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1.
Sci Rep ; 10(1): 75, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919417

RESUMO

The role of laparoscopic surgery for left-sided colon cancer has been supported by the results of randomized controlled trials. However, its benefits and disadvantages in the real world setting should be further assessed with population-based studies.The hospitalization data of patients undergoing open or laparoscopic surgery for left-sided colon cancer were sourced from the Taiwan National Health Insurance Research Database. Patient and hospital characteristics and perioperative outcomes including length of hospital stay, operation time, opioid use, blood transfusion, intensive care unit (ICU) admission, and use of mechanical ventilation were compared. The overall survival was also assessed. Patients undergoing laparoscopic surgery had shorter hospital stay (p < 0.0001) and less demand for opioid analgesia (p = 0.0005). Further logistic regression revealed that patients undergoing open surgery were 1.70, 2.89, and 3.00 times more likely to have blood transfusion, to be admitted to ICU, and to use mechanical ventilation than patients undergoing laparoscopic surgery. Operations performed in medical centers were also associated with less adverse events. The overall survival was comparable between the 2 groups.With adequate hospital quality and volume, laparoscopic surgery for left-sided colon cancer was associated with improved perioperative outcomes. The long-term survival was not compromised.

2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 1-4, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922584

RESUMO

OBJECTIVE: To explore susceptibility genes for autism spectrum disorders (ASD). METHODS: Whole-exome sequencing was carried out for 60 family trios affected with sporadic ASD. Genetic variants discovered in over 10% of the patients were selected for genotype-phenotype correlation and pathway enrichment analysis using Phenolyzer software and metascape database. Combining gene-phenotypic scores, pathway-related genes associated with neural and neurite triggering were screened for the candidates. RESULTS: A total of 170 common variants were found to be associated with the ASD phenotype. Among these, there was only one high-confidence gene [SHANK2(0.8146)] and four medium-confidence genes [ERBB2(0.1322), LAMC3(0.1117), PPFIA4(0.1059), DISC1(0.1002)]. Twenty-pathways and four biological processes were found to be statistically significant by pathway enrichment analysis, which included neuron projection morphogenesis (GO: 0048812), regulation of neuroblast proliferation (GO: 1902692), modulation of excitatory postsynaptic potential (GO: 0098815), and dendrite morphogenesis (GO: 0048813). Twenty-one genes were found to be closely associated with neurological and neurite triggering, among which only SHANK2, ERBB2, and DISC1 had above-medium confidence correlation scores with the ASD phenotypes. CONCLUSION: Abnormal neuron projection morphogenesis (GO: 0048812) may be closely related to the occurrence of ASD. SHANK2, ERBB2, and DISC1 are susceptibility genes for ASD.

3.
RNA Biol ; : 1-13, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31888402

RESUMO

Dysregulation of gene expression, often interpreted by gene transcription as an endpoint response, is tightly associated with human cancer. Long noncoding RNAs (lncRNAs), derived from the noncoding elements in the genome and appeared no less than 200nt in length, have emerged as a novel class of pivotal regulatory component. Recently, great attention has been paid to the cancer-related lncRNAs and growing evidence have shown that lncRNAs act as key transcriptional regulators in cancer cells through diverse mechanisms. Here, we focus on the nucleus-expressed lncRNAs and summarize their molecular mechanisms in transcriptional control during tumorigenesis and cancer metastasis. Six major mechanisms will be discussed in this review: association with transcriptional factor, modulating DNA methylation or histone modification enzyme, influencing on chromatin remodelling complex, facilitating chromosomal looping, interaction with RNA polymerase and direct association with promoter.

