The Association between Gallstone Disease and Incidence of Cardiovascular Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Gallstone Disease (GSD) is a multifactorial risk factor for various complications. OBJECTIVE: This study aimed to examine the relationship between GSD and Cardiovascular Disease (CVD) incidence through a systematic review and meta-analysis approach. METHODS: A thorough search was conducted across Web of Science, Scopus, MEDLINE/PubMed, Cochrane Library, and Embase databases. Only studies published between 1980 and December 2023 were included. Chi-square, I2, and forest plots were used to assess heterogeneity. Begg's and Egger's tests were used to evaluate publication bias. Statistical significance was considered at p <0.05, and all analyses were performed using Stata 17. RESULTS: This meta-analysis involved 21 studies and comprised 2,138,282 participants; there has been a significant association found between GSD and an increased risk of CVD (with a relative risk of 1.46, 95% confidence interval: 1.32-1.63, p <0.001). The analysis found no evidence of publication bias based on Begg's test (p =0.085) and Egger's test (p =0.231). Subgroup analysis of the studies showed a higher risk of CVD in studies with a sample size of less than 10,000 participants, conducted in 2016 or later, utilizing a cross-sectional design, in Asian countries; the analysis had a moderate quality score, with a follow-up period of equal to or less than ten years. CONCLUSION: There has been a significant association found between GSD and an increased risk of incidence of CVD. Taking proactive steps to implement targeted interventions for individuals with gallstone disease could potentially reduce the risk of cardiovascular disease within this population.

Biological Mechanisms of Polyphenols against Clostridium Difficile: A Systematic Review.

BACKGROUND: Clostridium difficile is an opportunistic infection that can lead to antibi-otic-associated diarrhea and toxic megacolon. OBJECTIVE: This systematic review study aimed to investigate polyphenols' antibacterial and anti-toxin properties and their effects on reducing complications related to C. difficile Infections (CDI). METHODS: This systematic review was conducted following the PRISMA guideline 2020. Multiple databases, including Web of Science, PubMed, Cochrane Library, EMBASE, and Scopus, were searched thoroughly for existing literature. After considering the inclusion and exclusion criteria for the review, 18 articles were included. Data were collected and registered into an Excel file for further investigations and conclusions. RESULTS: Polyphenols by reducing Reactive Oxygen Species (ROS) levels, increasing inflammatory factor Interleukin 10 (IL-10), reducing Nuclear Factor kappa B (NF-κB) and Tumour Necrosis Fac-tor-α (TNF-α), IL-6, IL-1α, IL-1ß, Granulocyte Colony-stimulating Factor (G-CSF), and Monocyte Chemoattractant Protein-1 (MCP-1) and Macrophage Inflammatory Protein-1 alpha (MIP-1α) lev-els, and regulating the expression of Bcl-2 and Bax, make the growth and replication conditions of C. difficile more difficult and prevent it from producing toxins. Furthermore, polyphenols can ex-hibit prebiotic properties, promoting the growth of beneficial Bifidobacterium and Lactobacillus species and consequently regulating gut microbiota, exerting antimicrobial activities against C. dif-ficile. They also induce their beneficial effects by inhibiting the production of C. difficile TcdA and TcdB. CONCLUSION: Polyphenols have been reported to inhibit C. difficile growth and toxin production by several mechanisms in preclinical studies. However, more clinical studies are needed to investigate their safety in humans.

Relationship between mucosal TNF-α expression and Th1, Th17, Th22 and Treg responses in Helicobacter pylori infection.

Helicobacter pylori (H. pylori)-induced gastric inflammation in the gastric mucosa and significantly increases the risk of developing gastritis and peptic ulcer disease (PUD). The objective of this research is to determine the role of tumor necrosis factor-α (TNF-α) expression in the gastric mucosa of patients with H. pylori-associated gastritis and PUD compared to uninfected patients, and we determined the relation between TNF-α expression and Th1/Th17/Th22, and Treg cells. Fifty-five patients with H. pylori-associated gastritis, 47 patients with H. pylori-associated PUD, and 48 uninfected patients were in this research. Antrum biopsy was used to detect H. pylori, virulence factors and histopathological assessments. Expression of TNF-α in the infected group was significantly higher than the uninfected group. Also, cagA/oipA-positive infected patients induce significantly more TNF-α expression than do cagA/oipA-negative infected patients. Expression of TNF-α was significantly increased in the PUD group than the gastritis group. Notably, TNF-α expression had a significant positive correlation with the frequency of Th1/Th17/Th22 lymphocytes in the PUD group. These findings indicate the importance of increasing TNF-α with Th1, Th17, Th22 responses increase as an important risk factor for PUD in context of H. pylori infection.

