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1.
J Antimicrob Chemother ; 79(4): 758-766, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38340039

RESUMO

OBJECTIVES: To compare the differences in antibiotic use between COPD and non-COPD residents, and to explore the effect of COPD on antibiotic use. METHODS: Participants aged 40 years old or over from the Songjiang Adult Cohort were included. Information on prescription and baseline survey was collected based on the health information system. A logit-negative binomial Hurdle model was used to explore correlations between COPD and percentage of antibiotic use and average rate of antibiotic prescribing of different types of antibiotic. Multinomial logistic regression was used to assess the association between COPD and antimicrobial combination therapy and routes of administration. RESULTS: A total of 34576 individuals were included and 1594 (4.6%) were COPD patients. During the 6 years' follow-up, the percentage of antibiotic use for COPD patients was 98.4%, which was 7.88 (95%CI: 5.24-11.85) times of that for non-COPD patients after adjusting for potential confounders. The prescribing rate was 3220 prescriptions (95%CI: 3063.6-3385.2) per 1000 person-years for COPD patients, which was 1.96 (95%CI: 1.87-2.06) times of that for non-COPD patients. Other beta-lactam antibacterials, Macrolides, lincosamides and streptogramins, and quinolone antibacterials were the most commonly used types of antibiotic. Except for aminoglycoside antibacterials, both percentage of antibiotic use and rate of antibiotic prescription were increased in COPD patients. COPD patients were more likely to be prescribed a maximum of two antibiotics (OR=1.34, 95%CI: 1.20-1.50); and were more likely to use antibiotics intravenously (OR=2.77, 95%CI: 2.47-3.11). CONCLUSION: COPD patients were more likely to have increased antibiotic use in a large-scale population-based adult cohort, suggesting COPD patients are a high-priority group for the management of antibiotic use in communities.


Assuntos
Sistemas de Informação em Saúde , Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Antibacterianos/uso terapêutico , Estreptograminas , Prescrições de Medicamentos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Padrões de Prática Médica
2.
Biomed Pharmacother ; 166: 115434, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37677965

RESUMO

Renal interstitial fibrosis (RIF), a progressive process affecting the kidneys in chronic kidney disease (CKD), currently lacks an effective therapeutic intervention. Traditional Chinese medicine (TCM) has shown promise in reducing RIF and slowing CKD progression. In this study, we demonstrated the dose-dependent attenuation of RIF by Ootheca mantidis (SPX), a commonly prescribed TCM for CKD, in a mouse model of unilateral ureteral obstruction (UUO). RNA-sequencing analysis suggested that SPX treatment prominently downregulated apoptosis and inflammation-associated pathways, thereby inhibiting the fibrogenic signaling in the kidney. We further found that transplantation of fecal microbiota from SPX-treated mice conferred protection against renal injury and fibrosis through suppressing apoptosis in UUO mice, indicating that SPX ameliorated RIF via remodeling the gut microbiota and reducing apoptosis in the kidneys. Further functional exploration of the gut microbiota combined with fecal metabolomics revealed increased levels of some probiotics, including Akkermansia muciniphila (A. muciniphila), and modulations in glutamine-related amino acid metabolism in UUO mice treated with SPX. Subsequent colonization of A. muciniphila and supplementation with glutamine effectively mitigated cell apoptosis and RIF in UUO mice. Collectively, these findings unveil a functionally A. muciniphila- and glutamine-involved gut-renal axis that contributes to the action of SPX, and provide important clue for the therapeutic potential of SPX, A. muciniphila, and glutamine in combatting RIF.


Assuntos
Microbioma Gastrointestinal , Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Camundongos , Glutamina , Apoptose , Fibrose
4.
Microbiome ; 10(1): 226, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36517893

