V intake.

17.
Mol Carcinog ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995261

RESUMO

Despite therapeutic advancements, there has been little improvement in the survival status of patients with oral squamous cell carcinoma (OSCC). HOX antisense intergenic RNA (HOTAIR) has been shown to be dysregulated in several cancer types. However, the roles of HOTAIR in OSCC remain largely unknown. In this study, we investigated the association of HOTAIR expression with clinicopathological features in OSCC patients and the crucial roles of HOTAIR in the modulation of tumor progression. Our results showed that HOTAIR was highly expressed both in OSCC tissue samples and cell lines compared with corresponding normal oral mucosa tissues and human oral keratinocytes. Its overexpression was positively correlated with TNM (tumor-node-metastases) stage, histological grade, and regional lymph node metastasis. The knockdown of HOTAIR by short hairpin RNA significantly decreased the migration, invasion, and epithelial-mesenchymal transition of OSCC cells in vitro. Moreover, there was a negative correlation between HOTAIR and microRNA-326 expression in OSCC tissue samples and cell lines. Luciferase reporter and loss-of-function assays revealed that HOTAIR acted as a competitive endogenous RNA effectively sponging miR-326, thereby regulating the derepression of metastasis-associated gene 2 (MTA2). Finally, the expression and clinical significance of MTA2 were analyzed in another cohort of OSCC tissue samples. High MTA2 expression was significantly correlated with clinicopathological features of advanced OSCC and poor prognosis for patients with OSCC. Collectively, HOTAIR overexpression promoted the progression of OSCC. The HOTAIR-miR-326-MTA2 axis may contribute to a better understanding of OSCC pathogenesis and be a potential therapeutic target for OSCC.

18.
Liver Int ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31903720

RESUMO

BACKGROUND AND AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH-associated fibrosis in a mouse NASH model and human specimens. METHODS: Mice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD-HF/G) for 16 weeks; HFCD-HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks. RESULTS: Along with NASH progression, fibrotic deposition was documented in HFCD-HF/G-fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase-A (SDH-A) in these mice; whereas, GPR-91 receptor expression was much enhanced in histology compared to control mice, and co-localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid-overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up-regulation of GPR-91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR-91 receptor expression abolished succinate stimulatory role in GPR-91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR-91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens. CONCLUSION: Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR-91 receptor signalling in NASH progression, and the cross-talk between hepatocytes and HSC through GPR-91 signalling is most likely to be the molecular basis of fibrogenesis in NASH.

19.
J Comp Neurol ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31997354

RESUMO

The cannabinoid 1 receptor (CB1 R) is the most abundant G protein-coupled receptor in the brain and plays crucial roles in emotion and behavior by modulating or mediating synaptic transmission and plasticity. Differences in CB1 R density between male and female rodents may be associated with distinct behavioral phenotypes. In the rat brain, CB1 R expression is significantly lower in the prefrontal cortex and amygdala of estrus females than in males. However, differences in CB1 R distribution due to sex over the whole mouse brain are still largely unknown. Here, we systemically investigated the expression of CB1 R mRNA in the brains of both male and female adult C57BL/6J mice using fluorescence in situ hybridization. There were significantly more CB1 R positive cells in males than in females in the orbital cortex, insular cortex, cingulate cortex, piriform cortex, secondary visual cortex, caudate putamen (striatum), and ventral hippocampal CA1. There were significantly more CB1 R mRNA cells in females than males in the fornix and dorsal hypothalamus. However, in some regions, strong hybridization signals without sex differences were detected, such as in the motor cortex, septum, medial habenular nucleus, and inferior colliculus. Moreover, female mice displayed different CB1 R mRNA expression patterns in the medial amygdala, basolateral amygdala, and parabrachial nucleus during different phases of the estrous cycle. These findings provide a basis for understanding sexual dimorphism in physiological and pathological brain functions related to CB1 R.

20.
Emerg Microbes Infect ; 9(1): 78-87, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31894728

RESUMO

The H7N9 influenza virus has been circulating in China for more than six years. The neuraminidase (NA) has gained great concern for the development of antiviral drugs, therapeutic antibodies, and new vaccines. In this study, we screened seven mouse monoclonal antibodies (mAbs) and compared their protective effects against H7N9 influenza virus. The epitope mapping from escape mutants showed that all the seven mAbs could bind to the head region of the N9 NA close to the enzyme activity sites, and four key sites of N9 NA were reported for the first time. The mAbs D3 and 7H2 could simultaneously inhibit the cleavage of the sialic acid of fetuin protein with large molecular weight and NA-XTD with small molecule weight in the NA inhibition experiment, prevent the formation of virus plaque at a low concentration, and effectively protect the mice from the challenge of the lethal dose of H7N9 virus.

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