Gut microbiota and childhood malnutrition: Understanding the link and exploring therapeutic interventions.

Childhood malnutrition is a metabolic condition that affects the physical and mental well-being of children and leads to resultant disorders in maturity. The development of childhood malnutrition is influenced by a number of physiological and environmental factors including metabolic stress, infections, diet, genetic variables, and gut microbiota. The imbalanced gut microbiota is one of the main environmental risk factors that significantly influence host physiology and childhood malnutrition progression. In this review, we have evaluated the gut microbiota association with undernutrition and overnutrition in children, and then the quantitative and qualitative significance of gut dysbiosis in order to reveal the impact of gut microbiota modification using probiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, and engineering biology methods as new therapeutic challenges in the management of disturbed energy homeostasis. Understanding the host-microbiota interaction and the remote regulation of other organs and pathways by gut microbiota can improve the effectiveness of new therapeutic approaches and mitigate the negative consequences of childhood malnutrition.

Short-term consequences of Helicobacter pylori treatment in patients with oral lichen planus: A prospective study.

Background: Oral lichen planus (OLP) is a multifactorial chronic inflammatory condition with unknown etiology. This condition has been associated with Helicobacter pylori. This study aimed to investigate the relationship between the treatment of H. pylori infection and improvements in OLP lesions. Methods: In this cohort study, 42 patients with erosive or ulcerative OLP lesions were evaluated in terms of H. pylori infection using the H. pylori stool antigen (HpSA) test. The patients were divided into three groups. The first group consisted of 12 H. pylori-negative patients. The second group consisted of 21 H. pylori-positive patients receiving antibacterial treatment. The third group included nine H. pylori-positive patients not willing to receive treatment. All the three groups underwent the usual OLP treatment. Patients in the second and third groups were re-evaluated by the HpSA test after two months. The efficacy indexes and visual analog scale were used to evaluate clinical improvements. Results: The efficiency index and pain scores were affected by the intervention (P<0.001). The logistic regression analysis showed that the severity index before treatment was significantly effective (OR=0.745 (95% CI: 0.602‒0.923; P=0.007). No statistical significance for factors affecting other variables (P>0.05) was obtained. Conclusion: Pain intensity was higher in patients with H. pylori than in those without H. pylori before treatment. Also, in patients with H. pylori, the treatment affects the complete recovery rate.

Xanthogranulomatous cholecystitis in a patient with ulcerative colitis and primary sclerosing cholangitis: A case report.

Chronic gallbladder disease due to xanthogranulomatous cholecystitis is uncommon, and its symptoms are generally vague. While there is no firm evidence to link xanthogranulomatous cholecystitis to primary sclerosing cholangitis or ulcerative colitis. The patient is a 41-year-old male with a history of ulcerative colitis, primary sclerosing cholangitis, and biliary stenting who complained of symptoms of anorexia, jaundice, and pruritus. In the initial ultrasound exam, there was evidence of intrahepatic and extra-hepatic bile duct dilation along with a significant and mass-like circumferential thickening of the gallbladder wall. Magnetic resonance cholangiopancreatography was performed for further evaluation, which indicated increased gallbladder wall thickness, containing multiple T2 hyper-signal nodules while the mucosal layer was intact. There was also a filling defect in the common bile duct's distal portion. These findings matched a xanthogranulomatous cholecystitis diagnosis and a possibly malignant lesion in the distal of the common bile duct. The patient ultimately had a cholecystectomy, and pathology findings confirmed the diagnosis of xanthogranulomatous cholecystitis. Biopsy specimens obtained from the distal of the common bile duct lesion were microscopically identified as intramucosal adenocarcinoma. In patients with a history of primary sclerosing cholangitis who present with nonspecific symptoms suggesting chronic gallbladder disease and radiologic evidence of circumferential gallbladder wall thickening containing intramural nodules and intact mucosa, xanthogranulomatous cholecystitis should be kept in mind.

MiR-146a Restoration Suppresses Triple-Negative Breast Cancer Cell Migration: A Bioinformatic and In Vitro Study.

