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1.
Cancer Lett ; 475: 53-64, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32006616

RESUMO

Clinical data analysis reveals that the expression of the EphB4 receptor tyrosine kinase is significantly elevated in HER2-positive breast cancer and high levels of EphB4 strongly correlate with poor disease prognosis. However, the impact of EphB4 activation on HER2-positive breast cancer cells and the potential of EphB4 as a therapeutic target remain to be explored. Here, we show that EphB4 overexpression confers gain-of-function activities to HER2-positive breast cancer cells, rendering resistance to a HER2/EGFR inhibitor Lapatinib. Furthermore, using integrated transcriptomic and tyrosine phosphoproteomic analyses, followed by biochemical confirmation, we establish that EphB4 activation engages the SHP2/GAB1-MEK signaling cascade and downstream c-MYC activation, and thereby limits the overall drug responses to Lapatinib. Finally, we demonstrate that, in HER2-positive breast tumors, inhibition of EphB4 combined with Lapatinib is more effective than either alone. These findings provide new insights into the signaling networks dictating therapeutic response to Lapatinib as well as a rationale for co-targeting EphB4 in HER2-positive breast cancer.

2.
BMC Musculoskelet Disord ; 21(1): 75, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024507

RESUMO

BACKGROUND: For patients with spinal canal stenosis in the upper cervical spine who undergo C3-7 laminoplasty alone, it remains impossible to achieve full decompression due to its limited range. This study explores the extension of expansive open-door laminoplasty (EODL) to C1 and C2 for the treatment of cervical spinal stenosis of the upper cervical spine and its effects on cervical sagittal parameters. METHODS: A retrospective analysis of 33 patients presenting with symptoms of cervical spondylosis myelopathy (CSM) and ossification in the posterior longitudinal ligament (OPLL) of the upper cervical spine from February 2013 to December 2015 was performed. Furthermore, the changes in the C0-2 Cobb angle, C1-2 Cobb angle, C2-7 Cobb angle, C2-7 SVA, and T1-Slope in lateral X-rays of the cervical spine were measured before, immediately after, and 1 year after the operation. JOA and NDI scores were used to evaluate spinal cord function. RESULTS: The C0-2 and C1-2 Cobb angles did not significantly increase (P = 0.190 and P = 0.081), but the C2-7 Cobb angle (P = 0.001), C2-7 SVA (P < 0.001), and T1-Slope (P < 0.001) significantly increased from preoperative to 1 year postoperative. In addition, C2-7 SVA was significantly correlated with the T1-Slope (Pearson = 0.376, P < 0.001) and C0-2 Cobb angle (Pearson = 0.287, P = 0.004), and the C2-7 SVA was negatively correlated with the C2-7 Cobb angle (Pearson = - 0.295, P < 0.001). The average preoperative and postoperative JOA scores were 8.3 ± 1.6 and 14.6 ± 1.4 points, respectively, indicating in a postoperative neurological improvement rate of approximately 91.6%. The average preoperative and final follow-up NDI scores were 12.62 ± 2.34 and 7.61 ± 1.23. CONCLUSIONS: The sagittal parameters of patients who underwent EODL extended to C1 and C2 included loss of cervical curvature, increased cervical anteversion and compensatory posterior extension of the upper cervical spine to maintain visual balance in the field of vision. However, the changes in cervical spine parameters were far less substantial than the alarm thresholds reported in previous studies. We believe that EODL extended to C1 and C2 for the treatment of patients with spinal canal stenosis in the upper cervical spine is a feasible and safe procedure with excellent outcomes.

