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1.
EMBO J ; 42(16): e114153, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37382276

RESUMO

Innate lymphoid cells (ILCs) are a diverse population of cells that include NK cells and contribute to tissue homeostasis and repair, inflammation, and provide protection from infection. The interplay between human blood ILCs, as well as their responses to HIV-1 infection, remains poorly understood. This study used transcriptional and chromatin profiling to explore these questions. Transcriptional profiling and flow cytometry analysis support that there are four main ILC subsets found in human blood. Unlike in mice, human NK cells expressed the tissue repair protein amphiregulin (AREG). AREG production was induced by TCF7/WNT, IL-2, and IL-15, and inhibited by TGFB1, a cytokine increased in people living with HIV-1. In HIV-1 infection, the percentage of AREG+ NK cells correlated positively with the numbers of ILCs and CD4+ T cells but negatively with the concentration of inflammatory cytokine IL-6. NK-cell knockout of the TGFB1-stimulated WNT antagonist RUNX3 increased AREG production. Antiviral gene expression was increased in all ILC subsets from HIV-1 viremic people, and anti-inflammatory gene MYDGF was increased in an NK-cell subset from HIV-1-infected people whose viral load was undetectable in the absence of antiretroviral therapy. The percentage of defective NK cells in people living with HIV-1 correlated inversely with ILC percentage and CD4+ T-cell counts. CD4+ T cells and their production of IL-2 prevented the loss of NK-cell function by activating mTOR. These studies clarify how ILC subsets are interrelated and provide insight into how HIV-1 infection disrupts NK cells, including an uncharacterized homeostatic function in NK cells.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Camundongos , Animais , Imunidade Inata , Linfócitos/metabolismo , HIV-1/metabolismo , Interleucina-2/metabolismo , Cromatina , Células Matadoras Naturais , Citocinas , Infecções por HIV/genética
2.
Plant Cell Environ ; 46(3): 850-864, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36573466

RESUMO

The maintenance of a proton gradient across the thylakoid membrane is an integral aspect of photosynthesis that is mainly established by the splitting of water molecules in photosystem II and plastoquinol oxidation at the cytochrome complex, and it is necessary for the generation of ATP in the last step of photophosphorylation. Although environmental stresses, such as high temperatures, are known to disrupt this fundamental process, only a few studies have explored the molecular mechanisms underlying proton gradient regulation during stress. The present study identified a heat-sensitive mutant that displays aberrant photosynthesis at high temperatures. This mutation was mapped to AtFtsH11, which encodes an ATP-dependent AAA-family metalloprotease. We showed that AtFtsH11 localizes to the chloroplast inner envelope membrane and is capable of degrading the ATP synthase assembly factor BFA3 under heat stress. We posit that this function limits the amount of ATP synthase integrated into the thylakoid membrane to regulate proton efflux from the lumen to the stroma. Our data also suggest that AtFtsH11 is critical in stabilizing photosystem II and cytochrome complexes at high temperatures, and additional studies can further elucidate the specific molecular functions of this critical regulator of photosynthetic thermotolerance.


Assuntos
Arabidopsis , ATPases de Cloroplastos Translocadoras de Prótons , ATPases de Cloroplastos Translocadoras de Prótons/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , Prótons , Arabidopsis/genética , Arabidopsis/metabolismo , Cloroplastos/metabolismo , Fotossíntese/fisiologia , Resposta ao Choque Térmico , Trifosfato de Adenosina/metabolismo , Citocromos/metabolismo
3.
Int J Mol Sci ; 23(8)2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35457261

RESUMO

High light intensity as one of the stresses could lead to generation of large amounts of reactive oxygen species (ROS) in plants, resulting in severe plant growth retardation. The photorespiration metabolism plays an important role in producing and removing a variety of ROS, maintaining the dynamic balance of the redox reaction, and preventing photoinhibition. Arabidopsis hydroxypyruvate reductase 1 (HPR1) is a primary metabolic enzyme in the photorespiration cycle. However, the role of HPR1 in plants response to high light is not clear. Here, we found that the expression of HPR1 could be induced by high light intensity. The growth and photosynthetic capacity of hpr1 mutants are seriously affected under high light intensity. The absence of HPR1 suppresses the rates of photorepair of Photosystem II (PSII), aggravates the production of ROS, and accelerates photorespiration rates. Moreover, the activity of ROS scavenging enzymes in the hpr1 mutants is significantly higher. These results indicate that HPR1 is involved in plant response to high light intensity and is essential for maintaining the dynamic balance of ROS and photorespiration.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Hidroxipiruvato Redutase/metabolismo , Luz , Fotossíntese/genética , Complexo de Proteína do Fotossistema II/genética , Complexo de Proteína do Fotossistema II/metabolismo , Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Elife ; 112022 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-35275061

RESUMO

Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n = 40), treated for COVID-19 as outpatients (n = 51), and in uninfected controls (n = 86), as well as in children with COVID-19 (n = 19), recovering from COVID-19 (n = 14), MIS-C (n = 11), recovering from MIS-C (n = 7), and pediatric controls (n = 17). Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls. Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males. Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.