Purpose: Breast cancer is one of the most commonly diagnosed types of cancer worldwide. This cancer is treated with various methods like mastectomy, chemotherapy, hormone therapy, and radiotherapy. Among them, targeted therapy, like microRNA (miRNA) replacement therapy, is considered a new approach to treating breast cancer. Methods: Data analysis from TCGA datasets were used to investigate the expression of hsa-miR-146a-5p in breast cancer. MTT assay was used to evaluate the viability of MDA-MB-231 cells after hsa-miR-146a-5p ectopic expression. A wound-healing assay was used to observe migration in the MDA-MB-231 cell line and the effect of the hsa-miR-146a-5p ectopic expression on migration. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used as a method to determine the effect of the hsa-miR-146a-5p ectopic expression on the expression of CXCR4, ß-catenin, MMP2, MMP9, and Vimentin genes known to be involved in invasion and migration of MDA-MB-231 cells. Results: Our results indicated that hsa-miR-146a-5p is not involved in apoptosis in the MDAMB-231 cells, while it is highly effective in migration inhibition. MMP9, MMP2, CXCR4, and Vimentin expressions were suppressed by hsa-miR-146a-5p induction; however, it induced the expression of ß-catenin. Conclusion: Some non-coding RNAs, such as hsa-miR-146a-5p, are effective in breast cancer targeted therapy. As cancer is a complicated disorder, therefore the combination of therapies might lead to novel therapeutic strategies.

microRNA-193a-5p Suppresses the Migratory Ability of Human KATO III Gastric Cancer Cells through Inhibition of Vimentin and MMP-9.

Purpose: microRNA-193a-5p is one of the well-known tumor suppressor miRNAs in the body but in many cases, its expression became reduced in patients suffering from gastric cancer (GC). The main purpose of this study was to restore the function of this miRNA in human GC cells and investigating the effects of enhanced expression of miR-193a-5p on proliferation, apoptosis, and migration of GC cells upon in vitro transfection. Methods: The KATO III GC cells were treated with 100 nM of miR-193a-5p or negative control sequences. Following that, the MTT assay, flow cytometry assay, and wound-healing assay were applied to estimate the impacts of enhanced expression of this miRNA on the viability, apoptosis, and migration rate of the cells, respectively. Moreover, the total RNA was isolated and alterations in the mRNA expression ratio of migratory genes were measured by qRT-PCR techniques. Results: The findings designated that enhanced expression of miR-193a-5p suppressed the migratory ability of the cells, but had no significant effects on cell survival or apoptosis of the transfected cells. In addition, this inhibitory function of miR-193a-5p on the migration rate of the KATO III cell line occurs with concurrent suppression of vimentin and MMP-9 gene expression. Conclusion: It can be concluded that miR-193a-5p negatively influences the migratory ability of the cancerous cells and restoring its effects can be regarded as a promising target of future therapeutic interventions, especially for GC metastasis.

Lactobacillus plantarum induces apoptosis in gastric cancer cells via modulation of signaling pathways in Helicobacter pylori.

Introduction: Gastric cancer is considered the second prevalent cause of death around the world. This type of cancer is generally induced by Helicobacter pylori which could colonize within the gastric mucosa of the infected cases. To date, triple antibiotic therapy has routinely been utilized for controlling the H. pylori- induced infection. However, this strategy has been unsuccessful, in large part because of issues such as occurring point mutations in the H. pylori genome that can induce resistance to the antibiotics administered. Recently, it has been shown that different probiotics may have strong anti-cancer effects, in which they are capable of inhibiting H. pylori by both immunological and non-immunological mechanisms. Here, we aimed at finding possible anti-cancer impacts of the probiotic bacterium Lactobacillus plantarum on gastric cancer, AGS cells. Methods: The anti-cancer effects of the conditioned media of the locally isolated L. plantarum on the AGS cells were evaluated by different analyses such as flow cytometry, DNA ladder assay, DAPI staining, and RT-PCR. Results: Our findings showed that the conditioned media of L. plantarum can inhibit both H. pylori and AGS cells through up-/down-regulation of PTEN, Bax, TLR4, and AKT genes. The exudates of the probiotic L. plantarum bacteria can increase the expression of PTEN, Bax, and TLR4, and also decrease the expression of AKT gene. Conclusion: In agreement with different reports, our results proved the anti-cancer effects of the locally isolated L. plantarum through some immunological cell signaling pathways. Accordingly, it seems the probiotics could be considered as at least a complementary treatment for different types of malignancies.

