miR-497-5p mediates starvation-induced death in colon cancer cells by targeting acyl-CoA synthetase-5 and modulation of lipid metabolism.

Modulation of fatty acids metabolism is an appropriate strategy for starvation-induced death in tumor cancers. Colon cancer cells express a high level of acyl-CoA synthetase-5 (ACSL5), and as yet no therapeutic approach has been achieved. Herein, ACSL5-related microRNAs (miRNAs) were identified via TargetScan, and their impacts on ACSL5 and lipid content along with metabolic activity, cell cycle, migration, and invasion of colorectal cancer (CRC) cells were examined, and subsequently compared with transcriptome for better visualization of intracellular-signaling networks. In vivo analysis was performed using BALB/c mice xenograft model of CRC injected with target miRNA. Clinical significances were also evaluated in 80 CRC tumors and matched adjacent normal tissues. There was a reverse correlation between ACSL5 and miR-497-5p, which miR-497-5p overexpression modulated CRC cell proliferation and development. A similar observation was received from the in vivo examination in which intratumoral injection of miR-497-5p reversed the tumor growth in the CRC xenograft model. Downregulation of miR-497-5p correlated with tumor differentiation, tumor, node, and metastasis staging, lymph node metastasis, and poor survival in patients with CRC. These results suggested that miR-497-5p upregulation could be considered as a therapeutic strategy for modulation of lipid metabolism in colon cancer.

Exosomes as a novel cell-free therapeutic approach in gastrointestinal diseases.

Cell communication through extracellular vesicles (EVs) has been defined for many years and it is not limited only to neighboring cells, but also distant ones in organisms receive these signals. These vesicles are secreted from the variety of cells and are composed of a distinctive component such as proteins, lipids, and nucleic acids. EVs have different classified subgroups regarding their cell origin, in this context, exosomes are the most appealing particles in cell biology, especially clinical in recent years and are represented as novel therapeutic agents with numerous advantages alongside and/or over cell therapy. However, cell therapy had a hopeful outcome in gastrointestinal diseases which have minimal alternatives in their treatments. Inflammatory bowel disease (IBD), liver fibrosis, gastrointestinal cancers are the examples that cell therapy and immunotherapy were applied in their treatment, therefore, the cell products like exosomes are the beneficial option in their treatment even cancers with promising results in animal models. In this review, we consider the main defined biogenesis, function, and component of secreted exosomes in different cells with a specific focus on the potential application of these exosomes as a cell-free therapeutic approach in gastrointestinal diseases like IBD, gastric cancer, and colon cancer. Additionally, exosomes role as therapeutic reagents mainly mesenchymal stem cells and dendritic cell-derived exosomes in different studies have been under intense investigation and even they are being studied in different clinical trials. Therefore, all these striking functions described for secretome implies the importance of these biocarriers.

Association Between Adipokines Levels with Inflammatory Bowel Disease (IBD): Systematic Reviews.

BACKGROUND: A combination of genetic and environmental factors is involved in the etiology of inflammatory bowel disease (IBD). Recent studies have shown that adipocytes play a crucial role, by actively participating in systemic immune responses in IBD patients. But findings remain controversial. To the best of our knowledge, no systematic review has evaluated the roles of adipokines in IBD, considering which this systematic review was undertaken to summarize the effects of these adipokines in IBD pathogenesis. METHODS: For this review, articles published between 1980 and 2016 were identified from the PubMed, EMBASE, Scopus, and Cochrane and Google scholar databases. Thirteen articles were ultimately selected for inclusion in this systematic review. RESULTS: Findings of the present study indicate that some of the adipokines such as leptin, adiponectin and resistin are associated with disease severity, body composition and glucose hemostasis in IBD patients, although some of these associations are stronger than others. CONCLUSIONS: Overall findings indicate that some adipokines may play a crucial role in IBD severity or other IBD related outcomes. Further studies are recommended to confirm the results.

Endoscopic and histological pitfalls in the diagnosis of celiac disease: A multicentre study assessing the current practice.

