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2.
Mitochondrial DNA B Resour ; 6(3): 938-940, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33796690

RESUMO

Agrimonia pilosa var. nepalensis (D. Don) Nakai is an herbaceous species of Rosaceae distributed in China. It has ornamental and ecological values. Lack of genetic background seriously hinders its further research and utilization. To provide genetic information for further study of it, complete chloroplast (cp) genome was characterized in this study. The genome is a circular molecule of 155,147 bp in length with overall GC content of 36.9%, which contains 85 protein-coding genes, eight ribosomal RNA genes, and 37 transfer RNA genes. It contains a typical tetrad structure, including a large single copy, a small single copy, and two inverted repeat regions. Phylogenetic analysis revealed that A. pilosa var. nepalensis and A. pilosa are closely related. Result of this study could provide genetic information for further research of A. pilosa var. nepalensis.

3.
Theranostics ; 10(23): 10606-10618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929369

RESUMO

Esophageal squamous cell carcinoma (ESCC) patients with a synchronous or metachronous lung tumor can be diagnosed with lung metastasis (LM) or a second primary tumor (SPT), but the accurate discrimination between LM and SPT remains a clinical dilemma. This study aimed to investigate the feasibility of using the whole-exome sequencing (WES) technique to distinguish SPT from LM. Methods: We performed WES on 40 tumors from 14 patients, including 12 patients with double squamous cell carcinomas (SCCs) of the esophagus and lung (lymph node metastases were sequenced as internal controls) diagnosed as LM according to pathological information and 2 patients with paired primary ESCC and non-lung metastases examined as external controls. Results: Shared genomic profiles between esophageal (T) and lung (D) tumors were observed in 7 patients, suggesting their clonal relatedness, thus indicating that the lung tumors of these patients should be LM. However, distinct genomic profiles between T and D tumors were observed in the other 5 patients, suggesting the possibility of SPTs that were likely formed through independent multifocal oncogenesis. Conclusions: Our data demonstrate the limitations and insufficiency of clinicopathological criteria and that WES could be useful in understanding the clonal relationships of multiple SCCs.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Neoplasias Pulmonares/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/secundário , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Esôfago/patologia , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/cirurgia , Pneumonectomia , Sequenciamento Completo do Exoma
4.
Cell Res ; 30(9): 717-731, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32355288

RESUMO

Metabolic diseases are the most common and rapidly growing health issues worldwide. The massive population-based human genetics is crucial for the precise prevention and intervention of metabolic disorders. The China Metabolic Analytics Project (ChinaMAP) is based on cohort studies across diverse regions and ethnic groups with metabolic phenotypic data in China. Here, we describe the centralized analysis of the deep whole genome sequencing data and the genetic bases of metabolic traits in 10,588 individuals from the ChinaMAP. The frequency spectrum of variants, population structure, pathogenic variants and novel genomic characteristics were analyzed. The individual genetic evaluations of Mendelian diseases, nutrition and drug metabolism, and traits of blood glucose and BMI were integrated. Our study establishes a large-scale and deep resource for the genetics of East Asians and provides opportunities for novel genetic discoveries of metabolic characteristics and disorders.

6.
J Virol ; 94(9)2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32051269

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi's sarcoma (KS), the most common malignancy in people living with human immunodeficiency virus (HIV)/AIDS. The oral cavity is a major route for KSHV infection and transmission. However, how KSHV breaches the oral epithelial barrier for spreading to the body is not clear. Here, we show that exosomes purified from either the saliva of HIV-positive individuals or the culture supernatants of HIV-1-infected T-cell lines promote KSHV infectivity in immortalized and primary human oral epithelial cells. HIV-associated saliva exosomes contain the HIV trans-activation response element (TAR), Tat, and Nef RNAs but do not express Tat and Nef proteins. The TAR RNA in HIV-associated exosomes contributes to enhancing KSHV infectivity through the epidermal growth factor receptor (EGFR). An inhibitory aptamer against TAR RNA reduces KSHV infection facilitated by the synthetic TAR RNA in oral epithelial cells. Cetuximab, a monoclonal neutralizing antibody against EGFR, blocks HIV-associated exosome-enhanced KSHV infection. Our findings reveal that saliva containing HIV-associated exosomes is a risk factor for the enhancement of KSHV infection and that the inhibition of EGFR serves as a novel strategy for preventing KSHV infection and transmission in the oral cavity.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi's sarcoma (KS), the most common malignancy in HIV/AIDS patients. Oral transmission through saliva is considered the most common route for spreading the virus among HIV/AIDS patients. However, the role of HIV-specific components in the cotransfection of KSHV is unclear. We demonstrate that exosomes purified from the saliva of HIV-positive patients and secreted by HIV-infected T-cell lines promote KSHV infectivity in immortalized and primary oral epithelial cells. HIV-associated exosomes promote KSHV infection, which depends on HIV trans-activation response element (TAR) RNA and EGFR of oral epithelial cells, which can be targeted for reducing KSHV infection. These results reveal that HIV-associated exosomes are a risk factor for KSHV infection in the HIV-infected population.