Regulatory mechanisms of microRNAs in colorectal cancer and colorectal cancer stem cells.

Colorectal cancer (CRC) is one of the most lethal and hard-to-treat cancers in the world, which in its advanced stages, surgery and chemotherapy are the main common treatment approaches. The microRNAs (miRNAs), as novel markers for CRC detection, promote their regulatory effects via the 3'-untranslated binding region (3'-UTR) of target messenger RNA in posttranscriptional regulation of genes and also play a pivotal role in modulating resistance to chemotherapeutic agents. These small noncoding RNAs have also a critical role in CRC stem cells (CRCSCs) regulation, comprising self-renewal, differentiation, and tumorigenesis. Cancer stem cells (CSCs) are distinctive cell types inside a tumor tissue that are believed to derive from normal somatic stem cells. The CSCs have self-renewal abilities, angiogenesis, as well as specific surface markers expression characteristics. Furthermore, they are frequently criticized for tumor maintenance, treatment resistance, tumor development, and distant metastasis. In this review, we discuss the current understandings of CRCSCs and their environment with a focus on the role of miRNAs on the regulation of CSCs and their targeting application in CRC treatment.

The Role of Nrf2 signaling in cancer stem cells: From stemness and self-renewal to tumorigenesis and chemoresistance.

Cancer stem cells (CSCs) are subpopulation of tumor mass with exclusive abilities in self-renewing, stemness maintaining, and differentiation into the various non-stem cancer cells to provoke tumorigenesis, metastasis dissemination, drug-resistant, and cancer recurrence. Reactive oxygen species (ROS) impair cellular function by oxidizing cell components containing proteins, lipids, and DNA. Tumor oxidant status is elevated due to high metabolic activity under influence of abnormal growth factors, cytokines and function ROS-producing enzymes, including nitric oxide synthases, cyclooxygenases, and lipoxygenases. Nuclear factor-erythroid 2-related factor 2 (NRF2) is a transcriptional master regulator element which is believed to recognize cellular oxidative stress followed by binding to promoter of cyto-protective and anti-oxidative genes to maintain cellular redox status through promoting antioxidant response participants (glutathione peroxidase, glutathione reductase, thioredoxin reductase, ferritin, NADPH: quinone oxidoreductase 1). However, Nrf2 signaling protects malignant cells from ROS damage against tumor growth and chemoresistance. In addition, Nrf2 is able to participate in differentiation of certain stem cells by modulating autophagy procedure, also NRF2 provokes DNA damage response and facilitates drug metabolism and drug resistance by controlling of downstream enzyme and transporter members. In this review, we discuss the role of NRF2 in stemness, self-renewal ability, tumorigenesis and chemoresistance of CSCs.

Nrf2/P-glycoprotein axis is associated with clinicopathological characteristics in colorectal cancer.

