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1.
Mol Plant ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31706032

RESUMO

Symbiotic microorganisms improve nutrient uptake by plants. To initiate mutualistic symbiosis with arbuscular mycorrhizal (AM) fungi, plants perceive Myc factors, including lipochitooligosaccharides (LCOs) and short-chain chitooligosaccharides (CO4/CO5), secreted by AM fungi. However, the molecular mechanism of Myc factors perception remains elusive. Here, we identified a heteromer of LysM receptor-like kinases, OsMYR1/OsLYK2 and OsCERK1, that mediates perception of AM fungi in rice. CO4 directly binds to OsMYR1, promoting the dimerization and phosphorylation of this receptor complex. Compared to control plants, Osmyr1 and Oscerk1 mutant rice plants are less sensitive to Myc factors and show decreased AM colonization. We engineered transgenic rice by expressing chimeric receptors that respectively replaced the ectodomains of OsMYR1 and OsCERK1 with those from the homologous Nod factor receptors MtNFP and MtLYK3 of Medicago truncatula. Transgenic plants displayed increased calcium oscillations in response to Nod factors compared to control rice. Our findings reveal a mechanism for mycorrhizal symbiotic signal perception in rice, and the ectopic expression of chimeric Nod/Myc receptors achieves a potentially important step towards generating cereals that host nitrogen-fixing bacteria.

2.
Cell Res ; 29(10): 820-831, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444468

RESUMO

The transient elevation of cytoplasmic calcium is essential for pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). However, the calcium channels responsible for this process have remained unknown. Here, we show that rice CDS1 (CELL DEATH and SUSCEPTIBLE to BLAST 1) encoding OsCNGC9, a cyclic nucleotide-gated channel protein, positively regulates the resistance to rice blast disease. We show that OsCNGC9 mediates PAMP-induced Ca2+ influx and that this event is critical for PAMPs-triggered ROS burst and induction of PTI-related defense gene expression. We further show that a PTI-related receptor-like cytoplasmic kinase OsRLCK185 physically interacts with and phosphorylates OsCNGC9 to activate its channel activity. Our results suggest a signaling cascade linking pattern recognition to calcium channel activation, which is required for initiation of PTI and disease resistance in rice.

3.
Am J Med Genet C Semin Med Genet ; 181(2): 262-268, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30897304

RESUMO

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with extreme clinical heterogeneity and significant differences between populations. East Asian populations are known to have higher prevalence and more severe clinical manifestations for SLE than Europeans. The difference could be the result of genetic and environmental factors, and the interactions between them. Thus, identifying genetic associations from diverse populations provides an opportunity to better understand the genetic architecture of this heterogeneous disease. It is also necessary to elucidate population differences and to apply the findings in future stratified treatment of the disease, with ethnicity likely a major factor to consider. Indeed, it has shown that there are significant differences between East Asians and European populations in several genetic loci for SLE. Genetic studies on SLE are very active in East Asian countries and there have been close collaborations among scientists in this region. Here, we document some work done in this region on SLE genetic research and discuss the aspect of population differences.

5.
Bioinformatics ; 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30169743

RESUMO

Availability: http://wyanglab.org:3838/RefPanelWebsite/. Supplementary information: Supplementary data are available at Bioinformatics online.

6.
Cell Physiol Biochem ; 49(2): 728-742, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30165360

RESUMO

BACKGROUND/AIMS: Arctigenin (ATG) has been shown to possess anti-inflammatory, immunemodulatory, anti-viral, anti-microbial, anti-carcinogenic, vasodilatory and anti-platelet aggregation properties. However, the protective role of ATG in prevention of arrhythmias induced by myocardial ischemia/reperfusion is unknown. The aim of this study was to investigate the anti-arrhythmia effect of ATG in an ischemia/reperfusion injured rat heart model and explore the related mechanisms. METHODS: Rats were randomly exposed to sham operation, myocardial ischemia/ reperfusion (MI/R) alone, ATG+ MI/R, pretreated with ATG in low (12.5 mg/kg/day), medium (50 mg/kg/day) and high dose (200 mg/kg/day), respectively. Ventricular arrhythmias were assessed. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the level of malondialdehyde (MDA) in myocardial tissue were determined by chemical analysis. RESULTS: Compared to MI/R, rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/day showed significantly reduced incidence and duration of ventricular fibrillation, ventricular tachycardia and ventricular ectopic beat (VEB), and decreased the arrhythmia score during the 30-min ischemia. Incidence and duration of ventricular tachycardia, infarction size and arrhythmia scores in these groups were significantly decreased during the 120-min reperfusion. No ventricular fibrillation occurred during the period of reperfusion. Rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/ day markedly enhanced the activities of antioxidant enzymes SOD and GSH-Px, reduced the level of MDA. No differences were observed between the group pretreated with a low dose of ATG and the sham group. Administration of ATG significantly increased the expression of antioxidant stress protein Nrf2, Trx1 and Nox1. CONCLUSION: Our data suggested that ATG plays anti-arrhythmia role in ischemia/reperfusion injury, which is probably associated with attenuating oxidative stress by Nrf2 signaling pathway.


