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2.
Cell Prolif ; 54(10): e13114, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34435402

RESUMO

OBJECTIVES: Bone marrow-derived cells (BMDCs), especially mesenchymal stem cells (MSCs), may be involved in the development of Helicobacter pylori-associated gastric cancer (GC) in mice, but the specific mechanism remains unclear, and evidence from human studies is lacking. MATERIALS AND METHODS: To verify the role of BM-MSCs in H pylori-associated GC, green fluorescent protein (GFP)-labelled BM-MSCs were transplanted into the subserosal layers of the stomach in a mouse model of chronic H pylori infection. Three months post-transplantation, the mice were sacrificed, and the gastric tissues were subjected to histopathological and immunofluorescence analyses. In addition, we performed fluorescence in situ hybridization (FISH) and immunofluorescence analyses of gastric tissue from a female patient with H pylori infection and a history of acute myeloid leukaemia who received a BM transplant from a male donor. RESULTS: In mice with chronic H pylori infection, GFP-labelled BM-MSCs migrated from the serous layer to the mucosal layer and promoted GC progression. The BM-MSCs differentiated into pan-cytokeratin-positive epithelial cells and α-smooth muscle actin-positive cancer-associated fibroblasts (CAFs) by secreting the protein thrombospondin-2. FISH analysis of gastric tissue from the female patient revealed Y-chromosome-positive cells. Immunofluorescence analyses further confirmed that Y-chromosome-positive cells showed positive BM-MSCs marker. These results suggested that allogeneic BMDCs, including BM-MSCs, can migrate to the stomach under chronic H pylori infection. CONCLUSIONS: Taken together, these findings imply that BM-MSCs participate in the development of chronic H pylori-associated GC by differentiating into both gastric epithelial cells and CAFs.


Assuntos
Células da Medula Óssea/metabolismo , Medula Óssea/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/metabolismo , Células-Tronco Mesenquimais/metabolismo , Neoplasias Gástricas/metabolismo , Trombospondinas/metabolismo , Animais , Medula Óssea/microbiologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Feminino , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Gástricas/microbiologia
3.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205064

RESUMO

Cortactin is a well-known regulatory protein of the host actin cytoskeleton and represents an attractive target of microbial pathogens like Helicobacter pylori. H. pylori manipulates cortactin's phosphorylation status by type-IV secretion-dependent injection of its virulence protein CagA. Multiple host tyrosine kinases, like FAK, Src, and Abl, are activated during infection, but the pathway(s) involved is (are) not yet fully established. Among them, Src and Abl target CagA and stimulate tyrosine phosphorylation of the latter at its EPIYA-motifs. To investigate the role of cortactin in more detail, we generated a CRISPR/Cas9 knockout of cortactin in AGS gastric epithelial cells. Surprisingly, we found that FAK, Src, and Abl kinase activities were dramatically downregulated associated with widely diminished CagA phosphorylation in cortactin knockout cells compared to the parental control. Together, we report here a yet unrecognized cortactin-dependent signaling pathway involving FAK, Src, and Abl activation, and controlling efficient phosphorylation of injected CagA during infection. Thus, the cortactin status could serve as a potential new biomarker of gastric cancer development.


Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Quinase 1 de Adesão Focal/genética , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Proteínas Oncogênicas v-abl/genética , Regulação Bacteriana da Expressão Gênica/genética , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno/genética , Humanos , Fosforilação/genética , Quinases da Família src/genética
4.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207192