RESUMO

OBJECTIVE: High intake of caffeoylquinic acid (CQA)-rich dietary supplements, such as green coffee bean extracts, offers health-promoting effects on maintaining metabolic homeostasis. Similar to many active herbal ingredients with high pharmacological activities but low bioavailability, CQA has been reported as a promising thermogenic agent with anti-obesity properties, which contrasts with its poor oral absorption. Intestinal tract is the first site of CQA exposure and gut microbes might react quickly to CQA. Thus, it is of interest to explore the role of gut microbiome and microbial metabolites in the beneficial effects of CQA on obesity-related disorders. RESULTS: Oral CQA supplementation effectively enhanced energy expenditure by activating browning of adipose and thus ameliorated obesity-related metabolic dysfunctions in high fat diet-induced obese (DIO) mice. Here, 16S rRNA gene amplicon sequencing revealed that CQA treatment remodeled the gut microbiota to promote its anti-obesity actions, as confirmed by antibiotic treatment and fecal microbiota transplantation. CQA enriched the gut commensal species Limosilactobacillus reuteri (L. reuteri) and stimulated the production of short-chain fatty acids, especially propionate. Mono-colonization of L. reuteri or low-dose CQA treatment did not reduce adiposity in DIO mice, while their combination elicited an enhanced thermogenic response, indicating the synergistic effects of CQA and L. reuteri on obesity. Exogenous propionate supplementation mimicked the anti-obesity effects of CQA alone or when combined with L. reuteri, which was ablated by the monocarboxylate transporter (MCT) inhibitor 7ACC1 or MCT1 disruption in inguinal white adipose tissues to block propionate transport. CONCLUSIONS: Our data demonstrate a functional axis among L. reuteri, propionate, and beige fat tissue in the anti-obesity action of CQA through the regulation of thermogenesis. These findings provide mechanistic insights into the therapeutic use of herbal ingredients with poor bioavailability via their interaction with the gut microbiota. Video Abstract.


Assuntos
Adiposidade , Limosilactobacillus reuteri , Camundongos , Animais , RNA Ribossômico 16S/metabolismo , Propionatos , Obesidade/complicações , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL
5.
Cytotherapy ; 23(5): 411-422, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33781710

RESUMO

Mesenchymal stromal cells (MSCs) possess remarkable tumor tropism, making them ideal vehicles to deliver tumor-targeted therapeutic agents; however, their value in clinical medicine has yet to be realized. A barrier to clinical utilization is that only a small fraction of infused MSCs ultimately localize to the tumor. In an effort to overcome this obstacle, we sought to enhance MSC trafficking by focusing on the factors that govern MSC arrival within the tumor microenvironment. Our findings show that MSC chemoattraction is only present in select tumors, including osteosarcoma, and that the chemotactic potency among similar tumors varies substantially. Using an osteosarcoma xenograft model, we show that human MSCs traffic to the tumor within several hours of infusion. After arrival, MSCs are observed to localize in clusters near blood vessels and MSC-associated bioluminescence signal intensity is increased, suggesting that the seeded cells expand after engraftment. However, our studies reveal that a significant portion of MSCs are eliminated en route by splenic macrophage phagocytosis, effectively limiting the number of cells available for tumor engraftment. To increase MSC survival, we transiently depleted macrophages with liposomal clodronate, which resulted in increased tumor localization without substantial reduction in tumor-associated macrophages. Our data suggest that transient macrophage depletion will significantly increase the number of MSCs in the spleen and thus improve MSC localization within a tumor, theoretically increasing the effective dose of an anti-cancer agent. This strategy may subsequently improve the clinical efficacy of MSCs as vehicles for the tumor-directed delivery of therapeutic agents.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Osteossarcoma , Humanos , Macrófagos , Osteossarcoma/terapia , Fagocitose , Microambiente Tumoral
6.
Mol Ther Oncolytics ; 17: 431-447, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32478167

RESUMO

Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to therapies. It is now clear that elevated levels of tumor-infiltrating T cells as well as a systemic anti-tumor immune response are requirements for successful immunotherapies. However, the tumor microenvironment imposes an additional resistance mechanism to immunotherapy. We have developed a practical and improved strategy for cancer immunotherapy using an oncolytic virus and anti-OX40. This strategy takes advantage of a preexisting T cell immune repertoire in vivo, removing the need to know about present tumor antigens. We have shown in this study that the replication-deficient oncolytic Sindbis virus vector expressing interleukin-12 (IL-12) (SV.IL12) activates immune-mediated tumor killing by inducing OX40 expression on CD4 T cells, allowing the full potential of the agonistic anti-OX40 antibody. The combination of SV.IL12 with anti-OX40 markedly changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated terminally differentiated effector T cells. These metabolically reprogrammed T cells demonstrate enhanced tumor infiltration capacity as well as anti-tumor activity capable of overcoming the repressive tumor microenvironment. Our findings identify SV.IL12 in combination with anti-OX40 to be a novel and potent therapeutic strategy that can cure multiple types of low-immunogenic solid tumors.

