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Role of PTPN2/22 polymorphisms in pathophysiology of Crohn's disease

World Journal of Gastroenterology 2018年第6期24卷 657-670页

作者： Robert C Sharp Shazia A Beg saleh a naser Burnett School of Biomedical Sciences College of Medicine University of Central Florida University of Central College of Medicine Health CenterOrlando

AIM To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22(PTPN2/22) polymorphisms and mycobacterial infections in Crohn's disease(CD). METHODS All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms(SNPs) in PTPN2/22 using TaqMan^(?) genotyping, while the effect of the SNPs on PTPN2/22 and IFN-γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis(MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin(PHA) mitogen or mycobacterial antigens by Brd U proliferation assays for T-cell activity. RESULTS Out of the nine SNPs examined, subjects with either heterozygous(TC)/minor(CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls(P-values < 0.05; OR = 3.03). Subjects with either heterozygous(GA)/minor(AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls(OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls(P-values < 0.05). IFN-γ expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found(P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls(P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. T h e average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP. CONCLUSION The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an

关键词： Crohn’s disease PTPN2 PTPN22 PTPN2/22 Mycobacteria single nucleotide polymorphisms

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Role of ATG16L,NOD2 and IL23R in Crohn's disease pathogenesis

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世界胃肠病学杂志：英文版 2012年第5期18卷 412-424页

作者： saleh a naser Melissa Arce Anam Khaja Marlene Fernandez Najih naser Sammer Elwasila Saisathya Thanigachalam Department of Molecular Biology and Microbiology Burnett School of Biomedical SciencesCollege of MedicineUniversity of Central FloridaOrlandoFL 32816United States Division of Research and Development BioSynseCaryNC 27513United States

Inflammatory bowel disease is a group of diseases that includes Crohn's disease (CD) and ulcerative colitis.CD is characterized as a chronic inflammatory disease of the gastrointestinal tract,ranging from the mouth to the anus.Although there are gross pathological and histological similarities between CD and Johne's disease of cattle,the cause of CD remains controversial.It is vital to understand fully the cause of this disease because it affects approximately 500 000 people in North America and Europe.It ranges from 27 to 48 cases per 100 000 people.There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the patients.Regardless of the environmental trigger,there is strong evidence that a genetic disposition is a major key in acquiring CD.Many studies have proven the link between mutations in the ATG16L,NOD2/CARD15,IBD5,CTLA4,TNFSF15 and IL23R genes,and CD.The purpose of this review is to examine all genetic aspects and theories of CD,including up to date multiple population studies performed worldwide.

关键词：发病机制溃疡性结肠炎慢性炎症环境因素 CTLA4 正常菌群全球范围遗传性

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Systematic review and meta-analysis on the association of tuberculosis in Crohn's disease patients treated with tumor necrosis factor-α inhibitors(Anti-TNFα)

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World Journal of Gastroenterology 2018年第25期24卷 2764-2775页

作者： Brent L Cao Ahmad Qasem Robert C Sharp Latifa S Abdelli saleh a naser Division of Molecular Microbiology Burnett School of Biomedical Sciences College of Medicine University of Central Florida

AIM To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis(TB) infection in Crohn's disease(CD) patients treated with tumor necrosis factoralpha(TNFα) inhibitors.METHODS A meta-analysis of randomized, double-blind, placebocontrolled trials of TNFα inhibitors for treatment of CD in adults was conducted. Arcsine transformation of TB incidence was performed to estimate risk difference. A novel epidemiologically-based correction(EBC) enabling inclusions of studies reporting no TB infection cases in placebo and treatment groups was developed to estimate relative odds.RESULTS Twenty-three clinical trial studies were identified, including 5669 patients. Six TB infection cases were reported across 5 studies, all from patients receiving TNFα inhibitors. Eighteen studies reported no TB infection cases in placebo and TNFα inhibitor treatment arms. TB infection risk was significantly increased among patients receiving TNFα inhibitors, with a risk difference of 0.028(95%CI: 0.0011-0.055). The odds ratio was 4.85(95%CI: 1.02-22.99) with EBC and 5.85(95%CI: 1.13-30.38) without EBC.CONCLUSION The risk of TB infection is higher among CD patients receiving TNFα inhibitors. Understanding the immunopathogenesis of CD is crucial, since using TNFα inhibitors in these patients could favor mycobacterial infections, particularly Mycobacterium avium subspecies paratuberculosis, which ultimately could worsen their clinical condition.