Correlation between clarithromycin resistance, virulence factors and clinical characteristics of the disease in Helicobacter pylori infected patients in Shahrekord, Southwest Iran.

The purpose of this study was to determine the mutations associated with clarithromycin resistance in Helicobacter pylori strains isolated from biopsy samples that were collected from the endoscopic ward of Shahrekord Hajar teaching Hospital and also to study the frequency of virulence factor and their correlation and pathological findings with clarithromycin resistance during the years 2019-2020. In this cross-sectional descriptive study, 152 patients with Helicobacter pylori infection were considered, and then, two common A2142G and A2143G mutations in the 23SrRNA gene associated with resistance were analyzed by Real-time PCR (Taq man). The presence of vacA, iceA1, iceA2, cagA, babA2, and oipA virulence genes was investigated by PCR and electrophoresis in 8% polyacrylamide gel. Then, data were analyzed using the relevant statistical tests. In this study, the frequency of Helicobacter pylori was 76% and the frequency of mutant isolates was 57.2%. The frequencies of A2142G and A2143G point mutations were 42.1% and 28.3%. There was a significant correlation among oipA, vacA, and iceA1 virulence factors, type of disease, chronic inflammatory score, and glandular atrophy with the antibiotic resistance to clarithromycin. There was no significant correlation between the age and sex of the patients with antibiotic resistance. According to the results of this study, it seems that the use of clarithromycin to combat this bacterium should be limited.

Frequency of virulence-associated genotypes of Helicobacter pylori and their correlation with clinical outcome and histological parameters in infected patients.

Helicobacter pylori (H. pylori) is a gram-negative which can cause several gastroduodenal diseases, including gastritis and peptic ulcer disease (PUD). H. pylori specific genotypes have been related to increased occurrence of gastritis and PUD. The aim of this study was to investigate the clinical relevance of the major virulence factors of H. pylori with clinical outcomes and histological parameters in Iranian patients. Totally, 200 subjects with PUD and gastritis disease who underwent gastroduodenal endoscopy were enrolled in this study. The presence of the cagA, vacA, oipA, babA2, and iceA genes in antral gastric biopsy specimens were determined by polymerase chain reaction (PCR) and the results were compared with clinical outcomes and histological parameters. The frequency of babA2 + , oipA + , vacA s1/m2, and vacA m2 genes was significantly higher in patients with peptic ulcer disease compared with patients with gastritis. In contrast, the frequency of vacA s1/m1 gene was significantly higher in gastritis subjects than PUD subjects. The high-density scores of H. pylori were strongly associated with iceA1 ¯ , babA2 + , and oipA + genes. Additionally, the high polymorphonuclear cell infiltration and high mononuclear cell infiltration scores were strongly associated with the cagA + , iceA1 ¯ , oipA + genes and cagA + , babA2 + , oipA + genes, respectively. Our study indicated that the vacA, babA2, and oipA virulence factors are related to a higher risk of PUD in subjects with H. pylori-infection. Infection with these strains was associated with a more severe gastropathy.

New insights into regulatory B cells biology in viral, bacterial, and parasitic infections.

B lymphocytes are primarily well known for their contribution to immunity by antibody production, antigen presentation and, the production of cytokines. In recent years several studies demonstrated the existence of B cells with regulatory functions, which have been termed regulatory B cells (Bregs), similar to regulatory T cells (Tregs). Bregs are a subpopulation of B cells that have immunosuppressive effects via the production of regulatory cytokines including interleukin-10 (IL-10), transforming growth factor-ß (TGF-ß), and IL-35. Bregs limit host defense against various pathogens. In addition, Bregs contribute to increased levels of regulatory cytokines and leads to an induction of suppressive Tregs, which exert broader suppressive functions against various pathogens. The high percentage of Bregs is positively associated with viral and bacterial load and can contribute to poor vaccine responses. Bregs can also facilitate pathogen survival at an early stage of infection, and subsequently cause increased severity of disease by inhibiting pro-inflammatory cytokine production, macrophage activation, and inflammatory T cells activation such as Th1, Th17, and Th22. Also, Bregs afford protection against the hyper-inflammatory response in parasitic infections. Here we review the central role of Bregs in many major bacterial and viral human infections, and provide an overview of the immunoregulatory mechanisms used by Bregs.