RESUMO

Gastric cancer is still an important disease causing many deaths worldwide, although there has been a marked reduction in prevalence during the last few decades. The decline in gastric cancer prevalence is due to a reduction in Helicobacter pylori infection which has occurred for at least 50 years. The most probable mechanism for the carcinogenic effect of H. pylori is hypergastrinemia since H. pylori infected individuals do not have increased risk of gastric cancer before the development of oxyntic atrophy. When atrophy has developed, the carcinogenic process continues independent of H. pylori. Autoimmune gastritis also induces oxyntic atrophy leading to marked hypergastrinemia and development of ECL cell neoplasia as well as adenocarcinoma. Similarly, long-term treatment with efficient inhibitors of acid secretion like the proton pump inhibitors (PPIs) predisposes to ECL cell neoplasia of a different degree of malignancy. Contrasting the colon where most cancers develop from polyps, most polyps in the stomach have a low malignant potential. Nevertheless, gastric polyps may also give rise to cancer and have some risk factors and mechanisms in common with gastric cancer. In this overview the most common gastric polyps, i.e., hyperplastic polyps, adenomatous polyps and fundic gland polyps will be discussed with respect to etiology and particularly use of PPIs and relation to gastric carcinogenesis.


Assuntos
Pólipos Adenomatosos/etiologia , Gastrite/microbiologia , Neoplasias Gástricas/etiologia , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/terapia , Animais , Gastrite/complicações , Gastrite/imunologia , Gastrite/patologia , Helicobacter pylori/patogenicidade , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia
5.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298992

RESUMO

Non-Hodgkin B-cell lymphomas (NHL) are a heterogeneous group of lymphoid neoplasms with complex etiopathology, rich symptomatology, and a variety of clinical courses, therefore requiring different therapeutic approaches. The hypothesis that an infectious agent may initiate chronic inflammation and facilitate B lymphocyte transformation and lymphogenesis has been raised in recent years. Viruses, like EBV, HTLV-1, HIV, HCV and parasites, like Plasmodium falciparum, have been linked to the development of lymphomas. The association of chronic Helicobacter pylori (H. pylori) infection with mucosa-associated lymphoid tissue (MALT) lymphoma, Borrelia burgdorferi with cutaneous MALT lymphoma and Chlamydophila psittaci with ocular adnexal MALT lymphoma is well documented. Recent studies have indicated that other infectious agents may also be relevant in B-cell lymphogenesis such as Coxiella burnettii, Campylobacter jejuni, Achromobacter xylosoxidans, and Escherichia coli. The aim of the present review is to provide a summary of the current literature on infectious bacterial agents associated with B-cell NHL and to discuss its role in lymphogenesis, taking into account the interaction between infectious agents, host factors, and the tumor environment.


Assuntos
Infecções Bacterianas/complicações , Linfoma de Burkitt/microbiologia , Infecções por Helicobacter/microbiologia , Interações Hospedeiro-Patógeno , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma Difuso de Grandes Células B/microbiologia , Infecções Bacterianas/imunologia , Linfoma de Burkitt/complicações , Linfoma de Burkitt/patologia , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
6.
EBioMedicine ; 69: 103462, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34229278

RESUMO

BACKGROUND: Gastric inflammation is a major risk factor for gastric cancer. Current endoscopic methods are not able to efficiently detect and characterize gastric inflammation, leading to a sub-optimal patients' care. New non-invasive methods are needed. Reflectance mucosal light analysis is of particular interest in this context. The aim of our study was to analyze reflectance light and specific autofluorescence signals, both in humans and in a mouse model of gastritis. METHODS: We recruited patients undergoing gastroendoscopic procedure during which reflectance was analysed with a multispectral camera. In parallel, the gastritis mouse model of Helicobacter pylori infection was used to investigate reflectance from ex vivo gastric samples using a spectrometer. In both cases, autofluorescence signals were measured using a confocal microscope. FINDINGS: In gastritis patients, reflectance modifications were significant in near-infrared spectrum, with a decrease between 610 and 725 nm and an increase between 750 and 840 nm. Autofluorescence was also modified, showing variations around 550 nm of emission. In H. pylori infected mice developing gastric inflammatory lesions, we observed significant reflectance modifications 18 months after infection, with increased intensity between 617 and 672 nm. Autofluorescence was significantly modified after 1, 3 and 6 months around 550 and 630 nm. Both in human and in mouse, these reflectance data can be considered as biomarkers and accurately predicted inflammatory state. INTERPRETATION: In this pilot study, using a practical measuring device, we identified in humans, modification of reflectance spectra in the visible spectrum and for the first time in near-infrared, associated with inflammatory gastric states. Furthermore, both in the mouse model and humans, we also observed modifications of autofluorescence associated with gastric inflammation. These innovative data pave the way to deeper validation studies on larger cohorts, for further development of an optical biopsy system to detect gastritis and finally to better surveil this important gastric cancer risk factor. FUNDING: The project was funded by the ANR EMMIE (ANR-15-CE17-0015) and the French Gastroenterology Society (SNFGE).