3.
Hum Gene Ther ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31950871

RESUMO

Renal fibrosis leads to end-stage renal disease, but anti-fibrotic drugs are difficult to develop. Chronic kidney disease often results in muscle wasting and thereby increases morbidity and mortality. In this work, adeno-associated virus (AAV)-mediated overexpressing miR-29a was hypothesized to counteract renal fibrosis and muscle wasting via muscle-kidney crosstalk in unilateral ureteral obstruction (UUO) mice. miR-29a level was downregulated in the kidney and skeletal muscle of UUO mice. The secretion of exosome-encapsulated miR-29a increased in cultured skeletal muscle satellite cells and HEK293 renal cells after stimulation with serum from UUO mice. This result was confirmed by qPCR and microRNA deep sequencing in the serum exosomes of mice with obstructed ureters. A recombinant AAV-miR-29a was generated to overexpress miR-29a and injected into the tibialis anterior muscle of the mice 2 weeks before UUO surgery. AAV-miR-29a abrogated the UUO-induced upregulation of YY1 and myostatin in skeletal muscles. Renal fibrosis was also partially improved in the UUO mice with intramuscular AAV-miR-29a transduction. AAV-miR-29a overexpression reversed the increase in TGF-ß, fibronectin, alpha-smooth muscle actin, and collagen 1A1 and 4A1 levels in the kidney of UUO mice. AAV-GFP was applied to trace the AAV route in vivo, and fluorescence was significantly visible in the injected/ un-injected muscles and in the kidneys. In conclusion, intramuscular AAV-miR-29a injection attenuates muscle wasting and ameliorates renal fibrosis by downregulating several fibrotic-related proteins in UUO mice.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31944535

RESUMO

The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non-cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture-based next-generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm-level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non-cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFRα) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.

5.
Ecotoxicol Environ Saf ; 189: 109960, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31784106

RESUMO

AHTN (tonalide) is a polycyclic musk that is widely used as fragrance additive in numerous consumer products. AHTN is of great worldwide concern owing to its adverse effects on aquatic organisms and frequent detection in both domestic and foreign aquatic environments. Therefore, derivation of the aquatic life criteria for AHTN exposure is urgently needed. In this work, AHTN toxicity data for eight Chinese native freshwater organisms were used to derive a criterion maximum concentration of 59.39 µg/L and a criterion continuous concentration of 22.43 µg/L using United States Environmental Protection Agency guidelines. Toxicity tests showed that the annelid L. hoffmeisteri and the amphibian R. nigromaculata were the least and most sensitive species to AHTN, respectively. The sensitivity of the planktonic crustacean D. magna to AHTN obviously differed from that of the benthic crustacean M. nipponense. The AHTN and HHCB correlation analysis exhibited a strong positive linear correlation (R2 = 0.8622) in water. The ecological risk assessment showed that AHTN and HHCB posed a higher risk in foreign surface waters than Chinese waters, but a lower risk in foreign wastewater treatment plant effluent than in China. The ecological risks of AHTN and HHCB in most surveyed water bodies of various countries were at acceptable levels, with a few exceptions.

6.
Chemosphere ; 243: 125328, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31733536

RESUMO

Ammonia has drawn great concern worldwide due to its ubiquity in surface water and high toxic effect. In China, ammonia pollution issues in the Liao River were highlighted from the Ministry of Ecology and Environment annual report. In this study, water quality criteria (WQC) for two types of ammonia (total ammonia nitrogen (TAN) and un-ionized ammonia (NH3-N)) and related temporal concentration distributions and ecological risks in the Liao River were investigated. For sampling sites (2014) and national monitoring sites (2008, 2013, 2016, 2017 and 2018) of the Liao River, there were seasonal variations identified for TAN and NH3-N. More specifically, high concentrations of TAN and NH3-N occurred separately in winter and summer, and there were increasing trends for TAN and NH3-N from 2013 to 2018. The acute and chronic WQC values for TAN based on the toxicity values of the Liao River species were 16.86 and 4.39 mg/L (pH of 7.0 and temperature of 20 °C), and the acute and chronic WQC values for NH3-N were 0.067 and 0.017 mg/L. The exceedance probabilities of 5% species affected for long-term exposure of TAN and NH3-N were ≥30% in 2014. In addition, the increasing trend of concentrations and ecological risks posed by NH3-N from 2013 should be paying more attention. This study could provide useful information for ammonia environmental risk management in China and ecological risk assessment procedure for NH3-N and TAN exposure in similar surface waters worldwide.

