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1.
Mol Genet Genomics ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32162118

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) and coronary artery disease (CAD), respectively. Nevertheless, these studies were generally performed for single-trait/disease and failed to assess the pleiotropic role of the identified variants. To identify novel functional loci and the pleiotropic relationship between CAD and T2D, the targeted cFDR analysis on CpG-SNPs was performed by integrating two independent large and multi-centered GWASs with summary statistics of T2D (26,676 cases and 132,532 controls) and CAD (60,801 cases and 123,504 controls). Applying the cFDR significance threshold of 0.05, we observed a pleiotropic enrichment between T2D and CAD by incorporating pleiotropic effects into a conditional analysis framework. We identified 79 novel CpG-SNPs for T2D, 61 novel CpG-SNPs for CAD, and 18 novel pleiotropic loci for both traits. Among these novel CpG-SNPs, 33 of them were annotated as methylation quantitative trait locus (meQTL) in whole blood, and ten of them showed expression QTL (eQTL), meQTL, and metabolic QTL (metaQTL) effects simultaneously. To the best of our knowledge, we performed the first targeted cFDR analysis on CpG-SNPs, and our findings provided novel insights into the shared biological mechanisms and overlapped genetic heritability between T2D and CAD.

3.
BMC Vet Res ; 16(1): 76, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131821

RESUMO

BACKGROUND: Vibrio alginolyticus is an important pathogen that has to be closely monitored and controlled in the mariculture industry because of its strong pathogenicity, quick onset after infection and high mortality rate in aquatic animals. Fast, simple and specific methods are needed for on-site detection to effectively control outbreaks and prevent economic losses. The detection specificity towards the pathogenic strains has to be emphasized to facilitate pointed treatment and prevention. Polymerase chain reaction (PCR)-based molecular approaches have been developed, but their application is limited due to the requirement of complicated thermal cycling machines and trained personnel. RESULTS: A fast, simple and highly specific detection method for V. alginolyticus pathogenic strains was established based on isothermal recombinase polymerase amplification (RPA) and lateral flow dipsticks (LFD). The method targeted the virulence gene toxR, which is reported to have good coverage for V. alginolyticus pathogenic strains. To ensure the specificity of the method, the primer-probe set of the RPA system was carefully designed to recognize regions in the toxR gene that diverge in different Vibrio species but are conserved in V. alginolyticus pathogenic strains. The primer-probe set was determined after a systematic screening of amplification performance, primer-dimer formation and false positive signals. The RPA-LFD method was confirmed to have high specificity for V. alginolyticus pathogenic strains without any cross reaction with other Vibrio species or other pathogenic bacteria and was able to detect as little as 1 colony forming unit (CFU) per reaction without DNA purification, or 170 fg of genomic DNA, or 6.25 × 103 CFU/25 g in spiked shrimp without any enrichment. The method finishes detection within 30 min at temperatures between 35 °C and 45 °C, and the visual signal on the dipstick can be directly read by the naked eye. In an application simulation, randomly spiked shrimp homogenate samples were 100% accurately detected. CONCLUSIONS: The RPA-LFD method developed in this study is fast, simple, highly specific and does not require complicated equipment. This method is applicable for on-site detection of V. alginolyticus pathogenic strains for the mariculture industry.

4.
Sci Rep ; 10(1): 4293, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152362

RESUMO

Whole body lean mass (WBLM) is a heritable trait predicting sarcopenia. To identify genomic locus underlying WBLM, we performed a genome-wide association study of fat-adjusted WBLM in the Framingham Heart Study (FHS, N = 6,004), and replicated in the Kansas City Osteoporosis Study (KCOS, N = 2,207). We identified a novel locus 3p27.1 that was associated with WBLM (lead SNP rs3732593 P = 7.19 × 10-8) in the discovery FHS sample, and the lead SNP was successfully replicated in the KCOS sample (one-sided P = 0.04). Bioinformatics analysis found that this SNP and its adjacent SNPs had the function of regulating enhancer activity in skeletal muscle myoblasts cells, further confirming the regulation of WBLM by this locus. Our finding provides new insight into the genetics of WBLM and enhance our understanding of sarcopenia.