BACKGROUND AND AIMS: the diagnosis of celiac disease requires small bowel biopsies to identify the characteristic mucosal changes. The current biopsy practice among endoscopists for celiac disease is in most part unknown. The aim of this study was to compare the different diagnostic policies in various centers in their current practice. METHOD: information from a total of 931 confirmed celiac disease patients was retrospectively obtained retrospectively from nine centers in European and Middle Eastern countries. The number of small-bowel biopsies obtained from the duodenal bulb and the second part of the duodenum was compared among different centers. RESULTS: the most frequent stage of mucosal changes amongst Iranian subjects was Marsh IIIa whereas in the rest of the study population was Marsh IIIc. Marsh I and Marsh II were more prevalent in adults (P < 0.05) and Marsh IIIc was significantly higher in pediatric ages between 1 and 15 (P < 0.05). The most common number of biopsy specimens obtained from Romanian subjects was 1 (52% of cases), followed by 2 for Iranian (56%), 3 for Lithuanian (66.7%) and British patients (65%) and 4 for Italian patients (48.3%). For majority of cases, anemia was the most prevalent symptom (18.7%) followed by malabsorption (10.5%), diarrhea (9.3%) and dyspepsia (8.2%), respectively. CONCLUSIONS: despite the evidence-based recommendations, this study revealed a poor compliance with major guidelines on diagnosis of celiac disease. We emphasize that taking adequate number of duodenal biopsies should be implemented for an accurate diagnosis and also for the exclusion of celiac disease.

Human Wharton's jelly mesenchymal stem cells derived-exosomes enriched by miR-124 promote an anti-fibrotic response in an experimental model of liver fibrosis.

BACKGROUND: Liver fibrosis is a significant challenge to global health that results in organ failure through inflammation and the release of fibrotic biomarkers. Due to the lack of effective treatments for liver fibrosis, anti-fibrotic and anti-inflammatory therapies are being developed. Since there has been an association between aberrant expression of miR-124 and liver disease progression, we investigated whether delivery of miR-124 through human Wharton's jelly mesenchymal stem cells derived-exosomes (hWJMSC-Exo) can improve liver fibrosis. METHODS: We established a 6-week carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis, then we administered hWJMSC-Exo and miR-124-3p-enriched exosomes (ExomiR-124) for three weeks. The extent of fibrosis and inflammation was assessed by histology, biochemistry, Real-time PCR, immunohistochemistry, and Enzyme-linked immunoassays (ELISA). The inflammatory status of the spleen was also investigated using flow cytometry. RESULTS: Based on the gene and protein expression measurement of IL-6, IL-17, TGF-ß, STAT3, α-SMA, and COL1, In vivo administration of Exo and ExomiR-124 effectively reduce collagen accumulation and inhibition of inflammation. Regarding histopathology findings, the therapeutic effect of ExomiR-124 against liver fibrosis was significantly greater than hWJMSC-Exo. In addition, we found that Exo and ExomiR-124 was capable of phenotype switching of splenic monocytes from inflammatory Ly6Chi to restorative Ly6Clo. CONCLUSIONS: MSC-derived exosomes demonstrated anti-inflammatory effect via different aspects. Aside from the therapeutic approach, enrichment of exosomes as a nanocarrier by miR-124 revealed the down-regulation of STAT3, which plays a crucial role in liver fibrosis. The anti-inflammatory and anti-fibrotic properties of ExomiR-124 could be a promising option in liver fibrosis combination therapies.

Oral targeted delivery of Imatinib by pH responsive copolymer modulates liver fibrosis in the mice model.

