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1.
J Comput Biol ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545074

RESUMO

This study was aimed at identifying differentially expressed genes (DEGs) with copy number changes in gastric cancer (GC) pathogenesis. Microarray data GSE33429, including array-based comparative genomic hybridization and gene expression profiles, were obtained. DEGs were screened between GC and adjacent noncancerous tissues. Genes located at Minimum Common Regions (MCRs) were identified, and overlapped genes between DEGs and genes with amplification or deletion were identified. Gene Ontology function and pathway enrichment analysis of DEGs were performed. A protein-protein interaction network for DEGs was built, and significant modules were mined from the network. Functional annotation of genes in modules was also performed. A total of 677 up- and 583 downregulated DEGs were identified, including 37 overexpressed genes located at gained MCRs and 28 downregulated genes located at deleted MCRs. In significant modules, upregulated genes with amplification, including DSN1 (MIS12 kinetochore complex component), MAPRE1 (microtubule-associated protein, RP/EB family, member 1), TPX2 (microtubule-associated), UBE2C (ubiquitin-conjugating enzyme E2C), and MYBL2 (v-myb avian myeloblastosis viral oncogene homolog-like 2), were associated with cell cycle, but downregulated genes with deletion, including UGT2B15 (UDP glucuronosyltransferase 2 family, polypeptide B15), UGT2B17 (UDP glucuronosyltransferase 2 family, polypeptide B17), ADH1B (alcohol dehydrogenase 1B), and ADH1A (alcohol dehydrogenase 1A), were related to metabolism. The identified genes DSN1, MAPRE1, TPX2, UBE2C, and MYBL2 located at gained MCRs and UGT2B15, UGT2B17, ADH1B, and ADH1A located at deleted MCRs may play an important role in GC progression through regulating cell cycle and metabolism.

2.
Acta Pharmacol Sin ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530901

RESUMO

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by ß-adrenergic receptors (ß-ARs). However, α1-adrenergic receptors (α1-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α1-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α1-AR agonist phenylephrine (PE, 5 or 10 mg/kg, s.c.) with or without pretreatment with α-AR antagonist prazosin (5 mg/kg, s.c.). PE injection caused cardiac dysfunction and cardiac inflammation, evidenced by the increased expression of inflammatory cytokine IL-6 and chemokines MCP-1 and MCP-5, as well as macrophage infiltration in myocardium. These effects were blocked by prazosin pretreatment. Furthermore, PE injection significantly increased the expression of NOD-like receptor protein 3 (NLRP3) and the cleavage of caspase-1 (p20) and interleukin-18 in the heart; similar results were observed in both Langendorff-perfused hearts and cultured cardiomyocytes following the treatment with PE (10 µM). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3-/- mice compared with wild-type mice. In conclusion, α1-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.

3.
Theranostics ; 9(16): 4740-4755, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31367254

RESUMO

Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods: RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results: Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin αLß2 (LFA-1) and α4ß1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro, MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion: In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications.

4.
Virol Sin ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31429011

RESUMO

While host proteins incorporated into virions during viral budding from infected cell are known to play essential roles in multiple process of the life cycle of progeny virus, these characteristics have been largely neglected in studies on rabies virus (RABV). Here, we purified the RABV virions with good purity and integrity, and analyzed their proteome by nano LC-MS/MS, followed by the confirmation with immunoblot and immuno-electronic microscopy. In addition to the 5 viral proteins, 49 cellular proteins were reproducibly identified to be incorporated into matured RABV virions. Function annotation suggested that 24 of them were likely involved in virus replication. Furthermore, cryo-EM was employed to observe the purified RABV virions, generating high-resolution pictures of the bullet-shaped virion structure of RABV. This study has provided new insights into the host proteins composition in RABV virion and shed the light for further investigation on molecular mechanisms of RABV infection, as well as the discovery of new anti-RABV therapeutics.