7.
Int Immunopharmacol ; 78: 106032, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31835089

RESUMO

MENK, as an immune adjuvant, has potential immune-regulatory activity on innate and adaptive immune cells. The aim of this work was to investigate the antiviral effect of MENK on influenza virus-infected murine macrophage cells (RAW264.7) and its underlying mechanisms. The results showed that MENK markedly inhibited influenza A virus (H1N1) replication in pre- and post-MENK treatment, especially in pre-MENK treatment. The mechanisms exploration revealed that MENK (10 mg/mL) significantly inhibited the nucleoprotein (NP) of influenza virus and up-regulated levels of IL-6, TNF-α and IFN-ß compared with those in H1N1 control group. Further experiments confirmed that antiviral effects of MENK was associated with promotion of opioid receptor (MOR) as well as activation of NF-κB p65 inducing cellular antiviral status. The data suggest that MENK should be potential candidate for prophylactic or therapeutic treatment against H1N1 influenza virus.

8.
Ecotoxicol Environ Saf ; 188: 109881, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31704324

RESUMO

N,N-diethyl-meta-toluamide (DEET) is the most widely used active ingredient in commercial insect repellents. In addition to its adverse effects in insects, DEET can affect non-target organisms in surface water systems. Nevertheless, the aquatic life criteria of DEET are not available. This study conducted both acute and chronic toxicity tests on DEET in native Chinese aquatic species, and derived its criterion maximum concentration (CMC) and criterion continuous concentration (CCC). The determined CMC and CCC of DEET were 21.53 and 0.52 mg/L, respectively. The toxicity data indicated that DEET exposure posed a higher toxicity to some algae than other aquatic species. Compared with other insect repellents, DEET exposure posed a moderate toxicity to aquatic species. Therefore, the exposure concentration of DEET in Chinese surface water was collected to assess the potential ecological risk. The preliminary ecological risk assessment showed that DEET posed negligible risk to aquatic ecosystems in China. However, considering its toxic effects on the growth and reproduction to aquatic organisms, the ecological risk posed by DEET is worth further concern.


Assuntos
Organismos Aquáticos/efeitos dos fármacos , DEET/toxicidade , Exposição Ambiental/análise , Repelentes de Insetos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Organismos Aquáticos/classificação , Organismos Aquáticos/crescimento & desenvolvimento , Organismos Aquáticos/fisiologia , China , DEET/análise , Repelentes de Insetos/análise , Medição de Risco , Especificidade da Espécie , Testes de Toxicidade , Poluentes Químicos da Água/análise
9.
Chemosphere ; 240: 124848, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31541901

RESUMO

Establishment of numerical water quality criteria (WQC) has brought increasing interest in China. However, toxicity data to develop robust WQC values (number of toxicity data ≥8) of contaminants based solely on endemic and indigenous species are insufficient. In this study, interspecies correlation estimation (ICE) models were developed using a combination of North American ICE models supplemented with China-specific species to resolve this problem. A total of 207 significant surrogate-predicted models (p < 0.05, F-test) were derived: 119, 66 and 22 models for vertebrates, invertebrates and plant surrogate species, respectively. Model cross-validation success rate (≥80%), mean square error (MSE, ≤ 0.54), R2 (≥0.78) and taxonomic distance (≤4, within the same class) were selected as guiding criteria to screen the resulted ICE models. The differences of 5th percentile hazard concentrations (HC5s) for 6 chemicals (2,4-dichlorophenol, triclosan, tetrabromobisphenol A, nitrobenzene, perfluorooctane sulfonate and octabromodiphenyl ether) calculated from ICE-based and measured toxicity-based SSDs were within 3-fold among models. Although the number of derived ICE models was not comprehensive and continues to be improved, they can already be used in the development of WQC targeting protection of aquatic life and environmental risk assessments for chemicals lacking toxicity data.