Liver fibrosis is a significant cause of morbidity and mortality without approved treatment. The therapeutic effects of Imatinib as a tyrosine kinase inhibitor on reversing liver fibrosis have already been shown. However, considering the conventional route of Imatinib administration, the amount of drug to be used is very high, and its side effects are raised. Therefore, we designed an efficient pH-sensitive polymer for the targeted delivery of Imatinib in treating a carbon tetrachloride (CCl4)-induced liver fibrosis. This nanotherapeutic system-based Vitamin A (VA)-modified Imatinib-loaded poly (lactic-co-glycolic acid)/Eudragit S100 (PLGA-ES100) has been successfully fabricated by adapting the solvent evaporation technique. The applying ES100 on the surface of our desired nanoparticles (NPs) protects drug release at the acidic pH of the gastric and guarantees the effective release of Imatinib at a higher pH of the intestine. Besides, VA-functionalized NPs could be an ideal efficient drug delivery system due to the high capacity of hepatic cell lines to absorb VA. For induction of liver fibrosis, CCL4 was intraperitoneally (IP) injected twice a week for six weeks in BALB/c mice. Oral administration of VA-targeted PLGA-ES100 NPs loaded with Rhodamine Red™ by live animal imaging showed a preferential accumulation of the selected NPs in the liver of mice. Besides, administrating targeted Imatinib-loaded NPs significantly decreased serum levels of ALT, and AST, and also reduced the expression of extracellular matrix components, including collagen I, collagen III, and α-SMA, considerably. Interestingly, histopathological evaluation of liver tissues through H&E and Masson's trichrome staining showed that oral administration of targeted Imatinib-loaded NPs reduced hepatic damage by enhancing hepatic structure condition. Also, the Sirius-red staining indicated a reduction in collagen expression during treatment with targeted NP containing Imatinib. The immunohistochemistry result on liver tissue shows a significant decrease in the expression of α-SMA in groups treated with targeted NP. In the meantime, administration of a very scarce dose of Imatinib via targeted NP caused a substantial decline in the expression of fibrosis marker genes (Collagen I, Collagen III, α-SMA). Our results confirmed that novel pH-sensitive VA-targeted PLGA-ES100 NPs could efficiently deliver Imatinib to the liver cells. Loading Imatinib in the PLGA-ES100/VA might overcome many challenges facing conventional Imatinib therapy, including gastrointestinal pH, the low concentration at the target region, and toxicity.

Lack of association between Helicobacter pylori infection and biliary tract diseases.

There are ambiguous results about the involvement of Helicobacter species in production of hepatobiliary diseases. This study was aimed to investigate any possible association between the presences of Helicobacter spp., their genotypes and occurrence of different biliary diseases. Cultures of 102 bile samples for Helicobacter spp. did not show any growth, but the presence of Helicobacter genus specific DNA (16s rRNA gene) was detected in 3.92% of them. No significant association was found between development of the diseases and presence of the bacteria. All the Helicobacter genus positive samples belonged to H. pylori species and showed vacA+ (s1/m2), cagA- genotypes.

Contribution of natural killer cells in innate immunity against colorectal cancer.

Natural killer cells are members of the innate immune system and promote cytotoxic activity against tumor or infected cells independently from MHC recognition. NK cells are modulated by the expression of activator/inhibitory receptors. The ratio of this activator/inhibitory receptors is responsible for the cytotoxic activity of NK cells toward the target cells. Owing to the potent anti-tumor properties of NK cells, they are considered as interesting approach in tumor treatment. Colorectal cancer (CRC) is the second most common cause of death in the world and the incidence is about 2 million new cases per year. Metastatic CRC is accompanied by a poor prognosis with less than three years of overall survival. Chemotherapy and surgery are the most adopted treatments. Besides, targeted therapy and immune checkpoint blockade are novel approach to CRC treatment. In these patients, circulating NK cells are a prognostic marker. The main target of CRC immune cell therapy is to improve the tumor cell's recognition and elimination by immune cells. Adaptive NK cell therapy is the milestone to achieve the purpose. Allogeneic NK cell therapy has been widely investigated within clinical trials. In this review, we focus on the NK related approaches including CAR NK cells, cell-based vaccines, monoclonal antibodies and immunomodulatory drugs against CRC tumoral cells.

Modulatory effects of gut microbiome in cancer immunotherapy: A novel paradigm for blockade of immune checkpoint inhibitors.