Assuntos
Exossomos/metabolismo , Sarcoma de Kaposi/metabolismo , Adulto , Linhagem Celular , Epitélio/metabolismo , Epitélio/virologia , Receptores ErbB/metabolismo , Infecções por HIV/virologia , HIV-1/metabolismo , HIV-1/fisiologia , Herpesvirus Humano 8/metabolismo , Herpesvirus Humano 8/patogenicidade , Humanos , Masculino , Saliva/química , Saliva/virologia , Sarcoma de Kaposi/virologia , Ativação Viral , Replicação Viral
7.
Nat Commun ; 9(1): 4585, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389917

RESUMO

People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDS-defining cancers (NADCs). However, the underlying mechanism for development and progression of certain NADCs remains obscure. Here we show that exosomes released from HIV-infected T cells and those purified from blood of HIV-positive patients stimulate proliferation, migration and invasion of oral/oropharyngeal and lung cancer cells. The HIV transactivation response (TAR) element RNA in HIV-infected T-cell exosomes is responsible for promoting cancer cell proliferation and inducing expression of proto-oncogenes and Toll-like receptor 3 (TLR3)-inducible genes. These effects depend on the loop/bulge region of the molecule. HIV-infected T-cell exosomes rapidly enter recipient cells through epidermal growth factor receptor (EGFR) and stimulate ERK1/2 phosphorylation via the EGFR/TLR3 axis. Thus, our findings indicate that TAR RNA-containing exosomes from HIV-infected T cells promote growth and progression of particular NADCs through activation of the ERK cascade in an EGFR/TLR3-dependent manner.


Assuntos
Progressão da Doença , Exossomos/metabolismo , Infecções por HIV/metabolismo , Repetição Terminal Longa de HIV/genética , HIV-1/fisiologia , Neoplasias/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Receptores ErbB/metabolismo , Exossomos/ultraestrutura , Regulação da Expressão Gênica , Células HEK293 , Infecções por HIV/sangue , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos Nus , Fosforilação , Linfócitos T/metabolismo , Linfócitos T/virologia , Receptor 3 Toll-Like/metabolismo
8.
Front Microbiol ; 9: 302, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535688

RESUMO

Human beta defensins (hBDs) are small cationic peptides, expressed in mucosal epithelia and important agents of innate immunity, act as antimicrobial and chemotactic agents at mucosal barriers. In this perspective, we present evidence supporting a novel strategy by which the oral bacterium Fusobacterium nucleatum induces hBDs and other antimicrobial peptides (AMPs) in normal human oral epithelial cells (HOECs) and thereby protects them from other microbial pathogens. The findings stress (1) the physiological importance of hBDs, (2) that this strategy may be a mechanism that contributes to homeostasis and health in body sites constantly challenged with bacteria and (3) that novel properties identified in commensal bacteria could, one day, be harnessed as new probiotic strategies to combat colonization of opportunistic pathogens. With that in mind, we highlight and review the discovery and characterization of a novel lipo-protein, FAD-I (Fusobacterium Associated Defensin Inducer) associated with the outer membrane of F. nucleatum that may act as a homeostatic agent by activating endogenous AMPs to re-equilibrate a dysregulated microenvironment. FAD-I has the potential to reduce dysbiosis-driven diseases at a time when resistance to antibiotics is increasing. We therefore postulate that FAD-I may offer a new paradigm in immunoregulatory therapeutics to bolster host innate defense of vulnerable mucosae, while maintaining physiologically responsive states of inflammation.