Assuntos
Gastrite/diagnóstico por imagem , Gastroscopia/métodos , Imagem Multimodal/métodos , Imagem Óptica/métodos , Adulto , Idoso , Animais , Feminino , Fluorescência , Gastrite/microbiologia , Gastrite/patologia , Helicobacter pylori/patogenicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Imagem Multimodal/instrumentação , Imagem Óptica/instrumentação , Gravação em Vídeo/métodos
7.
Anticancer Res ; 41(7): 3309-3315, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230126

RESUMO

BACKGROUND/AIM: Matrix metalloproteinase 9 (MMP9) is highly expressed in gastric cancer but the role of MMP9 is unclear. This study aimed at revealing the association of MMP9 promoter rs3918242 genotypes with gastric cancer risk. MATERIALS AND METHODS: MMP9 rs3918242 genotypes of 121 patients with gastric cancer and 363 healthy individuals were examined by polymerase chain reaction-restriction fragment length polymorphism methodology using serum samples. RESULTS: MMP9 rs3918242 TT genotype carriers had an elevated gastric cancer risk compared to wild-type CC carriers (odds ratio=3.92, 95% confidence interval=1.28-11.99; p=0.0103). Patients with CT/TT genotypes were at higher risk of metastasis (p=0.0178) than those with CC. No correlation was found between MMP9 rs3918242 genotype and gastric cancer risk with smoking or alcohol behavior, nor Helicobacter pylori infection. No correlation was observed for MMP9 rs3918242 genotypic distributions with age, gender, or body mass index. CONCLUSION: Carrying a T allele for MMP9 rs3918242 may be predictive for higher gastric cancer risk, and as a predictor for higher risk of metastasis.


Assuntos
Predisposição Genética para Doença/genética , Metaloproteinase 9 da Matriz/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Estudos de Casos e Controles , Feminino , Genótipo , Infecções por Helicobacter/genética , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição/genética , Fatores de Risco
8.
Front Immunol ; 12: 632154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093525

RESUMO

The human gastric pathogen Helicobacter pylori activates human epithelial cells by a particular combination of mechanisms, including NOD1 and ALPK1-TIFA activation. These mechanisms are characterized by a strong participation of the bacterial cag pathogenicity island, which forms a type IV secretion system (CagT4SS) that enables the bacteria to transport proteins and diverse bacterial metabolites, including DNA, glycans, and cell wall components, into human host cells. Building on previous findings, we sought to determine the contribution of lipopolysaccharide inner core heptose metabolites (ADP-heptose) in the activation of human phagocytic cells by H. pylori. Using human monocyte/macrophage-like Thp-1 cells and human primary monocytes and macrophages, we were able to determine that a substantial part of early phagocytic cell activation, including NF-κB activation and IL-8 production, by live H. pylori is triggered by bacterial heptose metabolites. This effect was very pronounced in Thp-1 cells exposed to bacterial purified lysates or pure ADP-heptose, in the absence of other bacterial MAMPs, and was significantly reduced upon TIFA knock-down. Pure ADP-heptose on its own was able to strongly activate Thp-1 cells and human primary monocytes/macrophages. Comprehensive transcriptome analysis of Thp-1 cells co-incubated with live H. pylori or pure ADP-heptose confirmed a signature of ADP-heptose-dependent transcript activation in monocyte/macrophages. Bacterial enzyme-treated lysates (ETL) and pure ADP-heptose-dependent activation differentiated monocytes into macrophages of predominantly M1 type. In Thp-1 cells, the active CagT4SS was less required for the heptose-induced proinflammatory response than in epithelial cells, while active heptose biosynthesis or pure ADP-heptose was required and sufficient for their early innate response and NF-κB activation. The present data suggest that early activation and maturation of incoming and resident phagocytic cells (monocytes, macrophages) in the H. pylori-colonized stomach strongly depend on bacterial LPS inner core heptose metabolites, also with a significant contribution of an active CagT4SS.