Assuntos
Poluentes Químicos da Água/química , Qualidade da Água/normas , Animais , China , Especificidade da Espécie
10.
Orthop Surg ; 11(6): 1180-1186, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31823498

RESUMO

OBJECTIVE: To investigate the efficacy and safety of ultrasonic bone curette in treating thoracic spinal stenosis. METHODS: A total of 30 patients of thoracic spinal stenosis who underwent posterior thoracic decompression in the hospital from December 2015 to 2017 were enrolled. Of these, 18 patients (group A) underwent posterior thoracic decompression using ultrasonic bone curette; and 12 patients underwent the treatment using a high-speed drill (group B). The time of laminectomy, amount of intraoperative blood loss, presence or absence of cerebrospinal fluid leakage, and nerve root injury were recorded. All patients underwent X-ray, computed tomography with three-dimensional reconstruction, and magnetic resonance imaging before and after surgery. The Frankel classification and the Japanese Orthopaedic Association (JOA) scores were used to assess the neurological function and neurological recovery in patients. The measured data were statistically processed and analyzed using SPSS21.0 software, and the measurement data were expressed as mean ± SD. RESULTS: In groups A and B, the average time for single-segment laminectomy was 3.3 ± 1.2 min and 6.0 ± 1.8 min and the mean bleeding volume was 105.5 ± 43.3 mL and 177.4 ± 54.7 mL, respectively, with a statistically significant difference between the groups. The difference in JOA scores before and after surgery in groups A and B was statistically significant. No significant difference was found between the groups, in group A, the improvement rate of nerve function at the last follow-up was 71% and in group B, the improvement rate at the last follow-up was 70%. In group A, at last follow-up, two patients had Frankel grade B injury, one had grade C injury, seven had grade D injury, and eight had grade E injury. In group B, at last follow-up, one patient had Frankel grade B injury, one had grade C injury, five had grade D injury, and five had grade E injury. The Frankel classification of both groups A and B significantly improved. Four patients experienced cerebrospinal fluid leakage in group A and five in group B, with no significant difference between the groups. There was no nerve root injury in both groups, and no complications, such as pulmonary infection and urinary tract infection, occurred after operation. CONCLUSIONS: With the use of ultrasonic bone curette in posterior thoracic decompression, the decompression surgery could be completed relatively safely and quickly. It effectively reduced the amount of intraoperative blood loss.

11.
Aging Dis ; 10(6): 1246-1257, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788336

RESUMO

Disability has become a critical issue among elderly populations, yet limited large-scale research related to this issue has been conducted in China, an aging society. This study explored sex and urban-rural differences in disability transitions and life expectancies among older adults in China. Data were collected from the Chinese Longitudinal Health Longevity Survey (CLHLS), which enrolled people aged 65 and older and was conducted in randomly selected counties and cities across 22 provinces in China. Disability was diagnosed based on basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). Several individual characteristics were assessed, including sociodemographic factors (age, sex and region, etc.) and health behaviors (currently smoking, currently drinking, etc.). Multistate models were applied to analyze the transition rates among 4 states: no disability, mild disability, severe disability and death. The transition rates from disabled states to the no-disability state were found to decrease markedly with age. The rates of recovery from mild disability in rural areas were higher than those in urban areas. Rural elderly individuals lived shorter lives than their urban counterparts, but they tended to live with better functional status, spending a larger fraction of their remaining life with less severe disability. Based on these findings, devoting more attention and resources to rural areas may help less severely disabled people recuperate and prevent severe disability. The study provides insights into health plan strategies to help guide the allocation of limited resources.

12.
Oncogene ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831835

RESUMO

The original version of this Article omitted the following from the Acknowledgements: Professor Stebbing sits on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare. This has now been corrected in both the PDF and HTML versions of the Article.