Assuntos
COVID-19 , Linfopenia , Anfirregulina , COVID-19/complicações , Criança , Feminino , Humanos , Imunidade Inata , Inflamação , Masculino , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Subpopulações de Linfócitos T
5.
GEN Biotechnol ; 1(3): 271-284, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38405215

RESUMO

Type V CRISPR-Cas12a systems are an attractive Cas9-alternative nuclease platform for specific genome editing applications. However, previous studies demonstrate that there is a gap in overall activity between Cas12a and Cas9 in primary cells.1 Here we describe optimization to the NLS composition and architecture of Cas12a to facilitate highly efficient targeted mutagenesis in human transformed cell lines (HEK293T, Jurkat, and K562 cells) and primary cells (NK cells and CD34+ HSPCs), regardless of Cas12a ortholog. Our 3xNLS Cas12a architecture resulted in the most robust editing platform. The improved editing activity of Cas12a in both NK cells and CD34+ HSPCs resulted in pronounced phenotypic changes associated with target gene editing. Lastly, we demonstrated that optimization of the NLS composition and architecture of Cas12a did not increase editing at potential off-target sites in HEK293T or CD34+ HSPCs. Our new Cas12a NLS variant provides an improved nuclease platform for therapeutic genome editing.

6.
medRxiv ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33469605

RESUMO

Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. This study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was higher in females than in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males.

7.
IEEE Trans Neural Netw Learn Syst ; 32(8): 3664-3676, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822310

RESUMO

Recently emerged deep learning methods have achieved great success in single image rain streaks removal. However, existing methods ignore an essential factor in the rain streaks generation mechanism, i.e., the motion blur leading to the line pattern appearances. Thus, they generally produce overderaining or underderaining results. In this article, inspired by the generation mechanism, we propose a novel rain streaks removal framework using a kernel-guided convolutional neural network (KGCNN), achieving state-of-the-art performance with a simple network architecture. More precisely, our framework consists of three steps. First, we learn the motion blur kernel by a plain neural network, termed parameter network, from the detail layer of a rainy patch. Then, we stretch the learned motion blur kernel into a degradation map with the same spatial size as the rainy patch. Finally, we use the stretched degradation map together with the detail patches to train a deraining network with a typical ResNet architecture, which produces the rain streaks with the guidance of the learned motion blur kernel. Experiments conducted on extensive synthetic and real data demonstrate the effectiveness of the proposed KGCNN, in terms of rain streaks removal and image detail preservation.

8.
Virus Res ; 292: 198246, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33249060

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.


Assuntos
Antivirais/farmacologia , Carbamatos/farmacologia , Carbazóis/farmacologia , Citocinas/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Chlorocebus aethiops , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/imunologia , Di-Hidro-Orotato Desidrogenase , Células HeLa , Humanos , Inflamação/tratamento farmacológico , Inflamação/virologia , Células Vero , Tratamento Farmacológico da COVID-19
9.
Cell ; 183(3): 739-751.e8, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32991842

RESUMO

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, including Chinese rufous horseshoe bat and Malayan pangolin. D614G did not alter S protein synthesis, processing, or incorporation into SARS-CoV-2 particles, but D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts an interprotomer contact and that the conformation is shifted toward an ACE2 binding-competent state, which is modeled to be on pathway for virion membrane fusion with target cells. Consistent with this more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated.


Assuntos
Betacoronavirus/fisiologia , Betacoronavirus/ultraestrutura , Glicoproteína da Espícula de Coronavírus/fisiologia , Glicoproteína da Espícula de Coronavírus/ultraestrutura , Enzima de Conversão de Angiotensina 2 , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Células Cultivadas , Infecções por Coronavirus/virologia , Feminino , Variação Genética , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Conformação Proteica , Processamento de Proteína Pós-Traducional , Receptores de Coronavírus , Receptores Virais/metabolismo , SARS-CoV-2 , Especificidade da Espécie
10.
bioRxiv ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32793904

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC 50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.