Assuntos
Arritmias Cardíacas/prevenção & controle , Furanos/farmacologia , Lignanas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Modelos Animais de Doenças , Furanos/uso terapêutico , Glutationa Peroxidase/metabolismo , Lignanas/uso terapêutico , Masculino , Malondialdeído/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , NADPH Oxidase 1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Superóxido Dismutase/metabolismo , Tiorredoxinas/metabolismo
7.
Plant Cell ; 30(6): 1258-1276, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29716991

RESUMO

Abscisic acid (ABA) regulates plant stress responses and development. However, how the ABA signal is transmitted in response to stresses remains largely unclear, especially in monocots. In this study, we found that rice (Oryza sativa) OsPM1 (PLASMA MEMBRANE PROTEIN1), encoded by a gene of AWPM-19 like family, mediates ABA influx through the plasma membrane. OsPM1 is predominantly expressed in vascular tissues, guard cells, and mature embryos. Phenotypic analysis of overexpression, RNA interference (RNAi), and knockout (KO) lines showed that OsPM1 is involved in drought responses and seed germination regulation. 3H-(±)ABA transport activity and fluorescence resonance energy transfer assays both demonstrated that OsPM1 facilitates ABA uptake into cells. The physiological isomer of ABA, (+)-ABA, is the preferred substrate of OsPM1. Higher ABA accumulation and faster stomatal closure in response to ABA treatment were observed in the overexpression lines compared with the wild-type control. Many ABA-responsive genes were upregulated more in the OsPM1-overexpression lines but less in the RNAi lines compared with wild-type plants. Further investigation revealed that OsPM1 expression is regulated by the AREB/ABF family transcription factor OsbZIP46. Our results thus revealed that OsPM1 is an ABA influx carrier that plays an important role in drought responses.

8.
Arthritis Res Ther ; 20(1): 92, 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29724251

RESUMO

BACKGROUND: Systemic lupus erythematous (SLE) is a complex autoimmune disease with female predominance, particularly affecting those of childbearing age. We performed analysis of three genome-wide genotyping datasets of populations of both Chinese and European origin. METHODS: This study involved 5695 cases and 10,357 controls in the discovery stage. The lead signal on chromosome X was followed by replication in three additional Asian cohorts, with 2300 cases and 4244 controls in total. Conditional analysis of the known associated loci on chromosome X was also performed to further explore independent signals. RESULTS: Single-nucleotide polymorphism rs13440883 in GPR173 was found to be significantly associated with SLE (Pmeta = 7.53 × 10- 9, ORmeta= 1.16), whereas conditional analysis provided evidence of a potential independent signal in the L1CAM-IRAK1-MECP2 region in Asian populations (rs5987175 [LCA10]). CONCLUSIONS: We identified a novel SLE susceptibility locus on the X chromosome. This finding emphasizes the importance of the X chromosome in disease pathogenesis and highlights the role of sex chromosomes in the female bias of SLE.

9.
Ann Rheum Dis ; 77(7): 1078-1084, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29625966

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. METHODS: We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. RESULTS: We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. CONCLUSION: This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