5.
CNS Neurosci Ther ; 26(4): 416-429, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32154670

RESUMO

INTRODUCTION: Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. AIM: To investigate whether P2Y6 receptor-mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. RESULTS: The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL-1α, IL-1ß, IL-6, IL-10, TNF-α, TGF-ß, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor-mediated phagocytosis. CONCLUSION: Our results indicate that P2Y6 receptor-mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

6.
Aging (Albany NY) ; 12(5): 4299-4321, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32155129

RESUMO

Brain ischemia results from cardiac arrest, stroke or head trauma. The structural basis of rescuing the synaptic impairment and cortical dysfunctions induced in the stage of ischemic-reperfusion can occur if therapeutic interventions are applied in time, but the functional basis for this resilience remains elusive. Here, we explore the changes in cortical activity and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA1 subunit in spine (sGluA1) after transient ischemia-reperfusion in vivo for 28 days. Using in vivo two-photon microscopy in the mouse somatosensory cortex, we found that the average frequency of Ca2+ transients in the spine (there was an unusual synchrony) was higher after 15 min of ischemia-reperfusion. In addition, the transient ischemia-reperfusion caused a reflective enhancement of AMPARs, which eventually restored to normal. The cortical hyperactivity (Ca2+ transients) and the increase in AMPARs were successfully blocked by an NMDA receptor antagonist. Thus, the increase of AMPARs, cortical hyperactivity and the unusual synchrony might be the reason for reperfusion injury after short-term transient ischemia.

7.
JAMA Netw Open ; 3(3): e201396, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32196104

RESUMO

Importance: Participation in cardiac rehabilitation (CR) programs at Veterans Affairs (VA) facilities is low. Most veterans receive CR through purchased care at non-VA programs. However, limited literature exists on the comparison of outcomes between VA and non-VA CR programs. Objective: To compare 1-year mortality and 1-year readmission rates for myocardial infarction or coronary revascularization between VA vs non-VA CR participants. Design, Setting, and Participants: This cohort study included 7320 patients hospitalized for myocardial infarction or coronary revascularization at the VA between 2010 and 2014 who did not die within 30 days of discharge and who participated in 2 or more CR sessions after discharge. The study excluded individuals hospitalized for ischemic heart disease after December 2014 when the VA Choice Act changed referral criteria for non-VA care. Data analysis was performed from November 2019 to January 2020. Exposures: Participation in 2 or more CR sessions within 12 months of discharge at a VA or non-VA facility. Main Outcomes and Measures: The 1-year all-cause mortality and 1-year readmission rates for myocardial infarction or coronary revascularization from date of discharge were compared between VA vs non-VA CR participants using Cox proportional hazards models with inverse probability treatment weighting. Results: The 7320 veterans with ischemic heart disease who participated in CR programs had a mean (SD) age of 65.13 (8.17) years and were predominantly white (6005 patients [82.0%]), non-Hispanic (6642 patients [91.0%]), and male (7191 patients [98.2%]). Among these 7320 veterans, 2921 (39.9%) attended a VA facility, and 4399 (60.1%) attended a non-VA CR facility. Black and Hispanic veterans were more likely to attend CR programs at VA facilities (509 patients [17.4%] and 378 patients [12.9%], respectively), whereas white veterans were more likely to attend CR programs at non-VA facilities (3759 patients [85.5%]). After inverse probability treatment weighting, rates of 1-year mortality were 1.7% among VA CR participants vs 1.3% among non-VA CR participants (hazard ratio, 1.32; 95% CI, 0.90-1.94; P = .15). Rates of readmission for myocardial infarction or revascularization during the 12 months after discharge were 4.9% among VA CR participants vs 4.4% among non-VA CR participants (hazard ratio, 1.06; 95% CI, 0.83-1.35; P = .62). Conclusions and Relevance: These findings suggest that rates of 1-year mortality and 1-year readmission for myocardial infarction or revascularization did not differ for participants in VA vs non-VA cardiac rehabilitation programs. Eligible patients with ischemic heart disease should participate in CR programs regardless of where they are provided.