Assuntos
Ilhas Genômicas/fisiologia , Helicobacter pylori/metabolismo , Heptoses/metabolismo , Macrófagos/imunologia , Monócitos/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Vias Biossintéticas , Helicobacter pylori/patogenicidade , Humanos , Imunidade Inata , Lipopolissacarídeos/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Monócitos/metabolismo , Transdução de Sinais , Transcriptoma , Sistemas de Secreção Tipo IV/genética , Sistemas de Secreção Tipo IV/metabolismo
9.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062919

RESUMO

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.


Assuntos
Vesículas Extracelulares/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Gastropatias/metabolismo , Membrana Externa Bacteriana/metabolismo , Progressão da Doença , Vesículas Extracelulares/genética , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Gastropatias/microbiologia , Gastropatias/patologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-33975683

RESUMO

Gastric carcinogenesis can be described as a consequence of multilevel molecular alterations that is triggered by a cascade of events. Historically, diet and environmental factors have been identified to substantially contribute to carcinogenesis before the discovery of Helicobacter pylori (H. pylori). But H. pylori infection has revolutionized the understanding of gastric carcinogenesis. Although the model of H. pylori-driven carcinogenesis remains valid, there is a continuous effort to precisely delineate the molecular pathways involved and to understand the interplay with additional risk factors including recent relevant knowledge on the stomach microbiota. In this review, we provide an updated view on the models of gastric carcinogenesis. This includes historically appreciated H. pylori-induced models and expands these taking recent molecular data into consideration. Based on the data provided, we conclude that indeed H. pylori-carcinogenesis remains one of the best-established models at least for a subset of gastric cancers. Implementation of the recently identified molecular subtypes in novel genetic animal models is required to expand our knowledge on H. pylori-independent carcinogenesis.


Assuntos
Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Neoplasias Gástricas/virologia , Animais , Humanos , Camundongos , Modelos Moleculares
12.
Clin Transl Gastroenterol ; 12(4): e00334, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33878048

RESUMO

INTRODUCTION: Functional dyspepsia (FD), although commoner than organic dyspepsia (OD) in-hospital studies, community data, particularly from rural areas, are lacking. We performed a rural community study in Bangladesh with the primary aims to evaluate (i) the prevalence of uninvestigated dyspepsia (UD), FD, and OD and (ii) the risk factors for UD. METHODS: This house-to-house survey was performed using a translated-validated enhanced Asian Rome III questionnaire and endoscopy with Helicobacter pylori tests, including genotyping. RESULTS: Of 3,351/3,559 responders ([94.15%], age 40.41 ± 16.05 years, female 1924 [57.4%]), 547 (16.3%) had UD (female 346 [18%] vs male 201 [14%]; P = 0.002); 201 (6%), 88 (2.6%), and 258 (7.7%) had postprandial distress (PDS), epigastric pain syndromes (EPS) and PDS-EPS overlap, respectively. On multivariate analysis, age >50 years (adjusted odds ratio [AOR] 1.34 [1.07-1.68]), female sex (AOR 1.42 [1.17-1.74]), being married (AOR 1.57 [1.21-2.07]), lower family income (AOR 1.79 [1.43-2.26]), nonsteroidal anti-inflammatory drug use (AOR 7.05 [2.11-23.55]), previous acute gastroenteritis (AOR 5.42 [1.83-16]), and psychological distress (AOR 5.02 [2.87-8.76]) were risk factors for UD. Of 346/547 (63.25%) undergoing endoscopy, 232 (67.05%) and 114 (32.95%) had FD and OD (peptic ulcers [PU] 99 [28.61%] and erosive esophagitis 13 [3.76%]). About 53% of FD subjects had EPS-PDS overlap, 32% had PDS, and only 15% had EPS. H. pylori was detected in 266/342 (78%) dyspeptics (FD 173/230 [75.2%], vs OD 92/114 [82.1%], P = 0.169). DISCUSSION: Sixteen percent, 11% and 5% of rural Bangladeshi Asian adults had UD, FD, and PU, respectively. One-third of UD subjects had OD, mostly PU.JOURNAL/cltg/04.03/01720094-202104000-00016/inline-graphic1/v/2021-04-15T161418Z/r/image-tiff.