7.
J Immunother Cancer ; 7(1): 185, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307539

RESUMO

BACKGROUND: Limitations to current therapies for treating non-Hodgkin B cell lymphoma include relapse, toxicity and high cost. Thus, there remains a need for novel therapies. Oncolytic viral (OV) therapy has become a promising cancer immunotherapy because of its potential effectiveness, specificity and long-lasting immunity. We describe and characterize a novel cancer immunotherapy combining Sindbis virus (SV) vectors and the agonistic monoclonal antibody (mAb) to the T cell costimulatory receptor, 4-1BB (CD137). METHODS: A20 lymphoma was transfected with luciferase and tumor cells were inoculated to BALB/c mice. Tumor growth was monitored by IVIS imaging. Tumor bearing mice were treated with Sindbis virus, α4-1BB Ab or SV plus α4-1BB Ab. On day 7 after treatment, splenocytes were harvested and surface markers, cytokines, and transcription factors were measured by flow cytometry or Elispot. Splenic T cells were isolated and RNA transcriptome analysis was performed. Tumor cured mice were rechallenged with tumor for testing immunological memory. RESULTS: SV vectors in combination with α4-1BB monoclonal antibody (mAb) completely eradicated a B-cell lymphoma in a preclinical mouse model, a result that could not be achieved with either treatment alone. Tumor elimination involves a synergistic effect of the combination that significantly boosts T cell cytotoxicity, IFNγ production, T cell proliferation, migration, and glycolysis. In addition, all mice that survived after treatment developed long lasting antitumor immunity, as shown by the rejection of A20 tumor rechallenge. We identified the molecular pathways, including upregulated cytokines, chemokines and metabolic pathways in T cells that are triggered by the combined therapy and help to achieve a highly effective anti-tumor response. CONCLUSIONS: Our study provides a novel, alternative method for B cell lymphoma treatment and describes a rationale to help translate SV vectors plus agonistic mAb into clinical applications.


Assuntos
Ligante 4-1BB/agonistas , Anticorpos Monoclonais/administração & dosagem , Perfilação da Expressão Gênica/métodos , Linfoma não Hodgkin/terapia , Sindbis virus/fisiologia , Animais , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Terapia Combinada , Citocinas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia , Terapia Viral Oncolítica , Transdução de Sinais/efeitos dos fármacos , Sindbis virus/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Microb Pathog ; 120: 140-146, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29709687

RESUMO

Mycoplasma genitalium adhesion protein (MgPa) is a major adhesin of M. genitalium, a human pathogen associated with a series of genitourinary tract diseases. MgPa plays a very important role in M. genitalium adhering to the host cells. However, the exact receptor peptides or proteins of MgPa are still poorly understood so far. Three polypeptides (V-H-W-D-F-R-Q-W-W-Q-P-S), (D-W-S-S-W-V -Y-R-D-P-Q-T) and (H-Y-I-D-F-R-W) were previously screened from a phage display random peptide library using recombinant MgPa (rMgPa) as a target molecule. In this study, three polypeptides were artificially synthesized and investigated as to whether they are potential receptors of MgPa. We found that rMgPa specifically bound to three synthesized polypeptides as determined via an indirect enzyme-linked immunosorbent assay (ELISA). Moreover, three polypeptides were further identified by indirect immunofluorescence microscopy (IFM). We confirmed that rMgPa and M. genitalium can adhere to SV-HUC-1 cells in vitro and that anti-rMgPa antibody and three synthesized polypeptides can partially inhibit the adherence of rMgPa and M. genitalium to SV-HUC-1 cells. In summary, these three polypeptides may be the essential receptor peptides of MgPa, and may aid in enhancing the understanding of biological function of MgPa and the possible pathogenic mechanism of M. genitalium.


Assuntos
Bacteriófagos/metabolismo , Mycoplasma genitalium/metabolismo , Biblioteca de Peptídeos , Peptídeos/metabolismo , Adesinas Bacterianas , Especificidade de Anticorpos , Aderência Bacteriana , Proteínas de Bactérias/metabolismo , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Humanos , Infecções por Mycoplasma , Peptídeos/química , Ligação Proteica , Proteínas Recombinantes/metabolismo
9.
Int J Med Microbiol ; 308(3): 405-412, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29551599