10.
Plant Cell Physiol ; 59(3): 614-623, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29390155

RESUMO

Diverse stimuli induce stomatal closure by triggering the efflux of osmotic anions, which is mainly mediated by the main anion channel SLAC1 in plants, and the anion permeability and selectivity of SLAC1 channels from several plant species have been reported to be variable. However, the genetic identity as well as the anion permeability and selectivity of the main S-type anion channel ZmSLAC1 in maize are still unknown. In this study, we identified GRMZM2G106921 as the gene encoding ZmSLAC1 in maize, and the maize mutants zmslac1-1 and zmslac1-2 harboring a mutator (Mu) transposon in ZmSLAC1 exhibited strong insensitive phenotypes of stomatal closure in response to diverse stimuli. We further found that ZmSLAC1 functions as a nitrate-selective anion channel without obvious permeability to chloride, sulfate and malate, clearly different from SLAC1 channels of Arabidopsis thaliana, Brassica rapa ssp. chinensis and Solanum lycopersicum L. Further experimental data show that the expression of ZmSLAC1 successfully rescued the stomatal movement phenotypes of the Arabidopsis double mutant atslac1-3atslah3-2 by mainly restoring nitrate-carried anion channel currents of guard cells. Together, these findings demonstrate that ZmSLAC1 is involved in stomatal closure mainly by mediating the efflux of nitrate in maize.


Assuntos
Canais Iônicos/metabolismo , Nitratos/metabolismo , Proteínas de Plantas/metabolismo , Estômatos de Plantas/fisiologia , Zea mays/fisiologia , Ânions , Arabidopsis/genética , Permeabilidade da Membrana Celular , Canais de Cloreto/metabolismo , Cloretos/metabolismo , Genes de Plantas , Fenótipo , Plantas Geneticamente Modificadas , Zea mays/genética , Zea mays/metabolismo
11.
PLoS Genet ; 13(10): e1007086, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29084222

RESUMO

Arabidopsis thaliana high-affinity potassium transporter 1 (AtHKT1) limits the root-to-shoot sodium transportation and is believed to be essential for salt tolerance in A. thaliana. Nevertheless, natural accessions with 'weak allele' of AtHKT1, e.g. Tsu-1, are mainly distributed in saline areas and are more tolerant to salinity. These findings challenge the role of AtHKT1 in salt tolerance and call into question the involvement of AtHKT1 in salinity adaptation in A. thaliana. Here, we report that AtHKT1 indeed drives natural variation in the salt tolerance of A. thaliana and the coastal AtHKT1, so-called weak allele, is actually hyper-functional in reducing flowers sodium content upon salt stress. Our data showed that AtHKT1 positively contributes to saline adaptation in a linear manner. Forward and reverse genetics analysis established that the single AtHKT1 locus is responsible for the variation in the salinity adaptation between Col-0 and Tsu-1. Reciprocal grafting experiments revealed that shoot AtHKT1 determines the salt tolerance of Tsu-1, whereas root AtHKT1 primarily drives the salt tolerance of Col-0. Furthermore, evidence indicated that Tsu-1 AtHKT1 is highly expressed in stems and is more effective compared to Col-0 AtHKT1 at limiting sodium flow to the flowers. Such efficient retrieval of sodium to the reproductive organ endows Tsu-1 with stronger fertility compared to Col-0 upon salt stress, thus improving Tsu-1 adaptation to a coastal environment. To conclude, our data not only confirm the role of AtHKT1 in saline adaptation, but also sheds light on our understanding of the salt tolerance mechanisms in plants.


Assuntos
Adaptação Fisiológica/genética , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas de Transporte de Cátions/genética , Flores/genética , Tolerância ao Sal/genética , Sódio/metabolismo , Simportadores/genética , Alelos , Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Salinidade , Cloreto de Sódio/metabolismo
13.
Plant Signal Behav ; 12(11): e1197999, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-27322818

RESUMO

We recently revealed that cyclic nucleotide-gated channel 18 (CNGC18) functioned as the main Ca2+ channel in pollen tube tips for pollen tube guidance to ovules by regulating external Ca2+ influx in Arabidopsis. In this study, we found that the reduction of external Ca2+ concentration ([Ca2+]ext) from 10 mM to 5 mM, and further to 2 mM, led to the decreases of pollen germination percentages, but led to the increases of the percentages of ruptured pollen grains and tubes, and branched pollen tubes in vitro in cngc18-17 compared with wild type. The second point mutant allele cngc18-22 showed similar phenotypes, including reduced pollen germination percentages, increased percentages of ruptured pollen tubes, but did not show obvious different percentages of ruptured pollen grains and branched pollen tubes compared with wild type. These data demonstrate that CNGC18 plays essential roles in pollen germination and tube growth as a Ca2+ channel in Arabidopsis.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Arabidopsis/fisiologia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Germinação/fisiologia , Pólen/metabolismo , Pólen/fisiologia , Proteínas de Arabidopsis/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Germinação/genética , Pólen/genética , Tubo Polínico/genética , Tubo Polínico/metabolismo , Tubo Polínico/fisiologia
15.
Nat Genet ; 48(8): 940-946, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399966