Assuntos
Dispepsia/epidemiologia , Dispepsia/microbiologia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori , Úlcera Péptica/epidemiologia , Úlcera Péptica/microbiologia , Adulto , Bangladesh/epidemiologia , Estudos Transversais , Dispepsia/tratamento farmacológico , Dispepsia/psicologia , Endoscopia Gastrointestinal , Feminino , Infecções por Helicobacter/psicologia , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Satisfação do Paciente , Úlcera Péptica/psicologia , Úlcera Péptica/terapia , Estudos Prospectivos , Qualidade de Vida , Fatores de Risco , População Rural , Fatores Socioeconômicos , Virulência
13.
Front Immunol ; 12: 625586, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841407

RESUMO

Background: Helicobacter pylori infection is the main cause of chronic gastritis in children. Little is known about the effect of Helicobacter pylori on microbiota and immunity. This study was aimed at characterizing stomach microbiota and immune-regulatory properties of children with Helicobacter pylori colonization. Methods: We studied 122 children who had undergone gastric endoscopy due to gastrointestinal symptoms, 57 were diagnosed with Helicobacter pylori infection. Endoscopic mucosal biopsy samples were obtained for DNA and RNA extraction. Microbiomes were analyzed by 16S rRNA profiling, with the differentially expressed genes analyzed using RNA sequencing. The RNA-sequencing results of selected genes were validated by qRT-PCR. Results: Bacterial diversity of Helicobacter pylori-positive gastric specimens were lower than those of negative, and both groups were clearly separated according to beta diversity. Helicobacter pylori-positive group significantly reduced proportions of six phyla and eight genera; only Helicobacter taxa were more abundant in Helicobacter pylori-negative group. Gastric tissues RNA sequencing showed increased expression of multiple immune response genes in Helicobacter pylori -infection. Helicobacter pylori -infected children with restructured gastric microbiota had higher levels of FOXP3, IL-10, TGF-ß1 and IL-17A expressions, which were consistent with increased CD4+T cell and macrophagocyte, compared with non-infected children. Conclusions: Presence of Helicobacter pylori significantly influences gastric microbiota and results in lower abundance of multiple taxonomic levels in children. Meanwhile, it affects gastric immune environment and promotes the occurrence of gastritis. Clinical Trial Registration: [http://www.chictr.org.cn], identifier [ChiCTR1800015190].


Assuntos
Duodeno/microbiologia , Mucosa Gástrica/microbiologia , Gastrite/microbiologia , Microbioma Gastrointestinal , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Imunidade nas Mucosas , Mucosa Intestinal/microbiologia , Adolescente , Fatores Etários , Biópsia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Estudos de Casos e Controles , Criança , Duodeno/imunologia , Disbiose , Endoscopia Gastrointestinal , Feminino , Fatores de Transcrição Forkhead/análise , Mucosa Gástrica/imunologia , Gastrite/diagnóstico , Gastrite/imunologia , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Interações Hospedeiro-Patógeno , Humanos , Interleucina-10/análise , Interleucina-17/análise , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Ribotipagem , Fator de Crescimento Transformador beta1/análise
14.
Helicobacter ; 26(3): e12806, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33843101