RESUMO

The Mycoplasma genitalium adhesion protein (MgPa), the most important outer membrane protein of M. genitalium, plays a vital role in the adhesion to and invasion of host cells by M. genitalium. Identification of MgPa receptors will help elucidate the pathogenic mechanism of M. genitalium. However, the receptor protein of MgPa has not been reported to date. In this study, an MgPa-binding protein with a molecular weight of approximately 17 kDa was screened from SV-HUC-1 cell membrane proteins by a modified virus overlay protein binding assay (VOPBA). Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the protein components of the 17-kDa protein. The results demonstrated that the MgPa-binding protein was most likely Cyclophilin A (CyPA). The binding activity and distribution of CyPA in SV-HUC-1 cells were detected using indirect ELISA, western blotting, far-western blotting and indirect immunofluorescence. We found that recombinant MgPa (rMgPa) could bind with CyPA from SV-HUC-1 cell membrane proteins and to recombinant CyPA, which indicated that CyPA was predominant component of the 17-kDa protein band and can interact with rMgPa. In addition, an indirect immunofluorescence assay showed that CyPA was partially distributed on the membrane surfaces of SV-HUC-1 cells and could partially inhibit the adhesion of rMgPa and M. genitalium to SV-HUC-1 cells. Co-localization assays further indicated that rMgPa and M. genitalium can interact with CyPA. These results suggested that the CyPA located on SV-HUC-1 cell membranes may be the potential receptor of MgPa, which could provide an experimental basis for elucidating the function of MgPa and the possible pathogenic mechanism of M. genitalium.


Assuntos
Adesinas Bacterianas/química , Aderência Bacteriana , Ciclofilina A/metabolismo , Mycoplasma genitalium/fisiologia , Adesinas Bacterianas/genética , Adesinas Bacterianas/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Western Blotting , Ensaio de Imunoadsorção Enzimática , Humanos , Infecções por Mycoplasma/microbiologia , Mycoplasma genitalium/patogenicidade , Proteínas Recombinantes/química
10.
Mol Med Rep ; 17(2): 3178-3185, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29257302

RESUMO

Neisseria meningitidis (N. meningitidis) is a major cause of meningitis and sepsis. Capsular polysaccharide­based vaccines against serogroups A, C, Y, and W135 are available; however, the development of a vaccine against N. meningitidis serogroup B (NMB) has been problematic. NMB0315 is an outer membrane protein of NMB that may be a virulence factor for N. meningitidis and a possible target for functional bactericidal antibodies. The present study aimed to develop a potent DNA vaccine against NMB by cloning the NMB0135 gene into the pcDNA3.1(+) vector to construct the recombinant plasmid pcDNA3.1(+)/NMB0315 (designated pNMB0315). pNMB0315 was transfected into eukaryotic COS­7 and RAW264.7 cells to express the recombinant (r)NMB0315 protein. Protective immunogenicity of the DNA vaccine was assessed in an in vivo mouse model. The levels of rNMB0315­specific immunoglobulin G (IgG), IgG1 and IgG2a antibodies in the pNMB0315­immunized group increased dramatically up to week 6 following the initial vaccination, and were significantly higher compared with the levels in the Control groups. The serum concentrations of interleukin­4 and interferon­Î³ were significantly higher in the pNMB0315­immunized group compared with the control groups. Following intraperitoneal challenge with a lethal dose of NMB strain MC58, the survival rate in the pNMB0315 + CpG group was 70% (14 out of 20 mice) at 14 days; by contrast, all mice in the control groups succumbed within 3 days. The serum bactericidal titers of the pNMB0315 + CpG group in vitro reached 1:128 following three immunizations. The results indicated that pNMB0315 may serve as a promising DNA vaccine against NMB.


Assuntos
Antígenos de Bactérias/genética , Neisseria meningitidis/imunologia , Vacinas de DNA/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/genética , Células COS , Chlorocebus aethiops , Cricetinae , Citocinas/análise , Feminino , Imunoglobulina G/imunologia , Infecções Meningocócicas/imunologia , Infecções Meningocócicas/metabolismo , Infecções Meningocócicas/prevenção & controle , Infecções Meningocócicas/veterinária , Camundongos , Camundongos Endogâmicos BALB C , Neisseria meningitidis/genética , Neisseria meningitidis/patogenicidade , Plasmídeos/genética , Plasmídeos/metabolismo , Células RAW 264.7 , Sorogrupo , Taxa de Sobrevida , Vacinas de DNA/genética , Vacinas de DNA/metabolismo
11.
Mol Med Rep ; 16(4): 4835-4842, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28765948