The human gastrointestinal (GI) tract harbors gut microbiome, which plays a crucial role in preserving homeostasis at the intestinal host-microbial interface. Conversely, specific gut microbiota may be altered during various pathological conditions and produce a number of toxic compounds and oncoproteins, in turn, to induce both inflammatory response and carcinogenesis. Recently, promising findings have been documented toward the implementation of certain intestinal microbiome in the next era of cancer biology and cancer immunotherapy. Notably, intestinal microbiota can cooperate with immune checkpoint inhibitors (ICIs) of its host, especially in enhancing the efficacy of programmed death 1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) blockade therapy for cancer. Herein, we review the dual function of gut microbiota in triggering GI cancers, its association with host immunity and its beneficial functions in modulation of cancer immunotherapy responses. Furthermore, we consider the significance of gut microbiota as a potential biomarker for predicting the efficacy of cancer immunotherapy. Finally, we summarize the relevant limitations that affect the effectiveness and clinical applications of gut microbiome in response to immunotherapy.

The relationship between 174 G/C and -572 G/C of IL-6 gene polymorphisms and susceptibility of celiac disease in the Iranian population.

INTRODUCTION: Celiac disease (CD) is a chronic inflammatory intestinal disorder. Different immunological factors, including inflammatory cytokines, may play an important role in disease susceptibility. AIM: To investigate the relationship between -174G/C and -572G/C gene polymorphisms and the serum level of interleukin 6 (IL-6) and susceptibility to CD in the Iranian population. MATERIAL AND METHODS: In this case-control study blood samples were collected of 105 patients with CD and 106 healthy subjects randomly in 2016 and evaluated by polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) method. A sequence was also used to confirm the results of both polymorphisms. The IL-6 concentration was measured using ELISA. RESULTS: The results showed a significant relationship between polymorphism -572G in CD patients when compared with control subjects by genotype (p = 0.001) and alleles (p = 0.022), respectively. There was no significant relationship between polymorphism 174G and frequency of genotype, but an association of this polymorphism with the frequency of alleles (p = 0.034), age (p = 0.001), and body mass index (p = 0.003) was seen. The serum level of interleukin-6 was significantly associated only with rs1800796 (p < 0.001). CONCLUSIONS: The results confirm previous studies in different parts of the world and indicate that IL-6 (572G/C) polymorphism may play a role in susceptibility to CD in the Iranian population.

Transmembrane TNF-α Density, but not Soluble TNF-α Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease.

OBJECTIVES: Anti-tumor necrosis factor (TNF)-α agents like Infliximab (IFX) are effective in the treatment of inflammatory bowel diseases (IBDs) and are widely used. However, a considerable number of patients do not respond or lose response to this therapy. Preliminary evidence suggests that transmembrane TNF-α (tmTNF-α) might be linked to response to IFX by promoting reverse signaling-induced apoptosis in inflammatory cells. The main aim of this study was the evaluation of this hypothesis in primary IFX non-responders. METHODS: A total of 47 IFX naive IBD patients were included in the study. Blood samples were taken before the start of IFX therapy (at week 0) and after induction therapy (at week 14). Endoscopic disease activity and markers of inflammation at baseline and at week 14 were used to evaluate response. Baseline soluble TNF-α (sTNF-α), percentage of circulating TNF-α positive cells, mean fluorescence intensity (MFI) of tmTNF-α, and apoptosis rate at week 14 in the peripheral blood mononuclear cells (PBMCs) were evaluated in IFX responders and non-responders. RESULTS: Mean sTNF-α was not significantly different in responders compared to non-responders (P=0.13). Mean percentage of tmTNF-α bearing lymphocytes and monocytes was higher in the PBMCs of responders (P=0.05 and P=0.014, respectively). Mean MFI of tmTNF-α in circulating lymphocytes and monocytes was greater in responders (P=0.002 and P<0.001, respectively). Moreover, the mean percentage of apoptosis in PBMCs was significantly greater in responders compared to non-responders (P=0.002). CONCLUSIONS: The percentage of tmTNF-α bearing lymphocytes and monocytes and the intensity of tmTNF-α in the circulating leukocyte population of IBD patients was directly related to primary response to IFX. This was likely due-as assessed by the apoptosis rate-to promotion of inflammatory cell death. Thus, our data suggest that peripheral leukocytes could in principle be used for predicting primary response to IFX in IBD patients.