11.
Cell Rep ; 32(5): 107998, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32755590

RESUMO

Adipocytes deficient in fatty acid synthase (iAdFASNKO) emit signals that mimic cold exposure to enhance the appearance of thermogenic beige adipocytes in mouse inguinal white adipose tissues (iWATs). Both cold exposure and iAdFASNKO upregulate the sympathetic nerve fiber (SNF) modulator Neuregulin 4 (Nrg4), activate SNFs, and require adipocyte cyclic AMP/protein kinase A (cAMP/PKA) signaling for beige adipocyte appearance, as it is blocked by adipocyte Gsα deficiency. Surprisingly, however, in contrast to cold-exposed mice, neither iWAT denervation nor Nrg4 loss attenuated adipocyte browning in iAdFASNKO mice. Single-cell transcriptomic analysis of iWAT stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type in iAdFASNKO mice, and their depletion abrogated iWAT beiging. Altogether, these findings reveal that divergent cellular pathways are sufficient to cause adipocyte browning. Importantly, adipocyte signaling to enhance alternatively activated macrophages in iAdFASNKO mice is associated with enhanced adipose thermogenesis independent of the sympathetic neuron involvement this process requires in the cold.


Assuntos
Adipócitos Bege/metabolismo , Macrófagos/metabolismo , RNA/metabolismo , Transdução de Sinais , Análise de Célula Única , Termogênese , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Polaridade Celular , Temperatura Baixa , AMP Cíclico/metabolismo , Denervação , Ácido Graxo Sintases/metabolismo , Ativação de Macrófagos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurregulinas/deficiência , Neurregulinas/metabolismo , Fenótipo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Regulação para Cima/genética
12.
bioRxiv ; 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32637944

RESUMO

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor.

13.
Gastroenterol Res Pract ; 2020: 7907195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256566

RESUMO

Secondary prevention is an important strategy in gastric cancer. Low-grade intraepithelial neoplasia (LGIN) is the last stage of precancerous lesion, and its timely diagnosis can greatly improve the detection rate of early gastric cancer. We performed a prospective study to analyze the risk factors of gastric LGIN in asymptomatic subjects undergoing physical examination. A total of 3437 subjects were included in this study, and 2259 asymptomatic subjects were investigated from March 2015 to April 2018. Risk factors were evaluated, and the endoscopic features of LGIN and prognosis were described. The overall incidence of LGIN was 19.73% (678/3437), while the incidence of LGIN in the asymptomatic and symptomatic groups was 19.65% (444/2259) and 19.86% (234/1178), respectively (P = 0.884). The rate of Helicobacter pylori infection in this physical examination population was 39.13% (35.8% asymptomatic group, 45.5% symptomatic group; P ≤ 0.001). Risk factors including age, H. pylori infection, history of antibiotic misuse, and spicy and high-fat diet (all P < 0.05) were further verified by multivariate analysis as independent risk factors. History of antibiotic misuse and H. pylori infection showed significant associations with LGIN (odds ratio (OR) = 6.767, 95% confidence interval (CI) 3.873-11.825 and OR = 3.803, 95% CI 3.009-4.808, respectively). The most common endoscopic classification of LGIN was erosive gastritis (50.78%), and the major endoscopic appearance was Paris IIa (flat with slight elevation located mostly in the antrum). During the mean follow-up period of 15.02 months, 49.4% of LGIN regressed, 0.61% of LGIN progressed, and 50% of LGIN remained unchanged. History of antibiotic misuse and H. pylori infection were predominant risk factors of LGIN in asymptomatic subjects, and those individuals should consider early screening for gastric cancer.

14.
Nat Immunol ; 21(3): 274-286, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066947

RESUMO

Human immunodeficiency virus 1 (HIV-1) infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer and other complications. These pathologies persist despite antiretroviral therapy. In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective antiretroviral therapy. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation and natural killer (NK) cell skewing towards an inflammatory state, with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo. These results show that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.