关键词： Tuberculosis Tumor necrosis factor-alpha inhibitors Crohn’s Disease Meta-analysis Systematic review

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Pathophysiology of autism spectrum disorders:Revisiting gastrointestinal involvement and immune imbalance

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World Journal of Gastroenterology 2014年第29期20卷 9942-9951页

作者： Mohtashem Samsam Raheleh Ahangari saleh a naser Burnett School of Biomedical Sciences (BSBS) College of MedicineUniversity of Central Florida

Autism spectrum disorders(ASD)comprise a group of neurodevelopmental abnormalities that begin in early childhood and are characterized by impairment of social communication and behavioral problems including restricted interests and repetitive behaviors.Several genes have been implicated in the pathogenesis of ASD,most of them are involved in neuronal synaptogenesis.A number of environmental factors and associated conditions such as gastrointestinal(GI)abnormalities and immune imbalance have been linked to the pathophysiology of ASD.According to the March 2012 report released by United States Centers for Disease Control and Prevention,the prevalence of ASD has sharply increased during the recent years and one out of 88 children suffers now from ASD symptoms.Although there is a strong genetic base for the disease,several associated factors could have a direct link to the pathogenesis of ASD or act as modifiers of the genes thus aggravating the initial problem.Many children suffering from ASD have GI problems such as abdominal pain,chronic diarrhea,constipation,vomiting,gastroesophageal reflux,and intestinal infections.A number of studies focusing on the intestinal mucosa,its permeability,abnormal gut development,leaky gut,and other GI problem raised many questions but studies were somehow inconclusive and an expert panel of American Academy of Pediatrics has strongly recommended further investigation in these areas.GI tract has a direct connection with the immune system and an imbalanced immune response is usually seen in ASD children.Maternal infection or autoimmune diseases have been suspected.Activation of the immune system during early development may have deleterious effect on various organs including the nervous system.In this review we revisited briefly the GI and immune system abnormalities and neuropeptide imbalance and their role in the pathophysiology of ASD and discussed some future research directions.

关键词： Autism spectrum disorders Gastrointestinal abnorma

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Mycobacterium avium subspecies paratuberculosis causes Crohn's disease in some inflammatory bowel disease patients

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World Journal of Gastroenterology 2014年第23期20卷 7403-7415页

作者： saleh a naser Sudesh R Sagramsingh Abed S naser Saisathya Thanigachalam Burnett School of Biomedical Sciences College of MedicineUniversity of Central FloridaOrlandoFL 32816United States

Crohn’s disease(CD)is a chronic inflammatory condition that plagues millions all over the world.This debilitating bowel disease can start in early childhood and continue into late adulthood.Signs and symptoms are usually many and multiple tests are often required for the diagnosis and confirmation of this disease.However,little is still understood about the cause(s)of CD.As a result,several theories have been proposed over the years.One theory in particular is that Mycobacterium avium subspecies paratuberculosis(MAP)is intimately linked to the etiology of CD.This fastidious bacterium also known to cause Johne’s disease in cattle has infected the intestines of animals for years.It is believed that due to the thick,waxy cell wall of MAP it is able to survive the process of pasteurization as well as chemical processes seen in irrigation purification systems.Subsequently meat,dairy products and water serve as key vehicles in the transmission of MAP infection to humans(from farm to fork)who have a genetic predisposition,thus leading to the development of CD.The challenges faced in culturing this bacterium from CD are many.Examples include its extreme slow growth,lack of cell wall,low abundance,and its mycobactin dependency.In this review article,data from 60 studies showing the detection and isolation of MAP by PCR and culture techniques have been reviewed.Although this review may not be 100%comprehensive of all studies,clearly the majority of the studies overwhelmingly and definitively support the role of MAP in at least30%-50%of CD patients.It is very possible that lack of detection of MAP from some CD patients may be due to the absence of MAP role in these patients.The latter statement is conditional on utilization of methodology appropriate for detection of human MAP strains.Ultimately,stratification of CD and inflammatory bowel disease patients for the presence or absence of MAP is necessary for appropriate and effective treatment which may lead to a cure.

关键词： Mycobacterium paratuberculosis Crohn’s disease Cul

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Correlation between rpoB gene mutation in Mycobacterium avium subspecies paratuberculosis and clinical rifabutin and rifampicin resistance for treatment of Crohn’s disease

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World Journal of Gastroenterology 2008年第17期14卷 2723-2730页

作者： Daniel R Beckler Sammer Elwasila George Ghobrial John F Valentine saleh a naser Department of Molecular Biology and Microbiology Burnett School of Biomedical Sciences Center for Biomolecular Sciences College of Medicine University of Central Florida Department of Medicine University of Florida Gainesville