RESUMO

BACKGROUND: Eradication of Helicobacter pylori infection is the most direct and effective way for preventing gastric cancer. Lactic acid bacteria are considered as alternative therapeutic agents against H. pylori infection. METHODS: Effects of Lactobacillus rhamnosus JB3 (LR-JB3) on the virulence gene expression of H. pylori and infection-induced cellular responses of AGS cells were investigated by co-cultivating infected AGS cells with different multiplicity of infections (MOIs) of LR-JB3. RESULTS: LR-JB3, specifically at a MOI of 25, suppressed the association ability of H. pylori and its induced IL-8 levels, as well as the mRNA levels of vacA, sabA, and fucT of H. pylori, infection-induced Lewis (Le)x antigen and Toll-like receptor 4 (TLR4) expressions in AGS cells. However, the apoptosis mediated by infection was inhibited by LR-JB3 in a dose-dependent manner. In addition, autoinducer (AI)-2 was observed to have increased the association ability and fucT expression of H. pylori, and Lex antigen and TLR4 expression of AGS cells. Interestingly, an unknown bioactive cue was hypothesized to have been secreted from LR-JB3 at a MOI of 25 to act as an antagonist of AI-2. CONCLUSIONS: LR-JB3 possesses various means to interfere with H. pylori pathogenesis and infection-induced cellular responses of AGS cells to fight against infection.


Assuntos
Antibiose , Helicobacter pylori , Lactobacillus rhamnosus , Apoptose , Linhagem Celular Tumoral , Células Epiteliais , Mucosa Gástrica , Infecções por Helicobacter , Helicobacter pylori/patogenicidade , Humanos , Lactobacillus rhamnosus/fisiologia
15.
Int J Mol Sci ; 22(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800082

RESUMO

Helicobacter pylori, a gastric pathogen associated with a broad range of stomach diseases, has a high tendency to become resistant to antibiotics. One of the most important factors related to therapeutic failures is its ability to change from a spiral to a coccoid form. Therefore, the main aim of our original article was to determine the influence of myricetin, a natural compound with an antivirulence action, on the morphological transformation of H. pylori and check the potential of myricetin to increase the activity of antibiotics against this pathogen. We observed that sub-minimal inhibitory concentrations (sub-MICs) of this compound have the ability to slow down the process of transformation into coccoid forms and reduce biofilm formation of this bacterium. Using checkerboard assays, we noticed that the exposure of H. pylori to sub-MICs of myricetin enabled a 4-16-fold reduction in MICs of all classically used antibiotics (amoxicillin, clarithromycin, tetracycline, metronidazole, and levofloxacin). Additionally, RT-qPCR studies of genes related to the H. pylori morphogenesis showed a decrease in their expression during exposure to myricetin. This inhibitory effect was more strongly seen for genes involved in the muropeptide monomers shortening (csd3, csd6, csd4, and amiA), suggesting their significant participation in the spiral-to-coccoid transition. To our knowledge, this is the first research showing the ability of any compound to synergistically interact with all five antibiotics against H. pylori and the first one showing the capacity of a natural substance to interfere with the morphological transition of H. pylori from spiral to coccoid forms.


Assuntos
Antibacterianos/farmacologia , Flavonoides/farmacologia , Helicobacter pylori/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Helicobacter pylori/patogenicidade , Helicobacter pylori/fisiologia , Testes de Sensibilidade Microbiana
16.
Int J Biol Macromol ; 181: 956-965, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33878358