4.
Nucleic Acids Res ; 48(D1): D189-D197, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31906603

RESUMO

Research on RNA-associated interactions has exploded in recent years, and increasing numbers of studies are not limited to RNA-RNA and RNA-protein interactions but also include RNA-DNA/compound interactions. To facilitate the development of the interactome and promote understanding of the biological functions and molecular mechanisms of RNA, we updated RAID v2.0 to RNAInter (RNA Interactome Database), a repository for RNA-associated interactions that is freely accessible at http://www.rna-society.org/rnainter/ or http://www.rna-society.org/raid/. Compared to RAID v2.0, new features in RNAInter include (i) 8-fold more interaction data and 94 additional species; (ii) more definite annotations organized, including RNA editing/localization/modification/structure and homology interaction; (iii) advanced functions including fuzzy/batch search, interaction network and RNA dynamic expression and (iv) four embedded RNA interactome tools: RIscoper, IntaRNA, PRIdictor and DeepBind. Consequently, RNAInter contains >41 million RNA-associated interaction entries, involving more than 450 thousand unique molecules, including RNA, protein, DNA and compound. Overall, RNAInter provides a comprehensive RNA interactome resource for researchers and paves the way to investigate the regulatory landscape of cellular RNAs.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31912200

RESUMO

Clonorchis sinensis (C. sinensis), an important fishborne zoonotic parasite threatening public health, is of major socioeconomic importance in epidemic areas. Effective strategies are still urgently expected to prevent against C. sinensis infection. In the present study, paramyosin of C. sinensis (CsPmy) was stably and abundantly expressed on the surface of Bacillus subtilis spores. The recombinant spores (B.s-CotC-CsPmy) were incorporated in the basal pellets diet in three different dosages (1 × 105, 1 × 108, 1 × 1011 CFU/g pellets) and orally administrated to grass carp (Ctenopharyngodon idella). The immune responses and intestinal microbiota in the treated grass carp were investigated. Results showed that specific anti-CsPmy IgM levels in sera, skin mucus, bile, and intestinal mucus, as well as mRNA levels of IgM and IgZ in the spleen and head kidney, were significantly increased in B.s-CotC-CsPmy-1011 group. Besides, transcripts levels of IL-8 and TNF-αin the spleen and head kidney were also significantly elevated than the control groups. Moreover, mRNA levels of tight junction proteins in the intestines of B.s-CotC-CsPmy-1011 group increased. Potential pathogenetic bacteria with lower abundance and higher abundances of candidate probiotics and bacteria associated with digestion in 1 × 1011 CFU/g B.s-CotC-CsPmy spores administrated fishes could be detected compared with control group. The amount of metacercaria in per gram fish flesh was statistically decreased in 1 × 1011 CFU/g B.s-CotC-CsPmy spores orally immunized group. Our work demonstrated that B. subtilis spores presenting CsPmy on the surface could be a promising effective, safe, and needle-free candidate vaccine against C. sinensis infection for grass carp.

6.
Chem Soc Rev ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913386

RESUMO

Correction for 'Voltage issue of aqueous rechargeable metal-ion batteries' by Zhuoxin Liu et al., Chem. Soc. Rev., 2020, DOI: 10.1039/c9cs00131j.

7.
Theranostics ; 10(2): 553-566, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903137

RESUMO

Mitochondrial dysfunction is involved in the pathogenesis of various cardiovascular disorders. Although mitochondrial dynamics, including changes in mitochondrial fission and fusion, have been implicated in the development of cardiac hypertrophy, the underlying molecular mechanisms remain mostly unknown. Here, we show that NFATc3, miR-153-3p, and mitofusion-1 (Mfn1) constitute a signaling axis that mediates mitochondrial fragmentation and cardiomyocyte hypertrophy. Methods: Isoprenaline (ISO) was used to stimulate the hypertrophic response and mitochondrial fragmentation in cultured cardiomyocytes and in vivo. We performed immunoblotting, immunofluorescence, and quantitative real-time PCR to validate the function of Mfn1 in cardiomyocyte hypertrophy. Bioinformatic analyses, a luciferase reporter assay, and gain- and loss-of-function studies were used to demonstrate the biological function of miR-153-3p, which regulates mitochondrial fragmentation and hypertrophy by targeting Mfn1. Moreover, ChIP-qPCR and a luciferase reporter assay were performed to identify transcription factor NFATc3 as an upstream regulator to control the expression of miR-153-3p. Results: Our results show that ISO promoted mitochondrial fission and enhanced the expression of miR-153-3p in cardiomyocytes. Knockdown of miR-153-3p attenuated ISO-induced mitochondrial fission and hypertrophy in cultured primary cardiomyocytes. miR-153-3p suppression inhibited mitochondrial fragmentation in ISO-induced cardiac hypertrophy in a mouse model. We identified direct targeting of Mfn1, a key protein of the mitochondrial fusion process, by miR-153-3p. Also, miR-153-3p promoted ISO-induced mitochondrial fission by suppressing the translation of Mfn1. We further found that NFATc3 activated miR-153-3p expression. Knockdown of NFATc3 inhibited miR-153-3p expression and blocked mitochondrial fission and hypertrophic response in cardiomyocytes. Conclusions: Our data revealed a novel signaling pathway, involving NFATc3, miR-153-3p, and Mfn1, which could be a therapeutic target for the prevention and treatment of cardiac hypertrophy.