RESUMO

The obligate intracellular bacterium Chlamydia psittaci is the causative agent of psittacosis in birds and humans. The capability of this zoonotic pathogen to develop a persistent phase may serve a role in the chronicity of infections, in addition to the failure of antibiotic therapy or immunoprophylaxis. In the present study, a C. psittaci strain 6BC persistent infection cell model was induced using interferon (IFN)­Î³, alterations in the infectivity and morphology of the pathogen were analyzed, and the transcript profile of seven selected genes was analyzed. Following treatment with IFN­Î³, the infectivity of C. psittaci 6BC was decreased, the inclusion bodies appeared to be smaller, reticulate bodies were larger and the number of infectious elementary bodies was decreased compared with acute infection. In IFN­Î³­induced persistently infected cells, the relative mRNA expression levels of the genes CPSIT­0208, CPSIT­0310, CPSIT­0846, CPSIT­0844 and CPSIT­0594 were upregulated at 2­48 h post­infection (p.i.). The genes CPSIT­0959 and CPSIT­0057 were downregulated at 2­36 h p.i. The results of the present study advanced the understanding of C. psittaci persistent infection and demonstrated a number of previously unknown alterations in chlamydial gene expression, which may provide novel targets to further analyze this particular host­pathogen interaction.


Assuntos
Chlamydophila psittaci/efeitos dos fármacos , Chlamydophila psittaci/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Interferon gama/farmacologia , Psitacose/microbiologia , Transcrição Gênica , Células Cultivadas , Chlamydophila psittaci/ultraestrutura , Imunofluorescência , Células HeLa , Interações Hospedeiro-Patógeno , Humanos
12.
Pathog Dis ; 75(4)2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28430965

RESUMO

A series of inflammatory responses caused by Mycoplasma pneumoniae largely depend on the lipid-associated membrane proteins (LAMPs). Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, is considered to be a critical modulator of inflammatory responses and cellular redox homeostasis. Monocytes play an important role in the invasion and immunity to resist pathogens. Here, we investigated the role of Nrf2 in the anti-inflammatory response stimulated by LAMPs using the human monocyte cell line THP-1. LAMPs were shown to affect the localization of Nrf2, and the levels of reactive oxygen species and inflammatory reactants, including nitric oxide (NO), prostaglandin E2 (PGE2) and cytokines (IL-6, IL-8), were highly elevated in LAMP-stimulated Nrf2-silenced THP-1 cells. Moreover, LAMPs induced the levels of mRNA and the expression of heme oxygenase-1 (HO-1). In summary, our results demonstrated that LAMPs cause nuclear translocation of Nrf2, which further suppresses the expression of inflammatory reactants in THP-1 cells.


Assuntos
Heme Oxigenase-1/biossíntese , Tolerância Imunológica , Inflamação , Proteínas Ligadas a Lipídeos/imunologia , Monócitos/imunologia , Mycoplasma pneumoniae/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Humanos , Fatores Imunológicos/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células THP-1
13.
Bull Environ Contam Toxicol ; 98(6): 784-790, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28421253

RESUMO

Twenty-two organochlorine pesticides (OCPs) were investigated in Anhui reach of Huaihe river, China. Seventeen out of 22 OCPs were detected by GC-MS. The mean concentrations of OCPs followed the order: HCHs > DDTs > HCB > chlordanes > endosulfans. Levels of total HCHs and total DDTs ranged from 2.54 to 13.91 ng g-1 (mean = 7.52 ng g-1) and 0.016 to 2.54 ng g-1 (mean = 0.45 ng g-1), respectively. The concentrations of DDTs were lower than those of HCHs. Compared with the other rivers in China, DDTs and HCHs were relatively lower or similar. Statistical analysis indicated that the OCPs concentration differences were not insignificant between upstream, midstream and downstream. The compound compositions suggested that historical usage of lindane and fresh DDT were the main sources. The regression analysis indicated that TOC has influence on the levels of HCHs and little influence on the levels of DDTs in the sediments.


