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1.
Ann Hum Genet ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691269

RESUMO

Single-nucleotide polymorphisms (SNPs) in the UHRF gene have been shown to be associated with systemic lupus erythematosus (SLE) in European and Hong Kong Chinese, but statistically significant evidence for association has not been found in a mainland Han Chinese population. Therefore, we selected SNP rs13205210 located in UHRF1BP1 as a candidate association from our previously published genome-wide association study (GWAS) data of SLE (1,047 cases and 1,205 controls from a mainland Han Chinese population) to explore the association between the UHRF1BP1 gene and SLE. We conducted a large-scale replication study in an additional independent sample of 3,509 cases and 8,246 controls from a mainland Han Chinese population. Real-time PCR was used to determine gene expression differences in peripheral blood mononuclear cells (PBMCs) from cases and controls. As a result, we replicated the association between the UHRF1BP1 gene and SLE (rs13205210, missense, Pmeta   = 2.26E-17, odds ratio = 1.41) by a meta-analysis of our previous GWAS and this replication study involving a total of 4,556 cases and 9,451 controls. The UHRF1BP1 mRNA expression level in PBMCs was significantly decreased in patients with SLE compared with that in healthy controls. SNP rs13205210 exhibited an expression quantitative trait loci effect on the UHRF1BP1 gene in PBMCs from patients. In conclusion, this study not only suggests that the UHRF1BP1 gene was associated with SLE in a mainland Han Chinese population, but also implied that it might be a common genetic factor contributing to SLE susceptibility in multiple populations.

2.
Rev Esp Enferm Dig ; 1112019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31595756

RESUMO

OBJECTIVES: the aim of this study was to evaluate the prognostic significance of preoperative serum lipid in patients with gallbladder cancer (GBC). METHODS: ninety-nine patients with GBC between October 2009 and December 2013 were reviewed in this retrospective study. Total serum cholesterol (TC), total triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A (Apo-A), apolipoprotein B (Apo-B) and free fatty acids (FFA) were measured before surgery. The correlation of serum lipid levels with clinical data, including gender, age, tumor size, lymph nodes metastasis, tumor differentiation, distant metastasis and TNM stage were analyzed by univariate and multivariate survival analysis to evaluate independent prognostic factors. RESULTS: compared with the normal HDL-C group (n = 57), the overall survival rate among GBC patients with low HDL-C levels (n = 42) was reduced (p < 0.05). However, there were no significant differences in overall survival for patients with different levels of TC, TG, Apo-A, Apo-B, LDL-C or FFA. The serum level of HDL-C was associated with TNM stage (p < 0.05) and distant metastasis (p < 0.001). The multivariate prognosis analysis showed that HDL-C and lymph nodes metastasis were independent prognostic factors (p < 0.05). A prognostic evaluation model based on HDL-C and lymph nodes metastasis was established. CONCLUSION: preoperative serum HDL-C level was closely associated with distant metastasis of patients with GBC. HDL-C level may be a valuable prognostic factor for GBC patients. The combination of HDLC and lymph nodes metastasis can better predict the prognosis of GBC.

3.
JAMA Netw Open ; 2(10): e1913619, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31626318

RESUMO

Importance: The role of induction chemotherapy (IC) or adjuvant chemotherapy (AC) in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC) remains controversial. Objectives: To update meta-analyses on the association of survival outcomes with IC and AC regimens in patients with locoregionally advanced NPC and assess whether the current evidence is conclusive by a trial sequential analysis (TSA) approach. Data Sources: PubMed, Embase, and Web of Science were searched for articles published from inception until June 1, 2019. Study Selection: Randomized clinical trials that assessed the efficacy of radiotherapy with or without chemotherapy among previously untreated patients and patients with nondistant metastatic NPC. Data Extraction and Synthesis: Data were extracted by 2 investigators from each trial independently and synthesized by the 2 investigators. All trial results were combined and analyzed by a fixed- or random-effects model. Main Outcomes and Measures: Overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS). Results: A total of 8036 patients (median age, 46.5 years; 5872 [73.1%] male) from 28 randomized clinical trials were included in the analysis. Pooled analyses revealed that concurrent chemoradiotherapy (CCRT) was significantly associated with improved OS, PFS, DMFS, and LRFS compared with radiotherapy across all subgroups. The TSA confirmed the treatment outcomes of CCRT compared with radiotherapy. The additional IC regimen was associated with an improvement in OS (hazard ratio [HR], 0.84; 95% CI, 0.74-0.95), PFS (HR, 0.73; 95% CI, 0.64-0.84), DMFS (HR, 0.67; 95% CI, 0.59-0.78), and LRFS (HR, 0.74; 95% CI, 0.64-0.85). These findings were consistent in subgroup analyses of multicenter trials with sample sizes greater than 250, years of survival rate of 5 or greater, median follow-up longer than 5 years, or low risk of bias. However, the additional AC regimen was not associated with a survival benefit in OS (HR, 0.98; 95% CI, 0.78-1.23), PFS (HR, 0.86; 95% CI, 0.70-1.07), DMFS (HR, 0.84; 95% CI, 0.64-1.10), or LRFS (HR, 0.80, 95% CI, 0.59-1.09). The TSA provided sound evidence on the additional benefit of IC but not AC. Conclusions and Relevance: These data suggest a significant association of survival outcomes with CCRT in patients with locoregionally advanced NPC. The addition of IC instead of AC could achieve survival benefits. The potential therapeutic gain of AC should be explored in the future.