Colorectal cancer (CRC) is the fourth leading cause of cancer-related death worldwide. Activation of ABCB1 gene and its main product, P-glycoprotein, is the common reason for chemoresistance. The nuclear factor-erythroid 2-related factor2 (Nrf2) is directly regulated by Kelch like ECH-associated protein1 (Keap1). In addition, Nrf2 is a key transcriptional factor that regulates efflux transporters, including P-gp. The aim of this study was to investigate the expression levels of Nrf2, Keap1 and ABCB1 in the biopsy samples and their association with clinicopathological features in CRC patients. Both mRNA and protein expression levels were measured by Real-time PCR and immunohistochemistry (IHC), respectively, in biopsies from colonoscopy in 65 CRC patients compared to those in 65 non-CRC individuals. While expression levels of Nrf2 and ABCB1 (P-gp) were markedly higher in both mRNA and protein levels in CRC biopsies (p < 0.01), Keap1 expression level was significantly lower in these samples (p < 0.05). Positive correlations between Nrf2 expression level and tumor size (p = 0.003), lymph node (p = 0.038), distant metastasis (p = 0.008), and smoking status (p = 0.02) were observed. However, P-gp expression was associated only with patient age and smoking status. In addition, there was a positive correlation between protein levels of Nrf2 and P-gp, in both CRC (r = 0.617, p < 0.001) and non-CRC tissues (r = 0.930, p < 0.001). In conclusion, over-expression of Nrf2 and ABCB1/P-gp, as well as down-regulation of mRNA expression level of Keap1 in CRC patients denotes the role of Keap1/Nrf2/ABCB1 axis in CRC progression and chemoresistance. Our data suggest that therapeutic inhibition of Nrf2/ABCB1 signaling can be considered as a novel strategy to improve the efficacy of chemotherapeutics against CRC.

Comparison of Salivary Bacterial Flora in Iranian Patients with Hiatal Hernia and Healthy Subjects

Objective: To evaluate salivary microbial flora of patients with hiatal hernia and compare it with that of healthy subjects. Material and Methods: In this cross-sectional study, 50 patients with hiatal hernia measuring >1 cm and 50 healthy subjects (as the controls) were selected using simple random technique. One mL of salivary sample was taken from each patient, transferred into 50-mL Falcon tubes and immediately carried to the microbiology Laboratory of Tabriz Faculty of Medicine. The salivary samples were cultured on specific Streptococcus viridans (S. mitis, S. mutans, S. salivarius and S. sanguis), Enterococcus spp. and Lactobacillus culture media. Then the samples were incubated at 37°C for 7 days, followed by evaluation of the bacterial colonies. Statistical significance was defined at p<0.05. Results: A total of 34% of subjects with hiatal hernia and 26% healthy subjects exhibited Lactobacillus gasseri in their salivary samples; 16% of subjects with hernia and 6% of healthy subjects exhibited Enterococci spp. in their salivary samples. In addition, 82% of subjects with hernia and 72% of healthy subjects exhibited S. mutans in their salivary samples; 74% and 4% of subjects with hernia and 76% and 4% of healthy subjects exhibited gram-positive and gram-negative bacilli in their salivary samples, respectively. Furthermore, 98% of subjects with hernia and 86% of healthy subjects exhibited gram-positive cocci in their salivary samples, however without significant difference between the groups (p>0.05). Conclusion: No significant differences in the counts of Lactobacillus spp., Enterococcus spp., Streptococcus viridans and gram-positive and gram-negative bacterial species between healthy controls and subjects with hiatal hernia.

Nrf2 overexpression is associated with P-glycoprotein upregulation in gastric cancer.

The efficacy of chemotherapeutic agents remains very poor in gastric cancer (GC) patients due to the development of multidrug resistance (MDR) phenotype. The nuclear factor erythroid 2-related factor 2 (Nrf2), is a pivotal transcriptional factor that regulates phase II detoxifying enzymes, antioxidants and efflux transporters including P-glycoprotein (P-gp). The aim of this study was to investigate the association of Nrf2 and P-gp and their correlations with clinicopathological criteria in GC patients.Nrf2 and MDR1/P-gp expressions in both mRNA and protein levels were examined by real-time PCR and immunohistochemical staining (IHC) respectively, in endoscopic biopsy samples from60 GC patients compared with those expressions in non-GC individuals. Our results from IHC examinations revealed that Nrf2 expression in GC patients (46.7%) is markedly higher than that in non-GC individuals (11.7%) (p<0.001, Mann-Whitney test) which was confirmed by real-time PCR in mRNA levels. Induction of P-gp as a drug efflux pump, was associated with Nrf2 overexpression in these samples (r=0.55, p<0.001). There was also a strong correlation between Nrf2 overexpression and tumor size, histological grade, lymph node and distant metastasis while P-gp upregulation was shown to be associated only with the histological grade and tumor size (Chi-square, all p<0.05). Our results suggest that therapeutic inhibition of Nrf2 expression can improve the efficacy of chemotherapeutic agents for GC patients by down regulation of P-gp expression.

