Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

Background and objectivesObesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Materials and methodsMale C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay.ResultsLentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.ConclusionsCathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity

Head-to-head comparison of risankizumab and ixekizumab in GenPs

Methodology; Figure 1c; Table

Long-term prognosis of combined chronic heart failure and chronic renal dysfunction after acute stroke

Aims To assess the prevalence of combined chronic heart failure and chronic renal dysfunction (CHF-CRD) in acute stroke patients and to investigate any prognostic significance on long-term outcome.Methods and resultsFirst-ever acute stroke patients (n = 831) were divided into four groups based on the presence of heart failure (HF, NYHA II-IV with or without left ventricular ejection fraction <40) and/or renal dysfunction (RD, estimated glomerular filtration rate <60 mL/min/1.73 m 2). Patients with acute kidney injury and/or acute decompensated HF were excluded. Group 1 comprised patients without HF or RD (nHF + nRD), Group 2 patients with RD but no HF (nHF + RD), Group 3 those with HF and no RD (HF + nRD), whereas Group 4 included patients with both HF and RD (HF + RD). HF and RD were independent predictors of mortality at 10 years. Patients in Groups 2, 3, and 4 had an increased probability of death during follow-up compared with Group 1: HR 1.34 (95 CI 1.02-1.77, P < 0.05) for group 2; HR 2.24 (95 CI 1.50-3.36, P < 0.001) for group 3; and HR 3.42 (95 CI 2.36-4.95, P < 0.001) for group 4. Age, history of transient ischaemic attacks and combined HF and RD were independent predictors of new cardiovascular events. When compared with Group 1, patients in Group 2 had an HR of 1.48 (95 CI 1.11-1.98, P < 0.01), those in Group 3 an HR of 2.21 (95 CI 1.48-3.29, P < 0.001), and those in Group 4 an HR of 3.59 (95 CI 2.40-5.39, P < 0.001).ConclusionThe combination of CHF-CRD after acute stroke is an independent predictor for mortality and new cardiovascular morbidity over 10 years. © 2010 The Author

Identification of a Novel Substance P–Neurokinin-1 Receptor MicroRNA-221-5p Inflammatory Network in Human Colonic Epithelial Cells

Background & AimsSubstance P (SP), a neuropeptide member of the tachykinin family, plays a critical role in colitis. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. We examined whether SP modulates expression of microRNAs in human colonic epithelial cells.MethodsWe performed microRNA profiling analysis of SP-stimulated human colonic epithelial NCM460 cells overexpressing neurokinin-1 receptor (NCM460-NK-1R). Targets of SP-regulated microRNAs were validated by real-time polymerase chain reaction (RT-PCR). Functions of miRNAs were tested in NCM460-NK-1R cells and the trinitrobenzene sulfonic acid (TNBS) and dextran sulfate sodium (DSS) models of colitis.ResultsSP stimulated differential expression of 29 microRNAs, including miR-221-5p, the highest up-regulated miR (by 12.6-fold) upon SP stimulation. Bioinformatic and luciferase reporter analyses identified interleukin-6 receptor (IL-6R) mRNA as a direct target of miR-221-5p in NCM460 cells. Accordingly, SP exposure of NCM460-NK-1R cells increased IL-6R mRNA expression, and overexpression of miR-221-5p reduced IL-6R expression. Nuclear factor κB and c-Jun N-terminal kinase inhibition decreased SP-induced miR-221-5p expression. MiR-221-5p expression was increased in both TNBS- and DSS-induced colitis and in colonic biopsy samples from ulcerative colitis but not Crohn’s disease patients compared with controls. In mice, intracolonic administration of a miR-221-5p chemical inhibitor exacerbated TNBS- and DSS-induced colitis and increased colonic tumor necrosis factor-α, C-X-C motif chemokine 10 (Cxcl10), and collagen, type II, α 1 (Col2α1) mRNA expression. In situ hybridization in TNBS- and DSS-exposed colons revealed increased miR-221-5p expression primarily in colonocytes.ConclusionsOur results reveal a novel NK-1R-miR-221-5p-IL-6R network that protects from colitis. The use of miR-221-5p mimics may be a promising approach for colitis treatment

Neurotensin—regulated miR-133α is involved in proinflammatory signalling in human colonic epithelial cells and in experimental colitis