Assuntos
Monitoramento Ambiental , Hidrocarbonetos Clorados/análise , Praguicidas/análise , Rios/química , Poluentes Químicos da Água/análise , China , Sedimentos Geológicos/análise , Hexaclorocicloexano/análise
14.
Pathog Dis ; 75(3)2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28204474

RESUMO

Chlamydia psittaci is an obligate intracellular bacteria that causes respiratory disease in poultry and humans. Currently, there are no licensed vaccines against chlamydial infection in humans. The transmembrane head protein CPSIT_0846 of C. psittaci is a putative member of the larger Inc protein family. In this study, we investigated immunogenicity and protective efficacy of the recombinant CPSIT_0846 protein in BALB/c mice. Mice immunized with CPSIT_0846 developed strong T-lymphocyte responses that were recalled by the immunogen CPSIT_0846 in an in vitro restimulation assay. These T cells displayed a strong Th1-biased cytokine profile with high levels of IFN-γ. At the same time, a strong humoral immune response was also detected in the immunized mice with high titers of Chlamydia psittaci-specific serum IgG antibodies. More importantly, the robust immune responses correlated well with significantly reduced chlamydial burden and inflammatory pathology in the mouse lungs upon an airway challenge infection. The above results together suggest that the CPSIT_0846 protein may be a potential vaccine candidate antigen for inducing protection against C. psittaci infection and disease in the airway.


Assuntos
Proteínas de Bactérias/imunologia , Chlamydophila psittaci/imunologia , Psitacose/imunologia , Proteínas Recombinantes/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HeLa , Humanos , Imunização , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Psitacose/metabolismo , Psitacose/microbiologia , Psitacose/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Células Th1/imunologia , Células Th1/metabolismo
15.
Biochem Biophys Res Commun ; 484(2): 311-317, 2017 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-28130110

RESUMO

Tumor necrosis factor (TNF)-α-inducing protein (Tipα) is a newly identified carcinogenic factor secreted by Helicobacter pylori (H. pylori). Although it has been proved that Tipα is a strong inducer of epithelial-mesenchymal transition (EMT), a crucial process of migration, the exact molecular mechanism is unknown. Current evidence indicates that the oncogenic transcription factor signal transducers and activators of transcription 3 (STAT3) is inappropriately activated in multiple malignancies, including gastric cancer. In this study, we showed that Tipα significantly down-regulated the expression of EMT-related markers E-cadherin as well as up-regulated N-cadherin and vimentin in SGC7901 cells, with typical morphological changes of EMT. Tipα also promoted proliferation and migration of SGC7901 cells. Furthermore, Tipα activated interleukin-6 (IL-6)/STAT3 signaling pathway in SGC7901 cells. The effects of Tipα treatment observed was abolished when we block IL-6/STAT3 signaling pathway. Altogether, our data demonstrated that Tipα may accelerate tumor aggressiveness in gastric cancer by promoting EMT through activation of IL-6/STAT3 pathway.


Assuntos
Proteínas de Bactérias/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Neoplasias Gástricas/metabolismo
16.
J Invest Dermatol ; 135(11): 2688-2696, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26099023

RESUMO

Phosphoinositide-dependent kinase-1 (PDK1) is a key signaling molecule downstream of the phosphatidylinositol 3-kinase pathway and is a master regulator of multiple kinases in cells of epithelial and hematopoietic lineages. The physiological role of PDK1 in regulating skin and immune homeostasis is not known. Here we developed a mouse model in which PDK1 is conditionally ablated in activated CD4 T cells, regulatory T cells, and mature keratinocytes through OX40-Cre recombinase expression. The resultant mice (PDK1-CKO) spontaneously developed severe dermatitis, skin fibrosis, and systemic T helper type 2 immunity, succumbing by 11 weeks of age. Through a series of T-cell transfers, bone marrow reconstitutions, and crossing to lymphocyte-deficient backgrounds, we demonstrate that ablation of PDK1 in keratinocytes is the major driver of disease pathogenesis. PDK1-deficient keratinocytes exhibit intrinsic defects in the expression of key structural proteins including cytokeratin-10 and loricrin, resulting in increased keratinocyte turnover, which in turn triggers inflammation, T-cell recruitment, and immune-mediated destruction. Our results reveal PDK1 as a central regulator of keratinocyte homeostasis that prevents skin immune infiltration and inflammation.