Up-regulated CCL18, CCL28 and CXCL13 Expression is Associated with the Risk of Gastritis and Peptic Ulcer Disease in Helicobacter Pylori infection.

BACKGROUND: Helicobacter pylori (H. pylori) infection causes inflammation and increases the risk of developing peptic ulcer disease (PUD); however, the exact molecular mechanisms of PUD development remain unclear. The aim of this study was to investigate the expression of CCL18, CCL28, and CXCL13 in H. pylori-positive subjects in comparison with H. pylori-negative subjects, and to determine its association with different clinical outcomes and virulence factors. METHODS: In total, 55 H. pylori-positive subjects with gastritis, 47 H. pylori-positive subjects with PUD, and 48 H. pylori-negative subjects were enrolled in this study. CCL18, CCL28, and CXCL13 expression were determined using real time polymerase chain reaction (PCR). The virulence factors of H. pylori such as cytotoxin-associated gene A (cagA), outer inflammatory protein A (oipA), blood group antigen-binding adhesin (babA), and vacuolating cytotoxin A (VacA) genes were evaluated using PCR. RESULTS: CCL18, CCL28, and CXCL13 expression in H. pylori-positive subjects were significantly higher than H. pylori-negative subjects. CCL18 and CXCL13 expression in H. pylori-positive subjects with oipA+ and babA2+were significantly higher than H. pylori-positive subjects with oipA¯ and babA2¯. CCL18 and CXCL13 expression were found to be significantly elevated in H. pylori-positive subjects with gastritis compared with H. pylori-positive subjects with PUD. CCL28 expression was significantly higher in H. pylori-positive subjects with PUD compared with H. pylori-positive subjects with gastritis. CONCLUSIONS: The increased of CCL18 and CXCL13 may be involved in the pathogenesis of H. pylori-associated gastritis, while the increased of CCL28 may be involved in the pathogenesis of H. pylori-associated PUD.

Increased Indoleamine 2, 3-Dioxygenase expression modulates Th1/Th17/Th22 and Treg pathway in humans with Helicobacter Pylori-Infected gastric mucosa.

INTRODUCTION AND PURPOSE: Indoleamine 2, 3- dioxygenase (IDO) plays an importantrole in immunosuppressive pathway, as inhibits responsesof T cells and promotes immune tolerance. Host responsetoHelicobacter pylori (H. pylori) is involved in the infection persistenceand it is also associatedwith different clinical outcomes. The aim of this study was to investigate the role of IDO in H. pylori-infected patients with gastritis diseases and peptic ulcer diseases (PUD) through the assessment of the relationship among IDO protein expression and the numbers of T helper (Th)-1, Th17, Th22, and T regulator (Treg) cells. MATERIALS AND METHODS: Antrum biopsy was obtained from H. pylori-negative patients (n = 48) and H. pylori-positive subjects (55 patients with gastritis and 47 patients with PUD), for performing H. pylori status and histopathological assessments. IDO protein expression was evaluated by Western blotting. RESULTS: IDO protein expression was significantly higher in gastric biopsies from H. pylori-positive subjects compared to the H. pylori-negative subjects, and also in H. pylori-positive subjects with gastritis disease compared to H. pylori-positive subjects with PUD. Moreover, in H. pylori-positive subjects, a positive correlation was observed between IDO protein expression and the frequency of Treg cells. In addition, a negative correlation was observed between IDO protein expression and the number of Th1, Th17, and Th22. CONCLUSION: Increased IDO protein expression is able to change the number of Th1, Th17, Th22, and Treg cells and these changes are possibly associated with an increase in the risk of PUD development in H. pylori-infected patients.

Determination of CagA EPIYA motif in Helicobacter pylori strains isolated from patients with digestive disorder.