5.
Prostate ; 79(15): 1731-1738, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454437

RESUMO

BACKGROUND: Inflammation is a hallmark of prostate cancer (PCa), yet no pathogenic agent has been identified. Men from Africa are at increased risk for both aggressive prostate disease and infection. We hypothesize that pathogenic microbes may be contributing, at least in part, to high-risk PCa presentation within Africa and in turn the observed ethnic disparity. METHODS: Here we reveal through metagenomic analysis of host-derived whole-genome sequencing data, the microbial content within prostate tumor tissue from 22 men. What is unique about this study is that patients were separated by ethnicity, African vs European, and environments, Africa vs Australia. RESULTS: We identified 23 common bacterial genera between the African, Australian, and Chinese prostate tumor samples, while nonbacterial microbes were notably absent. While the most abundant genera across all samples included: Escherichia, Propionibacterium, and Pseudomonas, the core prostate tumor microbiota was enriched for Proteobacteria. We observed a significant increase in the richness of the bacterial communities within the African vs Australian samples (t = 4.6-5.5; P = .0004-.001), largely driven by eight predominant genera. Considering core human gut microbiota, African prostate tissue samples appear enriched for Escherichia and Acidovorax, with an abundance of Eubacterium associated with host tumor hypermutation. CONCLUSIONS: Our study provides suggestive evidence for the presence of a core, bacteria-rich, prostate microbiome. While unable to exclude for fecal contamination, the observed increased bacterial content and richness within the African vs non-African samples, together with elevated tumor mutational burden, suggests the possibility that bacterially-driven oncogenic transformation within the prostate microenvironment may be contributing to aggressive disease presentation in Africa.

6.
FASEB J ; 33(11): 12630-12643, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31451021

RESUMO

The discovery of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF-PHI. Here, we explored the dose-dependent effect of MK-8617 (MK), a kind of HIF-PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro, the human proximal tubule epithelial cell line HK-2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose-dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high-dose MK treatment could significantly enhance TIF. Using RNA-sequencing, combined with in vivo and in vitro experiments, we found that Krüppel-like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF-1α with high-dose MK treatment but not low-dose MK. Furthermore, our study clarified that HIF-1α-KLF5-TGF-ß1 signaling activation is the potential mechanism of high-dose MK-induced TIF, as knockdown of KLF5 reduced TIF in vivo. Collectively, our study demonstrates that high-dose MK treatment initiates TIF by activating HIF-1α-KLF5-TGF-ß1 signaling. These findings provide novel insights into TIF induction by high-dose MK (HIF-PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.-Li, Z.-L., Lv, L.-L., Wang, B., Tang, T.-T., Feng, Y., Cao, J.-Y., Jiang, L.-Q., Sun, Y.-B., Liu, H., Zhang, X.-L., Ma, K.-L., Tang, R.-N., Liu, B.-C. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

7.
Carcinogenesis ; 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31306481

RESUMO

Upregulation of histone methyltransferase SETDB1 is associated with poor prognosis in cancer patients. However, the mechanism of oncogenicity of SETDB1 in cancer is hitherto unknown. Here, we show that SETDB1 is upregulated in human colorectal cancer (CRC) where its level correlates with poor clinical outcome. Ectopic SETDB1 promotes CRC cell proliferation, whereas SETDB1 attenuation inhibits this process. Flow cytometry reveals that SETDB1 promotes proliferation by driving the CRC cell cycle from G0/G1 phase to S phase. Mechanistically, SETDB1 binds directly to the STAT1 promoter region resulting in increased STAT1 expression. Functional characterization reveals that STAT1-CCND1/CDK6 axis is a downstream effector of SETDB1-mediated CRC cell proliferation. Furthermore, SETDB1 upregulation is sufficient to accelerate in vivo proliferation in xenograft animal model. Taken together, our results provide insight into the upregulation of SETDB1 within CRC and can lead to novel treatment strategies targeting this cell proliferation-promoting gene.

8.
J Virol ; 93(18)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31243136

RESUMO

Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3' untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3.IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3' UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.

9.
J Biol Chem ; 294(32): 12112-12121, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31217279

RESUMO

Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients may have heightened sensitivity to CEEs due to the inflammatory induction of STS activity.

10.
Trends Cell Biol ; 29(8): 623-634, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31153655

RESUMO

Cancer heterogeneity has long been recognized as an important clinical determinant of patient outcomes and, thus, many new cancer treatments have been designed to target these different cells. Despite the short-term achievements of current therapies, including chemotherapy, antiangiogenesis therapy, radiotherapy, and immunotherapy, the long-term success of cancer regression remains poor. Therefore, researchers have investigated a new property, cellular reprogramming, in cancer that not only contributes to the classic hallmarks of cancer, but also suggests that cancer is a dynamic event rather than a static cellular entity. Here, we discuss the mechanisms by which the cellular reprogramming of cancer cells can explain some of the phenotypic and functional heterogeneity observed among cancer cells.