ObjectiveNeurotensin (NT) mediates colonic inflammation through its receptor neurotensin receptor 1 (NTR1). NT stimulates miR-133α expression in colonic epithelial cells. We investigated the role of miR-133α in NT-associated colonic inflammation in vitro and in vivo.DesignmiR-133α and aftiphilin (AFTPH) levels were measured by quantitative PCR. Antisense (as)-miR-133α was administrated intracolonicaly prior to induction of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and dextran sodium sulfate (DSS)-induced colitis. The effect of AFTPH was examined by gene silencing in vitro.ResultsNT increased miR-133α levels in NCM-460 overexpressing NTR1 (NCM460-NTR1) and HCT-116 cells. NT-induced p38, ERK1/2, c-Jun, and NF-κB activation, as well as IL-6, IL-8 and IL-1β messenger RNA (mRNA) expression in NCM-460-NTR1 cells were reduced in miR-133α-silenced cells, while overexpression of miR-133α reversed these effects. MiR-133α levels were increased in TNBS (2 day) and DSS (5 day) colitis, while NTR1 deficient DSS-exposed mice had reduced miR-133α levels, compared to wild-type colitic mice. Intracolonic as-miR-133α attenuated several parameters of colitis as well expression of proinflammatory mediators in the colonic mucosa. In silico search coupled with qPCR identified AFTPH as a downstream target of miR-133α, while NT decreased AFTPH expression in NCM-460-NTR1 colonocytes. Gene silencing of AFTPH enhanced NT-induced proinflammatory responses and AFTPH levels were downregulated in experimental colitis. Levels of miR-133α were significantly upregulated, while AFTPH levels were downregulated in colonic biopsies of patients with ulcerative colitis compared to controls.ConclusionsNT-associated colitis and inflammatory signalling are regulated by miR-133α-AFTPH interactions. Targeting of miR-133α or AFTPH may represent a novel therapeutic approach in inflammatory bowel disease

Serum hepcidin levels are associated with serum triglycerides and interleukin-6 concentrations in patients with end-stage renal disease

Hepcidin has emerged as a peptide with a key role in the regulation of iron homeostasis in patients with chronic kidney disease (CKD), having a strong dependence on inflammation. Recent studies reveal that hepcidin may be also associated with the progression of atherosclerosis. This study was performed to analyze the relation of hepcidin to markers of atherosclerosis and inflammation in patients on dialysis. A total of 90 individuals were enrolled. Sixty patients with end-stage renal disease, who were on hemodialysis (HD) (N=30) and peritoneal dialysis (N=30) were compared with 30 normal controls (NC). Age, body mass index, time on dialysis, serum lipids, C-reactive protein (CRP) and interleukin-6 (IL-6) were measured and analyzed in correlation with hepcidin concentration. It was found that patients on HD and peritoneal dialysis have significantly higher (P<0.0001) levels of hepcidin, CRP and IL-6 than NC. Hepcidin in dialysis patients is significantly related to age (r=0.373, P=0.012), serum triglycerides (r=0.401, P=0.005), HDL-C (r=-0.268, P=0.048), CRP (r=0.436, P=0.0007) and IL-6 (r=0.569, P<0.0001). In multiple regression analysis, hepcidin correlated independently with triglycerides (β=0.402, P=0.041) and IL-6 (β=0.559, P=0.006). Moreover, patients with high triglycerides in combination with high IL-6 levels have significantly increased concentrations of hepcidin than those with low triglycerides and low IL-6 levels (P<0.0001). Elevated levels of hepcidin in patients with CKD on dialysis may be related to the occurrence of high triglycerides and high IL-6 serum concentrations. This probably suggests that hepcidin may play a role to the progression of atherosclerosis and inflammation, but this hypothesis should be further evaluated. © 2013 International Society for Apheresis

Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

Michelle Cheng,1,* Samantha Ho,1,* Jun Hwan Yoo,1,2,* Deanna Hoang-Yen Tran,1,* Kyriaki Bakirtzi,1 Bowei Su,1 Diana Hoang-Ngoc Tran,1 Yuzu Kubota,1 Ryan Ichikawa,1 Hon Wai Koon1 1Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Republic of Korea *These authors share co-first authorship Background: Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-ß1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. Conclusion: Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation. Keywords: colon cancer, epithelial–mesenchymal transition, fibroblast

Atrial fibrillation in chronic hemodialysis patients: Prevalence, types, predictors, and treatment practices in Greece

