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1.
J Exp Biol ; 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39263756

RESUMO

This study investigates how hibernation affects the surface activity of pulmonary surfactant with respect to temperature and breathing pattern. Surfactant was isolated from a hibernating species, the 13-lined ground squirrel, and a homeotherm, rabbit, and analyzed for biophysical properties on a constrained sessile drop surfactometer. The results showed that surfactant from ground squirrels reduced surface tension better at low temperatures, including when mimicking episodic breathing, as compared to rabbit surfactant. In addition, low temperature adaptation was also observed using only the hydrophobic components of surfactant from ground squirrels. Overall, the data supports the conclusion that ground squirrel surfactant has adapted to maintain surface activity during low temperature episodic breathing patterns, and that temperature adaptation is maintained with the hydrophobic components of the surfactant.

2.
Int J Biol Macromol ; 258(Pt 2): 129116, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38171192

RESUMO

Vascular Plant One­zinc Finger (VOZ) transcription factor can respond to a variety of abiotic stresses, however its function in cotton and the molecular mechanisms of response to salt tolerance remained unclear. In this study, we found that GhVOZ1 is highly expressed in stamen and stem of cotton under normal conditions. The expression of GhVOZ1 increased significantly after 3 h of salt treatment in three-leaf staged upland cotton. Overexpressed transgenic lines of GhVOZ1 in Arabidopsis and upland cotton were treated with salt stress and we found that GhVOZ1 could respond positively to salt stress. GhVOZ1 can regulate Arabidopsis Vacuolar Proton Pump Pyrophosphatase (H+-PPase) gene (AVP1) expression through specific binding to GCGTCTAAAGTACGC site on GhAVP1 promoter, which was examined through Dual-luciferase assay and Electrophoretic mobility shift assay (EMSA). AVP1 expression was significantly increased in Arabidopsis with GhVOZ1 overexpression, while GhAVP1 expression was decreased in virus induced gene silenced (VIGS) cotton plants of GhVOZ1. Knockdown of GhAVP1 expression in cotton plants by VIGS showed decreased superoxide dismutase (SOD) and peroxidase (POD) activities, whereas an increased malondialdehyde (MDA) content and ultimately decreased salt tolerance. The GhVOZ1-AVP1 module could maintain sodium ion homeostasis through cell ion transport and positively regulate the salt tolerance in cotton, providing new ideas and insights for the study of salt tolerance.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Gossypium/genética , Tolerância ao Sal/genética , Arabidopsis/genética , Plantas Geneticamente Modificadas/genética , Proteínas de Arabidopsis/metabolismo , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Pirofosfatase Inorgânica/genética , Pirofosfatase Inorgânica/metabolismo
3.
BMC Genomics ; 24(1): 467, 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37596513

RESUMO

BACKGROUND: Phloem protein 2 (PP2) proteins play a vital role in the Phloem-based defense (PBD) and participate in many abiotic and biotic stress. However, research on PP2 proteins in cotton is still lacking. RESULTS: A total of 25, 23, 43, and 47 PP2 genes were comprehensively identified and characterized in G.arboretum, G.raimondii, G.barbadense, and G.hirsutum. The whole genome duplication (WGD) and allopolyploidization events play essential roles in the expansion of PP2 genes. The promoter regions of GhPP2 genes contain many cis-acting elements related to abiotic stress and the weighted gene co-expression network analysis (WGCNA) analysis displayed that GhPP2s could be related to salt stress. The qRT-PCR assays further confirmed that GhPP2-33 could be dramatically upregulated during the salt treatment. And the virus-induced gene silencing (VIGS) experiment proved that the silencing of GhPP2-33 could decrease salt tolerance. CONCLUSIONS: The results in this study not only offer new perspectives for understanding the evolution of PP2 genes in cotton but also further explore their function under salt stress.