RESUMO

Chitosan (Cs) was cross-linked with four various quantities of 4,4'-(5,5'­carbonylbis(1,3-dioxoisoindoline-5,2-diyl))dibenzoyl isothiocyanate. Elemental analysis, FTIR and 1H NMR spectroscopy assured that the amino groups of chitosan reacted with the isothiocyanate groups of the cross-linker producing four new hydrogels namely as BBTU-Cs-1, BBTU-Cs-2, BBTU-Cs-3, and BBTU-Cs-4 according to the increment of their cross-linking content, respectively. SEM showed their porous structures and XRD indicated their amorphous nature. Their swell ability increased with decreasing the medium pH value and with increasing cross-linking density. In comparison with the popular COX inhibitor Celecoxib, these hydrogels showed an inhibition activity towards COX enzymes with selective inhibition towards COX-2. Their inhibition activity could be arranged as follows: Celecoxib > BBTU-Cs-4 > BBTU-Cs-3 > BBTU-Cs-2 > BBTU-Cs-1. BBTU-CS-4 hydrogel exhibited a potent inhibition against COX-2 (IC50 0.42 µg/ml) compared with that observed for the standard Celecoxib (IC50 0.26 µg/ml). BBTU-Cs-4 is more potent against H. pylori compared to the other hydrogels. BBTU-Cs-4 at a concentration of 7.81 µg/ml is able to kill 100% of the H. pylori and exhibits a preferential ability to inhibit 89.35% of COX-2 than COX-1 (0%). These findings make BBTU-Cs-4 a promising anti-H. pylori and selective anti-inflammatory agent.


Assuntos
Quitosana/farmacologia , Helicobacter pylori/efeitos dos fármacos , Hidrogéis/farmacologia , Inflamação/tratamento farmacológico , Antibacterianos/química , Antibacterianos/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Quitosana/química , Reagentes para Ligações Cruzadas , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Helicobacter pylori/patogenicidade , Humanos , Hidrogéis/química , Inflamação/microbiologia , Inflamação/patologia , Tioureia/química , Tioureia/farmacologia
17.
Biochem Biophys Res Commun ; 556: 192-198, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33845309

RESUMO

Helicobacter pylori (H. pylori) infection mainly causes gastroduodenal diseases, including chronic gastritis, peptic ulcer disease and gastric cancer. In recent years, several studies have demonstrated that infection with H. pylori, especially strains harboring the virulence factor CagA (cytotoxin-associated gene A), contribute to the development of non-gastric systemic diseases, including hypercholesterolemia and atherosclerotic cardiovascular diseases. However, mechanisms underlying this association has not been defined. In this study, we carried out a large-scale genetic screen using Drosophila and identified a novel CagA target low-density lipoprotein receptor (LDLR), which aids in the clearance of circulating LDL. We showed that CagA physically interacted with LDLR via its carboxy-terminal region and inhibited LDLR-mediated LDL uptake into cells. Since deficiency of LDLR-mediated LDL uptake has been known to increase plasma LDL and accelerate atherosclerosis, our findings may provide a novel mechanism for the association between infection with CagA-positive H. pylori and hypercholesterolemia leading to atherosclerotic cardiovascular diseases.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Lipoproteínas LDL/metabolismo , Receptores de LDL/metabolismo , Fatores de Virulência/metabolismo , Animais , Animais Geneticamente Modificados , Aterosclerose/microbiologia , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Olho/metabolismo , Feminino , Humanos , Hipercolesterolemia/microbiologia , Lipoproteínas LDL/sangue , Masculino , Ligação Proteica
18.
Cell Mol Life Sci ; 78(10): 4765-4783, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33825941

RESUMO

Infection with H. pylori induces a strong host cellular response represented by induction of a set of molecular signaling pathways, expression of proinflammatory cytokines and changes in proliferation. Chronic infection and inflammation accompanied by secretory dysfunction can result in the development of gastric metaplasia and gastric cancer. Currently, it has been determined that the regulation of many cellular processes involves ubiquitinylation of molecular effectors. The binding of ubiquitin allows the substrate to undergo a change in function, to interact within multimolecular signaling complexes and/or to be degraded. Dysregulation of the ubiquitinylation machinery contributes to several pathologies, including cancer. It is not understood in detail how H. pylori impacts the ubiquitinylation of host substrate proteins. The aim of this review is to summarize the existing literature in this field, with an emphasis on the role of E3 ubiquitin ligases in host cell homeodynamics, gastric pathophysiology and gastric cancer.


