• Helicobacter pylori
• cancer
• dysbiosis
• gastric microbiota
• immunity
• inflammation

• Humans
• Helicobacter Infections/complications
• Dysbiosis/complications
• Helicobacter pylori
• Stomach/pathology
• Inflammation/complications
• Endoscopy, Gastrointestinal
• Carcinogenesis
• Biomarkers
• Precancerous Conditions/diagnosis

• Fundação para a Ciência e a Tecnologia

• M1/M2 macrophage polarization
• bacteria
• cancer
• tumor microenvironment
• tumor-associated macrophages

• TLR9
• dichotomic role
• glioma
• tumor progression
• tumor regression

• Humans
• Toll-Like Receptor 9/genetics
• Glioma
• Brain Neoplasms/genetics
• Glioblastoma
• Adjuvants, Immunologic

• Melanoma
• Oleandrin
• Toll-like receptors
• miRNA

• Gastritis/immunology
• Gastritis/microbiology
• Gastritis, Atrophic/immunology
• Gastritis, Atrophic/microbiology
• Helicobacter Infections/immunology
• Helicobacter Infections/microbiology
• Helicobacter pylori
• Humans
• Stomach Neoplasms/immunology
• Stomach Neoplasms/microbiology

• H. pylori
• angiogenesis
• gastric cancer
• host-H. pylori interaction
• invasion
• metastasis
• molecular pathways
• therapeutic targets

• Cyclooxygenase-2
• Gastric cancer
• Genetic variant
• Inflammation
• Prostaglandin E2

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase 1
• Cyclooxygenase 2/genetics
• Cyclooxygenase 2 Inhibitors
• DNA Copy Number Variations
• Humans
• Inflammation
• Isoenzymes
• Membrane Proteins
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Tumor Microenvironment

Helicobacter pylori (H. pylori) is a gram-negative spiral bacterium that caused infections in half of the world’s population and had been identified as type I carcinogen by the World Health Organization. Compared with antibiotic treatment which could result in drug resistance, the vaccine therapy is becoming a promising immunotherapy option against H. pylori. Further, the multi-epitope vaccine could provoke a wider immune protection to control H. pylori infection. In this study, the in-silico immunogenicity calculations on 381 protein sequences of H. pylori were performed, and the immunogenicity of selected proteins with top-ranked score were tested. The B cell epitopes and T cell epitopes from three well performed proteins UreB, PLA1, and Omp6 were assembled into six constructs of multi-epitope vaccines with random orders. In order to select the optimal constructs, the stability of the vaccine structure and the exposure of B cell epitopes on the vaccine surface were evaluated based on structure prediction and solvent accessible surface area analysis. Finally Construct S1 was selected and molecular docking showed that it had the potential of binding TLR2, TLR4, and TLR9 to stimulate strong immune response. In particular, this study provides good suggestions for epitope assembly in the construction of multi-epitope vaccines and it may be helpful to control H. pylori infection in the future.

• Helicobacter pylori
• Immunoinformatics
• Multi-epitope vaccine
• Reverse vaccinology
• Structural vaccinology

• COX-2
• chondrocytes
• coagulansin A
• type II collagen
• urease

• Animals
• Canavalia/enzymology
• Cell Survival/drug effects
• Chondrocytes/drug effects
• Chondrocytes/metabolism
• Collagen Type II/metabolism
• Cyclooxygenase 2/metabolism
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/pharmacology
• Kinetics
• Mice
• Models, Molecular
• Molecular Conformation
• Rabbits
• Urease/antagonists & inhibitors
• Urease/metabolism
• Withania/chemistry
• Withanolides/chemistry
• Withanolides/pharmacology

• NF-kappaB signaling pathway
• TLR ligand
• TLR protein
• myeloid differentiation factor 88
• neoplasm

• Animals
• Humans
• Inflammation/pathology
• Molecular Targeted Therapy
• Neoplasm Metastasis/drug therapy
• Neoplasm Metastasis/pathology
• Signal Transduction
• Toll-Like Receptors/antagonists & inhibitors
• Tumor Microenvironment

• Gastric cancer: clinical practice and treatment (including surgery)
• Gastric cancer: clinical research
• Gastric cancer: epidemiology and surveillance
• Helicobacter pylori: diagnosis
• Helicobacter pylori: treatment and antimicrobial resistance