Comparison of genome-wide analysis techniques to DNA methylation analysis in human cancer.

DNA methylation was the first epigenetic modification to be detected in human cancers with specific relation to aberrant gene expression. Herein, DNA methylation analysis explains how epigenetic patterns affect gene expression level. Hypermethylation at tumor suppressor gene loci leads to increased tumorigenesis due to tumor suppressor gene silencing, whereas global hypomethylation of CpG islands (CGIs) is followed by genomic instability and aberrant activation of multiple oncogenes. Therefore, characterization of the genes which silenced or activated epigenetically in human tumor cells can improve our understanding of cancer biology. Different genome-wide methodologies are applied to evaluate methylation status. Various commonly conducted techniques for this evaluation are reviewed in this paper. We provided comparative description of the procedures, advantages, and drawbacks of genome-wide DNA methylation analysis methods and biological applications, to give information on selecting the appropriate method for different methylation studies.

TP53 Gene Pro72Arg (rs1042522) Single Nucleotide Polymorphism as Not a Risk Factor for Colorectal Cancer in the Iranian Azari Population

Background: The p53 protein participates critically in several cellular functions such as cell growth and DNA repair. Polymorphisms in the TP53 locus have repeatedly been implicated in the pathogenesis of cancers all over the world. Over 200 single nucleotide polymorphisms (SNPs) have been characterized, but one well-known example at at codon 72, Pro72Arg (rs1042522), has the displayed inconsistent results with regard to cancer risk. Herein, we aimed to evaluate whether Pro72Arg (rs1042522) single nucleotide polymorphism (SNP) in TP53 gene might be associated with risk of colorectal cancer in the Iranian Azari population. Methods: Blood samples were taken from 100 healthy controls and 100 colorectal cancer patients with Iranian-Azeri ethnicity. Genotyping was performed with Tetra-ARMS PCR. Results: The alleles of the TP53 gene Pro72Arg SNP did not significantly differ in prevalence between patients and controls (P>0.05). Additionally, genotypes of Pro72Arg SNP were not significantly associated with colorectal cancer risk in the studied population. Conclusions: Pro72Arg SNP of TP53 gene may not be involved in the disease pathogenesis in Iranian Azari patients with colorectal cancer.

Impact of postoperative chemoradiotherapy and chemoradiotherapy alone for esophageal cancer in North-West Iran.

BACKGROUND: To investigate the role of surgical treatment for locally advanced esophageal cancer, we compared the outcomes of chemoradiotherapy alone (CRT) to postoperative chemoradiotherapy (S/CRT), using, Regional Radiotherapy Center, database. MATERIALS AND METHODS: This retrospective study was conducted in North-West of Iran, included of 255 consecutive patients with esophageal cancer. Eligible operable and non-operable, were treated with S/CRT and CRT respectively. Radiotherapy (RT) was delivered at 1.8-2 Gy/day for five consecutive days in a given week. Chemotherapy (CT) consisted of cisplatin and 5-fluorouracil. RESULTS: From March 2006 to March 2011 255 patients: male/female 129/96, median age 68 (35-90), squamous/adeno 213/12, received CRT /S+CRT 166/59, median radiation dose 45 ± 13.6 Gy, Median survival 13.5 (11-15), overall survival (OS) One/ Two/Three 57/21/16%, Died/alive 158/97, Univariate analysis prognostic factors: age/stag/differentiation/dose of RT/fraction/treatment, Multivariate analysis predictor factor: dose of RT/fraction. CONCLUSIONS: Although this treatment offers some possibility for improvement of patients with esophageal cancer, there remains a significant need for development of new drug and new therapeutic approaches that can substantially impact survival.