Atrial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is associated with increased mortality and cardiovascular morbidity both in nonuremic and (recently) in dialysis patients. The aims of this study are: (i) to assess the prevalence of AF, the risk factors, and predictors of its presence in a cohort of incident hemodialysis (HD) patients in Greece and (ii) to report on current practices in the management of these patients. This is a prospective, cross-sectional, multicenter study of 574 patients on a regular HD program for >6 months. Demographic characteristics, cause of renal disease, cardiovascular risk factors, medication use, dialysis data (Kt/V, dialysis method, type of dialysate), 12-lead electrocardiogram (ECG) (interdialytic day), and cardiac echo data were collected. Pertinent demographic, ECG, and echocardiographic data were entered into univariate and multivariate analyses to evaluate associations with AF. The CHADS2 score (congestive heart failure [HF], hypertension, age ≥75, diabetes, previous stroke/transient ischemic attack [TIA]) was estimated and clinical practices in high-risk (CHADS2 score ≥2) patients were evaluated. The cohort included 368 men (64.1%) and 206 (35.8%) women (mean age 65.1±14.4 years) with a mean duration on dialysis of 72.1±60.4 months. Hypertension (75.6%) and coronary artery disease (47.2%) were the commonest cardiovascular risk factors for AF. The prevalence of AF was 23.2% and showed an age-dependent increase; in patients <50 years, AF was present in 9.3%, while in patients ≥80 years, its prevalence increased to 36.4%. Furthermore, 8.3% of patients had permanent, 1.8% persistent, 12.7% paroxysmal AF, while the prevalence of paroxysmal atrial flutter and sick sinus syndrome were 1.2 and 2%, respectively. Logistic regression analysis showed that age, smoking, left atrial and aortic root diameter, β-blocker and α-calcidol use, HF, and the presence of valvular calcifications (VC) on cardiac echo were independently associated to the presence of AF. VC on cardiac echo had an almost sevenfold increased association with AF (odds ratio 6.72, 95% confidence interval 3.23-13.98, P<0.0001). Only 25.5% of high-risk (CHADS2 score ≥2) patients were receiving anticoagulants. AF is a frequent arrhythmia in HD patients. Apart from well-known risk factors, VC merits special attention in this patient population. Less than one-third of high-risk AF patients receive anticoagulants, possibly reflecting the absence of definite guidelines for the management of AF in HD patients. © 2011, the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer: Inhibition of the metastasis-inducer Snail and induction of the metastasis-suppressor RKIP

The role of nitric oxide (NO) in cancer has been controversial and is based on the levels of NO and the responsiveness of the tumor type. It remains unclear whether NO can inhibit the epithelial to mesenchymal transition (EMT) in cancer cells. EMT induction is mediated, in part, by the constitutive activation of the metastasis-inducer transcription factor, Snail and EMT can be inhibited by the metastasis-suppressors Raf-1 kinase inhibitor protein (RKIP) and E-cadherin. Snail is transcriptionally regulated by NFκB and in turn, Snail represses RKIP transcription. Hence, we hypothesized that high levels of NO, that inhibit NFκB activity, may also inhibit Snail, induce RKIP and leading to inhibition of EMT. We show that treatment of human prostate metastatic cell lines with the NO donor, DETANONOate, inhibits EMT and reverses both the mesenchymal phenotype and the cell invasive properties. Further, treatment with DETANONOate inhibits Snail expression and DNA-binding activity in parallel with the upregulation of RKIP and E-cadherin protein levels. The pivotal roles of Snail inhibition and RKIP induction in DETANONOate-mediated inhibition of EMT were corroborated by both Snail silencing by siRNA and by ectopic expression of RKIP. The in vitro findings were validated in vivo in mice bearing PC-3 xenografts treated with DETANONOate. The present findings show, for the first time, the novel role of high, yet, subtoxic concentrations of NO in the inhibition of EMT. Thus, NO donors may exert therapeutic activities in the reversal of EMT and metastasis

The dermatoscopic spectrum of cutaneous lupus erythematosus: A retrospective analysis by clinical subtype with clinicopathological correlation

The skin is the most common organ of involvement during the course of lupus erythematosus (LE). The literature data concerning the dermatoscopic patterns of the different clinical variants of cutaneous LE (CLE), namely chronic (CCLE), subacute (SCLE), and acute (ACLE), are scarce. To determine the dermatoscopic spectrum of CLE and to correlate the dermatoscopic features with the histological findings. This was a retrospective, observational, multicenter, cohort study. We evaluated the dermatoscopic features in a cohort of patients diagnosed with CLE. Furthermore, we investigated their frequency per clinical subtype and correlated them with the anatomic alterations. We included 79 patients. The most prevalent dermatoscopic features of CCLE included follicular plugs (86.4%, P <.01), patchy distribution (75%, P =.1) of mostly linear curved vessels (56.8%, P =.8), white scales (68.2%, P <.01), and structureless white color (68.2%, P <.01). The most common criteria of SCLE were patchy distribution (90%, P =.1) of mostly linear curved vessels (53.3%, P =.8) and fine white scales (60%, P <.01), while ACLE was characterized by erythema (100%, P <.05) and patchy distribution (100%, P =.1) of mostly dotted vessels (60%, P =.4). Follicular plugs/rosettes in dermatoscopy strongly correlated with follicular plugs in histology (rho = 0.919). Hyperkeratosis significantly correlated with white (rho = 0.644) and yellow/brown scales (rho = 0.225), telangiectasia with linear curved vessels (rho = 0.321) and white color with dermal fibrosis (rho = 0.623). Depending on CLE subtype, distinct dermatoscopic patterns are recognized. In CLE there is a high correlation between certain dermatoscopic criteria and the underneath anatomic alteration