8.
Research (Wash D C) ; 2020: 5618021, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110779

RESUMO

Negative Poisson's ratio (NPR), also known as "auxetic", is a highly desired property in a wide range of future industry applications. By employing molecular dynamics (MD) simulation, metal matrix nanocomposites reinforced by graphene sheets are studied in this paper. In the simulation, single crystal copper with crystal orientation [1 1 0] is selected as the matrix and an embedded-atom method (EAM) potential is used to describe the interaction of copper atoms. An aligned graphene sheet is selected as reinforcement, and a hybrid potential, namely, the Erhart-Albe potential, is used for the interaction between a pair of carbon atoms. The interaction between the carbon atom and copper atom is approximated by the Lennard-Jones (L-J) potential. The simulation results showed that both graphene and copper matrix possess in-plane NPRs. The temperature-dependent mechanical properties of graphene/copper nanocomposites with in-plane NPRs are obtained for the first time.

9.
Nat Plants ; 6(2): 78-87, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32055044

RESUMO

Wheat and barley evolved from large-seeded annual grasses in the arid, low latitudes of Asia; their spread into higher elevations and northern latitudes involved corresponding evolutionary adaptations in these plants, including traits for frost tolerance and shifts in photoperiod sensitivity. The adaptation of farming populations to these northern latitudes was also a complex and poorly understood process that included changes in cultivation practices and the varieties of crops grown. In this article, we push back the earliest dates for the spread of wheat and barley into northern regions of Asia as well as providing earlier cultural links between East and West Asia. The archaeobotanical, palynological and anthracological data we present come from the Tongtian Cave site in the Altai Mountains, with a punctuated occupation dating between 5,200 and 3,200 calibrated years BP, coinciding with global cooling of the middle-late Holocene transition. These early low-investment agropastoral populations in the north steppe area played a major role in the prehistoric trans-Eurasian exchange.

10.
iScience ; 23(2): 100847, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-32058959

RESUMO

Osteoporosis is characterized by low bone mineral density (BMD). The advancement of high-throughput technologies and integrative approaches provided an opportunity for deciphering the mechanisms underlying osteoporosis. Here, we generated genomic, transcriptomic, methylomic, and metabolomic datasets from 119 subjects with high (n = 61) and low (n = 58) BMDs. By adopting sparse multiple discriminative canonical correlation analysis, we identified an optimal multi-omics biomarker panel with 74 differentially expressed genes (DEGs), 75 differentially methylated CpG sites (DMCs), and 23 differential metabolic products (DMPs). By linking genetic data, we identified 199 targeted BMD-associated expression/methylation/metabolite quantitative trait loci (eQTLs/meQTLs/metaQTLs). The reconstructed networks/pathways showed extensive biomarker interactions, and a substantial proportion of these biomarkers were enriched in RANK/RANKL, MAPK/TGF-ß, and WNT/ß-catenin pathways and G-protein-coupled receptor, GTP-binding/GTPase, telomere/mitochondrial activities that are essential for bone metabolism. Five biomarkers (FADS2, ADRA2A, FMN1, RABL2A, SPRY1) revealed causal effects on BMD variation. Our study provided an innovative framework and insights into the pathogenesis of osteoporosis.

11.
Commun Biol ; 3(1): 39, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969651

RESUMO

Osteoporosis is a highly prevalent chronic aging-related disease that frequently is only detected after fracture. We hypothesized that aminobutyric acids could serve as biomarkers for osteoporosis. We developed a quick, accurate, and sensitive screening method for aminobutyric acid isomers and enantiomers yielding correlations with bone mineral density (BMD) and osteoporotic fracture. In serum, γ-aminobutyric acid (GABA) and (R)-3-aminoisobutyric acid (D-BAIBA) have positive associations with physical activity in young lean women. D-BAIBA positively associated with hip BMD in older individuals without osteoporosis/osteopenia. Lower levels of GABA were observed in 60-80 year old women with osteoporotic fractures. Single nucleotide polymorphisms in seven genes related to these metabolites associated with BMD and osteoporosis. In peripheral blood monocytes, dihydropyrimidine dehydrogenase, an enzyme essential to D-BAIBA generation, exhibited positive association with physical activity and hip BMD. Along with their signaling roles, BAIBA and GABA might serve as biomarkers for diagnosis and treatments of osteoporosis.