Assuntos
Citocinas/sangue , HIV-1/imunologia , HIV-1/patogenicidade , Imunidade Inata , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Fator 1 de Transcrição de Linfócitos T/imunologia , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , Homeostase/imunologia , Humanos , Memória Imunológica , Técnicas In Vitro , Inflamação/genética , Inflamação/imunologia , Inflamação/virologia , Fator 1 de Transcrição de Linfócitos T/genética , Via de Sinalização Wnt/imunologia
15.
Front Plant Sci ; 11: 602782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33391315

RESUMO

Mitochondrial transcription termination factors (mTERFs) are highly conserved proteins in metazoans. Plants have many more mTERF proteins than animals. The functions and the underlying mechanisms of plants' mTERFs remain largely unknown. In plants, mTERF family proteins are present in both mitochondria and plastids and are involved in gene expression in these organelles through different mechanisms. In this study, we screened Arabidopsis mutants with pigment-defective phenotypes and isolated a T-DNA insertion mutant exhibiting seedling-lethal and albino phenotypes [seedling lethal 1 (sl1)]. The SL1 gene encodes an mTERF protein localized in the chloroplast stroma. The sl1 mutant showed severe defects in chloroplast development, photosystem assembly, and the accumulation of photosynthetic proteins. Furthermore, the transcript levels of some plastid-encoded proteins were significantly reduced in the mutant, suggesting that SL1/mTERF3 may function in the chloroplast gene expression. Indeed, SL1/mTERF3 interacted with PAP12/PTAC7, PAP5/PTAC12, and PAP7/PTAC14 in the subgroup of DNA/RNA metabolism in the plastid-encoded RNA polymerase (PEP) complex. Taken together, the characterization of the plant chloroplast mTERF protein, SL1/mTERF3, that associated with PEP complex proteins provided new insights into RNA transcription in the chloroplast.

16.
Proc Natl Acad Sci U S A ; 116(49): 24760-24769, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31740609

RESUMO

Intestinal innate lymphoid cells (ILCs) contribute to the protective immunity and homeostasis of the gut, and the microbiota are critically involved in shaping ILC function. However, the role of the gut microbiota in regulating ILC development and maintenance still remains elusive. Here, we identified opposing effects on ILCs by two Helicobacter species, Helicobacter apodemus and Helicobacter typhlonius, isolated from immunocompromised mice. We demonstrated that the introduction of both Helicobacter species activated ILCs and induced gut inflammation; however, these Helicobacter species negatively regulated RORγt+ group 3 ILCs (ILC3s), especially T-bet+ ILC3s, and diminished their proliferative capacity. Thus, these findings underscore a previously unknown dichotomous regulation of ILC3s by Helicobacter species, and may serve as a model for further investigations to elucidate the host-microbe interactions that critically sustain the maintenance of intestinal ILC3s.


Assuntos
Colite/imunologia , Infecções por Enterobacteriaceae/imunologia , Microbioma Gastrointestinal/imunologia , Helicobacter/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Animais , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/microbiologia , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Tolerância Imunológica , Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Linfócitos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo
17.
Pathol Res Pract ; 215(6): 152401, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31014553

RESUMO

BACKGROUND: MicroRNA-145 (miR-145) is commonly down-regulated and has been identified as a tumor-suppressive miRNA in multiple types of cancers, as well as in esophageal squamous cell carcinoma (ESCC). In the present study, the clinical significance and prognostic value were investigated in ESCC. METHODS: A total of 126 patients with ESCC who underwent surgery were included in the present study. miR-145 expression was determined using quantitative real-time polymerase chain reaction assay (qRT-PCR) and was further correlated with patients' clinicopathological parameters. Overall survival was estimated by using Kaplan-Meier method, and univariate analysis was conducted by log-rank test. The Cox proportional hazards model was used in the multivariate analysis. RESULTS: miR-145 expression levels in ESCC tissues were significantly decreased compared with the adjacent normal zones (P < 0.001). We observed that the expression level of miR-145 was positively correlated with the tumor differentiation (P = 0.015), lymph node status (P = 0.007), distant metastasis (P = 0.008), and TNM stage (P = 0.033). ESCC patients with low miR-145 expression level had shorter overall survival than those with high miR-145 expression level (log-rank test, P = 0.032). Furthermore, multivariate Cox regression analysis showed that miR-145 expression level was independent factor in predicting the overall survival of ESCC patients (HR = 1.993, 95% CI: 1.277-8.283, P = 0.023). CONCLUSIONS: Our findings indicated that miR-145 expression may be a useful prognostic marker that could be used for predicting overall survival of patients with ESCC.