13.
Sci Rep ; 9(1): 19382, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853002

RESUMO

Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Nevertheless, little is known regarding diaphragm dysfunction in HD patients. We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion during quiet and deep breathing. HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity (0.386 ± 0.144 cm vs. 0.439 ± 0.134 cm, p < 0.01) and thickening fraction (TF) (0.838 ± 0.618 vs. 1.127 ± 0.757; p < 0.01) compared to controls. The velocity and excursion of the diaphragm were significantly lower in the HD patients during deep breathing (3.686 ± 1.567 cm/s vs. 4.410 ± 1.720 cm/s, p < 0.01; 5.290 ± 2.048 cm vs. 7.232 ± 2.365 cm; p < 0.05). Changes in diaphragm displacement from quiet breathing to deep breathing (△m) were lower in HD patients than in controls (2.608 ± 1.630 vs. 4.628 ± 2.110 cm; p < 0.01). After multivariate adjustment, diaphragmatic excursion during deep breathing was associated with haemoglobin level (regression coefficient = 0.022; p < 0.01). We also found that the incidence of dyspnoea and hiccup and the fatigue scores, all of which were related to diaphragmatic dysfunction, were significantly higher in HD patients than in controls (all p < 0.01). Improving diaphragm function through targeted therapies may positively impact clinical outcomes in HD patients.

15.
Onco Targets Ther ; 12: 6639-6651, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695405

RESUMO

Background: Increasing evidence suggests that glutathione peroxidase 2 (GPX2) plays important roles in the tumorigenesis and progression of various human cancers, such as colorectal carcinomas and lung adenocarcinomas. However, the role of GPX2 in cervical cancer is unclear. In this study, we identified the role of GPX2 in cervical cancer tissues and cell lines. Materials and methods: The basal mRNA and protein expression of GPX2 in cervical cancer cells and a series of key molecules in the epithelial to mesenchymal transition (EMT) and WNT/ß-catenin pathways were examined via real time fluorescence quantitative PCR (qRT-PCR) and Western blot assays. The biological phenotype of the cervical cancer cell lines was detected by the cloning formation and transwell assays, and intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. Finally, the GPX2 expression level in 100 clinical cervical tissues was examined by immunohistochemistry. Results: We found that GPX2 was highly expressed in cervical cancer tissues compared to normal individuals and promoted the proliferation and metastasis of cervical cancer cells, and this promotion correlated with the activation of EMT and WNT/ß-catenin signaling in vitro. GPX2 was determined to reduce apoptotic damage by reducing hydroperoxides. According to the characteristics and verification of GPX2, this series of phenotypes is clearly related to oxidative stress in cells. Furthermore, we verified that GPX2 was highly expressed in cervical cancer tissues and promoted the metastasis of cervical cancer. Conclusion: In summary, we found that GPX2 was highly expressed in cervical cancer cells and promoted the proliferation and metastasis of cervical cancer by affecting oxidative stress. Our study provides a new target for the clinical treatment of cervical cancer.

16.
Oncogene ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754213

RESUMO

EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients' outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.

17.
BMC Bioinformatics ; 20(1): 497, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615418

RESUMO

BACKGROUND: It is widely believed that tertiary nucleotide-nucleotide interactions are essential in determining RNA structure and function. Currently, direct coupling analysis (DCA) infers nucleotide contacts in a sequence from its homologous sequence alignment across different species. DCA and similar approaches that use sequence information alone typically yield a low accuracy, especially when the available homologous sequences are limited. Therefore, new methods for RNA structural contact inference are desirable because even a single correctly predicted tertiary contact can potentially make the difference between a correct and incorrectly predicted structure. Here we present a new method DIRECT (Direct Information REweighted by Contact Templates) that incorporates a Restricted Boltzmann Machine (RBM) to augment the information on sequence co-variations with structural features in contact inference. RESULTS: Benchmark tests demonstrate that DIRECT achieves better overall performance than DCA approaches. Compared to mfDCA and plmDCA, DIRECT produces a substantial increase of 41 and 18%, respectively, in accuracy on average for contact prediction. DIRECT improves predictions for long-range contacts and captures more tertiary structural features. CONCLUSIONS: We developed a hybrid approach that incorporates a Restricted Boltzmann Machine (RBM) to augment the information on sequence co-variations with structural templates in contact inference. Our results demonstrate that DIRECT is able to improve the RNA contact prediction.