Assuntos
Gossypium , Proteínas de Plantas , Tolerância ao Sal , Gossypium/genética , Lectinas de Plantas , Estresse Salino , Tolerância ao Sal/genética , Proteínas de Plantas/metabolismo
4.
Psychiatry Res ; 322: 115138, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36871411

RESUMO

Hyperprolactinemia and metabolic disturbance are common side effects of antipsychotics that cause intolerance. Despite its potential influence on relapse, there are no established guidelines for antipsychotic switching. This naturalistic study explored the association between antipsychotic switching, baseline clinical status, metabolic changes, and relapse in patients with schizophrenia. In total, 177 patients with amisulpride-induced hyperprolactinemia and 274 with olanzapine-induced metabolic disturbance were enrolled. Relapse was determined by assessing changes in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to 6 months (increased over 20% or 10% reaching 70). Metabolic indices were measured at baseline and 3 months. Patients with baseline PANSS >60 were more likely to relapse. Further, patients switching to aripiprazole had a higher risk of relapse regardless of their original medication. Participants who originally used amisulpride had reduced prolactin levels following medication change, while switching to olanzapine caused increased weight and blood glucose levels. In patients originally using olanzapine, only switching to aripiprazole reduced insulin resistance. Adverse effects on weight and lipid metabolism were observed in patients who switched to risperidone, while amisulpride improved lipid profiles. Changing schizophrenia treatment requires careful consideration of multiple variables, particularly the choice of substituted drug and the patient's baseline symptoms.


Assuntos
Antipsicóticos , Hiperprolactinemia , Quinolonas , Esquizofrenia , Humanos , Amissulprida/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Benzodiazepinas/uso terapêutico , Doença Crônica , Hiperprolactinemia/induzido quimicamente , Olanzapina/efeitos adversos , Olanzapina/uso terapêutico , Piperazinas/efeitos adversos , Quinolonas/efeitos adversos , Recidiva , Esquizofrenia/tratamento farmacológico
5.
Int J Mol Sci ; 23(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36362330

RESUMO

Soil salinization conditions seriously restrict cotton yield and quality. Related studies have shown that the DUF4228 proteins are pivotal in plant resistance to abiotic stress. However, there has been no systematic identification and analysis of the DUF4228 gene family in cotton and their role in abiotic stress. In this study, a total of 308 DUF4228 genes were identified in four Gossypium species, which were divided into five subfamilies. Gene structure and protein motifs analysis showed that the GhDUF4228 proteins were conserved in each subfamily. In addition, whole genome duplication (WGD) events and allopolyploidization might play an essential role in the expansion of the DUF4228 genes. Besides, many stress-responsive (MYB, MYC) and hormone-responsive (ABA, MeJA) related cis-elements were detected in the promoters of the DUF4228 genes. The qRT-PCR results showed that GhDUF4228 genes might be involved in the response to abiotic stress. VIGS assays and the measurement of relative water content (RWC), Proline content, POD activity, and malondialdehyde (MDA) content indicated that GhDUF4228-67 might be a positive regulator of cotton response to salt stress. The results in this study systematically characterized the DUF4228s in Gossypium species and will provide helpful information to further research the role of DUF4228s in salt tolerance.


Assuntos
Gossypium , Tolerância ao Sal , Gossypium/metabolismo , Tolerância ao Sal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Família Multigênica
6.
Psychopharmacology (Berl) ; 239(1): 83-91, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35029705

RESUMO

RATIONALE: It is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear. OBJECTIVE: To study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism. METHODS: Disturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia. RESULTS: Olanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77, p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10µM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase. CONCLUSIONS: Lipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.


Assuntos
Dislipidemias , Esquizofrenia , Animais , Dislipidemias/induzido quimicamente , Humanos , Camundongos , Olanzapina , Pró-Proteína Convertase 9 , Esquizofrenia/tratamento farmacológico
7.
Front Plant Sci ; 12: 690754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34386026