RESUMO

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos
16.
Proc Natl Acad Sci U S A ; 113(11): 3096-101, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26929345

RESUMO

In flowering plants, pollen tubes are guided into ovules by multiple attractants from female gametophytes to release paired sperm cells for double fertilization. It has been well-established that Ca(2+) gradients in the pollen tube tips are essential for pollen tube guidance and that plasma membrane Ca(2+) channels in pollen tube tips are core components that regulate Ca(2+) gradients by mediating and regulating external Ca(2+) influx. Therefore, Ca(2+) channels are the core components for pollen tube guidance. However, there is still no genetic evidence for the identification of the putative Ca(2+) channels essential for pollen tube guidance. Here, we report that the point mutations R491Q or R578K in cyclic nucleotide-gated channel 18 (CNGC18) resulted in abnormal Ca(2+) gradients and strong pollen tube guidance defects by impairing the activation of CNGC18 in Arabidopsis. The pollen tube guidance defects of cngc18-17 (R491Q) and of the transfer DNA (T-DNA) insertion mutant cngc18-1 (+/-) were completely rescued by CNGC18. Furthermore, domain-swapping experiments showed that CNGC18's transmembrane domains are indispensable for pollen tube guidance. Additionally, we found that, among eight Ca(2+) channels (including six CNGCs and two glutamate receptor-like channels), CNGC18 was the only one essential for pollen tube guidance. Thus, CNGC18 is the long-sought essential Ca(2+) channel for pollen tube guidance in Arabidopsis.


Assuntos
Proteínas de Arabidopsis/fisiologia , Arabidopsis/fisiologia , Cálcio/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/fisiologia , Tubo Polínico/crescimento & desenvolvimento , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Canais de Cálcio/fisiologia , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/química , Canais de Cátion Regulados por Nucleotídeos Cíclicos/deficiência , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Genes Reporter , Teste de Complementação Genética , Células HEK293 , Humanos , Potenciais da Membrana , Mutação de Sentido Incorreto , Óvulo Vegetal , Técnicas de Patch-Clamp , Infertilidade das Plantas/genética , Plantas Geneticamente Modificadas , Mutação Puntual , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/metabolismo , Sistemas do Segundo Mensageiro
17.
Plant Cell ; 28(4): 949-955, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27002025

RESUMO

Drought stress induces stomatal closure and inhibits stomatal opening simultaneously. However, the underlying molecular mechanism is still largely unknown. Here we show that S-type anion channels SLAC1 and SLAH3 mainly inhibit inward K+ (K+in) channel KAT1 by protein-protein interaction, and consequently prevent stomatal opening in Arabidopsis. Voltage-clamp results demonstrated that SLAC1 inhibited KAT1 dramatically, but did not inhibit KAT2. SLAH3 inhibited KAT1 to a weaker degree relative to SLAC1. Both the N terminus and the C terminuses of SLAC1 inhibited KAT1, but the inhibition by the N terminus was stronger. The C terminus was essential for the inhibition of KAT1 by SLAC1. Furthermore, drought stress strongly up-regulated the expression of SLAC1 and SLAH3 in Arabidopsis guard cells, and the over-expression of wild type and truncated SLAC1 dramatically impaired K+in currents of guard cells and light-induced stomatal opening. Additionally, the inhibition of KAT1 by SLAC1 and KC1 only partially overlapped, suggesting that SLAC1 and KC1 inhibited K+in channels using different molecular mechanisms. Taken together, we discovered a novel regulatory mechanism for stomatal movement, in which singling pathways for stomatal closure and opening are directly coupled together by protein-protein interaction between SLAC1/SLAH3 and KAT1 in Arabidopsis.