12.
Am J Reprod Immunol ; 83(4): e13223, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31972050

RESUMO

The survival and development of a semi-allogeneic fetus during pregnancy require the involvement of a series of cytokines and immune cells. Chemokines are a type of special cytokine those were originally described as having a role in leukocyte trafficking. CXC chemokine ligand (CXCL) 16 is a member of the chemokine family, and CXC chemokine receptor (CXCR) 6 is its sole receptor. Emerging evidence has shown that CXCL16/CXCR6 is expressed at the maternal-fetal interface, by cell types that include trophoblast cells, decidual stroma cells, and decidual immune cells (eg, monocytes, γδT cells, and natural killer T (NKT) cells). The regulation of expression of CXCL16 is quite complex, and this process involves a multitude of factors. CXCL16 exerts a critical role in the establishment of a successful pregnancy through a series of molecular interactions at the maternal-fetal interface. However, an abnormal expression of CXCL16 is associated with certain pathological states associated with pregnancy, including recurrent miscarriage, pre-eclampsia, and gestational diabetes mellitus (GDM). In the present review, the expression and pleiotropic roles of CXCL16 under conditions of physiological and pathological pregnancy are systematically discussed.

13.
Epigenetics ; : 1-22, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31975641

RESUMO

A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

14.
BMJ Open ; 10(1): e032096, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948986

RESUMO

INTRODUCTION: Essential tremor (ET), a tremor disorder, is one of the most common movement disorders. Only oral drugs (propranolol, primidone, topiramate, etc)are still the first-line treatment recommended by the Food and Drug Administration. Propranolol is thought to potentially reduce upper limb action tremor. However, it has a poor effect on axial tremor symptoms, such as essential head tremor and voice tremor. Studies have shown that tremor severity develops over time, possibly producing other clinical tremors and neurological soft signs (such as memory loss, gait abnormalities, balance disorders, etc), which further increases the difficulty of treating tremors. However, some recent studies provide emerging evidence for oral propranolol on subgroups of ET, which is based on the anatomical distribution of ET (lower extremities, head, sound, tongue, etc). This systematic review aims to synthesise these new data to improve the efficacy of propranolol in ET subgroups. METHODS AND ANALYSIS: We will search for randomised controlled trials from the PubMed, MEDLINE, EMBASE, Cochrane Library, UptoDate and PEDro databases from inception to June 2019. All data will be extracted independently by two reviewers and compared at the end of the review. The two reviewers will screen the study quality, and the Cochrane Collaboration's tool in Review Manager (RevMan) V.5.3.3 will be used to evaluate risk of bias. Our primary outcome will be the functional disability component related to tremors, as measured by the Fahn-Tolosa-Marin Tremor Rating Scale subscales B and C. Secondary outcomes will include severity of tremors and quality of life. Narrative and meta-analytical syntheses are planned. ETHICS AND DISSEMINATION: Published aggregated data will be used in this review analysis and therefore no ethical approval is required. The results will be published in peer-reviewed journals, and proliferation activities will include diverse social stakeholders, non-academic groups and patients. PROSPERO REGISTRATION NUMBER: CRD42018112580.

15.
Sci Rep ; 10(1): 629, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959855

RESUMO

We present a 2.2 GHz modulated, 1.27 kW output power, monolithic fiber amplifier based on pseudo-random binary sequence (PRBS) phase modulation. The spectral line spacing of maximizing the threshold enhancement factor (plateau of trend) was found by theoretical simulation. The spectral line spacing was adjusted to 12.7 MHz by a pattern length of n = 9, which is close to the plateau of trend in the proposed architecture. A 2.2 GHz low-pass radio frequency filter was used to control the FWHM of the seed. A four-stage Yb-doped fiber amplifier chain was established to boost a distributed Bragg reflector (DBR) laser and a distributed feedback (DFB) diode laser to 1.2 kW and 1.27 kW with a backward reflectively of <1‰, which shows a good suppression of SBS effect.