RESUMO

The SWEET (sugars will eventually be exported transporter) proteins, a family of sugar transporters, mediate sugar diffusion across cell membranes. Pathogenic fungi can acquire sugars from plant cells to satisfy their nutritional demands for growth and infection by exploiting plant SWEET sugar transporters. However, the mechanism underlying the sugar allocation in cotton plants infected by Verticillium dahliae, the causative agent of Verticillium wilt, remains unclear. In this study, observations of the colonization of cotton roots by V. dahliae revealed that a large number of conidia had germinated at 48-hour post-inoculation (hpi) and massive hyphae had appeared at 96 hpi. The glucose content in the infected roots was significantly increased at 48 hpi. On the basis of an evolutionary analysis, an association analysis, and qRT-PCR assays, GhSWEET42 was found to be closely associated with V. dahliae infection in cotton. Furthermore, GhSWEET42 was shown to encode a glucose transporter localized to the plasma membrane. The overexpression of GhSWEET42 in Arabidopsis thaliana plants led to increased glucose content, and compromised their resistance to V. dahliae. In contrast, knockdown of GhSWEET42 expression in cotton plants by virus-induced gene silencing (VIGS) led to a decrease in glucose content, and enhanced their resistance to V. dahliae. Together, these results suggest that GhSWEET42 plays a key role in V. dahliae infection in cotton through glucose translocation, and that manipulation of GhSWEET42 expression to control the glucose level at the infected site is a useful method for inhibiting V. dahliae infection.

8.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857289

RESUMO

Gaining a mechanistic understanding of the expansion and maturation program of natural killer (NK) cells will provide opportunities for harnessing their inflammation-inducing and oncolytic capacity for therapeutic purposes. Here, we demonstrated that ID2, a transcriptional regulatory protein constitutively expressed in NK cells, supports NK cell effector maturation by controlling the amplitude and temporal dynamics of the transcription factor TCF1. TCF1 promotes immature NK cell expansion and restrains differentiation. The increased TCF1 expression in ID2-deficient NK cells arrests their maturation and alters cell surface receptor expression. Moreover, TCF1 limits NK cell functions, such as cytokine-induced IFN-γ production and the ability to clear metastatic melanoma in ID2-deficient NK cells. Our data demonstrate that ID2 sets a threshold for TCF1 during NK cell development, thus controlling the balance of immature and terminally differentiated cells that support future NK cell responses.


Assuntos
Fator 1-alfa Nuclear de Hepatócito/metabolismo , Proteína 2 Inibidora de Diferenciação/metabolismo , Células Matadoras Naturais/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/fisiologia , Citocinas/metabolismo , Expressão Gênica/fisiologia , Interferon gama/metabolismo , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Gênica/fisiologia
9.
Front Psychiatry ; 12: 611070, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33716817

RESUMO

Introduction: Affecting ~1% of the world population, schizophrenia is known as one of the costliest and most burdensome diseases worldwide. Antipsychotic medications are the main treatment for schizophrenia to control psychotic symptoms and efficiently prevent new crises. However, due to poor compliance, 74% of patients with schizophrenia discontinue medication within 1.5 years, which severely affects recovery and prognosis. Through research on intra and interindividual variability based on a psychopathology-neuropsychology-neuroimage-genetics-physiology-biochemistry model, our main objective is to investigate an optimized and individualized antipsychotic-treatment regimen and precision treatment for first-episode schizophrenic patients. Methods and Analysis: The study is performed in 20 representative hospitals in China. Three subprojects are included. In subproject 1, 1,800 first-episode patients with schizophrenia are randomized into six different antipsychotic monotherapy groups (olanzapine, risperidone, aripiprazole, ziprasidone, amisulpride, and haloperidol) for an 8-week treatment. By identifying a set of potential biomarkers associated with antipsychotic treatment response, we intend to build a prediction model, which includes neuroimaging, epigenetics, environmental stress, neurocognition, eye movement, electrophysiology, and neurological biochemistry indexes. In subproject 2, apart from verifying the prediction model established in subproject 1 based on an independent cohort of 1,800 first-episode patients with schizophrenia, we recruit patients from a verification cohort who did not get an effective response after an 8-week antipsychotic treatment into a randomized double-blind controlled trial with minocycline (200 mg per day) and sulforaphane (3 tables per day) to explore add-on treatment for patients with schizophrenia. Two hundred forty participants are anticipated to be enrolled for each group. In subproject 3, we tend to carry out one trial to construct an intervention strategy for metabolic syndrome induced by antipsychotic treatment and another one to build a prevention strategy for patients at a high risk of metabolic syndrome, which combines metformin and lifestyle intervention. Two hundred participants are anticipated to be enrolled for each group. Ethics and Dissemination: The study protocol has been approved by the Medical Ethics committee of the Second Xiangya Hospital of Central South University (No. 2017027). Results will be disseminated in peer-reviewed journals and at international conferences. Trial Registration: This trial has been registered on Clinicalrials.gov (NCT03451734). The protocol version is V.1.0 (April 23, 2017).