8.
Medicine (Baltimore) ; 99(1): e18571, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895801

RESUMO

BACKGROUND: There is a growing literature on the significance of systemic immune-inflammation index in hepatocellular carcinoma. However, the results were inconsistent due to the small sample size and different study endpoints. Therefore, the purpose of this study was to further systematically and comprehensively verify the prognostic role of the SII in HCC. METHODS: Several databases were searched systematically, and relevant papers were selected. The main outcome measure was overall survival (OS); the secondary outcome measure was a composite of time to recurrence (TTR), progression-free survival (PFS), and recurrence-free survival (RFS). RESULTS: Ten published retrospective studies involving 2796 HCC patients were included. The results revealed that elevated pre-treatment SII was related to lower OS (HR:1.54, P < .001) and earlier TTR (HR:1.77, P < .001). CONCLUSIONS: Elevated SII is a poor prognostic factor for patients with hepatocellular carcinoma. The clinical application of SII is encouraged to evaluate the progress of hepatocellular carcinoma.

9.
Clin Sci (Lond) ; 2020 Jan 03.
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 this study, an alcoholic renal fibrosis animal model was firstly employed which mice received liquid diet containing alcohol for 4-12 weeks. The Masson's Trichrome staining analysis showed that kidney fibrosis increased at week 8 and 12 in the animal model which was further confirmed by albumin assay, Western blot, immunostaining and real-time PCR of fibrotic indexes. In vitro analysis also confirmed that alcohol significantly induced fibrotic response 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 and Smad3. 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.

10.
Anal Chim Acta ; 1096: 184-192, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883586

RESUMO

A monolithic chip incorporated with graphene oxide (GO) based on deep eutectic solvents (DESs) was developed for solid phase extraction (SPE). The carboxylated GO was modified with p-aminostyrene (pAS) by amidation, and the obtained GO (pAS-COOH-GO) was covalently incorporated into poly(butyl methacrylate-co-ethylene glycol dimethyl methacrylate) monolithic chip. Due to the high viscosity characteristics of DESs, a uniform pAS-COOH-GO incorporated monolithic chip with good permeability can be achieved. A systematic study of the preparation parameters on the performance of the resulting monolith was carried out, including the content of pAS-COOH-GO, DESs composition and porogen ratio. The resulting pAS-COOH-GO incorporated monolith was characterized by nitrogen adsorption, scanning electron microscopy, and transmission electron microscopy. The GO-doped monolithic chip can be used for SPE of polycyclic aromatic hydrocarbons (phenanthrene, anthracene, fluoranthene, pyrene, benzo(a)anthracene, benzo(a) pyrene, dibenzo(a,h)anthracene and inden(1,2,3,-cd)pyrene). The recoveries were all higher than 90%, which was about twice as high as that of the monolithic chip prepared without GO. By comparing the SPE results with that of GO free monolithic chip, good enrichment effects were demonstrated on the pAS-COOH-GO incorporated monolithic chip.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31619447