This study was conducted to identify patterns of cagA EPIYA motifs in H. pylori strains isolated from patients with gastrointestinal diseases in Hospitals of Shahrekord, and investigate the association between these biomarkers and clinical outcomes of gastrointestinal diseases due to H. pylori. In this study, 253 patients with gastrointestinal diseases were studied within 1395-1396. Histopathological investigations and urease test showed that 207 isolates were H. pylori-positive. Then, screening using a molecular technique, PCR, confirmed that 159 isolates had cagA. Finally, the pattern and prevalence of the motifs were determined by PCR and identified a number of motifs were sequenced. Results of this study showed that the pattern of motifs was as follows: ABC (140 isolates) (93/7%), ABCC (6 isolates) (3/77%), ABCCC (4 isolates) (2/5%), AB (7 isolates) (4/4%), AC (1 isolate) (0/6%), and BC (1 isolate) (0/6%). Sequencing results showed the presence of changed EPIYA motif in some isolates. CM motif sequence was also seen in all isolates. In this study, no significant association was seen between the prevalence rate of different patterns and clinical symptoms (p = 0.71). There is a slight association between the presence of ABC motifs and the type of digestive disorder (p = 0.056). Results indicated that ABC was the most frequently seen pattern however, in such that positive cases of ABC motifs were more common in gastritis. All isolates had kinase phosphorylation region, and the observed pattern in this region was a generally western type (ABC).

The protective effects of resveratrol on ulcerative colitis via changing the profile of Nrf2 and IL-1ß protein.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with increasing incidence and prevalence in developed countries. The presence of inflammatory cytokines is considered the main detrimental factor in severe types of IBD. The Nrf2 transcription factor plays an important role in reducing the expression of inflammatory agents such as interleukin (IL)-1ß and increasing reparative factors such as IL-11. Resveratrol, a plant-derived phenolic compound, reduces the damage in chronic experimentally induced colitis. Twenty patients with UC and also 20 healthy controls were recruited in this study. The proteins expression of Nrf2 and IL-1ß was assessed in colonic biopsies by Western blotting. Caco-2 cells were challenged with TNF-α (in vitro simulation of UC), in the presence or not of 190 nM (24 h) and 75 nM (48 h) Resveratrol. Then, Nrf2 and IL-1ß in gene and protein expression were measured by real time-PCR and Western blotting in different treatments. Finally, IL-11 proteins expression was measured in culture supernatant by ELISA. A significant increase of IL-1ß protein was detected in inflamed colonic tissues from UC patients compared with the control individuals. In Caco-2 cells challenged with TNF-α, protein expression of IL-1ß and p-Nrf2 showed an increase, while gene expression of Nrf2 did not show a significant difference. After treatment with Resveratrol, both IL-1ß mRNA and protein levels were reduced, while IL-11 protein levels showed any increase. The p-Nrf2 is a dominant form which is prevalent in inflamed tissues from UC patients. Resveratrol can reverse the inflammatory effects of TNF-α by reducing IL-1ß and increasing IL-11 production.

Enhanced Frequency of CD19+IL-10+B Cells in Human Gastric Mucosa Infected by Helicobacter pylori.

BACKGROUND: CD19+IL-10+B cells are considered as a particular subset of immunosuppressive cells by producing interleukin 10 (IL-10), which plays an important role in infectious and autoimmune diseases. The aim of this study was to determine the number of CD19+IL-10+B cells in Helicobacter pylori (H. pylori) positive patients in comparison with H. pylori negative patients, and to determine the association with different clinical outcomes, such as gastritis and peptic ulcer disease (PUD), in infected patients. METHODS AND MATERIALS: We studied 25 infected patients with gastritis, 25 infected patients with PUD, and 25 patients negative for H. pylori. The number of CD19+IL-10+B cells was determined by immunofluorescence. RESULTS: The number of CD19+IL-10+B cells in patients infected with H. pylori was significantly 2.5-fold higher than uninfected patients (P < 0.0001). Also, the number of CD19+IL-10+B cells in infected patients with gastritis was significantly 1.45-fold elevated compared to infected patients with PUD (P = 0.001). CONCLUSIONS: These results demonstrate that the increased number of CD19+IL-10+B cells in infected patients and its association with other cells may play an important role in the pathogenesis of H. pylori infection.

Prevalence and risk factors of non-alcoholic fatty liver disease in southwest Iran: a population-based case-control study.