4.
Int J Biol Sci ; 15(10): 2170-2181, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31592097

RESUMO

Hyperproteinemia is a severe metabolic disease characterized by abnormally elevated plasma protein concentrations (PPC). However, there is currently no reliable animal model for PPC, and the pathological mechanism of hyperproteinemia thus remains unclear. In this study, we evaluated the effects of hyperproteinemia on reproductive development in an invertebrate silkworm model with a controllable PPC and no primary disease effects. High PPC inhibited the synthesis of vitellogenin and 30K protein essential for female ovarian development in the fat body of metabolic tissues, and inhibited their transport through the hemolymph to the ovary. High PPC also induced programmed cell death in testis and ovary cells, slowed the development of germ cells, and significantly reduced the reproductive coefficient. Furthermore, the intensities and mechanisms of high-PPC-induced reproductive toxicity differed between sexes in this silkworm model.

5.
Diabetes Care ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31658974

RESUMO

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NASH have increased risk for adverse clinical outcomes, leading to higher risk for mortality and morbidity. We built a Markov model with 1-year cycles and 20-year horizon to estimate the economic burden of NASH with T2DM in the U.S. RESEARCH DESIGN AND METHODS: Cohort size was determined by population size, prevalence of T2DM, and prevalence and incidence of NASH in 2017. The model includes 10 health states: NAFL, NASH-fibrosis stages 0-3, cirrhosis, hepatocellular carcinoma, 1 year post-liver transplant, post-liver transplant, and liver-related, cardiovascular, and background mortality. Transition probabilities were calculated from meta-analyses and literature. Annual costs for NASH and T2DM were taken from literature and billing codes. RESULTS: We estimated that there were 18.2 million people in the U.S. living with T2DM and NAFLD, of which 6.4 million had NASH. Twenty-year costs for NAFLD in these patients were $55.8 billion. Over the next 20 years, NASH with T2DM will account for 65,000 transplants, 1.37 million cardiovascular-related deaths, and 812,000 liver-related deaths. CONCLUSIONS: This model predicts significant clinical and economic burden due to NASH with T2DM over the next 20 years. In fact, this burden may be greater since we assumed conservative inputs for our model and did not increase costs or the incidence of T2DM over time. It is highly likely that interventions reducing morbidity and mortality in NASH patients with T2DM could potentially reduce this projected clinical and economic burden.

6.
Cell Death Dis ; 10(11): 791, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624236

RESUMO

Granulosa cells (GCs) play a critical role in driving the formation of ovarian follicles and building the cumulus-oocyte complex surrounding the ovum. We are particularly interested in assessing oocyte quality by examining the detailed gene expression profiles of human cumulus single cells. Using single-cell RNAseq techniques, we extensively investigated the single-cell transcriptomes of the cumulus GC populations from two women with normal ovarian function. This allowed us to elucidate the endogenous heterogeneity of GCs by uncovering the hidden GC subpopulation. The subsequent validation results suggest that CD24(+) GCs are essential for triggering ovulation. Treatment with human chorionic gonadotropin (hCG) significantly increases the expression of CD24 in GCs. CD24 in cultured human GCs is associated with hCG-induced upregulation of prostaglandin synthase (ARK1C1, PTGS2, PTGES, and PLA2G4A) and prostaglandin transporter (SLCO2A1 and ABCC4) expression, through supporting the EGFR-ERK1/2 pathway. In addition, it was observed that the fraction of CD24(+) cumulus GCs decreases in PCOS patients compared to that of controls. Altogether, the results support the finding that CD24 is an important mediator of ovulation and that it may also be used for therapeutic target of ovulatory disorders.