Erratum: Transmembrane TNF-α Density, But Not Soluble TNF-α Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease.

This corrects the article DOI: 10.1038/ctg.2017.44.

Prevalence and antimicrobial resistance of Campylobacter isolated from retail raw chicken and beef meat, Tehran, Iran.

Campylobacter spp. is a leading cause of human diarrhea. The common source of infection is contaminated food, particularly poultry. The veterinary use of antimicrobial drugs has been suggested to be largely responsible for resistance in human isolates of this zoonotic pathogen. From April to October 2004, 241 samples of chicken and beef meat for sale in retail outlets in Tehran (Iran) were analyzed for the presence of Campylobacter. Totally, 88 (36.5%) Campylobacter strains were isolated. Campylobacter was isolated from a significantly larger number of chicken (63%) than beef (10%) meat (P < 0.0001). Susceptibilities of 72 strains were determined for eight antimicrobial drugs using the disk diffusion assay. Resistance to nalidixic acid was the most common finding (75%), followed by resistance to ciprofloxacin (69.4%), tetracycline (45.8%), amoxicillin (11.1%), streptomycin (4.2%), chloramphenicol (2.8%) and gentamicin (1.4%). None of the isolates was resistant to erythromycin. Multidrug resistance was seen in 75% of the Campylobacter strains.

Evaluated outcomes in patients with Chronic Hepatitis C.

AIM: The objective of this study was to evaluate the real outcomes of chronic hepatitis C patients, who treated with interferon plus ribavirin (INF-RBV) and peg-interferon plus ribavirin (PEG-RBV). BACKGROUND: Despite the PEG-RBV has become a standard treatment of hepatitis C virus (HCV) around the world; and in Iran too, but in developing countries like as Iran, INF-RBV is still used among some patients for treating HCV, due to the high costs of treatment with PEG-RBV. PATIENTS AND METHODS: The present cross-sectional study was conducted on 77 naïve patients referred to a private gastroenterology clinic between years 2007 through 2009 in Tehran. Patients had participated in this study taking two types of combination therapies, based on standard protocol of the Iranian Ministry of Health. At the end of the treatment, sustain virological response (SVR) rate was evaluated. RESULTS: The outcomes showed in INF-RBV treatment; 11.6%, 16.3% and 34.9% patients were suffered from relapse, lost follow-up their treatment and non-responder, respectively, and finally 37.2% of the patients reached SVR. In PEG-RBV treatment outcomes were as follows; 2.9%, 14.7% and 14.7% patients were non-responder, lost follow-up their treatment and suffered from a relapse, respectively, and 67.6% of the patients reached SVR. The multivariate-adjusted odds ratios of outcomes showed that treated with PEG-RIB and also genotype 3a than the others genotypes in this treated had more chance to achieved SVR. CONCLUSION: The findings of the present study showed that the rate of SVR in patients who treated with PEG-RBV significantly was higher than patients who treated with INF-RBV. Also in PEG-RBV the chance of achieving SVR is higher among the patients with genotype 3a than among those with other genotypes.

Association of intron and exon polymorphisms of p53 gene in Iranian patients with gastritis.