AIM OF THE STUDY: Few population-based studies have been conducted to report the prevalence of non-alcoholic fatty liver disease (NAFLD) and determine its risk factors in Iran, particularly in Shahrekord, southwest Iran. The main aim of this population-based, case-control study was to determine the prevalence of NAFLD and its potential risk factors in an Iranian population-based cohort study in Shahrekord, Iran. MATERIAL AND METHODS: We compared 1153 cases with NAFLD at 35 to 70 years to 1153 frequency-matched NAFLD-free controls from a population-based Shahrekord cohort study. Data collection and assessed risk factors (demographics, anthropometrics, clinical and biochemical factors, and laboratory tests) were performed based on the Shahrekord cohort study protocol. Chi-square test, stepwise selection with backward likelihood ratio, logistic regression and log-binomial regression model with 95% confidence interval were performed to determine risk factors with significant effects on NAFLD. RESULTS: In this study, the mean (± standard deviation) age of the participants was 50.23 (±8.70) years. The prevalence of NAFLD and metabolic syndrome with 95% confidence interval were 16.47% (15.61-17.36%) and 32.74% (30.83-34.70%), respectively. There was a significant difference in the frequency of waist circumstance, triglycerides, body mass index, blood pressure, and alanine aminotransferase between cases and controls (p < 0.001). According to log-binomial model results, socioeconomic status, hypertension, diabetes, and physical activity were significantly associated with NAFLD. CONCLUSIONS: Our findings have important clinical and public health implications in southwest Iran for monitoring the prevalence of NAFLD and important risk factors to manage, screen, prevent, and reduce NAFLD and related factors.

T-bet+ Cells Polarization in Patients Infected with Helicobacter pylori Increase the Risk of Peptic Ulcer Development.

BACKGROUND: Peptic ulcer disease (PUD) is a common disease worldwide moreover known as stomach ulcer or peptic ulcer. Increased the number of T CD4+ helper cells in response to gastric infection by Helicobacter pylori (H. pylori) play an important role in the development of PUD. The aim of this study was to determine the frequency of T-bet+ cells in H. pylori-infection, its interaction with Th17/Treg cells and its association with the clinical consequences of the infection. METHODS: A total of 63 patients with PUD, 89 patients with gastritis and 48 H. pylori-negative subjects were enrolled in this study. The number of T-bet+ cells were determined by immunohistochemistry. RESULTS: The numbers of T-bet+ cells and INF-γ expression in infected patients were significantly higher than uninfected. Moreover, the number of T-bet+ cells and INF-γ expression in infected patients with PUD were significantly higher than infected patients with gastritis. Additionally, the number of T-bet+ cells and INF-γ expression were found to be inversely correlated with degree of H. pylori density and chronic inflammation score (CIS) in infected patients with gastritis disease, but this correlation was positive in the infected patients with PUD. The number of T-bet+ cells was found to be positively correlated with the number of Th17 cells and inversely correlated with the number of Treg cells in infected patients with gastritis and PUD. CONCLUSION: Abnormal hyper-activation of T-bet+ cells during H. pylori-infection may lead to tissue damage caused by immunopathologic reactions.

Role of Th22 cells in Helicobacter pylori-related gastritis and peptic ulcer diseases.

Helicobacter pylori (H. pylori) has been shown to be one of the leading causes of peptic ulcer diseases (PUDs) and gastritis. T helper-22 (Th22) cells and its most important cytokine, interleukin-22 (IL-22) are importantly active in inflammation and inflammatory tissues. Since inflammation is one of the main attributes of infection caused by H. pylori and resulting complications (gastritis and gastrointestinal ulcer), this study was designed to evaluate the Th22 cells count and the IL-22 protein expression in people suffering from PUD and gastritis. The present study was conducted on 55 patients with gastritis, 47 patients with PUD and 48 uninfected subjects. After preparation of section and extraction of protein from antral biopsies, immunohistochemistry and western blot methods were used to evaluate the Th22 cells and IL-22 protein expression level, respectively. According to findings, the Th22 cells count and the IL-22 protein expression level in the infected subjects were siginficantly more than in the uninfected subjects. It should be noted that the Th22 cells count and the IL-22 protein expression level in the infected subjects with PUD were significantly greater than those in the infected subjects with gastritis. In addition, the Th22 cells count had positive correlation with the density of H. pylori, chronic inflammation score and acute inflammatory score in the infected subjects with PUD. The Th22 cells count had positive correlation with the Th17 cells count and inverse correlation with the Treg cells count in the infected subjects with PUD and gastritis. Our data demonstrated that abnormal hyper-activation of Th22 cells as well as its correlation with the Th17 cells during infection caused by H. pylori might damage tissues through immunopathological responses.