AIM: To investigate overlapping regions of the rpoB gene previously involved with rifamycin resistance in M. tuberculosis and seek correlation between rpoB mutations in clinical MAP strains with susceptibility to RIF and RFB. METHODS: We designed a molecular-based PCR method for the evaluation of rifabutin (RFB) and rifampicin (RIF) resistance based on probable determinant regions within the rpoB gene of MAP, including the 81 bp variable site located between nucleotides 1363 and 1443. The minimum inhibitory concentration (MIC) for RIF was also determined against 11 MAP isolates in attempt to seek correlation with rpoB sequences. RESULTS: We determined that MAP strain 18 had an MIC of > 30 mg/L and ≤ 5 mg/L for RIF and RFB respectively, and a significant and novel rpoB mutation C1367T, compared to an MIC of ≤ 1.0 mg/L for both drugs in the wild type MAP. The 30-fold increase in the MIC was a direct result of the rpoB mutation C1367T, which caused an amino acid change Thr456 to Ile456 in the drug’s binding site. In addition, MAP strain 185 contained five silent rpoB mutations and exhibited an MIC comparable to the wild-type. Moreover, our in vitroselected mutation in MAP strain UCF5 resulted in the generation of a new resistant strain (UCF5-RIF16r) that possessed T1442C rpoB mutation and an MIC > 30 mg/L and > 10 mg/L for RIF and RFB respectively. Sequencing of the entire rpoB gene in MAP strains UCF4, 18, and UCF5-RIF16r revealed an rpoB mutation A2284C further downstream of the 81 bp variable region in UCF4, accounting for observed slight increase in MIC. In addition, no other significant mutations were found in strains 18 and UCF-RIF16r. CONCLUSION: The data clearly illustrates that clinical and in vitro-selected MAP mutants with rpoB mutations result in resistance to RIF and RFB, and that a single amino acid change in the beta subunit may have a significant impact on RIF resistance. Unconventional drug susceptibility testing such as our molecular approach will be beneficial for evaluation of antibiotic effectiv

关键词：分支杆菌副结核克罗恩氏病抗结核药疗效

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The 19 kDa Protein from <i>Mycobacterium avium subspecies paratuberculosis</i>Is a Glycolipoprotein

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Advances in Microbiology 2013年第7期3卷 520-528页

作者： saleh A. naser Saisathya Thanigachalam Natalia Spinelli Mitra M. Safavi Najih naser Omar Khan BioSynse Cary US Burnett School of Biomedical Sciences College of Medicine University of Central Florida Orlando USA

This study characterizes the 19 kDa protein expressed by Mycobacterium avium subspecies paratuberculosis (MAP) as a glycolipoprotein, providing the foundation for future experiments regarding its antigenicity and role in disease pathogenicity. We have previously shown that a 4.8 kb insert from MAP will produce a 16 kDa recombinant protein when expressed in Escherichia coli and 19 kDa recombinant protein when expressed in M. smegmatis (smeg19K). The difference of 3 kDa in size of these expressed proteins may be related to post translational modifications that occur in Mycobacterium species. We hypothesized that smeg19K is a glycolipoprotein since BLAST analysis revealed approximately 76% amino acid identity between the MAP 19 kDa protein and a known lipoglycoprotein, the 19 kDa protein of M. tuberculosis. This prediction was confirmed by the following positive staining of smeg19K with Sudan Black 4B, a postelectrophoresis dye used to stain for lipids. Smeg19K has also stained positively for glycosylation with the lectin concavalin A, a highly specific stain for mannose residues. As expected, treatment with tunicamycin (an antibiotic known to inhibit N-glycosylation) and treatment with deglycosylation assay (non-specific for mannose), showed no reduction in size of 19 kDa glycolipoprotein.

关键词： Mycobacterium Avium Subspecies Paratuberculosis Glycolipoprotein 19 KDa Protein Post Translational Modification

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Domino effect of hypomagnesemia on the innate immunity of Crohn's disease patients

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World Journal of Diabetes 2014年第4期5卷 527-535页

作者： saleh a naser Almatmed Abdelsalam Saisathya Thanigachalam Abed S naser Karel Alcedo Burnett School of Biomedical Sciences College of Medicine University of Central Florida Orlando FL 32816 United States

Digestive diseases play major role in development and complications of other disorders including diabetes.For example,Crohn’s disease(CD)is an inflammatory bowel disease associated with Mycobacterium avium subspecies paratuberculosis.The inflammation is a complex process that involves the activity of both innate and adaptive immune responses.CD lesions are primarily due to T cell response,however;innate immune response has a significant role in initiating its pathogenesis.Toll-like receptors and NOD-like receptors promote the activity of nuclear factor(NF)-κB pathway for cytokines production.This results in the production of high levels of tumor necrosis factor-α,interleukin(IL)-1βand IL-6.Moreover,intestinal inflammation of CD is related to increased activity of NMDA receptors and the release of substance P.Imbalanced magnesium homeostasis in CD is a frequent finding in CD,Diabetes and others.The loss of such a major mineral affects many physiological processes in the body including its role as an immunomodulator.This review aims to(1)describe the significance of hypomagnesemia in the release of pro-inflammatory mediators in CD;(2)demonstrate effects of magnesium on pathways like NF-κB;(3)address the role of hypomagnesemia in the activity of CD;and(4)examine possible future research to establish a standard magnesium supplementation strategy;helping patients with CD or other disorders to maintain a sustained remission.