9.
Carcinogenesis ; 39(5): 708-718, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29546405

RESUMO

Synchronous colorectal cancers (syCRCs), which present two or more lesions at diagnosis, are rare and pose a great challenge for clinical management. Although some predisposing factors associated with syCRCs have been studied with limited accession, the full repertoire of genomic events among the lesions within an individual and the causes of syCRCs remain unclear. We performed whole-exome sequencing of 40 surgical tumour samples of paired lesions from 20 patients to characterize the genetic alterations. Lesions from same patient showed distinct landscapes of somatic aberrations and shared few mutations, which suggests that they originate and develop independently, although they shared the similar genetic background. Canonical genes, such as APC, KRAS, TP53 and PIK3CA, were frequently mutated in the syCRCs, and most of them show different mutation profile compared with solitary colorectal cancer. We identified a recurrent somatic alteration (K15fs) in RPL22 in 25% of the syCRCs. Functional analysis indicated that mutated RPL22 may suppress cell apoptosis and promote the epithelial-mesenchymal transition (EMT). Potential drug targets were identified in several signalling pathways, and they present great discrepancy between lesions from the same patient. Our data show that the syCRCs within the same patient present great genetic heterogeneity, and they may be driven by distinct molecular events and develop independently. The discrepancy of potential drug targets and mutation burden in lesions from one patient provides valuable information in clinical management for patients with syCRCs.


Assuntos
Neoplasias Colorretais/genética , Apoptose/genética , Variações do Número de Cópias de DNA/genética , Transição Epitelial-Mesenquimal/genética , Exoma/genética , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação/genética , Transdução de Sinais/genética
10.
Sci Rep ; 7(1): 15324, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127303

RESUMO

Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs). PTEN, DCDC1 and CUL3 were first reported as SMGs in ESCC. Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC. Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2. Moreover, database annotation suggested that two significantly differential CNA genes (PIK3CA and FBXW7) between subtype3 and subtype2 may serve as therapeutic drug targets. This study has extended our knowledge of the genetic basis of ESCC and shed some light into the clinical relevance, which would help improve the therapy and prognosis of ESCC patients.


Assuntos
Carcinoma de Células Escamosas/genética , Bases de Dados de Ácidos Nucleicos , Neoplasias Esofágicas/genética , Mutação , Proteínas de Neoplasias/genética , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Feminino , Humanos , Masculino , Prognóstico
11.
Virology ; 487: 172-87, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26539799

RESUMO

We previously showed that expression of the anti-HIV innate proteins human beta-defensin 2 (hBD2) and hBD3 in adult oral epithelial cells reduces HIV transepithelial transmission by inactivation of virus. However, fetal/infant oral epithelia lack beta-defensin expression, leading to transmission of HIV. The mechanisms of hBD2- and hBD3-mediated HIV inactivation in adult oral epithelial cells are poorly understood. Here we found that heparan sulfate proteoglycans (HSPGs) on the apical surfaces of epithelial cells facilitate simultaneous binding of hBDs and HIV gp120 to the cell surface. HSPG-facilitated binding of hBDs and HIV gp120 to the cell surface did not affect viral attachment. HBD2 or -3 cointernalized with virions in endosomes, formed oligomers, and reduced infectivity of HIV. The anti-HIV effect of combining hBD2 and hBD3 was substantially higher than that of the individual peptides. These findings advance our understanding of the mechanisms of anti-HIV resistance in adult oral epithelium.