Correlation between expression of MMP-9 and MMP-3 in Helicobacter pylori infected patients with different gastroduodenal diseases.

BACKGROUND AND STUDY AIMS: Helicobacter pylori (H. pylori) has been implicated in the pathogenesis of most important gastro-duodenal diseases, such as gastritis, peptic ulcer disease (PUD) and gastric cancer. H. pylori upregulates the expression and activity of several matrix metalloproteinases (MMPs) in the gastric mucosa, but the role of MMP-3 and MMP-9 in infected patients with H. pylori have not been clearly defined yet. We examined mucosal MMP-3 and MMP-9 mRNA levels in gastric mucosa of H. pylori infected patients and evaluated the effects of virulence factors cagA and vacA allelic variants on these levels. We also determined correlation between mucosal MMP-3 and MMP-9 mRNA levels and types of disease. PATIENTS AND METHODS: Total RNA was extracted from gastric biopsies of 50 H. pylori-infected patients and 50 H. pylori-negative patients. Mucosal MMP-3 and MMP-9 mRNA expression level in H. pylori-infected and non-infected gastric biopsies were determined by real time-polymerase chain reaction (PCR). Presence of vacA (vacuolating cytotoxin A) and cagA (cytotoxin associated gene A) virulence factors were evaluated using PCR. RESULTS: The levels of MMP-3 in gastric mucosa were not different between H. pylori-positive and H. pylori-negative patients. There was no correlation between MMP-3 mRNA expression and virulence factor (cagA and vacA allelic variants) and the different types of disease (gastritis and PUD) in infected patients. But MMP-9 mRNA expression was significantly higher in biopsies of H. pylori-infected patients compared to H. pylori-negative patients. Also mucosal MMP-9 mRNA expression in H. pylori-infected patients was significantly associated with cagA status PUD. CONCLUSION: Our results suggest that MMP-9 might be involved in the pathogenesis of H. pylori. PUD could be associated with cag PAI-dependent MMP-9 upregulation.

The regulatory role of Nrf2 in antioxidants phase2 enzymes and IL-17A expression in patients with ulcerative colitis.

BACKGROUND: Reactive oxygen species (ROS) is one of the pathogenic factors responsible for intestinal injury in Ulcerative colitis (UC). Nuclear factor erythroid-2 related factor 2 (Nrf2) plays a critical role against ROS factors to conserve epithelial integrity. This study aimed to localize Nrf2 and IL-17A protein in the inflamed mucosa of patients with ulcerative colitis. The gene expression of Nrf2 was also correlated with GST-A4 and PRDX1. MATERIALS AND METHODS: A total of 20 patients and 20 healthy controls with definite UC based on the clinical criteria were enrolled for this study. The expression pattern of Nrf2 and IL-17A protein was compared in inflamed and non-inflamed colonic biopsies by immunohistochemical staining. Nrf2, GST-A4 and PRDX1 gene expression were determined by real-time polymerase chain reaction (RT-PCR). RESULTS: In inflamed colonic biopsies, an increased level of Nrf2 protein factor was detected in epithelial cells. Conversely, IL-17A protein was presented more in mononuclear cells in mucosa and lamina propria regions. A significant increase of Nrf2, GST-A4 gene expression was observed in both mild and severe patients with ulcerative colitis. GST-A4 gene expression indicated a high exponential rate in logistic regression. CONCLUSION: Oxidative stress in inflamed colonic tissue can induce Nrf2 gene expression. The performance of Nrf2 transcription factor may lead to the induction of GST-A4 and PRDX1. IL-17A is less detected in intestinal inflammation, presenting Nrf2 factor. The present findings suggest that Nrf2 function in the gut plays a role in arresting both inflammatory response and oxidative damages of UC.

The expression analysis of Fra-1 gene and IL-11 protein in Iranian patients with ulcerative colitis.