7.
J Am Chem Soc ; 141(38): 14976-14980, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31523954

RESUMO

The traditional NH3 production method (Haber-Bosch process) is currently complemented by electrochemical synthesis at ambient conditions, but the rather low selectivity (as indicated by the Faradaic efficiency) for the electrochemical reduction of molecular N2 into NH3 impedes the progress. Here, we present a powerful method to significantly boost the Faradaic efficiency of Au electrocatalysts to 67.8% for the nitrogen reduction reaction (NRR) by increasing their electron density through the construction of inorganic donor-acceptor couples of Ni and Au nanoparticles. The unique role of the electron-rich Au centers in facilitating the fixation and activation of N2 was also investigated via theoretical simulation methods and then confirmed by experimental results. The highly coupled Au and Ni nanoparticles supported on nitrogen-doped carbon are stable for reuse and long-term performance of the NRR, making the electrochemical process more sustainable for practical application.

8.
Mar Drugs ; 17(9)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470583

RESUMO

Penicillum citreonigrum XT20-134 (MCCC 3A00956) is a fungus with cytotoxic activity, derived from deep-sea sediment. Five new compounds, adeninylpyrenocine (1), 2-hydroxyl-3-pyrenocine-thio propanoic acid (2), ozazino-cyclo-(2,3-dihydroxyl-trp-tyr) (3), 5,5-dichloro-1-(3,5-dimethoxyphenyl)-1,4-dihydroxypentan-2-one (4), and 2,3,4-trihydroxybutyl cinnamate (5), together with 19 known compounds (6-24), were isolated from an ethyl acetate (EtOAc) extract of its fermentation. The structures of the new compounds were comprehensively characterized by high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). All isolates were evaluated for their cytotoxic activities. The heteroatom-containing new compounds 2 and 4 showed potent cytotoxicity to the human hepatoma tumor cell Bel7402 with IC50 values of 7.63 ± 1.46, 13.14 ± 1.41 µM and the human fibrosarcoma tumor cell HT1080 with IC50 values of 10.22 ± 1.32, 16.53 ± 1.67 µM, respectively.

9.
Nat Microbiol ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477895

RESUMO

The special organelle-located MAVS, STING and TLR3 are important for clearing viral infections. Although TLR4 triggers NF-κB activation to produce pro-inflammatory cytokines for bacterial clearance, effectors with special organelle localization have not been identified. Here, we screened more than 280 E3 ubiquitin ligases and discovered that the endoplasmic reticulum-located Hrd1 regulates TLR4-induced inflammation during bacterial infection. Hrd1 interacts directly with the deubiquitinating enzyme Usp15. Unlike the classical function of Hrd1 in endoplasmic reticulum-associated degradation, Usp15 is not degraded but loses its deubiquitinating activity for IκBα deubiquitination, resulting in excessive NF-κB activation. Importantly, Hrd1 deficiency in macrophages protects mice against lipopolysaccharide-induced septic shock, and knockdown of Usp15 in Hrd1-knockout macrophages restores the reduced IL-6 production. This study proposes that there is crosstalk between Hrd1 and TLR4, thereby linking the endoplasmic reticulum-plasma membrane function during bacterial infection.

10.
Mar Pollut Bull ; 146: 718-728, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31426214

RESUMO

The sorption of 5 Polyhalogenated carbazoles (PHCs) [3,6-dibromocarbazole (3,6-BCZ), 3,6-dichlorocarbazole (3,6-CCZ), 3,6-diiodocarbazole (3,6-ICZ), 2,7-dibromocarbazole (2,7-BCZ) and 3-bromocarbazole (3-BCZ)] on to three microplastics [polyethylene (PE), polypropylene (PP), and polyvinyl chloride (PVC)] in a simulated seawater system are studied. Sorption isotherms demonstrated that PVC had the maximum sorption capacity, which can be attributed to polar-polar interaction. The sorption kinetics model showed that the sorption process was controlled by both intraparticle and film diffusion. The sorption of PHCs to microplastics was significantly influenced by temperature, the sorption capacity first increased gradually and then decreased with the increasing temperature. Increasing the salinity decreased the sorption of PHCs onto PP, PE, PVC microplastics. Our results indicated that all three kinds of microplastics can serve as carriers for PHCs in the aquatic environment, which put marine ecosystems at higher risks.