11.
Analyst ; 144(14): 4175-4179, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31237576

RESUMO

In this work, we report a facile, sensitive, selective, and reproducible DNA impedimetric sensor device. We demonstrate that, combined with exonuclease III, the easily prepared electrochemically reduced graphene oxide (rGO) could be a desirable platform to amplify signals in electrochemical impedance spectroscopy for ultrasensitive DNA detection. Guided by enzyme assisted target recycling, efficient interfacial tuning can be obtained, from the situation with high impedance caused by single-stranded DNA probes directly adsorbed onto rGO to the one with low impedance due to the continuous desorption of target-probe DNA hybrids and the consequent digestion of DNA probes. Just a few DNA targets can specifically trigger the enzymatic digestion of a large number of DNA probes. It is the excellent electrical conductivity of rGO that further enlarges the changes of electron transfer resistance after the removal of DNA probes. As a result of synergistically combining both enzymatic and electrical amplification, the enlarged changes of impedimetric signals can be measured to sensitively report DNA targets. The specificity has been guaranteed by the intrinsic recognition of hybrids through both rGO and exonuclease III. A limit of detection as low as 10 aM target DNA in the matrix of cell culture medium, as well as a wide linear range and good discrimination of mismatched sequences even at the one-base level, suggests its great application prospect in biosensing and biomedical analysis. It also has other advantages including easy operation, low cost, and convenient regeneration, with more competitive performance in developing impedimetric biosensors.

12.
Mol Med Rep ; 20(1): 693-700, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180534

RESUMO

Colon cancer is one of the most commonly diagnosed malignancies and is a leading cause of cancer­associated mortality. The aim of the present study was to investigate the molecular mechanisms underlying colon cancer and identify potentially significant genes associated with the disease using weighted gene co­expression network analysis (WGCNA). The test datasets used were downloaded from The Cancer Genome Atlas (TCGA) database. WGCNA was applied to analyze microarray data obtained from colon adenocarcinoma samples to identify significant modules and highly associated genes. A gene co­expression network was constructed and different gene modules were selected. Functional and pathway enrichment analyses were performed to investigate the molecular mechanisms of colon cancer. In addition, highly connected hub genes associated with the most significant module were selected for further analysis. Nine specific modules associated with colon cancer were identified, of which the turquoise module was observed to exhibit the greatest association with the disease. Pathway enrichment analysis of the turquoise module suggested that genes in the turquoise module were associated with 'RNA polymerase' and 'purine metabolism'. Furthermore, gene ontology enrichment analysis revealed the top 30 hub genes with a higher degree in the turquoise module, such as σ­non­opioid intracellular receptor 1, transmembrane protein 147  TMEM147) and carbamoyl­phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, were predominantly enriched in the biological processes 'translation' and 'gene expression'. Experimental verification demonstrated that the expression of TMEM147 in colon cancer was significantly increased compared with the control. Therefore, the results suggested that genes associated with RNA polymerase and the purine metabolic pathways may be substantially involved in the pathogenesis of colon cancer. Furthermore, TMEM147 may represent a biomarker for colon cancer.

13.
Biosens Bioelectron ; 138: 111302, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31112917

RESUMO

The early detection of bacterium plays a significant role in addressing serious public health issues. In this paper, a supersensitive multichannel series piezoelectric quartz crystal (MSPQC) sensor of bacterium based on 16S rRNA and "DNA-RNA switch" was constructed. The fragment in specific region of 16S rRNA was used as the biomarker of bacterium to ensure high specificity and to achieve the accurate judgment of microbial vitality. "DNA-RNA switch" was designed to conduct two electrodes by switching insulated "gene-link" into conductive "silver-link", which achieved the super-sensitivity of MSPQC to bacteria. To demonstrate the feasibility of this strategy, a proof-of-concept method for Escherichia coli (E. coli) assay was designed. The detection limit was down to 2 cfu/mL. Staphylococcus aureus, Salmonella enteritidis, Listeria innocua and Pseudomonas aeruginosa did not interfere with the detection results. Proposed method was highly sensitive, and specific for bacterium detection, which might find widely use in early detection of bacterium in the field of public safety monitoring and clinical diagnosis.