Assuntos
Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , beta-Defensinas/metabolismo , Adulto , Linhagem Celular Tumoral , Pré-Escolar , Endossomos/imunologia , Endossomos/virologia , Células Epiteliais/citologia , Células Epiteliais/virologia , Infecções por HIV/transmissão , HIV-1/imunologia , Células HeLa , Humanos , Lactente , Membrana Mucosa/imunologia , Membrana Mucosa/virologia , Tonsila Palatina/citologia , Tonsila Palatina/virologia , Ligação Proteica , Transporte Proteico , Ligação Viral , Internalização do Vírus , beta-Defensinas/imunologia
12.
Microbes Infect ; 18(3): 211-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26548606

RESUMO

Defensins, RNases and cytokines are present at mucosal barriers, main ports of HIV entry, and are potential mediators of the resistant phenotype exhibited by HIV-1-exposed seronegative individuals (HESN) during sexual exposure. We aimed to determine the role of soluble factors in natural resistance to HIV-1 infection. Vaginal/endocervical/oral mucosal samples were taken from 60 HESN, 60 seropositive (SP) and 61 healthy controls (HC). Human neutrophil peptide 1 (hNP-1), human beta defensin (hBD) 2 and 3, RNases, MIP-1ß and RANTES mRNA transcripts were quantified by qPCR and in vitro single-round, recombinant-based viral infectivity assay was used to evaluate the anti-HIV-1 activity of hBDs and RNases. HESN expressed significantly higher levels of hNP-1, hBDs mRNA in oral mucosa compared to HC (P < 0.05). In genital mucosa, significantly higher mRNA levels of MIP-1ß, RANTES and RNases were found in HESN compared to HC (P < 0.05). HBDs and RNases inhibit HIV-1 replication, particularly R5 at entry, reverse transcription and nuclear import of the viral life cycle. hNP-1, hBDs, MIP-1ß, RANTES and RNases, collectively could contribute to HIV-1 resistance during sexual exposure. Moreover, the inhibition of HIV-1 infection in vitro by hBDs and RNases suggests that they may be exploited as potential antiretrovirals.


Assuntos
Resistência à Doença , HIV-1/imunologia , Imunidade Inata , Imunidade nas Mucosas , Fatores Imunológicos/análise , Adolescente , Adulto , Feminino , Perfilação da Expressão Gênica , Humanos , Fatores Imunológicos/genética , Masculino , Adulto Jovem
13.
Cell Immunol ; 297(2): 61-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26302933

RESUMO

We previously showed that human beta defensin-3 (hBD-3) activates mDC via TLR1/2. Here we investigated the effects of hBD-3 on NK cell activation state and effector functions. We observed that hBD-3 activates PBMC to secrete IFN-γ and kill K562 and HUH hepatoma target cells in an NK dependent fashion, and both TLR1/2 and CCR2 are involved. TLR1, TLR2 and CCR2 were expressed on NK cells, and in purified NK culture experiments we observed hBD-3 to directly act on NK cells, resulting in CD69 upregulation and IFNγ secretion. We also observed mDC-hBD-3 enhanced NK cytolytic activity and IFNγ production. These results implicate hBD-3 in its ability to directly activate NK cells and increase NK cell effector function, as well as promote mDC-dependent NK activity. HBD-3 may therefore act as a mediator of innate cell interactions that result in bridging of innate and adaptive immunity.


Assuntos
Células Dendríticas/imunologia , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , beta-Defensinas/imunologia , Imunidade Adaptativa , Comunicação Celular/imunologia , Técnicas de Cocultura , Citotoxicidade Imunológica , Células Dendríticas/classificação , Humanos , Imunidade Inata , Células K562 , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Receptores CCR2/imunologia , Receptor 1 Toll-Like/imunologia , Receptor 2 Toll-Like/imunologia
14.
Beijing Da Xue Xue Bao Yi Xue Ban ; 47(1): 98-103, 2015 Feb 18.
Artigo em Chinês | MEDLINE | ID: mdl-25686337