Assuntos
Infecções por Helicobacter/metabolismo , Helicobacter pylori/patogenicidade , Neoplasias Gástricas/metabolismo , Ubiquitina/metabolismo , Animais , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/complicações , Humanos , Transdução de Sinais/fisiologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/microbiologia , Ubiquitina-Proteína Ligases/metabolismo
19.
Toxins (Basel) ; 13(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804551

RESUMO

The tumor necrosis factor-α (TNF-α)-inducing protein (tipα) gene family, comprising Helicobacter pylori membrane protein 1 (hp-mp1) and tipα, has been identified as a tumor promoter, contributing to H. pylori carcinogenicity. Tipα is a unique H. pylori protein with no similarity to other pathogenicity factors, CagA, VacA, and urease. American H. pylori strains cause human gastric cancer, whereas African strains cause gastritis. The presence of Tipα in American and Euro-Asian strains suggests its involvement in human gastric cancer development. Tipα secreted from H. pylori stimulates gastric cancer development by inducing TNF-α, an endogenous tumor promoter, through its interaction with nucleolin, a Tipα receptor. This review covers the following topics: tumor-promoting activity of the Tipα family members HP-MP1 and Tipα, the mechanism underlying this activity of Tipα via binding to the cell-surface receptor, nucleolin, the crystal structure of rdel-Tipα and N-terminal truncated rTipα, inhibition of Tipα-associated gastric carcinogenesis by tumor suppressor B-cell translocation gene 2 (BTG2/TIS21), and new strategies to prevent and treat gastric cancer. Thus, Tipα contributes to the carcinogenicity of H. pylori by a mechanism that differs from those of CagA and VacA.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Neoplasias Gástricas/microbiologia , Animais , Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Bactérias/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/terapia , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Proteínas Imediatamente Precoces/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fatores de Risco , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Supressoras de Tumor/metabolismo
20.
Molecules ; 26(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809289

RESUMO

Matrix metalloproteinases (MMPs), key molecules of cancer invasion and metastasis, degrade the extracellular matrix and cell-cell adhesion molecules. MMP-10 plays a crucial role in Helicobacter pylori-induced cell-invasion. The mitogen-activated protein kinase (MAPK) signaling pathway, which activates activator protein-1 (AP-1), is known to mediate MMP expression. Infection with H. pylori, a Gram-negative bacterium, is associated with gastric cancer development. A toxic factor induced by H. pylori infection is reactive oxygen species (ROS), which activate MAPK signaling in gastric epithelial cells. Peroxisome proliferator-activated receptor γ (PPAR-γ) mediates the expression of antioxidant enzymes including catalase. ß-Carotene, a red-orange pigment, exerts antioxidant and anti-inflammatory properties. We aimed to investigate whether ß-carotene inhibits H. pylori-induced MMP expression and cell invasion in gastric epithelial AGS (gastric adenocarcinoma) cells. We found that H. pylori induced MMP-10 expression and increased cell invasion via the activation of MAPKs and AP-1 in gastric epithelial cells. Specific inhibitors of MAPKs suppressed H. pylori-induced MMP-10 expression, suggesting that H. pylori induces MMP-10 expression through MAPKs. ß-Carotene inhibited the H. pylori-induced activation of MAPKs and AP-1, expression of MMP-10, and cell invasion. Additionally, it promoted the expression of PPAR-γ and catalase, which reduced ROS levels in H. pylori-infected cells. In conclusion, ß-carotene exerts an inhibitory effect on MAPK-mediated MMP-10 expression and cell invasion by increasing PPAR-γ-mediated catalase expression and reducing ROS levels in H. pylori-infected gastric epithelial cells.


Assuntos
Mucosa Gástrica/efeitos dos fármacos , Helicobacter pylori/patogenicidade , Metaloproteinase 10 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , beta Caroteno/farmacologia , Catalase/metabolismo , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , Mucosa Gástrica/enzimologia , Mucosa Gástrica/microbiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/enzimologia , Infecções por Helicobacter/patologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 10 da Matriz/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , PPAR gama/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Fator de Transcrição AP-1/metabolismo
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