16.
Respir Res ; 21(1): 22, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931796

RESUMO

Airway remodeling consists of the structural changes of airway walls, which is often considered the result of longstanding airway inflammation, but it may be present to an equivalent degree in the airways of children with asthma, raising the need for early and specific therapeutic interventions. The arachidonic acid cytochrome P-450 (CYP) pathway has thus far received relatively little attention in its relation to asthma. In this study, we studied the inhibition of soluble epoxide hydrolase (sEH) on airway remodeling and hyperresponsiveness (AHR) in a chronic asthmatic model which long-term exposure to antigen over a period of 12 weeks. The expression of sEH and CYP2J2, the level of 14, 15-epoxyeicosatrienoic acids (EETs), airway remodeling, hyperresponsiveness and inflammation were analyzed to determine the inhibition of sEH. The intragastric administration of 3 or 10 mg/kg ZDHXB-101, which is a structural derivative of natural product honokiol and a novel soluble epoxide hydrolase (sEH) inhibitor, daily for 9 weeks significantly increased the level of 14, 15-EETs by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. ZDHXB-101 reduced the expression of remodeling-related markers such as interleukin (IL)-13, IL-17, MMP-9 N-cadherin, α-smooth muscle actin, S100A4, Twist, goblet cell metaplasia, and collagen deposition in the lung tissue or in bronchoalveolar lavage fluid. Moreover, ZDHXB-101 alleviated AHR, which is an indicator that is used to evaluate the airway remodeling function. The inhibitory effects of ZDHXB-101 were demonstrated to be related to its direct inhibition of the extracellular signal-regulated kinase (Erk1/2) phosphorylation, as well as inhibition of c-Jun N-terminal kinases (JNK) and the signal transducer and activator of transcription-3 (STAT3) signal transduction. These findings first revealed the anti-remodeling potential of ZDHXB-101 lead in chronic airway disease.

17.
Cancer Lett ; 470: 75-83, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655086

RESUMO

Disordered lipid metabolisms have been evidenced in lung cancer as well as its subtypes. Lipidomics with in-depth mining is considered as a critical member of the multiple omics family and a lipid-specific tool to understand disease-associated lipid metabolism and disease-specific dysfunctions of lipid species, discover biomarkers and targets for monitoring therapeutic strategies, and provide insights into lipid profiling and pathophysiological mechanisms in lung cancer. The present review describes the characters and patterns of lipidomic profiles in patients with different lung cancer subtypes, important values of comprehensive lipidomic profiles in understanding of lung cancer heterogeneity, urgent needs of standardized methodologies, potential mechanisms by lipid-associated enzymes and proteins, and the importance of integration between clinical phenomes and lipidomic profiles. The characteristics of lipidomic profiles in different lung cancer subtypes are extremely varied among study designs, objects, methods, and analyses. Preliminary data from recent studies demonstrate the specificity of lipidomic profiles specific for lung cancer stage, severity, subtype, and response to drugs. The heterogeneity of lipidomic profiles and lipid metabolism may be part of systems heterogeneity in lung cancer and be responsible for the development of drug resistance, although there are needs for direct evidence to show the existence of intra- or inter-lung cancer heterogeneity of lipidomic profiles. With an increasing understanding of expression profiles of genes and proteins, lipidomic profiles should be associated with activities of enzymes and proteins involved in the processes of lipid metabolism, which can be profiled with genomics and proteomics, and to provide the opportunity for the integration of lipidomic profiles with gene and protein expression profiles. The concept of clinical trans-omics should be emphasized to integrate data of lipidomics with clinical phenomics to identify disease-specific and phenome-specific biomarkers and targets, although there are still a large number of challenges to be overcome in the integration between clinical phenomes and lipidomic profiles.

