Caulerpin Mitigates Helicobacter pylori-Induced Inflammation via Formyl Peptide Receptors.
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ABSTRACT:
SUBMITTER: Cuomo P
PROVIDER: S-EPMC8658387 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Formyl peptide receptors (FPRs) are cell surface pattern recognition receptors (PRRs), belonging to the chemoattractant G protein-coupled receptors (GPCRs) family. They play a key role in the innate immune system, regulating both the initiation and the resolution of the inflammatory response. FPRs were originally identified as receptors with high binding affinity for bacteria or mitochondria N-formylated peptides. However, they can also bind a variety of structurally different ligands. Among FPRs, formyl peptide receptor-like 1 (FPRL1) is the most versatile, recognizing N-formyl peptides, non-formylated peptides, and synthetic molecules. In addition, according to the ligand nature, FPRL1 can mediate either pro- or anti-inflammatory responses. Hp(2-20), a Helicobacter pylori-derived, non-formylated peptide, is a potent FPRL1 agonist, participating in Helicobacter pylori-induced gastric inflammation, thus contributing to the related site or not-site specific diseases. The aim of this review is to provide insights into the role of FPRs in H. pylori-associated chronic inflammation, which suggests this receptor as potential target to mitigate both microbial and sterile inflammatory diseases.
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Project description:Helicobacter pylori (H. pylori) classified as a class I carcinogen by the World Health Organization (WHO) plays an important role in the progression of chronic gastritis and the development of gastric cancer. A major bioactive component of Evodia rutaecarpa, evodiamine, has been known for its anti-bacterial effect and anti-cancer effects. However, the inhibitory effect of evodiamine against H. pylori is not yet known and the inhibitory mechanisms of evodiamine against gastric cancer cells are yet to be elucidated concretely. In this study, therefore, anti-bacterial effect of evodiamine on H. pylori growth and its inhibitory mechanisms as well as anti-inflammatory effects and its mechanisms of evodiamine on H. pylori-induced inflammation were investigated in vitr. Results of this study showed the growth of the H. pylori reference strains and clinical isolates were inhibited by evodiamine. It was considered one of the inhibitory mechanisms that evodiamine downregulated both gene expressions of replication and transcription machineries of H. pylori. Treatment of evodiamine also induced downregulation of urease and diminished translocation of cytotoxin-associated antigen A (CagA) and vacuolating cytotoxin A (VacA) proteins into gastric adenocarcinoma (AGS) cells. This may be resulted from the reduction of CagA and VacA expressions as well as the type IV secretion system (T4SS) components and secretion system subunit protein A (SecA) protein which are involved in translocation of CagA and VacA into host cells, respectively. In particular, evodiamine inhibited the activation of signaling proteins such as the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) pathway induced by H. pylori infection. It consequently might contribute to reduction of interleukin (IL)-8 production in AGS cells. Collectively, these results suggest anti-bacterial and anti-inflammatory effects of evodiamine against H. pylori.
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Project description:H. pylori is classified as a group I carcinogen by WHO because of its involvement in gastric cancer development. Several reports have suggested anti-bacterial effects of menadione, although the effect of menadione on major virulence factors of H. pylori and H. pylori-induced inflammation is yet to be elucidated. In this study, therefore, we demonstrated that menadione has anti-H. pylori and anti-inflammatory effects. Menadione inhibited growth of H. pylori reference strains and clinical isolates. Menadione reduced expression of vacA in H. pylori, and translocation of VacA protein into AGS (gastric adenocarcinoma cell) was also decreased by menadione treatment. This result was concordant with decreased apoptosis in AGS cells infected with H. pylori. Moreover, cytotoxin-associated protein A (CagA) translocation into H. pylori-infected AGS cells was also decreased by menadione. Menadione inhibited expression of several type IV secretion system (T4SS) components, including virB2, virB7, virB8, and virB10, that are responsible for translocation of CagA into host cells. In particular, menadione inhibited nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation and thereby reduced expression of the proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α in AGS as well as in THP-1 (monocytic leukemia cell) cell lines. Collectively, these results suggest the anti-bacterial and anti-inflammatory effects of menadione against H. pylori.