11.
Blood Cancer Discov ; 1(2): 178-197, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32924017

RESUMO

Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements. Using complementary genetic approaches in mouse models, we show that ablation of Ets1 leads to strong Notch-mediated suppressive effects on T-cell development and leukemogenesis, but milder intestinal effects than pan-Notch inhibitors. Mechanistically, genome-wide chromatin profiling studies demonstrate that Ets1 inactivation impairs recruitment of multiple Notch-associated factors and Notch-dependent activation of transcriptional elements controlling major Notch-driven oncogenic effector pathways. These results uncover previously unrecognized hierarchical heterogeneity of Notch-controlled genes and points to Ets1-mediated enucleation of Notch-Rbpj transcriptional complexes as a target for developing specific anti-Notch therapies in T-ALL that circumvent the barriers of pan-Notch inhibition.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia de Células T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteína Proto-Oncogênica c-ets-1 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Leucemia de Células T/tratamento farmacológico , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Proteína Proto-Oncogênica c-ets-1/antagonistas & inibidores , Receptor Notch1/antagonistas & inibidores , Transdução de Sinais/fisiologia
12.
Adv Immunol ; 146: 1-28, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32327150

RESUMO

Natural killer cells are lymphocytes that respond rapidly to intracellular pathogens or cancer/stressed cells by producing pro-inflammatory cytokines or chemokines and by killing target cells through direct cytolysis. NK cells are distinct from B and T lymphocytes in that they become activated through a series of broadly expressed germ line encoded activating and inhibitory receptors or through the actions of inflammatory cytokines. They are the founding member of the innate lymphoid cell family, which mirror the functions of T lymphocytes, with NK cells being the innate counterpart to CD8 T lymphocytes. Despite the functional relationship between NK cells and CD8 T cells, the mechanisms controlling their specification, differentiation and maturation are distinct, with NK cells emerging from multipotent lymphoid progenitors in the bone marrow under the control of a unique transcriptional program. Over the past few years, substantial progress has been made in understanding the developmental pathways and the factors involved in generating mature and functional NK cells. NK cells have immense therapeutic potential and understanding how to acquire large numbers of functional cells and how to endow them with potent activity to control hematopoietic and non-hematopoietic malignancies and autoimmunity is a major clinical goal. In this review, we examine basic aspects of conventional NK cell development in mice and humans and discuss multiple transcription factors that are known to guide the development of these cells.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica , Imunidade Inata , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Animais , Citocinas/metabolismo , Humanos , Camundongos , Fatores de Transcrição/metabolismo
13.
JCI Insight ; 5(3)2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32051339

RESUMO

Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients, and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL-17 receptor A (IL-17ra-/-) or pharmacological blockade of IL-17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL-17A positively correlated with the alcohol use in excessive drinkers and was further increased in patients with ALD as compared with healthy individuals. Our data suggest that IL-17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL-17A may provide a novel strategy for treatment of alcohol-induced pathology.


Assuntos
Consumo de Bebidas Alcoólicas , Interleucina-17/sangue , Hepatopatias Alcoólicas/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Astrócitos/imunologia , Etanol/administração & dosagem , Humanos , Interleucina-17/imunologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores
14.
J Hepatol ; 72(5): 946-959, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31899206

RESUMO

BACKGROUND & AIMS: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. RESULTS: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra-/- and major urinary protein-urokinase-type plasminogen activator/Il-17ra-/- mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17raΔMΦ and Il-17raΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17raΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17raΔHep mice developed the fewest tumors (compared with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC. CONCLUSIONS: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. LAY SUMMARY: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Interleucina-17/metabolismo , Células de Kupffer/metabolismo , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/metabolismo , Neoplasias Hepáticas/metabolismo , Transdução de Sinais/genética , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Etanol/efeitos adversos , Deleção de Genes , Humanos , Cirrose Hepática/patologia , Hepatopatias Alcoólicas/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Transcriptoma
15.
Cell Rep ; 29(5): 1203-1220.e7, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665634