AIM: The propose of this study was to evaluate the probable correlation between exon and intron polymorphisms of p53 gene and their association with clinicopathological aspects of gastritis. BACKGROUND: Regarding to the decisive role of p53 in the development of a variety of human cancers, a comprehensive study concerning probable correlation between polymorphisms in the p53 intron and exon in gastritis lesions, may open new insight toward gastric cancer development and prevention. PATIENTS AND METHODS: PCR-Sequencing was done for exons and introns 2-7 on the 97 gastritis and normal samples, age range of 15-83 years. Also, microsatellite status was evaluated using five mono nucleotide repeat markers. Variation at codon 72 was associated with IVS2 + 38, p53INS3 and IVS3-29. In addition, IVS2 + 38 had association with polymorphism at codon 36 & 245. Gastritis samples had stable microsatellite except nine patients showing polymorphism for NR-21 and one for Bat-25. RESULTS: Most of patients with stable microsatellites (83.9%) had allele G at codon72 without p53INS3. In addition, all patients with GA and CG at codon 36 / IVS2 + 38 had stable microsatellites. Severity and activity of gastritis were in association with genotypes combined of codon 36/IVS2 + 38 and 245/IVS2 + 38 respectively. In addition, the profiles of combined variation at codon 72/IVS3-29 and codon 72/IVS6 + 31 were different between patients with ages less and greater than 45 years. CONCLUSION: As, some exon variations of p53 gene specially codon 72, were in association with alterations at introns and their combined genotypes were correlated with microsatellite status, pathological findings and age, therefore, it could be inferred that the these combinations of p53 gene polymorphisms work as a whole, not as single.

Prevalence and antimicrobial resistance of diarrheagenic Escherichia coli and Shigella species associated with acute diarrhea in Tehran, Iran.

A study was performed to determine the prevalence and antimicrobial resistance of Shigella species and diarrheagenic Escherichia coli isolates cultured from patients with acute diarrhea in Tehran, Iran. Between May 2003 and May 2005, 1120 diarrheal specimens were collected and assayed for bacterial enteropathogens by conventional and molecular methods. Etiological agents were isolated from 564 (50.3%) specimens, and included 305 (54%) E coli, 157 (27.8%) Shigella species, and 102 (18%) from other genera of bacteria. The predominant E coli was Shiga toxin-producing E coli (105 isolates [34.5%]) and the predominant Shigella serotype was Shigella sonnei (88 isolates [56.1%]). A high rate of antibiotic resistance was observed among E coli, with 40 of 53 (75.5%) Shiga toxin-producing E coli isolates resistant to amoxicillin and tetra-cycline, and eight (5.2%) E coli isolates resistant to more than six antibiotics. Most Shigella isolates were resistant to tetracycline (95%) and trimethoprim-sulfamethoxazole (91.7%), with greatest antibiotic resistance observed among S sonnei (53 of 88 [60.2%] isolates). Antibiotic resistance is widespread in diarrheagenic E coli and Shigella in children with acute diarrhea in Tehran, Iran; hence, updated strategies for appropriate use of antimicrobial agents in Iran are needed.

Genotype characterization and phylogenetic analysis of hepatitis B virus isolates from Iranian patients.

Hepatitis B virus (HBV) is one of the major causative agents of acute and chronic liver disease worldwide and is believed to be responsible for a million deaths annually. Eight genotypes of HBV, A to H, have been described on the basis of similarity of the complete genomes sequence. Although, it is reported that the predominant HBV genotype in the Mediterranean area and the middle east is genotype D, there are no reports on HBV genotypes prevalent in Iran. In this study, the C and S regions of HBV from 26 chronic hepatitis B Iranian patients were amplified and sequenced. Phylogenetic analysis revealed that all Iranian HBV isolates sequences were classified into genotype D with bootstrap values of 100%, 73%, and 100% (1,000 replicates each) for S, C, and preS2 regions, respectively. The mean percent intra-distance of S and C regions were 0.8% and 2.3%, respectively. The mean percent inter-distance of S and C regions between Iranians and genotype D isolates were 1.7% and 3.0%, respectively, and the range of mean percent nucleotide distance of S and C regions between Iranians and the other reference isolates were 7.9%-17.5% and 4.8%-14.7%, respectively. Thirteen out of 23 HBV C region sequences showed nucleotide "A" at position 1896 (precore mutant) in C region. Nucleotide 1858 showed presence of "T" in all isolates. No insertion or deletion was found in both regions. SimPlot and BootScanning analyses did not show any recombination between Iranian isolates and other genotypes in both regions.