Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells

The expression of CCL20 (MIP-3alpha), which chemoattracts leukocytes to sites of inflammation, has been shown in intestinal epithelial cells (IEC). Aim of this study was to analyze the role of the CCL20 receptor CCR6 in IEC and colorectal cancer (CRC) cells. Expression of CCR6 and CCL20 was analyzed by RT-PCR and immunohistochemistry. Signaling was investigated by Western blotting, proliferation by MTS assays and chemotactic cell migration by wounding assays. The effect of CCL20 on Fas-induced apoptosis was determined by flow cytometry. CCR6 and its ligand CCL20 are expressed in IEC. Moreover, CRC and CRC metastases express CCR6, which is upregulated during IEC differentiation. Stimulation of IEC with CCL20 and proinflammatory stimuli (TNF-alpha, IL-1beta, LPS) significantly upregulates CCL20 mRNA expression. CCL20 expression was significantly increased in inflamed colonic lesions in Crohn's disease and correlated significantly with the IL-8 mRNA expression in these lesions (r = 0.71) but was downregulated in CRC metastases. CCL20 activated Akt, ERK-1/2, and SAPK/JNK MAP kinases and increased IL-8 protein expression. The CCL20 mediated activation of these pathways resulted in a 2.6-fold increase of cell migration (P = 0.001) and in a significant increase of cell proliferation (P < 0.05) but did not influence Fas-induced apoptosis. In conclusion, IEC and CRC express CCL20 and its receptor CCR6. CCL20 expression is increased in intestinal inflammation, while CCR6 is upregulated during cell differentiation. CCR6 mediated signals result in increased IEC migration and proliferation suggesting an important role in intestinal homeostasis and intestinal inflammation by mediating chemotaxis of IEC but also in mediating migration of CRC cells.     

Monitoring diabetes in patients with and without rheumatoid arthritis: a Medicare study

Introduction

Diabetes mellitus is a key predictor of mortality in rheumatoid arthritis (RA) patients. Both RA and diabetes increase the risk of cardiovascular disease (CVD), yet understanding of how comorbid RA impacts the receipt of guideline-based diabetes care is limited. The purpose of this study was to examine how the presence of RA affected hemoglobin A1C (A1c) and lipid measurement in older adults with diabetes.

Methods

Using a retrospective cohort approach, we identified beneficiaries ≥65 years old with diabetes from a 5% random national sample of 2004 to 2005 Medicare patients (N = 256,331), then examined whether these patients had comorbid RA and whether they received guideline recommended A1c and lipid testing in 2006. Multivariate logistic regression was used to examine the effect of RA on receiving guideline recommended testing, adjusting for baseline sociodemographics, comorbidities and health care utilization.

Results

Two percent of diabetes patients had comorbid RA (N = 5,572). Diabetes patients with comorbid RA were more likely than those without RA to have baseline cardiovascular disease (such as 17% more congestive heart failure), diabetes-related complications including kidney disease (19% higher), lower extremity ulcers (77% higher) and peripheral vascular disease (32% higher). In adjusted models, diabetes patients with RA were less likely to receive recommended A1c testing (odds ratio (OR) 0.84, CI 0.80 to 0.89) than those without RA, but were slightly more likely to receive lipid testing (OR 1.08, CI 1.01 to 1.16).

Conclusions

In older adults with diabetes, the presence of comorbid RA predicted lower rates of A1c testing but slightly improved lipid testing. Future research should examine strategies to improve A1c testing in patients with diabetes and RA, in light of increased CVD and microvascular risks in patients with both conditions.     

IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro

The IL-10-like cytokine IL-22 is produced by activated T cells. In this study, we analyzed the role of this cytokine system in hepatic cells. Expression studies were performed by RT-PCR and quantitative PCR. Signal transduction was analyzed by Western blot experiments and ELISA. Cell proliferation was measured by MTS and [(3)H]thymidine incorporation assays. Hepatocyte regeneration was studied in in vitro restitution assays. Binding of IL-22 to its receptor complex expressed on human hepatic cells and primary human hepatocytes resulted in the activation of MAPKs, Akt, and STAT proteins. IL-22 stimulated cell proliferation and migration, which were both significantly inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin. IL-22 increased the mRNA expression of suppressor of cytokine signaling (SOCS)-3 and the proinflammatory cytokines IL-6, IL-8, and TNF-alpha. SOCS-1/3 overexpression abrogated IL-22-induced STAT activation and decreased IL-22-mediated liver cell regeneration. Hepatic IL-22 mRNA expression was detectable in different forms of human hepatitis, and hepatic IL-22 mRNA levels were increased in murine T cell-mediated hepatitis in vivo following cytomegalovirus infection, whereas no significant differences were seen in an in vivo model of ischemia-reperfusion injury. In conclusion, IL-22 promotes liver cell regeneration by increasing hepatic cell proliferation and hepatocyte migration through the activation of Akt and STAT signaling, which is abrogated by SOCS-1/3 overexpression.     