Assuntos
Algoritmos , Modelos Moleculares , Conformação de Ácido Nucleico , Análise de Sequência de RNA/métodos , Software
18.
FASEB J ; 33(12): 13590-13601, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31593640

RESUMO

Kidney fibrosis occurs in almost every type of chronic kidney disease. We found that microRNA (miR)-26a was decreased in the kidney, muscle, and exosomes of unilateral ureteral obstruction (UUO) mice. We hypothesized that exogenous miR-26 could suppresses renal fibrosis and muscle wasting in obstructive kidney disease. For this purpose, we generated exosomes that encapsulated miR-26, then injected these into skeletal muscle of UUO mice. The expression of miR-26a was elevated in serum exosomes from UUO mice following exosome-miR-26a injection. In these mice, muscle wasting has been ameliorated as evidenced by increased muscle weights. In addition, a muscle atrophy marker, myostatin, is increased in UUO muscle; provision of miR-26a abolished this increase. We detected a remote effect of exosomes containing miR-26a in UUO-induced renal fibrosis. The intervention of miR-26a attenuated UUO-induced renal fibrosis as determined by immunohistological assessment of α-smooth muscle actin and Masson's trichrome staining. Furthermore, exogenous miR-26a decreased the protein levels of 2 profibrosis proteins, connective tissue growth factor (CTGF) and TGF-ß1, in UUO kidney. Our data showed that exosomes containing miR-26a prevented muscle atrophy by inhibiting the transcription factor forkhead box O1. Likewise, the exosome-carried miR-26a limited renal fibrosis by directly suppressing CTGF. Our findings provide an experimental basis for exosome-mediated therapy of muscle atrophy and renal fibrosis.-Zhang, A., Wang, H., Wang, B., Yuan, Y., Klein, J. D., Wang, X. H. Exogenous miR-26a suppresses muscle wasting and renal fibrosis in obstructive kidney disease.

19.
Int J Environ Health Res ; : 1-12, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621392

RESUMO

BACKGROUND: The main aim of this study was to explore the spatial-temporal patterns of cause-specific CVD admission in Beijing using retrospective SaTScan analysis. METHODS: A spatial-temporal analysis was conducted at the district level based on the rates of total and cause-specific CVD admissions, including coronary heart disease (CHD), atrial fibrillation (AF), and heart failure (HF) from 2013 to 2017. We used joint point regression, Global Moran's I and Anselin's local Moran's I, together with Kulldorff's scan statistic. RESULTS: Hospital admission trend decreased during the study period. Admission rates followed a spatially clustered pattern with differences occurring between cause-specific CVDs. Clusters were mainly identified in ecological preservation areas, with a more likely cluster found in Daxing, Fangshan, Xicheng district for total CVD, CHD, AF and HF, respectively. CONCLUSIONS: Hospital admission of cause-specific CVD showed spatial clustered pattern, especially in ecological preservation areas.

20.
Biotechnol Bioeng ; 116(12): 3349-3359, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31529699

RESUMO

Microbial biosynthesis has been extensively adapted for the production of commodity chemicals using renewable feedstocks. This study integrated metabolite biosensors into rationally designed microbial cocultures to achieve high-efficiency bioproduction of phenol from simple carbon substrate glucose. Specifically, two sets of E. coli-E. coli cocultures were first constructed for accommodation of two independent phenol biosynthesis pathways via 4-hydroxybenzoate (4HB) and tyrosine (TYR), respectively. Biosensor-assisted microbial cell selection mechanisms were subsequently incorporated into the coculture systems to address the insufficient pathway intermediate provision that limited the overall bioproduction. For the 4HB- and TYR-dependent pathways, this approach improved the phenol production by 2.3- and 3.9-fold, respectively, compared to the monoculture controls. Notably, the use of biosensor-assisted cell selection strategy in monocultures resulted in reduced phenol production, highlighting the advantage of coculture engineering for coupling with biosensing. After stepwise optimization, the phenol bioproduction yield of the engineered coculture's reached 0.057 g/g glucose. Furthermore, the coculture biosynthesis was successfully scaled up at both shake flask and bioreactor levels. Overall, the findings of this study demonstrate the outstanding potential of coupling biosensing and modular coculture engineering for advancing microbial biosynthesis of valuable molecules from renewable carbon substrates.

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