11.
J Phycol ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31390066

RESUMO

The evolutionary and population demographic history of marine red algae in East Asia is poorly understood. Here, we reconstructed the phylogeographies of two upper intertidal species endemic to East Asia, Gelidiophycus divaricatus and G. freshwateri. Phylogenetic and phylogeographic inferences of 393 mitochondrial cox1, 128 plastid rbcL, and 342 nuclear ITS2 sequences were complemented with ecological niche models. Gelidiophycus divaricatus, a southern species adapted to warm water, is characterized by a high genetic diversity and a strong geographical population structure, characteristic of stable population sizes and sudden reduction to recent expansion. In contrast, G. freshwateri, a northern species adapted to cold temperate conditions, is genetically relatively homogeneous with a shallow population structure resulting from steady population growth and recent equilibrium. The overlap zone of the two species roughly matches summer and winter isotherms, indicating that surface seawater temperature is a key feature influencing species range. Unidirectional genetic introgression was detected at two sites on Jeju Island where G. divaricatus was rare while G. freshwateri was common, suggesting the occurrence of asymmetric natural hybrids, a rarely reported event for rhodophytes. Our results illustrate that Quaternary climate oscillations have left strong imprints on the current day genetic structure and highlight the importance of seawater temperature and sea level change in driving speciation in upper intertidal seaweed species.

12.
Soft Matter ; 15(34): 6867-6877, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31411231

RESUMO

In this study, a two-component lattice Boltzmann method (TLBM) in combination with a discrete element approach (DEA) based on a representative volume element (RVE) with respect to a bidisperse magnetorheological fluid (MRF) was performed to simulate the behavior and microstructure formation of magnetic particles in a carrier liquid. The bidisperse MRF reported herein is a suspension dispersed by soft micron carbonyl iron (CI) particles and Fe3O4 nanoparticles dual-coated with gelatin and multi-walled carbon nanotubes (MWCNTs) in the carrier liquid. In the TLBM of two-component liquid and particle simulation, the inter-particle interactions were completely ignored; on the other hand, the DEA was just employed for calculating the dynamic behavior of particles. Therefore, due to the explicit nature of the combination of TLBM and DEA, it is a more efficient and accurate strategy for the simulation and calculation of complex MRF systems. Moreover, the immersed boundary method (IBM) was used to describe the interactions between the magnetic particles and the carrier liquid. The RVE of the bidisperse MRF was selected to eliminate specific operational conditions and reduce the calculation costs. New numerical results were obtained for the motion velocities, microstructure evolution and kinetic energy of bidisperse magnetic particles (BMPs) under the effect of a magnetic field; when the mass fraction of the nanoparticles was 0.1, the bidisperse MRF exhibited an improved response time in terms of the particle motion and microstructure formation. In addition, the effects of the Reynolds (Re) and Hartmann (Ha) numbers on the fluid-particle interaction and flow velocity were illustrated.

13.
J Zhejiang Univ Sci B ; 20(9): 713-727, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379142

RESUMO

Production of reactive oxygen species (ROS) is a conserved immune response primarily mediated by NADPH oxidases (NOXs), also known in plants as respiratory burst oxidase homologs (RBOHs). Most microbe-associated molecular patterns (MAMPs) trigger a very fast and transient ROS burst in plants. However, recently, we found that lipopolysaccharides (LPS), a typical bacterial MAMP, triggered a biphasic ROS burst. In this study, we isolated mutants defective in LPS-triggered biphasic ROS burst (delt) in Arabidopsis, and cloned the DELT1 gene that was shown to encode RBOHD. In the delt1-2 allele, the antepenultimate residue, glutamic acid (E919), at the C-terminus of RBOHD was mutated to lysine (K). E919 is a highly conserved residue in NADPH oxidases, and a mutation of the corresponding residue E568 in human NOX2 has been reported to be one of the causes of chronic granulomatous disease. Consistently, we found that residue E919 was indispensable for RBOHD function in the MAMP-induced ROS burst and stomatal closure. It has been suggested that the mutation of this residue in other NADPH oxidases impairs the protein's stability and complex assembly. However, we found that the E919K mutation did not affect RBOHD protein abundance or the ability of protein association, suggesting that the residue E919 in RBOHD might have a regulatory mechanism different from that of other NOXs. Taken together, our results confirm that the antepenultimate residue E is critical for NADPH oxidases and provide a new insight into the regulatory mechanisms of RBOHD.

