Genome wide association studies have identified several genes that might be associated with increase susceptibility to Type 1 Diabetes (T1D) and Crohn's disease. Both Crohn's disease and T1D have a profound impact on the lives of patients and it is pivotal to investigate the genetic role in patients acquiring these diseases. Understanding the effect of single nucleotide polymorphisms (SNP's) in key genes in patients suffering from T1D and Crohn's disease is crucial to finding an effective treatment and generating novel therapeutic drugs. This review article is focused on the impact of SNP's in PTPN2 (protein tyrosine phosphatase, non-receptor type 2) and PTPN22 (protein tyrosine phosphatase non-receptor type 22) on the development of Crohn's disease and T1D. The PTPN2 gene mutation in T1D patients play a direct role in the destruction of beta cells while in Crohn's disease patients, it modulates the innate immune responses. The PTPN22 gene mutations also play a role in both diseases by modulating intracellular signaling. Examining the mechanism through which these genes increase the susceptibility to both diseases and gaining a better understanding of their structure and function is of vital importance to understand the etiology and pathogenesis of Type 1 Diabetes and Crohn's disease.
BackgroundSeveral pathogens have been debated to play a role in inflammatory bowel disease (IBD) including Crohn’s disease (CD). None of these pathogens have been investigated together in same clinical samples. We developed a multiplex PCR and multi-color fluorescent in situ hybridization (m-FISH) protocols for simultaneous detection of CD-associated pathogens including Mycobacterium avium subspecies paratuberculosis (MAP), Klebsiella pneumoniae, and adherent-invasive Escherichia coli strain LF82.MethodsThe multiplex PCR is based on 1-h DNAzol® extraction protocol modified for rapid extraction of bacterial DNA from culture, blood, and intestinal biopsies. Oligonucleotide primers sequences unique to these pathogens were evaluated individually and in combinations using bioinformatics and experimental approaches. m-FISH was based on fluorescent-tagged oligonucleotides and confocal scanning laser microscopy (CSLM).ResultsFollowing several attempts, the concentration of the oligonucleotide primers and DNA templates and the PCR annealing temperatures were optimized. Multiplex PCR analyses revealed excellent amplification signal in trials where a single primer set and combinations of two and three primers sets were tested against a mixture of DNA from three different bacteria or a mixture of three bacterial cultures mixed in one tube before DNA extraction. Slides with individual and mixtures of bacterial cultures and intestinal tissue sections from IBD patients were tested by m-FISH and the CSLM images verified multiplex PCR results detected on 3% agarose gel.ConclusionWe developed a 4-h multiplex PCR protocol, which was validated by m-FISH images, capable of detecting up to four genes from major pathogens associated with CD. The new protocol should serve as an excellent tool to support efforts to study multi-pathogens involved in CD and other autoimmune disease.
Recently, we reported that nicotine plays a role in the failure of the macrophage in the clearance of Mycobacterium avium subspecies paratuberculosis (MAP) during infection in Crohn’s disease smokers. We also demonstrated that nicotine enhances macrophages cellular survival during MAP infection. Blocking α7 nicotinic acetylcholine receptor (α7nAChR) with the pharmacological antagonist—mecamylamine—subverted the anti-inflammatory effect of nicotine in macrophages. Yet, it is still unknown how α7nAChR is involved in the modulation of the macrophage response during MAP infection. Here, we studied the mechanistic role of nicotine-α7nAChR interaction in modulating NF-ĸB survival pathway, autophagy, and effect on cathelicidin production in MAP-infected macrophages using THP-1 cell lines. Our results showed that nicotine upregulated α7nAChR expression by 5-folds during MAP infection compared to controls. Bcl-2 expression was also significantly increased after nicotine exposure. Moreover, Nicotine inhibited autophagosome formation whereas infection with MAP in absence of nicotine has significantly increased LC-3b in macrophages. Nicotine also further upregulated NF-ĸB subunits expression including Rel-B and p100, and increased nuclear translocation of p52 protein. We also discovered that cathelicidin production was significantly suppressed in MAP-infected macrophages, treatment with nicotine showed no effect. Overall, the study provides new insight toward understanding the cellular role of nicotine through α7nAChR/NF-ĸB p100/p52 signaling pathway in inducing anti-apoptosis and macrophage survival during MAP infection in Crohn’s disease smokers.
The Homeless population is the most socioeconomic underprivileged community in the United States. Cardiovascular complications are one of the leading causes of death among homeless individuals. This study highlights the major risk factors of hypertension among the homeless community in the Orlando metropolitan area, in order to provide solutions and to modify associated risk factors. Adult homeless individuals (N=167) were randomly selected during daily lunch shares at St. George Orthodox Church, Orlando Florida. Each consented participant completed a survey with inquiries about demographic, lifestyle and hypertension related risk factors. Blood pressure was measured twice using an automatic Welch Allyn Connex ProBP 2400 digital device and the readings average was calculated. The Body Mass Index (BMI) was also calculated according to the World Health Organization (WHO) criteria. Average age of participants was 42.3 ± 11 years, and 83% were men. The overall prevalence of hypertension among participants was 52% (87 out of 167). The prevalence of hypertension among individuals who reported to be homeless over one year was 73% (38 out of 52), compared to only 51.3% among those with less than one year. Among diabetic homeless, 70% suffers from hypertension. The prevalence of hypertension among smokers was 51% (48 out of 95), while hypertension according to BMI group was significantly higher in both overweight and obese groups compared to individuals with normal BMI. Hypertension was significantly prevalent among homeless receiving no assistance (75.67%) compared to those receiving both financial and social assistance (47.61%). However, financial assistance had a major effect on lowering hypertension prevalence in comparison to social assistance (58.62% and 74.41%, respectively). In conclusion, hypertension is prevalent among Orlando homeless cohort and it has surpassed the national average. Clearly, social and financial services seem to lower hypertension prevalence among homeless individuals receiving benefits. The outcome of the study supports data from other countries offering affordable and accessible health care services, and certainly, it renews the call for more resources to help the homeless communities.
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