RESUMO

The basic leucine zipper transcription factor activating transcription factor-like (Batf) contributes to transcriptional programming of multiple effector T cells and is required for T helper 17 (Th17) and T follicular helper (Tfh) cell development. Here, we examine mechanisms by which Batf initiates gene transcription in developing effector CD4 T cells. We find that, in addition to its pioneering function, Batf controls developmentally regulated recruitment of the architectural factor Ctcf to promote chromatin looping that is associated with lineage-specific gene transcription. The chromatin-organizing actions of Batf are largely dependent on Ets1, which appears to be indispensable for the Batf-dependent recruitment of Ctcf. Moreover, most of the Batf-dependent sites to which Ctcf is recruited lie outside of activating protein-1-interferon regulatory factor (Ap-1-Irf) composite elements (AICEs), indicating that direct involvement of Batf-Irf complexes is not required. These results identify a cooperative role for Batf, Ets1, and Ctcf in chromatin reorganization that underpins the transcriptional programming of effector T cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fator de Ligação a CCCTC/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Cromatina/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Animais , Montagem e Desmontagem da Cromatina , Genoma , Humanos , Fatores Reguladores de Interferon/metabolismo , Interleucinas/metabolismo , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Ligação Proteica , Regulação para Cima/genética
16.
Cell Rep ; 27(11): 3124-3138.e13, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31189100

RESUMO

Biomineralization of the extracellular matrix is an essential, regulated process. Inappropriate mineralization of bone and the vasculature has devastating effects on patient health, yet an integrated understanding of the chemical and cell biological processes that lead to mineral nucleation remains elusive. Here, we report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADP-ribose) polymerases in response to oxidative and/or DNA damage. We use ultrastructural methods to show poly(ADP-ribose) can form both calcified spherical particles, reminiscent of those found in vascular calcification, and biomimetically calcified collagen fibrils similar to bone. Importantly, inhibition of poly(ADP-ribose) biosynthesis in vitro and in vivo inhibits biomineralization, suggesting a therapeutic route for the treatment of vascular calcifications. We conclude that poly(ADP-ribose) plays a central chemical role in both pathological and physiological extracellular matrix calcification.


Assuntos
Biomineralização , Dano ao DNA , Poli Adenosina Difosfato Ribose/metabolismo , Calcificação Vascular/metabolismo , Adolescente , Adulto , Idoso , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Bovinos , Linhagem Celular , Células Cultivadas , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteoblastos/patologia , Estresse Oxidativo , Ratos , Ratos Wistar , Ovinos
17.
Front Psychiatry ; 9: 620, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30542300

RESUMO

Antipsychotic-induced weight gain is one of the most common adverse effects of antipsychotic treatment. However, there are no well-established interventions for the weight gain yet. In this study, we pooled the data from two clinical trials, which were originally examining the efficacy of betahistine and the efficacy of metformin in treating antipsychotic-induced weight gain and insulin resistance. A total of 67 people with schizophrenia or bipolar disorder treated with antipsychotics were assigned to 36 mg day-1 betahistine (n = 13) or 1,000 mg day-1 metformin (n = 25) or placebo (n = 29) treatment for 12 weeks, with evaluation at baseline and week 12. The primary outcome was the body mass index (BMI). After treatment, metformin group had a mean decrease in BMI of 1.46 ± 0.14 (p < 0.001) and insulin resistance index (IRI) of 4.30 ± 2.02 (p < 0.001). The betahistine group had no significant alteration in BMI or IRI. However, placebo group had a mean increase in BMI of 1.27 ± 0.77 (p < 0.001) and IRI of 0.45 ± 0.86 (p < 0.001). Between the two treatment groups, metformin significantly decreased weight, BMI, fasting glucose, insulin level, and IRI but not waist circumference when compared with betahistine. Moreover, metformin significantly decreased weight, BMI, waist circumference, fasting glucose, insulin level, and IRI when compared with placebo, whereas betahistine significantly decreased body weight, waist circumference, BMI, insulin level, and IRI but not fasting glucose when compared with placebo. In this study, we found that both metformin treatment and betahistine treatment were efficacious in improving antipsychotic-induced weight gain and insulin resistance, and metformin was more efficacious in preventing and revising the weight gain induced by antipsychotics. Clinical Trial Registration: www.ClinicalTrials.gov, NCT00451399(Study 1), NCT00709202(Study 2).