RESUMO

OBJECTIVE: To describe the detailed clinical characteristics, immunotherapy, and long-term outcomes of patients with anti-NMDA receptor (NMDAR) encephalitis in China. METHODS: A single-center, prospective study. Patients who met the diagnostic criteria were enrolled from 2011 to 2017 and followed up. The clinical features, treatment, and long-term outcomes were collected prospectively. Factors affecting the long-term prognosis were analyzed. RESULTS: The study included 220 patients. The most common clinical presentations were psychosis (82.7%) and seizures (80.9%). Of the patients, 19.5% had an underlying neoplasm; of which ovarian teratoma was 100% of tumors in females and only one male had lung cancer. Most patients (99.5%) received first-line therapy (glucocorticoids, IV immunoglobulin, or plasmapheresis alone or combined), and only 7.3% received second-line immunotherapy (rituximab, cyclophosphamide alone, or combined). Long-term immunotherapy (mycophenolate mofetil or azathioprine >1 year) was administered to 53.2% of patients. During the first 12 months, 207 (94.1%) patients experienced improvement, and 5 (2.3%) died, whereas 38 (17.3%) experienced relapses. At 12-month follow-up, 92.7% had favorable clinical outcomes (modified Rankin Scale score ≤2). CONCLUSIONS: Patients in China present with psychosis and seizure frequently but have a low percentage of underlying neoplasms. Re-enforced first-line immunotherapy is effective in managing anti-NMDAR encephalitis in the acute phase. Although relapse is relatively common, with combined first-line and long-term immunotherapy, most patients reached favorable outcomes.

12.
Nanoscale ; 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31833533

RESUMO

A near-infrared (NIR) fluorescent nanoprobe that enables to circumvent the interference of background absorption and fluorescence in whole blood was developed for the direct sensing of blood glucose. Here, NIR fluorescent protein (iRFP) and glucose oxidase (GOx) were collectively deployed as the templates for the biomineralization of Mn2+ to prepare a NIR fluorescent nanoprobe (iRFP-GOx-MnO2 nanoparticles, iRGMs), in which the fluorescence of iRFP was effectively quenched by MnO2 via energy transfer. When the iRGMs were mixed with whole blood samples, GOx can convert blood glucose into gluconic acid, as well as H2O2, which will reduce MnO2 and decompose the iRGMs. As a result, the NIR fluorescence of iRFPs was restored, providing a fluorometric assay for the direct detection of blood glucose. Owing to the high efficiency of the cascade reaction and the low background interference of the NIR fluorescence signal, accurate and rapid analysis of the glucose levels in whole blood samples was achieved using the iRGMs. Moreover, an iRGM-based paper device that only requires 5 microliters of samples was also demonstrated in the direct assay of blood glucose without any pretreatment, affording an alternative approach for the accurate monitoring of blood glucose levels.

13.
Eur J Med Chem ; 187: 111913, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31837501

RESUMO

In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aß activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 µM) and cellular damage induced by H2O2 (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 µM) or Aß (astrocytes protection = 70.2 ± 6.5%, 10 µM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aß42 and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1ß, IL-6 and TNF-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H2O2-induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aß activities.

14.
J Mol Neurosci ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31838722

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. Whole-exome sequencing studies have shown that de novo single-nucleotide variations (SNVs) play an important role in sporadic ASD. The present study aimed to search for de novo SNVs using whole-exome sequencing in 59 unrelated Chinese ASD sporadic trios, and found 24 genes (including five reported ASD candidate genes CACNA1D, ACHE, YY1, TTN, and FBXO11) with de novo harmful SNVs. Five genes (CACNA1D, JAK2, ACHE, MAPK7, and PRKAG2) classified as "medium-confidence" genes were found to be related to ASD using the Phenolyzer gene analysis tool, which predicts the correlation between the candidate genes and the ASD phenotype. De novo SNVs in JAK2, MAPK7, and PRKAG2 were first found in ASD. Both JAK2 and MAPK7 were involved in the regulation of the MAPK signaling pathway. Gene co-expression and inter-gene interaction networks were constructed and gene expression data in different brain regions were further extracted, revealing that JAK2 and MAPK7 genes were associated with certain previously reported ASD genes and played an important role in early brain development. The findings of this study suggest that the aforementioned five reported ASD genes and JAK2 and MAPK7 may be related to ASD susceptibility. Further investigations of expression studies in cellular and animal models are needed to explore the mechanism underlying the involvement of JAK2 and MAPK7 in ASD.