Assuntos
Bactérias/genética , DNA/química , RNA Ribossômico 16S/análise , Bactérias/isolamento & purificação , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas , Eletrodos , Ouro/química , Limite de Detecção , Nanopartículas Metálicas/química , Quartzo , Sensibilidade e Especificidade , Prata/química
14.
BMC Genomics ; 20(1): 398, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117944

RESUMO

BACKGROUND: Salmonella enterica consists of over 2500 serovars and displays dichotomy in disease manifestations and host range. Except for the enrichment of pseudogenes in genomes for human-restricted serovars, no hallmark has been identified to distinguish those with host-generalist serovars. The serovar Sendai is rare and human-restricted. Notably, it exhibits an O, H antigen formula as the host-generalist serovar Miami. RESULTS: We sequenced the complete genomes of the two serovars Sendai and Miami. Analysis at both nucleotide identity and gene content level demonstrates the same high degree of similarity between Sendai and Paratyphi A, but their distinct CRISPR spacers suggests a recent divergence history. A frameshift mutation occurred in rfbE for the entire lineage of Paratyphi A but not in Sendai, which may explain their distinct O antigens. The nucleotide sequence of Miami's fliC is nearly identical to Sendai's. The incongruent phylogeny of this gene with that of the adjacent genes suggests a recombination event responsible for Sendai and Miami possessing the same H antigen. Sendai's even greater number of pseudogenes than that of Paratyphi A and Typhi indicates its undergoing continued genomic degradation. The phylogenetically distinct human-restricted serovars/strains share pseudogenes with the same inactivation mutations, therefore suggesting that recombination may have occurred and have been facilitated by their overlap in niches. CONCLUSIONS: Analysis of Sendai's genome and comparison with others reflect the finer evolutionary signatures of Salmonella in the process of niches changing from facultative to obligate parasite.


Assuntos
Antígenos de Bactérias/genética , Variação Genética , Genoma Bacteriano , Salmonella enterica/genética , Salmonella paratyphi A/genética , Salmonella/classificação , Salmonella/genética , Sorogrupo , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Evolução Molecular , Genômica , Humanos , Filogenia , Salmonella/metabolismo , Salmonella enterica/metabolismo , Salmonella paratyphi A/metabolismo , Análise de Sequência de DNA , Sequenciamento Completo do Genoma
15.
Cell Death Differ ; 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097789

RESUMO

Tubulointerstitial inflammation is a common characteristic of acute and chronic kidney injury. However, the mechanism by which the initial injury of tubular epithelial cells (TECs) drives interstitial inflammation remains unclear. This paper aims to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation. Global microRNA(miRNA) expression profiling of renal exosomes was examined in a LPS induced acute kidney injury (AKI) mouse model and miR-19b-3p was identified as the miRNA that was most notably increased in TEC-derived exosomes compared to controls. Similar results were also found in an adriamycin (ADR) induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-κB/SOCS-1. A dual-luciferase reporter assay confirmed that SOCS-1 was the direct target of miR-19b-3p. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptively transferred of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and were correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy. Thus, our studies demonstrated that exosomal miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation. The exosome/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31120000

RESUMO

Combination antiretroviral therapy (cART) has significantly reduced the mortality rate and morbidity, and has increased life expectancy of human immunodeficiency virus (HIV) infected patients. However, current cART is incapable of eradicating viruses from the human body, and HIV remains one of the most notorious viruses mankind has ever faced. HIV-1 enters target cells through the binding of gp120 viral protein to a CD4 receptor and then to a coreceptor, C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). Individuals homozygous for a 32-bp deletion in the CCR5 allele, CCR5Δ32, are almost completely resistant to HIV-1 acquisition. Moreover, several of natural CXCR4 mutants which have been identified can reduce HIV-1 entry without impairing either ligand binding or signaling. In order to get rid of indefinite treatment for HIV patients, there is a growing interest in creating an HIV-resistant immune system through the use of CCR5 and CXCR4-modified hematopoietic stem cells (HSCs). Proof of concept for this approach has been provided in the instance of "Berlin patient" transplanted with allogeneic stem cells from a donor with homozygosity for the CCR5Δ32 deletion. Here, we review the progress of coreceptor-based HSC gene therapy for HIV disease and present new strategies.