18.
Genes Genomics ; 42(2): 127-133, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31736008

RESUMO

OBJECTIVES: MUC16 (mucin 16, also known as CA-125, cancer antigen 125, carcinoma antigen 125, or carbohydrate antigen 125) has been predicted as tumor biomarker for therapy. We determined to investigate effects and regulatory mechanism of MUC16 on cervical tumorigenesis. METHODS: Expression levels of MUC16 in cervical cancer cell lines was analyzed via qRT-PCR (quantitative real-time polymerase chain reaction). Knockdown of MUC16 was conducted via shRNA (Short hairpin RNA) transfection. MTT and colony formation assays were used to investigate effect of MUC16 on cell proliferation. Wound healing assay was utilized to detect migration and transwell assay to detect invasion. The underlying mechanism was demonstrated via western blot analysis. RESULTS: MUC16 was elevated in cervical cancer cell lines. MUC16 knockdown inhibited cell proliferation, invasion and migration. Gain- and loss-of functional assays revealed that over-expression of MUC16 activated Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) via phosphorylation, thus facilitating cyclooxygenase-2 (COX-2) expression, while knockdown of MUC16 demonstrated the reverse effect on JAK2/STAT3 activation and COX-2 expression. Moreover, inhibition of JAK2/STAT3 attenuated the regulation of MUC16 on COX-2. CONCLUSIONS: MUC16 enhanced proliferation and invasion of cervical cancer cells via JAK2/STAT3 phosphorylation-mediated cyclooxygenase-2 expression, suggesting the potential therapeutic target ability of MUC16 to treat cervical cancer.

19.
Nat Rev Endocrinol ; 16(2): 91-103, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31792439

RESUMO

Osteoporosis is a highly prevalent disorder characterized by low bone mineral density and an increased risk of fracture, termed osteoporotic fracture. Notably, bone mineral density, osteoporosis and osteoporotic fracture are highly heritable; however, determining the genetic architecture, and especially the underlying genomic and molecular mechanisms, of osteoporosis in vivo in humans is still challenging. In addition to susceptibility loci identified in genome-wide association studies, advances in various omics technologies, including genomics, transcriptomics, epigenomics, proteomics and metabolomics, have all been applied to dissect the pathogenesis of osteoporosis. However, each technology individually cannot capture the entire view of the disease pathology and thus fails to comprehensively identify the underlying pathological molecular mechanisms, especially the regulatory and signalling mechanisms. A change to the status quo calls for integrative multi-omics and inter-omics analyses with approaches in 'systems genetics and genomics'. In this Review, we highlight findings from genome-wide association studies and studies using various omics technologies individually to identify mechanisms of osteoporosis. Furthermore, we summarize current studies of data integration to understand, diagnose and inform the treatment of osteoporosis. The integration of multiple technologies will provide a road map to illuminate the complex pathogenesis of osteoporosis, especially from molecular functional aspects, in vivo in humans.

20.
Immunol Invest ; 49(1-2): 81-87, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31401905

RESUMO

BACKGROUND: Interleukin (IL)-34 is a new pro-inflammatory cytokine. Previous studies showed that IL-34 plays a key role in inflammation and osteoporosis in rheumatoid arthritis (RA). However, whether IL-34 participates in angiogenesis in RA remains unknown. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) play critical roles in the angiogenesis of RA. METHODS: 22 patients with RA, 18 patients with ankylosing spondylitis (AS), and 8 healthy subjects were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated and purified from peripheral blood by density gradient centrifugation. PBMCs were stimulated using anti-CD3/CD28 antibody and different concentrations of recombinant human (rh) IL-34 (0, 10, 20, 50, 100 ng/mL). Cell-free supernatants were collected after 72 h incubation, and VEGF and HIF-1α levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: IL-34 promotes the secretion of VEGF and HIF-1α by PBMCs in RA patients in a dose-dependent manner. In contrast, IL-34 has no effect on VEGF and HIF-1α secretion by PBMCs in AS and healthy controls. CONCLUSION: IL-34 may indirectly contribute to angiogenesis by promoting the production of VEGF and HIF-1α and participate in the pathogenesis of RA.

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