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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 *** 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 *** 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 *** 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 *** 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 *** tract has a direct connection with the immune system and an imbalanced immune response is usually seen in ASD *** infection or autoimmune diseases have been *** of the immune system during early development may have deleterious effect on various organs including the nervous *** 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 abnormalities Immune activation Crohn's disease Neuropeptides Brain-derived neurotrophic factor Mycobacterium paratuberculosis

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) *** 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 *** 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 *** 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

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

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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 im

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

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 *** debilitating bowel disease can start in early childhood and continue into late *** and symptoms are usually many and multiple tests are often required for the diagnosis and confirmation of this ***,little is still understood about the cause(s)of *** a result,several theories have been proposed over the *** theory in particular is that Mycobacterium avium subspecies paratuberculosis(MAP)is intimately linked to the etiology of *** fastidious bacterium also known to cause Johne’s disease in cattle has infected the intestines of animals for *** 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 *** 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 *** challenges faced in culturing this bacterium from CD are *** include its extreme slow growth,lack of cell wall,low abundance,and its mycobactin *** this review article,data from 60 studies showing the detection and isolation of MAP by PCR and culture techniques have been *** 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 *** is very possible that lack of detection of MAP from some CD patients may be due to the absence of MAP role in these *** latter statement is conditional on utilization of methodology appropriate for detection of human MAP ***,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 Culture PCR Johne's disease Inflammatory bowel disease

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 dinical 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 vitro selected 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 wi

关键词： Mycobacterium paratuberculosis Crohn's disease Rifabutin Rifampicin rpoB Minimum inhibitoryconcentration

Baroreflex Control of Heart Rate in Mice Overexpressing Human SOD1: Functional Changes in Central and Vagal Efferent Components

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Neuroscience Bulletin 2019年第1期35卷 91-97页

作者： Jin Chen He Gu Robert D.Wurster Zixi Cheng Division of Neuroscience and Division of Metabolic and Cardiovascular Sciences Burnett School of Biomedical SciencesCollege of MedicineUniversity of Central FloridaOrlandoFL 32816USA Department of Cellular and Molecular Physiology Stritch School of MedicineLoyola UniversityMaywoodIL 60153USA

Excessive reactive oxygen species(ROS)(such as the superoxide radical) are commonly associated with cardiac autonomic dysfunctions. Though superoxide dismutase 1(SOD1) overexpression may protect against ROS damage to the autonomic nervous system, superoxide radical reduction may change normal physiological functions. Previously, we demonstrated that human SOD1(hSOD1) overexpression does not change baroreflex bradycardia and tachycardia but rather increases aortic depressor nerve activity in response to arterial pressure changes in C57 B6 SJL-Tg(SOD1)2 Gur/J mice. Since the baroreflex arc includes afferent, central, and efferent components, the objective of this study was to determine whether hSOD1 overexpression alters the central and vagal efferent mediation of heart rate(HR) responses. Our data indicate that SOD1 overexpression decreased the HR responses to vagal efferent nerve stimulation but did not change the HR responses to aortic depressor nerve(ADN)stimulation. Along with the previous study, we suggest that SOD1 overexpression preserves normal baroreflex function but may differentially alter the functions of the ADN, vagal efferents, and central components. While SOD1 overexpression likely enhanced ADN function and the central mediation of bradycardia, it decreased vagal efferent control of HR.

关键词： SOD1 Parasympathetic Baroreflex

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

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World Journal of Gastroenterology 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 dis- ease 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 pa- tients. 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, IBDS, 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 popu- lation studies performed worldwide.

关键词： Crohn's disease ATG16L NOD2/CARD15 IBDS CTLA4 TNFSF15 IL23R

Promising applications of D-amino acids in periprosthetic joint infection

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Bone Research 2023年第2期11卷 248-272页

作者： Matthew Caldwell Megan Hughes Fei Wei Christopher Ngo Raven Pascua Abinaya Sindu Pugazhendhi Melanie J.Coathup Biionix Cluster&College of medicine University of Central FloridaBlvdOrlandoFL32827USA school of Biosciences Cardiff UniversityCF103AT WalesUK burnett school of Biomedical Sciences College of MedicineUniversity of Central Florida6900 Lake NonaBlvdOrlandoFL32827USA

Due to the rise in our aging population,a disproportionate demand for total joint arthroplasty(TJA)in the elderly is *** joint infection(PJI)represents one of the most challenging complications that can occur following TJA,and as the number of primary and revision TJAs continues to rise,an increasing PJI burden is *** advances in operating room sterility,antiseptic protocols,and surgical techniques,approaches to prevent and treat PJI remain difficult,primarily due to the formation of microbial *** difficulty motivates researchers to continue searching for an effective antimicrobial *** dextrorotatory-isoforms of amino acids(D-AAs)are essential components of peptidoglycan within the bacterial cell wall,providing strength and structural integrity in a diverse range of *** many tasks,D-AAs regulate cell morphology,spore germination,and bacterial survival,evasion,subversion,and adhesion in the host immune *** administered exogenously,accumulating data have demonstrated that D-AAs play a pivotal role against bacterial adhesion to abiotic surfaces and subsequent biofilm formation;furthermore,D-AAs have substantial efficacy in promoting biofilm *** presents D-AAs as promising and novel targets for future therapeutic *** their emerging antibacterial efficacy,their role in disrupting PJI biofilm formation,the disassembly of established TJA biofilm,and the host bone tissue response remains largely *** review aims to examine the role of D-AAs in the context of *** to date suggest that D-AA bioengineering may serve as a promising future strategy in the prevention and treatment of PJI.

关键词： prevention spite furthermore

Divide and conquer: two stem cell populations in squamous epithelia, reserves and the active duty forces

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International Journal of Oral Science 2019年第4期11卷 252-264页

作者： Spencer Dunaway Alexandra Rothaus Yuhang Zhang Ana Luisa Kadekaro Thomas Andl Claudia DAndl Department of Dermatology College of MedicineUniversity of CincinnatiCincinnatiOHUSA burnett school of Biomedical Sciences University of Central FloridaOrlandoFLUSA Division of Pharmaceutical Sciences College of PharmacyUniversity of CincinnatiCincinnatiOHUSA

Stem cells are of great interest to the scientific community due to their potential role in regenerative and rejuvenative ***,their role in the aging process and carcinogenesis remains *** DNA replication in stem cells may contribute to the background mutation rate and thereby to cancer,reducing proliferation and establishing a relatively quiescent stem cell compartment has been hypothesized to limit DNA replication-associated *** the other hand,as the main function of stem cells is to provide daughter cells to build and maintain tissues,the idea of a quiescent stem cell compartment appears *** observations in mice have led to the idea of separated stem cell compartments that consist of cells with different proliferative *** epithelia of short-lived rodents appear to lack quiescent stem *** stem cells of different species and different organs(comparative stem cell biology)may allow us to elucidate the evolutionary pressures such as the balance between cancer and longevity that govern stem cell biology(evolutionary stem cell biology).The oral mucosa and its stem cells are an exciting model system to explore the characteristics of quiescent stem cells that have eluded biologists for decades.

关键词： organs elude stem