The role of interleukin-22 in hepatitis C virus infection

In this study, we analyzed if IL-22 displays, similar to other IL-10 like cytokines such as IL-28A, antiviral properties in hepatic cells. Using RT-PCR and immunoblotting, we demonstrated that hepatic cell lines and primary hepatocytes express the functional IL-22 receptor complex consisting of IL-22R1 and IL-10R2. Hepatic IL-22 mRNA expression as measured by quantitative PCR was up-regulated in autoimmune and viral hepatitis compared to cholestatic liver diseases, while IL-22 serum levels did not differ significantly between patients with viral hepatitis and normal controls. IL-22 did not significantly change the expression levels of IFN-α/-β and of the antiviral proteins MxA and 2′,5′-OAS. Consequently, it had in comparison to IFN-α no relevant antiviral activity in in vitro models of HCV replication and infection. Taken together, hepatic IL-22 expression is up-regulated in viral hepatitis but IL-22 does not directly regulate antiviral proteins and has, in contrast to IFN-α, no effect on HCV replication.     

Molecular docking analysis of bioactive compounds from Plectranthus amboinicus with glucokinase

Natural remedies from medicinal plants are known to be effective and reliable appropriate medicine for illnesses. The current research examined Plectranthus amboinicus'' anti diabetic property by docking the bioactive compounds of certain target proteins. We document the molecular docking analysis of bioactive compounds from Plectranthus amboinicus with protein Glucokinase. Molecular docking experiments were carried out in PyRx software. Results of these docking experiments showed that most of the compounds showed very strong interaction with the target protein Glucokinase. Based on the scoring parameters we have selected best four compounds (Rutin, Salvianolic acid, Luteolin and Salvigenin) which showed very good docking score and hydrogen bond interaction for diabetics.     

Motif kernel generated by genetic programming improves remote homology and fold detection

Background  

Protein remote homology detection is a central problem in computational biology. Most recent methods train support vector machines to discriminate between related and unrelated sequences and these studies have introduced several types of kernels. One successful approach is to base a kernel on shared occurrences of discrete sequence motifs. Still, many protein sequences fail to be classified correctly for a lack of a suitable set of motifs for these sequences.     

Role of HLA DRB1*15 and HLA DRB1*16alleles in the genetic susceptibility to develop systemic lupus erythematosus (SLE) after Chikungunya and Zika viruses infection in México

Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous disease particularly prevalent in Mexico. Althoughits etiology is unknown, genetic factors strongly influence its presenceas well as triggering factors, such as viral infections, including Cytomegalovirus and Epstein-Barr virus. Here,the study presents the appearance of de novoSLE (patients who did not present SLE before de virus infection, corroborated by serological analysis and negative for antinuclear antibodies) cases in Mexicans who live near the southern border of Mexico, who presented clinical symptoms of arthritic, hematological, mucocutaneous and renal SLE, after Zika and/ or Chikungunya virus infection. Low resolution class Ⅱ HLA typing was performed, which found a significantly increased frequency of HLA DRB1*02 (15 and 16)when compared to a group of 99 healthy individuals (P =0.001, OR=4.5, IC95% 1.8~11.0). All the patients were diagnosed with SLE 1 to 3 years after being confirmed with the Zika, and/or Chikungunya infection. At the point of acute viral infection, none of the patients presented clinical signs or symptoms of autoimmunity or were negative for antinuclear antibodies. In genetically susceptible individuals, Zika and Chikungunya viral infection can trigger SLE.     

Solid Organ Transplantation in Patients with Inflammatory Bowel Diseases (IBD): Analysis of Transplantation Outcome and IBD Activity in a Large Single Center Cohort

Background

Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.

Methods

Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.

Results

4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn’s disease (CD) underwent SOT (p = 2.69 x 10⁻⁶, UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26–84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).

Conclusions

SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.