RESUMO

OBJECTIVE: To evaluate facial soft tissue 3-deminsion changes of skeletal Class III malocclusion patients after orthognathic surgery using structure light scanning technique. METHODS: Eight patients [3 males and 5 females, aged (27.08 ± 4.42) years] with Class III dentoskeletal relationship who underwent a bimaxillary orthognathic surgical procedure involving advancement of the maxilla by Le Fort I osteotomy and mandibular setback by bilateral sagittal split ramus osteotomy (BSSO) and genioplasty to correct deformity were included. 3D facial images were obtained by structure light scanner for all the patients 2 weeks preoperatively and 6 months postoperatively. The facial soft tissue changes were evaluated in 3-dimension. The linear distances and angulation changes for facial soft tissue landmarks were analyzed. The soft tissue volumetric changes were assessed too. RESULTS: There were significant differences in the sagittal and vertical changes of soft tissue landmarks. The greatest amount of soft tissue change was close to lips. There were more volumetric changes in the chin than in the maxilla, and fewer in the forehead. CONCLUSION: After biomaxillary surgery, there were significant facial soft tissue differences mainly in the sagittal and vertical dimension for skeletal Class III patients. The structure light 3D scanning technique can be accurately used to estimate the soft tissue changes in patients who undergo orthognathic surgery.


Assuntos
Cefalometria , Face/anatomia & histologia , Imageamento Tridimensional , Cirurgia Ortognática , Adulto , Queixo , Ossos Faciais , Feminino , Humanos , Lábio , Masculino , Má Oclusão Classe III de Angle , Mandíbula , Maxila , Procedimentos Cirúrgicos Ortognáticos , Osteotomia Sagital do Ramo Mandibular , Dimensão Vertical , Adulto Jovem
15.
Virology ; 474: 65-81, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25463605

RESUMO

HIV patients with severe periodontitis have high levels of residual virus in their saliva and plasma despite effective therapy (HAART). Multiple short chain fatty acids (SCFAs) from periodontal pathogens reactivate HIV-1 in both Jurkat and primary T-cell models of latency. SCFAs not only activate positive transcription elongation factor b (P-TEFb), which is an essential cellular cofactor for Tat, but can also reverse chromatin blocks by inducing histone modifications. SCFAs simultaneously increase histone acetylation by inhibiting class-1/2 histone deacetylases (HDACs) and decrease repressive histone tri-methylation at the proviral LTR by downregulating expression of the class-3 HDAC sirtuin-1 (SIRT1), and the histone methyltransferases enhancer of Zeste homolog 2 (EZH2) and suppressor of variegation 3-9 homolog 1 (SUV39H1). Our findings provide a mechanistic link between periodontal disease and enhanced HIV-1 replication, and suggest that treatment of periodontal disease, or blocking the activities of SCFAs, will have a therapeutic benefit for HIV patients.


Assuntos
Ácidos Graxos Voláteis/metabolismo , HIV-1/fisiologia , Histonas/metabolismo , Fator B de Elongação Transcricional Positiva/metabolismo , Linfócitos T/metabolismo , Linfócitos T/virologia , Latência Viral/fisiologia , Acetilação , Bactérias/metabolismo , Células Cultivadas , Proteína Potenciadora do Homólogo 2 de Zeste , Técnicas de Silenciamento de Genes , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Repetição Terminal Longa de HIV , HIV-1/genética , HIV-1/patogenicidade , Histona Desacetilases/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Células Jurkat , Metiltransferases/metabolismo , Modelos Biológicos , Periodontite/complicações , Periodontite/metabolismo , Periodontite/microbiologia , Complexo Repressor Polycomb 2/metabolismo , Proteínas Repressoras/metabolismo , Saliva/metabolismo , Saliva/virologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Sirtuína 1/metabolismo , Ativação Transcricional , Ativação Viral/fisiologia , Latência Viral/genética
16.
Infect Immun ; 82(11): 4458-65, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25114113

RESUMO

Currently, Acinetobacter baumannii is recognized as one of the major pathogens seriously threatening our health care delivery system. Aspects of the innate immune response to A. baumannii infection are not yet well understood. Human ß-defensins (hBDs) are epithelial cell-derived cationic antimicrobial peptides (AMPs) that also function to bridge the innate and adaptive immune system. We tested the induction of hBD-2 and -3 by A. baumannii on primary oral and skin epithelial cells and found that A. baumannii induces hBD-3 transcripts to a greater extent than it induces hBD-2 transcripts on both types of cells. In addition, we found that A. baumannii is susceptible to hBD-2 and -3 killing at submicromolar concentrations. Moreover, hBD-3 induction by A. baumannii was found to be dependent on epidermal growth factor receptor (EGFR) signaling. Inhibition of mitogen-activated protein kinase resulted in reduced expression of both hBD-2 and -3. Lastly, a disintegrin and metalloprotease 17 (ADAM17; also known as TACE) was found to be critical for hBD-3 induction, while ADAM10 and dual oxidase 1 (Duox1) were not required for hBD-3 induction. Induction of AMPs is an important component of innate sensing of pathogens and may play an important role in triggering systemic immune responses to A. baumannii infection. Further studies on the interactions between epithelial cells and A. baumannii will help us understand early stages of infection and may shed light on why some individuals are more vulnerable to A. baumannii infection.