18.
Immunity ; 47(3): 389-390, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930650

RESUMO

The transcriptional repressor Id2 is constitutively expressed in all innate lymphoid cells (ILCs) and is required for their development. In this issue of Immunity, Mowel et al. (2017) demonstrate that Id2 expression is regulated by a cell type-specific cis-regulatory element in group 1 ILCs that is demarcated by a long non-coding RNA.


Assuntos
Imunidade Inata/genética , Linfócitos/imunologia , Humanos , RNA Longo não Codificante , Sequências Reguladoras de Ácido Nucleico
19.
J Clin Invest ; 127(4): 1254-1270, 2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-28287406

RESUMO

Cholestatic liver fibrosis is caused by obstruction of the biliary tract and is associated with early activation of portal fibroblasts (PFs) that express Thy-1, fibulin 2, and the recently identified marker mesothelin (MSLN). Here, we have demonstrated that activated PFs (aPFs) and myofibroblasts play a critical role in the pathogenesis of liver fibrosis induced by bile duct ligation (BDL). Conditional ablation of MSLN+ aPFs in BDL-injured mice attenuated liver fibrosis by approximately 50%. Similar results were observed in MSLN-deficient mice (Msln-/- mice) or mice deficient in the MSLN ligand mucin 16 (Muc16-/- mice). In vitro analysis revealed that MSLN regulates TGF-ß1-inducible activation of WT PFs by disrupting the formation of an inhibitory Thy-1-TGFßRI complex. MSLN also facilitated the FGF-mediated proliferation of WT aPFs. Therapeutic administration of anti-MSLN-blocking Abs attenuated BDL-induced fibrosis in WT mice. Liver specimens from patients with cholestatic liver fibrosis had increased numbers of MSLN+ aPFs/myofibroblasts, suggesting that MSLN may be a potential target for antifibrotic therapy.


Assuntos
Antígeno Ca-125/metabolismo , Fibroblastos/metabolismo , Proteínas Ligadas por GPI/metabolismo , Cirrose Hepática Biliar/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Antígeno Ca-125/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Fibroblastos/patologia , Proteínas Ligadas por GPI/genética , Humanos , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/patologia , Masculino , Proteínas de Membrana/genética , Mesotelina , Camundongos , Camundongos Knockout , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
20.
Eur J Immunol ; 47(5): 800-805, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28276053

RESUMO

Group 1 innate lymphoid cells include natural killer (NK) cells and ILC1s, which mediate the response to intracellular pathogens. Thymic NK (tNK) cells were described with hybrid features of immature NK cells and ILC1 but whether these cells are related to NK cells or ILC1 has not been fully investigated. We report that murine tNK cells expressed the NK-cell associated transcription factor EOMES and developed independent of the essential ILC1 factor TBET, confirming their placement within the NK lineage. Moreover, tNK cells resemble NK cells rather than ILC1 in their requirements for the E protein transcription factor inhibitor ID2. We provide further insight into the mechanisms governing tNK-cell development by showing that the transcription factor ETS1 prevented tNK cell acquisition of the conventional NK-cell maturation markers CD11b and KLRG1. Our data reveal few ILC1 in the thymus and clarify the identity and developmental requirements of tNK cells.


Assuntos
Células Matadoras Naturais/fisiologia , Linfócitos/fisiologia , Timo/imunologia , Fatores de Transcrição/metabolismo , Animais , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Diferenciação Celular , Linhagem da Célula , Imunidade Inata , Proteína 2 Inibidora de Diferenciação/genética , Proteína 2 Inibidora de Diferenciação/metabolismo , Células Matadoras Naturais/imunologia , Lectinas Tipo C , Linfócitos/imunologia , Camundongos , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Proteínas com Domínio T/genética , Timócitos/citologia , Timócitos/fisiologia , Timo/citologia , Fatores de Transcrição/genética
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