Rong Fan

Polymorphisms of the vitamin D receptor gene and the risk of inflammatory bowel disease: a meta-analysis.

The gene encoding vitamin D receptor (VDR) is recognized as a promising candidate for indicating the development of inflammatory bowel disease (IBD). Four genetic polymorphisms (ApaI, BsmI, FokI, TaqI) in VDR have been widely evaluated to determine their association with IBD, and the results of these evaluations are often inconsistent. Therefore, we conducted a meta-analysis to shed some light on this issue and explored the sources of the heterogeneity between studies. We identified six articles for ApaI (cases/controls: 1902/1468), eight for TaqI (3053/2145), and five each for BsmI (1512/1616) and FokI (2315/1676). Data were analyzed under the random-effects model, and heterogeneity was explored by subgroup analyses. Overall, except for TaqI in allelic comparison [odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.83-0.98], ApaI, BsmI, and FokI polymorphisms showed no significant associations with IBD across different genetic models of inheritance. However, subgroup analyses indicated significance for the association of ApaI with Crohns disease (CD) risk (AA versus aa: OR = 1.40; 95%CI = 1.05-1.88), for BsmI in East Asians (BB plus Bb versus bb: OR = 1.77, 95%CI = 1.14-2.74), for TaqI in Caucasians (TT plus Tt versus tt: OR = 0.79, 95%CI = 0.63- 1.00), and with ulcerative colitis (UC) risk (T versus t: OR = 0.89, 95%CI = 0.80-0.99). There was a low probability of publication bias for all studied polymorphisms. Pooling previous individual studies on IBD, our findings demonstrated that the ApaI polymorphism may increase the risk of CD, whereas the TaqI polymorphism may decrease the risk of UC, especially in Caucasians. Moreover, this study leaves open the question of divergent genetic profiles across different ethnic groups.

Association between CD14 Gene C-260T Polymorphism and Inflammatory Bowel Disease: A Meta-Analysis

Background The gene encoding CD14 has been proposed as an IBD-susceptibility gene with its polymorphism C-260T being widely evaluated, yet with conflicting results. The aim of this study was to investigate the association between this polymorphism and IBD by conducting a meta-analysis. Methodology/Principal Findings Seventeen articles met the inclusion criteria, which included a total of 18 case-control studies, including 1900 ulcerative colitis (UC) cases, 2535 Crohns disease (CD) cases, and 4004 controls. Data were analyzed using STATA software. Overall, association between C-260T polymorphism and increased UC risk was significant in allelic comparison (odds ratio [OR]  = 1.21, 95% confidence interval [CI]: 1.02–1.43; P = 0.027), homozygote model (OR  = 1.44, 95% CI: 1.03–2.01; P = 0.033), as well as dominant model (OR  = 1.36, 95% CI: 1.06–1.75; P = 0.016). However, there was negative association between this polymorphism and CD risk across all genetic models. Subgroup analyses by ethnicity suggested the risk-conferring profiles of -260T allele and -260 TT genotype with UC in Asians, but not in Caucasians. There was a low probability of publication bias. Conclusions/Significance Expanding previous results of individual studies, our findings demonstrated that CD14 gene C-260T polymorphism might be a promising candidate marker in susceptibility to UC, especially in Asians.

mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile

It has been established that mammalian target of Rapamycin (mTOR) inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS)-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD). Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL)-17A, IL-1β,IL-6 and tumor necrosis factor(TNF)-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1) cells and TH17 cells and increases regulatory T (Treg) cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.

RAGE gene three polymorphisms with Crohn's disease susceptibility in Chinese Han population.

AIM To investigate the association of three polymorphisms in the receptor for advanced glycation end product (RAGE) gene with Crohns disease (CD) risk in a Chinese population. METHODS A hospital-based case-control association study involving 312 CD patients and 479 healthy controls was conducted. Peripheral blood samples were collected from 791 study subjects, and genomic DNA was extracted. Genotyping was performed using polymerase chain reaction-ligase detection reaction method. The association between polymorphic genotype and CD predisposition was determined using odds ratio and 95% confidence interval (CI). Data were analyzed using Haplo.stats program. RESULTS Significant differences were observed between patients and controls in allele/genotype distributions of rs1800624 (P(allele)=0.012; P(genotype)=0.005) and in allele distributions of rs2070600 (P=0.02). The risk for CD associated with the rs1800624-A mutant allele decreased by 36% (95%CI: 0.47-0.88, P = 0.005) under the additive model and by 35% (95%CI: 0.46-0.91, P=0.013) under the dominant model. Carriers of rs2070600-A mutant allele showed a 37% (95%CI: 1.02-1.83, P=0.036) increased risk of developing CD relative to the GG genotype carriers. In haplotype analysis, haplotype T-A-G (in the order rs1800625, rs1800624, and rs2070600) decreased the odds of CD by 33% (95%CI: 0.49-0.94, P=0.018). CONCLUSION CD is an immune-related disease with genetic predisposition. Genetic defects in the RAGE gene are strongly associated with CD in Chinese population.