Assuntos
Acinetobacter baumannii/fisiologia , Células Epiteliais/metabolismo , Imunidade Inata/fisiologia , Proteínas ADAM/antagonistas & inibidores , Proteína ADAM10 , Proteína ADAM17 , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Técnicas de Cocultura , Dipeptídeos/farmacologia , Células Epiteliais/imunologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas de Membrana/antagonistas & inibidores , beta-Defensinas/metabolismo
17.
Zhonghua Er Ke Za Zhi ; 52(2): 128-32, 2014 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-24739725

RESUMO

OBJECTIVE: To study the effect of thrombelastography (TEM) in the diagnosis of disseminated intravascular coagulation (DIC) in children. METHOD: The data of 117 children suffering from DIC in the pediatric intensive care unit (PICU) and Cardiologic ICU (CICU) in the authors' hospital from January 2010 to June 2012 were collected. Ninety-four children without DIC were enrolled into the control group. The platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimers and TEM were determined. The sensitivity and specificity of TEM were measured and the relevance of TEM and DIC was investigated to evaluate the effect of TEM and the conventional tests of the coagulation system in the diagnosis of DIC in children. RESULT: The average R reaction time in the DIC group was significantly longer than that in the control group[(13.3 ± 3.3)s vs. (4.5 ± 2.6)s, P = 0.000 5], and the average α-angle in the DIC group was smaller than that in the control group significantly (37.2° ± 1.4° vs. 55.6° ± 3.8°, P = 0.001 0). There was significant decrease in the maximal amplitude (MA) and amplitude (A) in the DIC group, compared with the control group. The OR value (95%CI) of the R reaction time,α-angle and MA was 3.538 (1.298-5.389), 2.472 (1.820-2.224) and 0.256 (0.263-0.831) respectively, which suggests good correlation with the existence of DIC (all P < 0.01). The specificity of R reaction time, α-angle and MA was higher than that of PT, APTT and D-dimers (85.7%, 73.5% and 72.9% vs. 27.0%, 42.1% and 68.2%) . The average R reaction time of children suffering from hemorrhage of severe liver disease(n = 36) was significantly longer than that of 40 healthy children [(9.2 ± 2.7) vs. (2.3 ± 1.8)s, P = 0.001 0], while the α-angle (42.8° ± 7.6° vs. 59.2° ± 10.8°, P = 0.040 0) and the MA value [(33.9 ± 5.1) vs.(56.0 ± 8.1) mm, P = 0.020 0] were significantly smaller. The average R reaction time of children suffering from congenital coagulopathy was significantly longer than that of healthy children [(6.8 ± 3.1) vs. (2.3 ± 1.8)s, P = 0.003 0], too. CONCLUSION: TEM, which has high specificity, is beneficial to the diagnosis of DIC in children.


Assuntos
Coagulação Sanguínea , Coagulação Intravascular Disseminada/diagnóstico , Tromboelastografia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estado Terminal , Coagulação Intravascular Disseminada/sangue , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Tempo de Tromboplastina Parcial , Contagem de Plaquetas , Tempo de Protrombina , Curva ROC , Sensibilidade e Especificidade
18.
J Virol ; 88(8): 4466-79, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24501407

RESUMO

UNLABELLED: Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE: About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.