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Project description:Background & aimsThe association between cellular senescence and Helicobacter pylori-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori-induced atrophic gastritis and the underlying mechanism.MethodsC57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro.ResultsGastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori-infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression.ConclusionsOur study showed a new mechanism of H pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori-induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.
| S-EPMC7859172 | biostudies-literature
Project description:The bacterial species, Helicobacter pylori, is associated with several gastrointestinal diseases, and poses serious health threats owing to its resistance to antibiotics. Lactobacillus spp., on the other hand, possess probiotic activities that have beneficial effects in humans. However, the mechanisms by which Lactobacillus spp. harbor favorable functions and act against H. pylori infection remain to be explored. The aim of this study was to investigate the ability of bacterial strains, Lactobacillus rhamnosus and Lactobacillus acidophilus, termed GMNL-74 and GMNL-185, respectively, to inhibit H. pylori growth and inflammation. Our results showed that GMNL-74 and GMNL-185 possess potent antimicrobial activity against multidrug resistant (MDR)-H. pylori. In addition, an in vitro cell-based model revealed that the inhibition of H. pylori adhesion and invasion of gastric epithelial cells and interleukin-8 production were significantly decreased by treatment with both the Lactobacillus strains. In vivo studies demonstrated that colonization of H. pylori and induced inflammation in the mouse stomach were also alleviated by these Lactobacillus strains. Furthermore, the abundance of beneficial gut bacteria, including Bifidobacterium spp. and Akkermansia muciniphilia, were significantly increased in H. pylori-infected mice treated with GMNL-74 and GMNL-185. These results demonstrate that Lactobacillus spp. ameliorate H. pylori-induced inflammation and supports beneficial gut specific bacteria that act against H. pylori infection.
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Project description:The sequence of events associated with the development of gastric cancer has been described as "the gastric precancerous cascade". This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.
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Project description:BackgroundThe aim of this study was to investigate the role of long non-coding RNA (lncRNA) H19 in gastric cancer (GC) with Helicobacter pylori (H. pylori).MethodsH19 expression in peripheral blood from H. pylori+/- GC patients and healthy donors (control) as well as in GC tissues and cells were detected by qRT-PCR. Cell proliferation was evaluated by CCK-8 assay. Cell migration and invasion were evaluated by Transwell assay. The levels of pro-inflammatory cytokines were determined by ELISA. The protein levels of I?B?, p-I?B? and p65 were determined by western blotting.ResultsH19 expression was upregulated in H. pylori-infected GC tissues and cells. Furthermore, H. pylori promoted GC cell viability, migration, invasion and inflammatory response. Moreover, H19 overexpression promoted the proliferation, migration and invasion of H. pylori-infected GC cells via enhancing NF-?B-induced inflammation.ConclusionsLncRNA H19 promotes H. pylori-induced GC cell growth via enhancing NF-?B-induced inflammation.
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Project description:G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases.
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Project description:Helicobacter pylori (H. pylori) infects the human stomach during infancy and develops into chronic active inflammation. The majority of H. pylori tend to colonize within the mucous gel layer of the stomach. The stomach lacks its own immune function, thus innate immunity as the first line of defense is vital for specific immunity against H. pylori. We review recent discoveries in the pathophysiologic roles of toll-like receptors (TLRs), mainly TLR2 and TLR4, in H. pylori-induced inflammation. In addition, the TLR pathways activated by H. pylori-induced inflammation have been shown to be closely associated not only with gastric carcinogenesis, but also with formation of the tumor microenvironment through the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species. Although the correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear, a recent study demonstrated that STAT3-driven up-regulation of TLR2 might promote gastric tumorigenesis independent of inflammation. Further research on the regulation of TLRs in H. pylori-associated gastric carcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.
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Project description:The application of fluid shear stress on leukocytes is critical for physiological functions including initial adhesion to the endothelium, the formation of pseudopods, and migration into tissues. The formyl peptide receptor (FPR) on neutrophils, which binds to formyl-methionyl-leucyl-phenylalanine (fMLP) and plays a role in neutrophil chemotaxis, has been implicated as a fluid shear stress sensor that controls pseudopod formation. The role of shear forces on earlier indicators of neutrophil activation, such as L-selectin shedding and α(M)β(2) integrin activation, remains unclear. Here, human neutrophils exposed to uniform shear stress (0.1-4.0 dyn/cm(2)) in a cone-and-plate viscometer for 1-120 min showed a significant reduction in both α(M)β(2) integrin activation and L-selectin shedding after stimulation with 0.5 nM of fMLP. Neutrophil resistance to activation was directly linked to fluid shear stress, as the response increased in a shear stress force- and time-dependent manner. Significant shear-induced loss of FPR surface expression on neutrophils was observed, and high-resolution confocal microscopy revealed FPR internalized within neutrophils. These results suggest that physiological shear forces alter neutrophil activation via FPR by reducing L-selectin shedding and α(M)β(2) integrin activation in the presence of soluble ligand.
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