• Helicobacter pylori
• Toll-like receptor 9
• gastritis

• H. pylori
• NF-κB
• TLR
• microRNA
• polymorphism

Pattern recognition receptors (PRRs) are critical to the early detection and innate immune responses to pathogens. In particular, the TLR system and its associated adaptor proteins play essential roles in early host responses to infection. Epidemic keratoconjunctivitis, caused by the human adenovirus, is a severe ocular surface infection associated with corneal inflammation (stromal keratitis). We previously showed that adenovirus capsid was a key molecular pattern in adenovirus keratitis, with viral DNA playing a lesser role. We have now investigated the role of the adaptor molecule MyD88 in a mouse model of adenovirus keratitis in which there is no viral replication. In MyD88^−/− mice infected with human adenovirus type 37, clinical keratitis was markedly reduced, along with infiltration of CD45⁺ cells, and expression of inflammatory cytokines. Reduction of inflammatory cytokines was also observed in infected primary human corneal fibroblasts pretreated with a MyD88 inhibitory peptide. Keratitis similar to wild type mice was observed in TLR2, TLR9, and IL-1R knockout mice, but was reduced in TLR2/9 double knockout mice, consistent with synergy of TLR2 and TLR9 in the response to adenovirus infection. MyD88 co-immunoprecipitated with Src kinase in mice corneas and in human corneal fibroblasts infected with adenovirus, and MyD88 inhibitory peptide reduced Src phosphorylation, linking MyD88 activation to inflammatory gene expression through a signaling cascade previously shown to be directed by Src. Our findings reveal a critical role for the PRRs TLR2 and 9, and their adaptor protein MyD88, in corneal inflammation upon adenovirus infection.

• Cyclooxygenase 1 (COX-1)
• Cyclooxygenase 2 (COX-2)
• Hymenolepis diminuta
• Prostaglandin E(2) (PGE(2))
• Thromboxane B(2) (TXB(2))

• Cyclooxygenase-2
• Escherichia coli lipopolysaccharide
• Helicobacter pylori
• Toll-like receptor 2
• Toll-like receptor 4

Helicobacter pylori is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA⁺H. pylori strains do not develop cancer, suggesting that other microbial effectors also play a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.

• Colon cancer
• Ghrelin
• PI3K/Akt
• Proliferation
• Ras
• mTOR

• Streptococcus pneumoniae
• inflammation
• innate immunity
• lung
• pneumonia

Toll-like receptors (TLRs) are crucial for pathogen recognition and downstream signaling to induce effective immunity. The gastric pathogen Helicobacter pylori is a paradigm of persistent bacterial infections and chronic inflammation in humans. The chronicity of inflammation during H. pylori infection is related to the manipulation of regulatory cytokines. In general, the early detection of H. pylori by TLRs and other pattern recognition receptors (PRRs) is believed to induce a regulatory cytokine or chemokine profile that eventually blocks the resolution of inflammation. H. pylori factors such as LPS, HSP-60, NapA, DNA, and RNA are reported in various studies to be recognized by specific TLRs. However, H. pylori flagellin evades the recognition of TLR5 by possessing a conserved N-terminal motif. Activation of TLRs and resulting signal transduction events lead to the production of pro- and anti-inflammatory mediators through activation of NF-κB, MAP kinases, and IRF signaling pathways. The genetic polymorphisms of these important PRRs are also implicated in the varied outcome and disease progression. Hence, the interplay of TLRs and bacterial factors highlight the complexity of innate immune recognition and immune evasion as well as regulated processes in the progression of associated pathologies. Here we will review this important aspect of H. pylori infection.

Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori (H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.

• Helicobacter pylori
• Gastrin
• Cyclooxygenase-2
• Gastric cancer

• Animals
• Anti-Bacterial Agents/therapeutic use
• Anticarcinogenic Agents/therapeutic use
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Cyclooxygenase 2/metabolism
• Cyclooxygenase 2 Inhibitors/therapeutic use
• DNA Methylation
• Epigenesis, Genetic
• Gastrins/metabolism
• Gene Expression Regulation, Neoplastic
• Helicobacter Infections/complications
• Helicobacter Infections/drug therapy
• Helicobacter Infections/enzymology
• Helicobacter Infections/microbiology
• Helicobacter pylori/drug effects
• Helicobacter pylori/pathogenicity
• Humans
• Risk Factors
• Signal Transduction
• Stomach/drug effects
• Stomach/enzymology
• Stomach/microbiology
• Stomach/pathology
• Stomach Neoplasms/enzymology
• Stomach Neoplasms/etiology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/pathology
• Stomach Neoplasms/prevention & control

Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.

• Helicobacter pylori
• NOD-like receptors
• Toll-like receptors
• genetic polymorphism
• inflammation
• pattern-recognition receptors
• stomach neoplasm
• therapeutics

• Active Transport, Cell Nucleus/physiology
• Agammaglobulinaemia Tyrosine Kinase
• Amphotericin B/pharmacology
• Animals
• CHO Cells
• CSK Tyrosine-Protein Kinase
• Calcium/metabolism
• Calcium Channel Blockers/pharmacology
• Cell Nucleus/metabolism
• Cricetinae
• Cytokines/biosynthesis
• Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
• Intracellular Signaling Peptides and Proteins/metabolism
• Male
• Mice
• Mice, Inbred BALB C
• Monocytes/drug effects
• Monocytes/metabolism
• Phosphorylation/drug effects
• Protein Kinase C/antagonists & inhibitors
• Protein Kinase C/metabolism
• Protein-Tyrosine Kinases/antagonists & inhibitors
• Protein-Tyrosine Kinases/metabolism
• Signal Transduction/drug effects
• Toll-Like Receptor 2/metabolism
• Toll-Like Receptors/metabolism
• Transcription Factor RelA/immunology
• Transcription Factor RelA/metabolism
• Type C Phospholipases/antagonists & inhibitors
• Type C Phospholipases/metabolism
• src-Family Kinases