Assuntos
Coinfecção/microbiologia , Coinfecção/virologia , Ácidos Graxos Voláteis/metabolismo , Herpesvirus Humano 8/fisiologia , Metiltransferases/genética , Complexo Repressor Polycomb 2/genética , Proteínas Repressoras/genética , Sarcoma de Kaposi/enzimologia , Replicação Viral , Adulto , Idoso , Coinfecção/enzimologia , Coinfecção/metabolismo , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Fusobacterium nucleatum/metabolismo , Herpesvirus Humano 8/genética , Humanos , Masculino , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Doenças Periodontais/microbiologia , Complexo Repressor Polycomb 2/metabolismo , Porphyromonas gingivalis/metabolismo , Proteínas Repressoras/metabolismo , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/metabolismo , Sarcoma de Kaposi/virologia
19.
FEBS J ; 280(14): 3365-75, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23659571

RESUMO

Previously, we reported that human ß-defensin (hBD)-3 can both antagonize CXCR4 function on T cells and promote receptor internalization in the absence of activation. In the present study, we explored the important structural elements of hBD-3 that are involved in blocking CXCR4 activation by its natural ligand, stromal-derived factor 1α (SDF-1α; CXCL12). Results from site-directed mutagenesis studies suggest that the ability of hBD-3 to inhibit SDF-1α-CXCR4 interaction, as assayed either by blocking SDF-1 binding to CXCR4 or antagonizing SDF-1-induced Ca(2+) mobilization, is correlated with the presence of hBD-3 cysteine residues, specific surface-distributed cationic residues, and the electrostatic properties and availability of both hBD-3 termini. Specifically, hBD-3 activity against CXCR4 is reduced by: (a) replacing all six cysteines; (b) replacing the cationic residues with acidic ones in the N-terminus and C- terminus; (c) removal of the first 10 N-terminal residues; and (d) replacing the surface-exposed basic residues Lys8, Lys32 and Arg36 with neutral ones. The hBD-3-CXCR4 interaction has potentially wide-ranging implications for HIV-related biology, as well as for a host of CXCR4-dependent activities, including hematopoiesis, neurogenesis, angiogenesis, carcinogenesis, and immune cell trafficking. CXCR4 is highly expressed on T cells, monocytes, and epithelial cells. Therefore, understanding the structure-function relationship between hBD-3 and CXCR4 that accounts for the antagonistic interaction between the two molecules may provide new insights into HIV/highly active antiretroviral therapy-related pathology, as well as novel insights into the interaction between innate and adaptive immunity at mucosal sites.


Assuntos
Receptores CXCR4/metabolismo , Transdução de Sinais , beta-Defensinas/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Substituição de Aminoácidos , Ligação Competitiva , Linhagem Celular , Quimiocina CXCL12/metabolismo , Cistina/genética , Cistina/metabolismo , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Propriedades de Superfície , beta-Defensinas/química , beta-Defensinas/genética
20.
J Leukoc Biol ; 92(5): 1083-91, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22837529

RESUMO

Interactions of AMPs with plasma membranes of primary human immune cells are poorly characterized. Analysis of PI exclusion as a measure of membrane integrity indicated that hBD-3 caused membrane perturbations in monocytes but not T or B cells at concentrations typically used to kill bacteria or to induce activation of APCs. Bleb-like structures were observed in monocytes exposed to hBD-3. These cells also increased surface expression of LAMP1, a membrane repair marker after exposure to hBD-3. Furthermore, cell death was enhanced by adding an inhibitor of membrane repair. Removal of cholesterol from membranes resulted in greater susceptibility of cells to hBD-3, but cholesterol content was not different between the cell types, as assessed by filipin staining. Freshly isolated monocytes expressed higher levels of the negatively charged phospholipid, PS, on their outer leaflet compared with B or T cells. Preincubation of monocytes with molecules that bind PS protected these cells from hBD-3-induced membrane damage, suggesting that outer-membrane PS expression can at least partially explain monocyte susceptibility to hBD-3. The potential for membrane disruption caused by AMPs should be evaluated in various cell types when considering these molecules for therapeutic applications in humans.


Assuntos
Membrana Celular/metabolismo , Membrana Celular/patologia , Monócitos/metabolismo , Monócitos/patologia , beta-Defensinas/metabolismo , Membrana Celular/imunologia , Células Cultivadas , Citometria de Fluxo , Imunofluorescência , Humanos , Monócitos/imunologia , beta-Defensinas/imunologia
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