Assuntos
Dermatite/genética , Deleção de Genes , Regulação da Expressão Gênica , Proteínas Serina-Treonina Quinases/genética , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Dermatite/imunologia , Dermatite/patologia , Modelos Animais de Doenças , Epiderme/metabolismo , Citometria de Fluxo , Imuno-Histoquímica , Queratinócitos/metabolismo , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piruvato Desidrogenase Quinase de Transferência de Acetil , Distribuição Aleatória , Sensibilidade e Especificidade , Linfócitos T Reguladores/metabolismo
17.
APMIS ; 123(7): 571-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26010562

RESUMO

Helicobacter pylori (H. pylori), one of the most common infections, is associated with various clinical outcomes. In addition to inducing inflammation, immunological clearance of the pathogen is often incomplete. Regulatory T cells (Treg cells) have been recently demonstrated to play an important role in H. pylori infection and the final clinical outcome. The aim of this study was to investigate the number and localization of CD4(+) Foxp3(+) Treg cells in stomachs and spleens of H. pylori-infected mice. The expression levels of Foxp3 as well as anti- and pro-inflammatory cytokines before and after H. pylori triple eradication therapy were examined. We found that the percentages of CD4(+) Foxp3(+) Treg cells out of the lamina propria lymphocytes (LPLs) and spleen lymphocytes in the infection group were higher than the PBS negative control group and the treatment group. H. pylori antigen stimulation was associated with an increased number of Treg cells in vitro. Furthermore, compared with the PBS and treatment groups, a higher mRNA expression level of Foxp3 in the gastric tissue was detected in the infection group. IL-10 and TGF-ß1 contents were increased significantly in the culture supernatant of spleen lymphocyte stimulated with H. pylori antigen. A marked elevation in serum IFN-γ level was observed in H. pylori-infected mice. In addition, gastric tissues of the infection group contained more Foxp3(+) cells. These results indicate that the percentage of CD4(+) Foxp3(+) Treg cells are increased in H. pylori-infected mice, suggesting a role of Treg cells in H. pylori-induced pathologies, even at the early stages of chronic gastritis and gastric tumorigenesis.


Assuntos
Mucosa Gástrica/imunologia , Gastrite/imunologia , Infecções por Helicobacter/imunologia , Linfócitos T Reguladores/citologia , Animais , Fatores de Transcrição Forkhead/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter/patologia , Helicobacter pylori , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Baço/citologia , Baço/microbiologia , Baço/patologia , Fator de Crescimento Transformador beta1/metabolismo
18.
Pathog Dis ; 73(4)2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25834143

RESUMO

This study investigated whether Helicobacter pylori could activate the nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome in human macrophages and the involvement of reactive oxygen species (ROS) in inflammasome activation. Phorbol-12-myristate-13-acetate (PMA)-differentiated human acute monocytic leukemia cell line THP-1 was infected with H. pylori. The levels of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18 in supernatant were measured by ELISA. Intracellular ROS level was analyzed by flow cytometry. Quantitative real-time PCR and western blot analysis were employed to determine the mRNA and protein expression levels of NLRP3 and caspase-1 in THP-1 cells, respectively. Our results showed that H. pylori infection could induce IL-1ß and IL-18 production in PMA-differentiated THP-1 cells in a dose- and time-dependent manner. Moreover, secretion of IL-1ß and IL-18 in THP-1 cells following H. pylori infection was remarkably reduced by NLRP3-specific small interfering RNA treatment. In addition, the intracellular ROS level was elevated by H. pylori infection, which could be eliminated by the ROS scavenger N-acetylcysteine (NAC). Furthermore, NAC treatment could inhibit NLRP3 inflammasome formation and caspase-1 activation and suppress the release of IL-1ß and IL-18 from H. pylori-infected THP-1 cells. These findings provide novel insights into the innate immune response against H. pylori infection, which could potentially be used for the prevention and treatment of H. pylori-related diseases.


Assuntos
Proteínas de Transporte/metabolismo , Helicobacter pylori/imunologia , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Monócitos/imunologia , Espécies Reativas de Oxigênio/metabolismo , Western Blotting , Caspase 1/análise , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Monócitos/microbiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
19.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 31(2): 194-8, 2015 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-25652861