17.
J Acoust Soc Am ; 145(3): 1417, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31067939

RESUMO

A jet pump with an asymmetrical channel can induce a time-averaged pressure drop in oscillatory flow, which can effectively suppress Gedeon streaming in looped thermoacoustic engines. In this work, the flow characteristics and time-averaged pressure drop caused by a jet pump in turbulent oscillatory flow are investigated through numerical simulation. Through the analysis of the dimensionless governing equations, the emphasis is put on the effects of Womersley number and maximum acoustic Reynolds number on the performance of the jet pump. Meanwhile, the steady flow resistance coefficients are also measured numerically. The results indicate that the oscillatory flow resistance coefficients are relatively insensitive to Womersley number when it is less than 46. Moreover, the oscillatory flow resistance coefficients agree well with the steady state flow results, which validate the quasi-static assumption in turbulent oscillatory flow. However, further increasing Womersley number will lead to a reduction in the time-averaged pressure drop. The simulation method and results, as well as the hydrodynamic mechanism beneath the results, are presented and discussed in detail.

18.
J Vis Exp ; (147)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31107453

RESUMO

To detect rabies virus and other member species of the genus Lyssavirus within the family Rhabdoviridae, the pan-lyssavirus nested reverse transcription polymerase chain reaction (nested RT-PCR) was developed to detect the conserved region of the nucleoprotein (N) gene of lyssaviruses. The method applies reverse transcription (RT) using viral RNA as template and oligo (dT)15 and random hexamers as primers to synthesize the viral complementary DNA (cDNA). Then, the viral cDNA is used as a template to amplify an 845 bp N gene fragment in first-round PCR using outer primers, followed by second-round nested PCR to amplify the final 371 bp fragment using inner primers. This method can detect different genetic clades of rabies viruses (RABV). The validation, using 9,624 brain specimens from eight domestic animal species in 10 years of clinical rabies diagnoses and surveillance in China, showed that the method has 100% sensitivity and 99.97% specificity in comparison with the direct fluorescent antibody test (FAT), the gold standard method recommended by the World Health Organization (WHO) and the World Organization for Animal Health (OIE). In addition, the method could also specifically amplify the targeted N gene fragment of 15 other approved and two novel lyssavirus species in the 10th Report of the International Committee on Taxonomy of Viruses (ICTV) as evaluated by a mimic detection of synthesized N gene plasmids of all lyssaviruses. The method provides a convenient alternative to FAT for rabies diagnosis and has been approved as a National Standard (GB/T36789-2018) of China.

19.
J Phys Condens Matter ; 31(34): 345303, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31100744

RESUMO

Using density function theory combined with the non-equilibrium Green's function method, the thermoelectric properties of para-Xylene-based molecular devices are investigated. It is found that destructive quantum interference can be triggered in n-type of para-connected para-Xylene-based molecular device and can obviously enhance the thermoelectric performance of the devices. Moreover, bridge atom electrophilic substitution can significantly improve the thermoelectric properties of p-type monolayer molecular device. The ZT value of p-type monolayer molecular device with doped electrodes can be optimized to 2.2 at 300 K and 2.8 at 500 K, and n-type bilayer molecular device can achieve the value of 1.2 at 300 K and 2.0 at 500 K. These results offer the information to design the complete molecular thermoelectric device with p-type and n-type of components and to promote the thermoelectric properties of bilayer molecular junctions by employing destructive quantum interference effects.

20.
Sheng Li Xue Bao ; 71(2): 225-234, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31008482

RESUMO

The autonomic nervous system consists of the sympathetic nervous system and the parasympathetic nervous system. These two systems control the heart and work in a reciprocal fashion to modulate myocardial energy metabolism, heart rate as well as blood pressure. Multiple cardiac pathological conditions are accompanied by autonomic imbalance, characterized by sympathetic overactivation and parasympathetic inhibition. Studies have shown that overactive sympathetic nervous system leads to increased cardiac inflammatory reaction. Orchestrated inflammatory response serves to clear dead cardiac tissue and activate reparative process, whereas excessive inflammation may result in pathological cardiac remodeling. Since the discovery of the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic anti-inflammatory pathway (CAP), the protective effects of the parasympathetic nervous system in cardiac inflammation have attracted more attention recently. In this review, we summarized the role and underlying mechanisms of the sympathetic and parasympathetic nervous systems in cardiac inflammation, in order to provide new insight into cardiac inflammatory response in cardiovascular diseases.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Coração/fisiopatologia , Inflamação/fisiopatologia , Sistema Nervoso Parassimpático/fisiologia , Humanos , Receptor Nicotínico de Acetilcolina alfa7/fisiologia
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