15.
Vet Res ; 50(1): 109, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831050

RESUMO

The function of Autoinducer-2 (AI-2) which acts as the signal molecule of LuxS-mediated quorum sensing, is regulated through the lsr operon (which includes eight genes: lsrK, lsrR, lsrA, lsrC, lsrD, lsrB, lsrF, and lsrG). However, the functions of the lsr operon remain unclear in avian pathogenic Escherichia coli (APEC), which causes severe respiratory and systemic diseases in poultry. In this study, the presence of the lsr operon in 60 APEC clinical strains (serotypes O1, O2, and O78) was investigated and found to be correlated with serotype and has the highest detection rate in O78. The AI-2 binding capacity of recombinant protein LsrB of APEC (APEC-LsrB) was verified and was found to bind to AI-2 in vitro. In addition, the lsr operon was mutated in an APEC strain (APEC94Δlsr(Cm)) and the mutant was found to be defective in motility and AI-2 uptake. Furthermore, deletion of the lsr operon attenuated the virulence of APEC, with the LD50 of APEC94Δlsr(Cm) decreasing 294-fold compared with wild-type strain APEC94. The bacterial load in the blood, liver, spleen, and kidneys of ducks infected with APEC94Δlsr(Cm) decreased significantly (p < 0.0001). The results of transcriptional analysis showed that 62 genes were up-regulated and 415 genes were down-regulated in APEC94Δlsr(Cm) compared with the wild-type strain and some of the down-regulated genes were associated with the virulence of APEC. In conclusion, our study suggests that lsr operon plays a role in the pathogenesis of APEC.

16.
Foods ; 8(12)2019 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-31817958

RESUMO

The seasonal changes in the chemical composition of Olea europaea leaves from January to December at Liangshan (China) have been investigated. The highest total phenolic content (TPC), total flavonoid content (TFC), and free amino acid content (FAAC) levels were found in May and December, while the lowest levels were detected in April and September. The soluble protein content (SPC) and the soluble sugar content (SSC) were highest in spring but lowest in summer and winter. The levels of major phenolic compounds, including oleuropein, and luteolin-4'-O-glucoside, followed by apigenin-7-O-glucoside, quercetin, rutin, luteolin, and apigenin, increased during spring and winter but decreased during summer and autumn. In addition, phenolic extracts (PEs) showed dose-dependent antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and superoxide radical scavenging activity assays; the reducing power was tested. The anticancer activities of PE at various concentrations were assessed by a cell counting kit-8 (CCK-8), and the IC50 (50% effective concentration) to HEK293, HeLa, and S180 cells were 841.48, 7139, and 457.69 µg/mL, respectively. PE-treated S180 cells inhibited proliferation through activation of caspase-3/9 and disruption of the mitochondrial membrane potential. Thus, PE in Liangshan olive leaves possessed strong antioxidant and anticancer potential, and spring and winter were determined as optimal harvesting seasons.