14.
J Hepatol ; 71(4): 793-801, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279902

RESUMO

BACKGROUND & AIMS: Although non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and NASH with advanced fibrosis are closely associated with type 2 diabetes mellitus (T2DM), their global prevalence rates have not been well described. Our aim was to estimate the prevalence of NAFLD, NASH, and advanced fibrosis among patients with T2DM, by regions of the world. METHODS: We searched for terms including NAFLD, NASH and T2DM in studies published from January 1989 to September 2018, using PubMed, Ovid MEDLINE®, EMBASE and Web of Science. Strict exclusion criteria were applied. Regional and global mean prevalence weighted by population size in each country were estimated and pooled using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression. RESULTS: Among 80 studies from 20 countries that met our inclusion criteria, there were 49,419 individuals with T2DM (mean age 58.5 years, mean body mass index 27.9 kg/m2, and males 52.9%). The global prevalence of NAFLD among patients with T2DM was 55.5% (95% CI 47.3-63.7). Studies from Europe reported the highest prevalence (68.0% [62.1-73.0%]). Among 10 studies that estimated the prevalence of NASH, the global prevalence of NASH among individuals with T2DM was 37.3% (95% CI 24.7-50.0%). Seven studies estimated the prevalence of advanced fibrosis in patients with NAFLD and T2DM to be 17.0% (95% CI 7.2-34.8). Meta-regression models showed that geographic region and mean age (p <0.5) were associated with the prevalence of NAFLD, jointly accounting for 63.9% of the heterogeneity. CONCLUSIONS: This study provides the global prevalence rates for NAFLD, NASH, and advanced fibrosis in patients with T2DM. These data can be used to estimate the clinical and economic burden of NASH in patients with T2DM around the world. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent chronic liver disease worldwide. Type 2 diabetes mellitus (T2DM) is an important risk factor for NAFLD. Additionally, T2DM seems to accelerate the progression of liver disease in NAFLD. Despite the high prevalence and serious clinical implications of NAFLD in patients with T2DM, it is usually overlooked in clinical practice. This meta-analysis provides evidence of the high prevalence of NAFLD and NASH in patients with T2DM. In this context, increasing awareness about the importance of NAFLD in patients with T2DM among all important stakeholders (primary care physicians, specialists, and health policy makers) must be prioritized.

15.
Mar Pollut Bull ; 144: 129-133, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31179978

RESUMO

The effects of time, temperature, and salinity on the adsorption of Tonalide (AHTN), Musk Xylene (MX), Galaxolide (HHCB), and Musk Ketone (MK) by microplastics of polyethylene (PE) and polyvinyl chloride (PVC) are studied. Results indicate that the equilibrium sorption time was about 10 h and the adsorption kinetics model conformed to the first-order adsorption kinetic model and pseudo-second order kinetic model, this indicates that the main adsorption mechanism might be chemical adsorption and physical absorption. Adsorption reached a nadir at 15 °C and 14% salinity. The adsorption capacity gradually increases, and then decreases, finally increases with an increase in NaCl concentration. Due to the specific surface area and the pore volume of PVC was larger than PE, the adsorption capacity of PVC was higher than that of PE in the equal conditions.


Assuntos
Cosméticos/química , Modelos Teóricos , Polietileno/química , Cloreto de Polivinila/química , Poluentes Químicos da Água/química , Adsorção , Benzopiranos/análise , Benzopiranos/química , Cosméticos/análise , Cinética , Polietileno/análise , Cloreto de Polivinila/análise , Salinidade , Água do Mar/química , Tetra-Hidronaftalenos/análise , Tetra-Hidronaftalenos/química , Poluentes Químicos da Água/análise , Xilenos/análise , Xilenos/química
16.
Pest Manag Sci ; 75(12): 3135-3143, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31251458