RESUMO

OBJECTIVE: To observe the expression of heme oxygenase-1 (HO-1) in regulation of cytokines response induced by Mycoplasma genitalium-derived lipid-associated membrane proteins (LAMPs) in placental trophoblast cells. METHODS: Placental trophoblast cells were cultured in vitro and stimulated by 0.5-5 µg/mL LAMPs for 4 to 12 hours. Expression of HO-1 mRNA and protein, and nuclear translocation of nuclear factor erythroid-2 related factor 2 (Nrf2) were detected by real-time quantitative PCR and Western blotting, respectively. The intracellular formation of reactive oxygen species (ROS) was detected by the fluorescent probe H2DCFDA. N-acetyl-cysteine (NAC) and nuclear factor erythroid-2 related factor 2 (Nrf2) siRNA were respectively used to analyze the roles of ROS and Nrf2 in mediating HO-1 expression. Finally, placental trophoblast cells were transfected with HO-1 siRNA, or preincubated by the HO-1 agonist cobalt protoporphyrin (CoPP) or its inhibitor zinc protoporphyrin (ZnPP), and LAMPs-induced secretion of TNF-α and IL-1ß were detected by ELISA. RESULTS: M. genitalium LAMPs induced the expression of HO-1 mRNA and protein, the accumulation of ROS and the nuclear translocation of Nrf2 in placental trophoblast cells. NAC treatment inhibited LAMPs-induced HO-1 expression and Nrf2 nuclear translocation, and the transfection of Nrf2 siRNA significantly abrogated HO-1 expression. Furthermore, HO-1 siRNA and ZnPP treatment increased LAMPs-induced TNF-α and IL-1ß secretion, while the HO-1 agonist CoPP treatment further decreased their production. CONCLUSION: M. genitalium LAMPs could induce placental trophoblast cells to express HO-1 through ROS/Nrf2 pathways. Up-regulation of HO-1 negatively regulates excessive production of cytokines.


Assuntos
Proteínas de Bactérias/metabolismo , Heme Oxigenase-1/genética , Infecções por Mycoplasma/enzimologia , Mycoplasma genitalium/metabolismo , NF-kappa B/metabolismo , Placenta/citologia , Trofoblastos/enzimologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Proteínas de Bactérias/genética , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Heme Oxigenase-1/metabolismo , Humanos , Infecções por Mycoplasma/genética , Infecções por Mycoplasma/microbiologia , Mycoplasma genitalium/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , Placenta/enzimologia , Placenta/microbiologia , Gravidez , Espécies Reativas de Oxigênio/metabolismo , Trofoblastos/citologia , Trofoblastos/microbiologia , Fator de Necrose Tumoral alfa/genética
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 30(12): 1266-70, 2014 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-25481183

RESUMO

OBJECTIVE: To observe the expression of human ß-defensin-2 (hBD-2) induced by Mycoplasma genitalium-derived lipid-associated membrane proteins (LAMPs) and its potential mechanism. METHODS: Human endocervical epithelial End1/E6E7 cells were cultured in vitro and stimulated by different concentrations of LAMPs for 48 hours, and the expressions of hBD-2 mRNA and protein were detected by real-time RT-PCR and Western blotting, respectively. Toll-like receptor 2 (TLR2) and TLR6 neutralizing antibodies for End1/E6E7 cell cultivation, and dominant negative plasmids for cell transfection were used to analyze the roles of TLR2, TLR6 and MyD88 in mediating hBD-2 expression. Nuclear translocation of the nuclear factor κB (NF-κB) p65 subunit, and its DNA-binding activity were detected by Western blotting and electrophoretic mobility shift assay (EMSA), respectively. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, was used to investigate the effect of NF-κB on hBD-2 expression. RESULTS: Mycoplasma genitalium-derived LAMPs induced the expressions of hBD-2 mRNA and protein in End1/E6E7 cells. The expressions could be abrogated by TLR2 and TLR6 neutralizing antibodies, or their dominant negative plasmids. In addition, dominant negative plasmids of MyD88 significantly decreased LAMPs-induced hBD-2 expression. Western blotting showed that p65 was translocated to the nucleus, and the DNA binding activity of NF-κB was enhanced after LAMPs treatment. Furthermore, PDTC treatment decreased LAMPs- induced hBD-2 expression. CONCLUSION: Mycoplasma genitalium-derived LAMPs can induce End1/E6E7 cells to express hBD-2, which may be involved in the TLR2, TLR6/Myd88/NF-κB pathways.


Assuntos
Colo do Útero/metabolismo , Proteínas Ligadas a Lipídeos/fisiologia , Mycoplasma genitalium/fisiologia , beta-Defensinas/genética , Células Cultivadas , Células Epiteliais/metabolismo , Feminino , Humanos , Fator 88 de Diferenciação Mieloide/fisiologia , NF-kappa B/fisiologia , Receptor 2 Toll-Like/fisiologia , Receptor 6 Toll-Like/fisiologia
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