关键词： Diabetes Crohn’s disease Hypomagnesemia Inflammatory bowel disease Mycobacterium paratuberculosis

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Resolution of Crohn's disease and complex regional pain syndrome following treatment of paratuberculosis

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World Journal of Gastroenterology 2015年第13期21卷 4048-4062页

作者： J Todd Kuenstner William Chamberlin saleh a naser Michael T Collins Coad Thomas Dow John M Aitken Stuart Weg Grzegorz Telega Kuruvilla John David Haas Torsten M Eckstein Maher Kali Christine Welch Thomas Petrie Department of Pathology Charleston Area Medical CenterCharlestonWV 25304United States Department of Gastroenterology Mountain View Regional HospitalLas CrucesNM 88011United States Burnett School of Biomedical Sciences UCF College of MedicineOrlandoFL 32816United States Department of Pathobiological Sciences the University of Wisconsin School of Veterinary MedicineMadisonWI 53706United States 5 Damon Street Eau ClaireWI 54701United States Otakaro Pathways Ltd. 63 Bibiana StreetChristchurch 8011New Zealand Patients Medical Alternative Pain Management800 Second Avenue Suite 900New York CityNY 10017United States Children’s Hospital of Wisconsin 8915 W.Connell Ave.MilwaukeeWI 53226United States Department of Neurosciences Charleston Area Medical CenterCharlestonWV 25304United States Department of Chemistry University of CharlestonCharlestonWV 25304United States Department of Microbiology Colorado State UniversityImmunology and PathologyCO 80523United States CAMC Clinical Trials Center 3100 Mac Corkle Avenue S.E.Suite 806CharlestonWV 25304United States CAMC Clinical Trials Center CharlestonWV 25304United States AVIcure Bioscience LLC Superior Quartz ProductsBethlehemPA 18020United States

A cohort of family members with various chronic diseases including Crohn's disease, asthma, complex regional pain syndrome, hypothyroidism, type 1 diabetes mellitus, and lymphangiomatosis and/or evidence of infection by Mycobacterium avium subsp. paratuberculosis(MAP) are described in this series of case reports. MAP was cultured from the blood of three members affected by the first five diseases and there was accompanying elevated anti-MAP Ig G in two members. The patient affected by the sixth disease has a markedly elevated anti-MAP titer. The two patients affected by the first four diseases have been treated with a combination of anti-MAP antibiotics and ultraviolet blood irradiation therapy with resolution of the disease symptomatology and inability to culture MAP in post treatment blood samples. These case reports of patients with MAP infections provide supportive evidence of a pathogenic role of MAP in humans.

关键词： Crohn’s disease Complex regional pain syndrome Lym

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Predictors of Obesity among Adults Who Have Diabetes Mellitus Type Two

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Open Journal of Nursing 2018年第8期8卷 580-589页

作者： Reem Ahmad Jarrad Zyad saleh naser Mahmoud Clinical Nursing Department School of Nursing The University of Jordan Amman Jordan Jordan Ministry of Health Amman Jordan

Background and Purpose: Obesity and Diabetes Mellitus type two (DMII) have a known association. Yet, the socio-demographic predictors of obesity in special populations such as people who have DMII remain unclear. The purpose of this study was to determine the socio-demographic predictors of obesity among adults who have DMII. Materials and Methods: This was a descriptive cross-sectional study targeting 488 adult clients who had the diagnosis of DMII. The participants were asked to complete a survey covering demographic and clinical variables of age, gender, employment, income, education, weight, height, medical insurance, duration of diabetes and type of treatment taken to control diabetes. Besides, Body Mass Index (BMI), the dependent variable, was calculated. Descriptive statistics were used to present clients’ socio-demographic and clinical characteristics. Univariate Binary logistic regression was used to determine the socio-demographic predictors of obesity. Results: Results showed that age, household income and employment were independent predictors of BMI in adults who have DMII. Gender and level of education were not significant predictors of higher BMI. Conclusion: Those results suggest that understanding of the contributing variables of obesity in adults who have DMII can help identify the at-risk groups allowing for early diagnosis and establishment of effective prevention and management plans.

关键词： Obesity Diabetes Predictors

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