BACKGROUND: Fra-1 (fosl1) belongs to the activator protein1 (AP-1) family inducing IL-11 expression in oxidative stress condition. IL-11 plays a pivotal role in protecting epithelial barriers integrity. In this study, we investigated the Fra-1 gene expression in the inflamed mucosa of patients with ulcerative colitis (UC) as well as its relation to IL-11 expression. MATERIALS AND METHODS: We enrolled 20 patients and 20 healthy controls with definite UC based on the clinical criteria. Fra-1 gene expression in inflamed and non-inflamed colonic biopsies was determined by real-time polymerase chain reaction (RT-PCR). The IL-11 protein concentration was measured by Enzyme-Linked Immunosorbent Assay (ELISA) method. Pearson correlation was applied to calculate the relation between Fra-1 and IL-11. RESULTS: An increased level of Fra-1 gene expression was observed in patients with mild ulcerative colitis. The protein concentration of IL-11 was also increased in mild UC patients. Conversely, a significant decrease of IL-11 protein level was detected in severe UC patients compared to control group. CONCLUSION: Oxidative stress in inflamed intestinal biopsies can induce fra-1 gene expression. Our findings suggest that Fra-1 transcription factor leads to the production of IL-11 protein in UC patients.

Intensified Th9 Response is Associated with the Immunopathogenesis of Active Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine histologically characterized by indistinct sustained inflammatory responses. Genetical susceptibility and environmental factors' effects play the roles in disease occurrence and it can be life threatening if remains untreated. It seems that intensification of inflammatory responses in this condition is not restricted to a specific cell line of T lymphocytes. Our aim was to determine the number of T helper 9 (Th9) cells in inflamed colonic biopsies of UC patients. We also correlated it with interleukin (IL)-9 protein level in addition to certain genes expressions associated with Th9 phenotype. METHODS: Expression of CD4 and IL-9 were evaluated by immunohistochemical staining. Enzyme linked immunosorbent assay (ELISA) was performed to determine the colonic expression of IL-9 protein and finally mRNA expressions of interferon regulatory factor 4 (Irf4), Smad2, and Smad3 were measured by real-time polymerase chain reaction (RT-PCR) as critical transcription factors of Th9 differentiation. RESULTS: Number of Th9 cells was significantly increased in inflamed samples as compared with normal tissues. Also quantitative measurement of IL-9 by ELISA and mRNA expressions of Irf4, Smad2, and Smad3 showed notable correlative enhancements in patient's samples. CONCLUSION: Function and number of Th9 cells are up-regulated in the inflamed mucosa of UC patients as with the protein secretion of IL-9 and mRNA expressions of Irf4, Smad2, and Smad3, so Th9 cells and IL-9 may become remarkable therapeutic targets for IBD treatment in the future.

Up-regulated Th17 cell function is associated with increased peptic ulcer disease in Helicobacter pylori-infection.

BACKGROUND: During Helicobacter pylori (H. pylori) infection CD4+ T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by Treg cells. The objective of this study was to determine the number of Th17 cells in gastric mucosa of patients with gastritis and peptic ulcer and determined the relationship between main virulence factor of H. pylori and Th17 cells. METHODS AND MATERIALS: A total of 89 H. pylori-infected gastritis patients, 63 H. pylori-infected peptic ulcer patients and 48 H. pylori-negative non-ulcer dysplasia patients were enrolled in this study. The number of Th17 was determined by immunohistochemistry. IL-8 and IL-17A expressions were determined by real-time polymerase chain reaction (qPCR). Also, the grade of chronic and active inflammation was investigated for involvement according to the density of neutrophils and mononuclear in gastric mucosal crypts, from one to all crypts. RESULTS: The number of Th17 cells and the expression of IL-8 and IL-17A in infected patients were significantly higher than uninfected subjects. The number of Th17 cells and the expression of IL-8 and IL-17A in infected patients with peptic ulcer were significantly higher than patients with gastritis. Additionally, the numbers of Th17 cells as well as the expression of IL-8 and IL-17A were positively correlated with the degree of H. pylori density in infected patients with peptic ulcer, while this correlation was negative in infected patients with gastritis. The numbers of Th17 cells as well as the expression of IL-8 and IL-17A were positively correlated with the degree of chronic inflammation. CONCLUSION: The predominant Th17 cell responses may play a role in the pathogenesis of peptic ulcers disease in infected patients.