Assuntos
Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , MicroRNAs/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico
18.
Pathobiology ; 85(5-6): 322-331, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30223275

RESUMO

OBJECTIVE: This study aims to investigate the mechanism of proliferation potential-related protein (PP-RP) in influencing the proliferation, migration, and apoptosis of esophageal cancer cells. METHODS: Quantitative real-time PCR and western blotting were performed to analyze the expression of PP-RP gene, p53, and interleukin (IL)-17 in human normal tissues and tumor tissues, as well as the expression of p53 and IL-17 in Eca109 and TE3 cells. The esophageal cancer cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell apoptosis was detected by flow cytometry, and cell migration was detected by transwell migration. RESULTS: PP-RP expressed highly in tumor tissue and Eca109 and TE3 cells, PP-RP overexpression inhibited the expression of p53 and promoted the expression of IL-17 in Eca109 and TE3 cells. PP-RP overexpression increased the expression of F-actin, promoted cell proliferation, and migration and suppressed cell apoptosis. Cell proliferation ability and cell migration ability were significantly strengthened while apoptosis was suppressed by PP-RP + pyruvate carboxylase deoxyribonucleic acid (PCDNA)-p53 group and PP-RP + IL-17 siRNA group in TE3 cells. CONCLUSION: Our data suggest that PP-RP promotes esophageal cancer cell proliferation and migration, and suppresses apoptosis by mediating the expression of p53 and IL-17.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica/genética , Interleucina-17/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Humanos , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/metabolismo
19.
BMC Cancer ; 16: 212, 2016 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-26968702

RESUMO

BACKGROUND: Studies examining the association between alcohol intake and the risk of pancreatic cancer have given inconsistent results. The purpose of this study was to summarize and examine the evidence regarding the association between alcohol intake and pancreatic cancer risk based on results from prospective cohort studies. METHODS: We searched electronic databases consisting of PubMed, Ovid, Embase, and the Cochrane Library identifying studies published up to Aug 2015. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) for the risk of pancreatic cancer, examining different alcohol intake categories compared with a low alcohol intake category were included. Results of individual studies were pooled using a random-effects model. RESULTS: We included 19 prospective studies (21 cohorts) reporting data from 4,211,129 individuals. Low-to-moderate alcohol intake had little or no effect on the risk of pancreatic cancer. High alcohol intake was associated with an increased risk of pancreatic cancer (risk ratio [RR], 1.15; 95% CI: 1.06-1.25). Pooled analysis also showed that high liquor intake was associated with an increased risk of pancreatic cancer (RR, 1.43; 95% CI: 1.17-1.74). Subgroup analyses suggested that high alcohol intake was associated with an increased risk of pancreatic cancer in North America, when the duration of follow-up was greater than 10 years, in studies scored as high quality, and in studies with adjustments for smoking status, body mass index, diabetes mellitus, and energy intake.. CONCLUSIONS: Low-to-moderate alcohol intake was not significantly associated with the risk of pancreatic cancer, whereas high alcohol intake was associated with an increased risk of pancreatic cancer. Furthermore, liquor intake in particular was associated with an increased risk of pancreatic cancer.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/patologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Álcoois/toxicidade , Índice de Massa Corporal , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Metabolismo Energético , Feminino , Humanos , Masculino , América do Norte , Neoplasias Pancreáticas/induzido quimicamente , Fatores de Risco
20.
Int J Clin Exp Pathol ; 8(11): 15307-11, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26823885

RESUMO

Lesions occur in hepatogastric gap is common, but most of these lesions are from stomach, lower esophagus and pancreas lesions extending or transferring to the gap. Lesions occurred in the hepatogastric ligament are rare, especially bronchogenic cysts in the hepatogastric ligament. So far, there were no relevant cases reported. Here, we report a case of bronchogenic cyst in the hepatogastric ligament that masquerading as an esophageal mesenchymal tumor. A 24-year-old young man presented with abdominal bloating was diagnosed as esophageal mesenchymal tumor in previous hospital by gastroscopy, endoscopic ultrasonography (EUS) and computed tomography (CT) examination. For the sake of endoscopic submucosal dissection (ESD), the man was transferred to our hospital. During surgery, we found no lesions in lower esophagus, but external pressure ridge lesions in the distal esophagus right side wall. Then laparoscopic surgery and pathology confirmed as bronchogenic cyst in the hepatogastric ligament. We report what is, to the best of our knowledge, the first case of a bronchogenic cyst in the hepatogastric ligament masquerading as an esophageal mesenchymal tumor.


Assuntos
Cisto Broncogênico/diagnóstico , Erros de Diagnóstico , Neoplasias Esofágicas/diagnóstico , Biópsia , Cisto Broncogênico/cirurgia , Endossonografia , Gastroscopia , Humanos , Laparoscopia , Masculino , Valor Preditivo dos Testes , Tomografia Computadorizada por Raios X , Adulto Jovem
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