Association between STAT3 gene Polymorphisms and Crohn’s diseasesusceptibility: a case–control study in a Chinese Han population

BackgroundCrohn’s disease (CD) is an immune-related disease with geneticpredisposition. This study aimed to investigate the association of threepolymorphisms in the signal transducer and activator of transcription 3(STAT3) gene with CD risk in a Chinese population.MethodsWe conducted a hospital-based case–control study involving 232 CDpatients and 272 controls. Genotyping was performed using polymerase chainreaction with sequence-specific primer method. Statistical analyses wereconducted using logistic regression and genotype risk scoring.ResultsSignificant differences were found between patients and controls inallele/genotype distributions of rs744166(P allele = 0.0008;P genotype = 0.003) and allele distributions ofrs4796793 (P = 0.03). The risk for CD associated withthe rs744166-A mutant allele decreased by 37% [95% confidence interval (CI):0.48–0.83] under the additive model, 39% (95% CI: 0.43–0.81)under the dominant model and 57% (95% CI: 0.24–0.77) under therecessive model. Carriers of the rs4796793-G mutant allele exhibited 25%(95% CI: 0.58–0.98; P = 0.03) and 47% (95% CI:0.30–0.95) decreased risks of developing CD under the additive andrecessive models, respectively.ConclusionsSTAT3 rs744166 and rs4796793 polymorphisms may be associated with CDoccurrence and used as a predictive factor of CD in Chinese Hanpopulations.Virtual SlidesThe virtual slide(s) for this article can be found here:http://diagnosticpathology.slidepath.com/webViewer.php?snapshotId=1297687014

Association between STAT3 gene polymorphisms and ulcerative colitis susceptibility: a case-control study in the Chinese Han population.

Ulcerative colitis (UC) is a chronic inflammation of the large intestine. The aim of this study was to investigate the association of two polymorphisms in STAT3 with the risk of UC development in the Chinese Han population. This is a hospital-based case-control study involving 56 UC patients and 274 controls. Genotyping was performed using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. Statistical analyses were conducted using logistic regression and genotype risk score. Overall, there was a significant difference between patients and controls in the genotype distribution of rs2293152 (P = 0.044). The risk for UC associated with the rs2293152-G mutant allele was increased (odds ratio = 2.76; 95% confidence interval = 1.06- 7.24) under the dominant model. However, we failed to find any obvious differences in the rs4796793 genotype or allele distributions between the UC patients and controls, and did not detect any significant association of the rs4796793 polymorphism with UC across different genetic models of inheritance. Our study implies that the STAT3 rs2293152 polymorphism may be associated with the occurrence of UC and might be used as a predictive factor for UC in the Chinese Han population.

Potential model for differential diagnosis between Crohn's disease and primary intestinal lymphoma

AIM To evaluate the usefulness of different parameters to differentiate Crohn’s disease (CD) from primary intestinal lymphoma (PIL). METHODS The medical records of 85 patients with CD and 56 patients with PIL were reviewed retrospectively. Demographic, clinical, laboratory, endoscopic, and computed tomographic enterography (CTE) parameters were collected. The univariate value of each parameter was analyzed. A differentiation model was established by pooling all the valuable parameters. Diagnostic efficacy was analyzed, and a receiver operating characteristic (ROC) curve was plotted. RESULTS The demographic and clinical parameters that showed significant values for differentiating CD from PIL included age of onset, symptom duration, presence of diarrhea, abdominal mass, and perianal lesions (P < 0.05). Elevated lactate dehydrogenase and serum β2-microglobulin levels suggested a PIL diagnosis (P < 0.05). The endoscopic parameters that showed significant values for differentiating CD from PIL included multiple-site lesions, longitudinal ulcer, irregular ulcer, and intraluminal proliferative mass (P < 0.05). The CTE parameters that were useful in the identification of the two conditions included involvement of ≤ 3 segments, circular thickening of the bowel wall, wall thickness > 8 mm, aneurysmal dilation, stricture with proximal dilation, “comb sign”, mass showing the “sandwich sign”, and intussusceptions (P < 0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the differentiation model were 91.8%, 96.4%, 93.6%, 97.5%, and 88.5%, respectively. The cutoff value was 0.5. The area under the ROC curve was 0.989. CONCLUSION The differentiation model that integrated the various parameters together may yield a high diagnostic efficacy in the differential diagnosis between CD and PIL.

Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation.

Neddylation, a newly identified post-translational modification, is significant for the activity and stability of target proteins. The exact role of neddylation in the pathogenesis of inflammatory bowel disease, specifically those mediated by dendritic cells (DCs), was still rarely reported. Here, we showed that inhibition of neddylation protected mice from mucosal inflammation. Targeting neddylation also inhibited DC maturation characterized by reduced cytokine production, down-regulated costimulatory molecules and suppressed capacity in allogeneic T cell stimulation. Additionally, inactivation of neddylation promotes caspase dependent apoptosis of DCs. These phenomena were attributed to the inactivation of mTOR, which was caused by Cullin-1 deneddylation induced Deptor accumulation. Together, our findings revealed that neddylation inhibition suppressed DC functions through mTOR signaling pathway and provided a potential therapeutic opportunity in inflammatory bowel diseases.

Molecular design and structural optimization of potent peptide hydroxamate inhibitors to selectively target human ADAM metallopeptidase domain 17

Human ADAMs (a disintegrin and metalloproteinases) have been established as an attractive therapeutic target of inflammatory disorders such as inflammatory bowel disease (IBD). The ADAM metallopeptidase domain 17 (ADAM17 or TACE) and its close relative ADAM10 are two of the most important ADAM members that share high conservation in sequence, structure and function, but exhibit subtle difference in regulation of downstream cell signaling events. Here, we described a systematic protocol that combined computational modeling and experimental assay to discover novel peptide hydroxamate derivatives as potent and selective inhibitors for ADAM17 over ADAM10. In the procedure, a virtual combinatorial library of peptide hydroxamate compounds was generated by exploiting intermolecular interactions involved in crystal and modeled structures. The library was examined in detail to identify few promising candidates with both high affinity to ADAM17 and low affinity to ADAM10, which were then tested in vitro with enzyme inhibition assay. Consequently, two peptide hydroxamates Hxm-Phe-Ser-Asn and Hxm-Phe-Arg-Gln were found to exhibit potent inhibition against ADAM17 (Ki=92 and 47nM, respectively) and strong selectivity for ADAM17 over ADAM10 (∼7-fold and ∼5-fold, S=0.86 and 0.71, respectively). The structural basis and energetic property of ADAM17 and ADAM10 interactions with the designed inhibitors were also investigated systematically. It is found that the exquisite network of nonbonded interactions involving the side chains of peptide hydroxamates is primarily responsible for inhibitor selectivity, while the coordination interactions and hydrogen bonds formed by the hydroxamate moiety and backbone of peptide hydroxamates confer high affinity to inhibitor binding.

Comparison between Intestinal Behçet’s Disease and Crohn’s Disease in Characteristics of Symptom, Endoscopy, and Radiology

Aim To evaluate different parameters in differentiating intestinal BD from CD. Methods The medical records of inpatients with intestinal BD and CD were retrospectively reviewed. The univariate value of different parameters was analyzed, respectively. A differentiation model was established by pooling all valuable parameters together. Diagnostic efficacy was evaluated, and a receiver operating curve (ROC) was plotted. Results Forty-two BD patients and ninety-seven CD patients were reviewed. Demographic and clinical parameters that showed significant value included diarrhea, fever, perianal disease, oral ulcers, genital ulcers, skin lesions, and musculoskeletal lesions. Endoscopic parameters reaching clinical significance included multiple-site lesions, lesions confined to the ileocecal region, longitudinal ulcers, round or oval ulcers, punch-out ulcers, ulcers with discrete margin, ulcer size > 2 cm, stricture of bowel, and anorectal involvement. Radiologic parameters aiding the differentiation included involvement segments ≤ 3, asymmetrical pattern of involvement, intraluminal pseudopolyp formation, target sign, stricture with proximal dilation, comb sign, and fistula. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the differentiation model were 90.5%, 93.8%, 92.8%, 86.4%, and 95.8%, respectively. The cutoff value was 0.5 while the area under the ROC curve was 0.981. Conclusion The differentiation model that integrated the various parameters together may yield a high diagnostic efficacy in the differential diagnosis between intestinal BD and CD.