• Animals
• Antineoplastic Agents/therapeutic use
• Humans
• Molecular Targeted Therapy
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/metabolism
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/metabolism

• P30 CA016672 NCI NIH HHS
• R01CA138671 NCI NIH HHS
• R0ACA172741 PHS HHS
• R01 CA172741 NCI NIH HHS
• R01 CA138671 NCI NIH HHS

• EGFR
• Helicobacter pylori
• cyclooxygenase-2

Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Line, Tumor
• Cyclooxygenase 2/genetics
• Cyclooxygenase 2/metabolism
• Cyclooxygenase 2 Inhibitors/pharmacology
• Cyclooxygenase 2 Inhibitors/therapeutic use
• Disease Models, Animal
• Gene Expression
• Humans
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/enzymology
• Stomach Neoplasms/pathology

Although the iceA (induced by contact with epithelium) allelic types of Helicobacter pylori have been reported to be associated with peptic ulcer, the importance of iceA on clinical outcomes based on subsequent studies is controversial. The aim of this study was to estimate the magnitude of the risk for clinical outcomes associated with iceA.

A literature search was performed using the PubMed and EMBASE databases for articles published through April 2011. Published case-control studies examining the relationship between iceA and clinical outcomes (gastritis, peptic ulcer, including gastric ulcer and duodenal ulcer, and gastric cancer) were included.

Fifty studies with a total of 5,357 patients were identified in the search. Infection with iceA1-positive H. pylori increased the overall risk for peptic ulcer by 1.26-fold (95% confidence interval [CI], 1.09–1.45). However, the test for heterogeneity was significant among these studies. Sensitivity analysis showed that the presence of iceA1 was significantly associated with peptic ulcer (odds ratio [OR] = 1.25, 95% CI = 1.08–1.44). The presence of iceA2 was inversely associated with peptic ulcer (OR = 0.76, 95% CI = 0.65–0.89). The presence of iceA was not associated with gastric cancer. Most studies examined the cagA status; however, only 15 studies examined the correlation and only 2 showed a positive correlation between the presence of cagA and iceA1.

Our meta-analysis confirmed the importance of the presence of iceA for peptic ulcer, although the significance was marginal.

• Antigens, Bacterial/genetics
• Bacterial Proteins/genetics
• Case-Control Studies
• Duodenal Ulcer/complications
• Gastritis/complications
• Gene Expression Regulation, Bacterial
• Genotype
• Helicobacter Infections/complications
• Helicobacter pylori/genetics
• Humans
• Peptic Ulcer/complications
• Prognosis
• Stomach Neoplasms/complications

• R01 DK062813 NIDDK NIH HHS
• DK62813 NIDDK NIH HHS

In mouse macrophages and dendritic cells, the CHIP E3 ubiquitin ligase is needed for transduction of signals initiated by TLR4 and TLR9 stimulation.

The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)–interacting protein (CHIP, also known as Stub1) is a U box–containing E3 ubiquitin ligase that is important for protein quality control. The role of CHIP in innate immunity is not known. Here, we report that CHIP knockdown inhibits Toll-like receptor (TLR) 4– and TLR9-driven signaling, but not TLR3-driven signaling; proinflammatory cytokine and type 1 interferon (IFN) production; and maturation of antigen-presenting cells, including macrophages and dendritic cells. We demonstrate that CHIP can recruit the tyrosine kinase Src and atypical protein kinase C ζ (PKCζ) to the TLR complex, thereby leading to activation of IL-1 receptor–associated kinase 1, TANK-binding kinase 1, and IFN regulatory factors 3 and 7. CHIP acts as an E3 ligase for Src and PKCζ during TLR signaling. CHIP-mediated enhancement of TLR signaling is inhibited by IFNAR deficiency or expression of ubiquitination resistant mutant forms of Src or PKCζ. These findings suggest that CHIP facilitates the formation of a TLR signaling complex by recruiting, ubiquitinating, and activating Src and PKCζ.

• Aged
• Cyclooxygenase 2/genetics
• Female
• Gene Expression Regulation, Neoplastic
• Haplotypes
• Helicobacter Infections/complications
• Helicobacter pylori/isolation & purification
• Humans
• Male
• Middle Aged
• Polymorphism, Genetic
• Promoter Regions, Genetic
• Risk Factors
• Stomach Neoplasms/etiology
• Stomach Neoplasms/genetics