18.
Planta ; 243(2): 489-500, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26481009

RESUMO

MAIN CONCLUSION: OsSAPK8 is an essential activator of OsSLAC1 by phosphorylation, and OsSLAC1 is a nitrate-selective anion channel. S-type anion channel AtSLAC1 and protein kinase AtOST1 have been well-characterized as two core components of ABA signaling cascade in Arabidopsis guard cells, and AtOST1 functions as a main upstream activator of AtSLAC1 for drought stress- and ABA-induced stomata closure. However, the identity of the ortholog of AtOST1 in rice, the main activator of OsSLAC1, is still unknown. Here, we report that protein kinase OsSAPK8 interacts with and activates OsSLAC1 mainly by phosphorylating serine 129 (S129) of OsSLAC1, and this phosphorylating site corresponds to the specific phosphorylating site serine 120 (S120) of AtSLAC1 for AtOST1. Additionally, we found that OsSLAC1 is a nitrate-selective anion channel without obvious permeability to chloride, malate, and sulfate, and the expression of OsSLAC1 in Arabidopsis slac1-3 (atslac1-3) mutant successfully rescued the hypersensitive phenotype of this mutant to drought stress. Together, this research suggests that OsSAPK8 is a counterpart of AtOST1 for the activation of OsSLAC1, which is a nitrate-selective anion channel.


Assuntos
Proteínas de Membrana/fisiologia , Nitratos/metabolismo , Oryza/metabolismo , Proteínas de Plantas/fisiologia , Animais , Arabidopsis/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Permeabilidade , Fosforilação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estômatos de Plantas/metabolismo , Estômatos de Plantas/fisiologia , Xenopus laevis
19.
J Neurooncol ; 125(1): 79-89, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26297046

RESUMO

There are some evidences that pituitary tumors may be sensitive to the anti-proliferative effects of mammalian target of rapamycin (mTOR) inhibitors, while the mechanism and effects remains unclear, it is necessary to find if a specific mTOR inhibition, including the blocking of both mTOR function and expression, generate any effects on pituitary adenoma cells. The object of this study was to examine if specific inhibition of mTOR induced anti-proliferative effect and decreased the GH and PRL hormones secretion in GH3 and MtT/E pituitary adenoma cells by using a kind of mTOR shRNA lentiviral vector. The in vitro experiments results showed mTOR shRNA transfection robustly reduced the GH3 and MtT/E cells viability in all durations (1-6 days) we performed, also specifically decreased both GH and PRL hormones external secretion in GH3 cells. Further results suggested that specific inhibition of mTOR decreased the hormones secretion through anti-proliferation effects on GH3 cells and reducing the hormones synthesis, but not through affecting the process of hormones secretion. Then we used phosphatidic acid (PA), a kind of mTOR activator, to promote the cell proliferation and GH and PRL hormones secretion in GH3 cells while the effects were blocked by mTOR shRNA transfection. In addition, we examined in vitro effects of PA treatment and mTOR shRNA gene transfection on major proteins expressed in the mTOR pathway in GH3 cells, and confirmed that PA treatment significant increased the protein levels of pmTOR, pS6 K and p4EBP1 in the scramble shRNA group, while the increase of protein levels was blocked by mTOR shRNA gene transfection. Moreover, mTOR shRNA gene transfection definitely inhibited the expression of mTOR and reduced the expression of pmTOR, pS6K and p4EBP1 in either PA or no PA treatment groups. These findings indicated that specific inhibition of mTOR pathway induced anti-proliferative effect and decreased the GH and PRL hormones secretion in cultured pituitary adenoma cells, which may be a novel promising and potential treatment modality for patients with secreting or non-secreting pituitary adenomas.


Assuntos
Proliferação de Células/fisiologia , Hormônio do Crescimento/metabolismo , Prolactina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Análise de Variância , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaio de Imunoadsorção Enzimática , Humanos , Ácidos Fosfatídicos/farmacologia , Neoplasias Hipofisárias/patologia , RNA Interferente Pequeno/genética , Ratos , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/genética , Fatores de Tempo , Transfecção
20.
Arthritis Res Ther ; 17: 67, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25880549

RESUMO

INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking. METHODS: Through meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, comprising a total of 1,659 cases and 3,398 controls matched geographically, we closely examined the 22q11.21 region, especially on the reported single-nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant associations of SNPs with SLE using 2,612 cases and 2,323 controls of Asian ancestry. RESULTS: All reported SNPs in the 22q11.21 region with different autoimmune diseases were examined using the two GWAS data and meta-analysis results, and supportive evidence of association with SLE was found (meta-analysis: P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta =2.70E-09). It showed independent effects through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand comprising a total of 2,612 cases and 2,323 controls (joint analysis of GWAS and replication result: P_all =1.31E-11, odds ratio =1.23). SNP rs2298428 was shown to be an expression quantitative locus for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in patients with SLE. CONCLUSIONS: Association with distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms in these diseases.


Assuntos
Alelos , Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 22/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Vigilância da População , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Fatores de Risco
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