RESUMO

Many insects, especially nocturnal insects, exhibit positive phototaxis to artificial lights. Light traps are currently used to monitor and manage insect pest populations, and play a crucial role in physical pest control. Efficient use of light traps to attract target insect pests is an important topic in the application of integrated pest management (IPM). Phototactic responses of insects vary among species, light characteristics and the physiological status of the insects. In addition, light can cause several biological responses, including biochemical, physiological, molecular and fitness changes in insects. In this review, we discuss several hypotheses on insect phototaxis, factors affecting insect phototaxis, insect-sensitive wavelengths, biological responses of insects to light, and countermeasures for conserving beneficial insects and increasing the effect of trapping. In addition, we provide information on the different sensitivities to wavelengths causing positive phototactic behavior in > 70 insect pest and beneficial insect species. The use of advanced light traps equipped with superior light sources, such as light-emitting diodes (LEDs), will make physical pest control in IPM more efficient. © 2019 Society of Chemical Industry.

17.
Toxins (Basel) ; 11(5)2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035652

RESUMO

Entomopathogenic fungus as well as their toxins is a natural threat surrounding social insect colonies. To defend against them, social insects have evolved a series of unique disease defenses at the colony level, which consists of behavioral and physiological adaptations. These colony-level defenses can reduce the infection and poisoning risk and improve the survival of societal members, and is known as social immunity. In this review, we discuss how social immunity enables the insect colony to avoid, resist and tolerate fungal pathogens. To understand the molecular basis of social immunity, we highlight several genetic elements and biochemical factors that drive the colony-level defense, which needs further verification. We discuss the chemosensory genes in regulating social behaviors, the antifungal secretions such as some insect venoms in external defense and the immune priming in internal defense. To conclude, we show the possible driving force of the fungal toxins for the evolution of social immunity. Throughout the review, we propose several questions involved in social immunity extended from some phenomena that have been reported. We hope our review about social 'host-fungal pathogen' interactions will help us further understand the mechanism of social immunity in eusocial insects.

18.
J Invest Dermatol ; 139(11): 2302-2312.e14, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31078570

RESUMO

Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis. Specifically, we identified 12 common, 9 low-frequency, and 8 rare InDels that explained approximately 1.29% of the heritability of psoriasis. Further analyses identified KIAA0319, RELN, NCAPG, ABO, AADACL2, LMAN1, FLG, HERC5, CCDC66, LEKR1, AFF3, ABCG2, ANXA7, SYTL2,GIPR, METTL1, and FYCO1 as unreported genes for psoriasis. In addition, identified InDels were associated with the following reported genes: IFIH1, ERAP1, ERAP2, LNPEP, UBLCP1, and STAT3; unreported independent associations for exonic InDels were found within GJB2 and ZNF816A. Our study enriched the genetic basis and pathogenesis of psoriasis and highlighted the non-negligible impact of InDels on complex human diseases.

19.
Acta Pharmacol Sin ; 40(9): 1193-1204, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30833709

RESUMO

Gluconeogenesis is a major source of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), thus targeting gluconeogenesis to suppress glucose production is a promising strategy for anti-T2DM drug discovery. In our preliminary in vitro studies, we found that a small-molecule (E)-3-(2-(quinoline-4-yl)vinyl)-1H-indol-6-ol (QVO) inhibited the hepatic glucose production (HGP) in primary hepatocytes. We further revealed that QVO suppressed hepatic gluconeogenesis involving calmodulin-dependent protein kinase kinase ß- and liver kinase B1-adenosine monophosphate-activated protein kinase (AMPK) pathways as well as AMPK-independent mitochondrial function-related signaling pathway. To evaluate QVO's anti-T2DM activity in vivo, which was impeded by the complicated synthesis route of QVO with a low yield, we designed and synthesized 4-[2-(1H-indol-3-yl)vinyl]quinoline (IVQ) as a prodrug with easier synthesis route and higher yield. IVQ did not inhibit the HGP in primary hepatocytes in vitro. Pharmacokinetic studies demonstrated that IVQ was quickly converted to QVO in mice and rats following administration. In both db/db and ob/ob mice, oral administration of IVQ hydrochloride (IVQ-HCl) (23 and 46 mg/kg every day, for 5 weeks) ameliorated hyperglycemia, and suppressed hepatic gluconeogenesis and activated AMPK signaling pathway in the liver tissues. Furthermore, IVQ caused neither cardiovascular system dysfunction nor genotoxicity. The good druggability of IVQ has highlighted its potential in the treatment of T2DM and the prodrug design for anti-T2DM drug development.

20.
Cell ; 176(6): 1447-1460.e14, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30799039

RESUMO

The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.

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