17.
Int J Chron Obstruct Pulmon Dis ; 14: 2563-2573, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819394

RESUMO

Background: Pseudomonas aeruginosa (PA) colonization confers poor prognosis in bronchiectasis. However, the biomarkers and biological pathways underlying these associations are unclear. Objective: To identify the roles of PA colonization in bronchiectasis by exploring for sputum exosomal microRNA profiles. Methods: We enrolled 98 patients with clinically stable bronchiectasis and 17 healthy subjects. Sputum was split for bacterial culture and exosomal microRNA sequencing, followed by validation with quantitative polymerase chain reaction. Bronchiectasis patients were stratified into PA and non-PA colonization groups based on sputum culture findings. We applied Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis to explore biological pathways corresponding to the differentially expressed microRNAs (DEMs) associated with PA colonization. Results: Eighty-two bronchiectasis patients and 9 healthy subjects yielded sufficient sputum that passed quality control. We identified 10 overlap DEMs for the comparison between bronchiectasis patients and healthy subjects, and between PA and non-PA colonization group. Both miR-92b-5p and miR-223-3p could discriminate PA colonization (C-statistic >0.60) and independently correlated with PA colonization in multiple linear regression analysis. The differential expression of miR-92b-5p was validated by quantitative polymerase chain reaction (P<0.05), whereas the differential expression of miR-223 trended towards statistical significance (P=0.06). These DEMs, whose expression levels correlated significantly with sputum inflammatory biomarkers (interleukin-1ß and interleukin-8) level, were implicated in the modulation of the nuclear factor-κB, phosphatidylinositol and longevity regulation pathways. Conclusion: Sputum exosomal microRNAs are implicated in PA colonization in bronchiectasis, highlighting candidate targets for therapeutic interventions to mitigate the adverse impacts conferred by PA colonization.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31821039

RESUMO

We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid (SFA), and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS, and treated with or without ASMase inhibitor amitriptyline. Neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of S1P production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- Mice and indicated that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.

19.
J Clin Invest ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31821173

RESUMO

Cantu Syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can be reversed once manifest. Using combined transgenic and pharmacological approaches in a knock-in mouse model of CS, we have shown that reversal of vascular and cardiac phenotypes can be achieved (1) by genetic downregulation of KATP channel activity specifically in VSM, and (2) by chronic administration of the clinically-used KATP channel inhibitor, glibenclamide. These findings demonstrate (i) that VSM KATP channel GoF underlies CS cardiac enlargement, (ii) reversibility of CS-associated abnormalities and (iii) evidence of in vivo efficacy of glibenclamide as a therapeutic agent in CS.

20.
Antiviral Res ; : 104675, 2019 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-31825852

RESUMO

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus endemic in the Asia Pacific region. Despite use of several highly effective vaccines, it is estimated that up to 44,000 new cases of Japanese encephalitis (JE) occur every year including 14,000 deaths and 24,000 survivors with permanent sequelae. Humoral immunity induced by vaccination is critical for effective protection. Potently neutralizing antibodies reactive with the JEV envelope (E) protein are important since protective immune responses induced by both live-attenuated and inactivated JE vaccines target the E protein. Our understanding of how vaccine-induced humoral immunity protects vaccinees from morbidity and mortality is, however, limited and largely obtained from in vitro studies. With the exception of neurovirulence mouse models, very few platforms are available for evaluating the protective efficacy of neutralizing antibodies against JEV in vivo. Swine are a major amplifying host in the natural JEV transmission cycle and develop multiple pathological outcomes similar to humans infected with JEV. In this study, prophylactic passive immunization was performed in a miniature swine model, using two vaccination-induced monoclonal antibodies (mAb), JEV-31 and JEV-169. These were selected as representatives for antibodies reactive with the major antigenic structures in the E protein of JEV and related flaviviruses. JEV-31 recognizes the lateral ridge of E protein domain III (EDIII) whilst JEV-169 has a broad footprint of binding involving residues throughout domains I (EDI) and II (EDII) of the E protein. Detection of neutralizing antibodies in the serum of immunized animals mimics the presence of neutralizing antibodies in vaccinated individuals. Passive immunization with both mAbs significantly reduced the severity of diseases that resemble the symptoms of human JE including fever, viremia, viral shedding, systemic infection, and neuroinvasion. In contrast to the uniformed decrease of viral loads in lymphoid and central nervous systems, distinct kinetics in the onset of fever and viremia between animals receiving JEV-31 and JEV-169 suggest potential differences in immune protection mechanisms between anti-EDI and anti-EDIII neutralizing antibodies elicited by vaccination. Our data demonstrate the feasibility of using swine models in characterizing the protective humoral immunity against JEV and increase our understanding of how clonal populations of anti-E mAbs derived from JE vaccination protect against infection in vivo.

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