Candidate gene studies of fibromyalgia: a systematic review and meta-analysis

The aim of this study was to explore whether the candidate gene polymorphisms contribute to fibromyalgia susceptibility. The authors conducted a meta-analysis on associations between serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) S/L allele, catechol-O-methltransferase (COMT) val158Met, and serotonin 2A (5-HT2A) receptor 102T/C polymorphisms and fibromyalgia susceptibility as determined using the following: (1) allele contrast, (2) recessive, (3) dominant models, and (4) contrast of homozygotes. We also performed a systematic review with available data of the candidate genes. A total of 21 separate comparisons were considered in this systematic review and meta-analysis. Seventeen candidate genes and over 35 different polymorphisms were identified in studies on fibromyalgia susceptibility. Meta-analysis of the 5-HTTLPR S/L allele and COMT val158Met failed to reveal any association with fibromyalgia. However, meta-analysis of the C allele, CC + CT genotype, and CC versus TT genotype of the 5-HT2A receptor 102T/C polymorphism showed significant association with fibromyalgia. The overall OR of the association between the C allele and fibromyalgia was 1.333 (95% CI = 1.053–1.688, P = 0.017). The ORs for the CC + CT genotype, and CC versus TT genotype showed the same pattern as that observed for the C allele (OR = 1.541, 95% CI = 1.032–2.303, P = 0.035; OR = 1.838, 95% CI = 1.151–2.936, P = 0.011). This meta-analysis demonstrates that the 5-HT2A receptor 102T/C polymorphism confers susceptibility to fibromyalgia. In contrast, no association was found between the 5-HTTLPR S/L allele, COMT val158Met, and susceptibility to fibromyalgia.     

Adipose-derived stem cells on the healing of ischemic colitis: a therapeutic effect by angiogenesis

Background

There has been no specific treatment for ischemic colitis. We verified the effects of adipose-derived stem cells (ASCs) on ischemia-induced colitis in a rat model.

Methods

Forty male Sprague–Dawley rats (10?weeks old; weight, 350?±?20?g) were divided into two groups: a control group (only fibrinogen and thrombin injected, n?=?20) and an ASC group (local implantation of ASCs mixed with thrombin and fibrinogen, n?=?20). An ischemic colitis model was established by modifying Nagahata's methods with double-blind randomization. ASCs (1?×?10⁶ cells) were implanted intramurally into the ischemic area using a fibrin glue mixture. The severity of adhesion, degree of ileus, the number and size of the ulcers, Wallace macroscopic and microscopic scores, and microvascular density were measured.

Results

The degree of ileus was significantly lower, and significantly fewer and smaller ulcerations were found in the ASC group than those in the control group. Wallace macroscopic and microscopic scores were lower in the ASC group than in the control group (1.90?±?1.22 versus 3.25?±?1.83, p?<?0.01 and 1.55?±?1.88 versus 2.84?±?1.89, p?<?0.05, respectively). Microvascular density was higher in the ASC group than in the control (54.45?±?19.45 versus 26.54?±?13.14, p?<?0.01, respectively).

Conclusions

Local implantation of ASCs into an ischemic-injured colonic wall reduced the grade of ischemic injury and enhanced tissue healing by promoting angiogenesis.     

CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling

A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133(+) liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133(+) cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133(+) liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133(+) liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133(+) liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133(+) liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling. CONCLUSION: CD133(+) liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade.     

Nonalcoholic fatty liver disease is associated with coronary artery calcification

Nonalcoholic fatty liver disease (NAFLD) is related to risk factors of coronary artery disease, such as dyslipidemia, diabetes, and metabolic syndrome, which are closely linked with visceral adiposity. The aim of this study was to investigate whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis independent of computed tomography (CT)-measured visceral adiposity. Out of 5,648 subjects who visited one of our health screening centers between 2003 and 2008, we enrolled 4,023 subjects (mean age, 56.9 ± 9.4 years; 60.7% males) without known liver disease or a history of ischemic heart disease. CAC score was evaluated using the Agatston method. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein cholesterol, triglycerides, and increased risk of diabetes, hypertension, smoking, and NAFLD. Increasing CAC scores (0, <10, 10-100, ≥ 100) were associated with higher prevalence of NAFLD (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.61-2.10; P<0.001). Multivariable ordinal regression analysis was adjusted for traditional risk factors, and CT-measured visceral adipose tissue area in a subgroup of subjects showed that the increased CAC scores were significantly associated with the presence of NAFLD (OR, 1.28, 95% CI, 1.04-1.59; P = 0.023) independent of visceral adiposity. CONCLUSION: Patients with NAFLD are at increased risk for coronary atherosclerosis independent of classical coronary risk factors, including visceral adiposity. These data suggest that NAFLD might be an independent risk factor for coronary artery disease.     

A comparison of vitamin D activity in paired non-malignant and malignant human breast tissues

Links between a low vitamin D status and an increased risk of breast cancer have been observed in epidemiological studies. These links have been investigated in human tissue homogenates and cultured cell lines. We have used non-malignant, malignant and normal reduction mammoplasty breast tissues to investigate the biological and metabolic consequences of the application of vitamin D to intact ex vivo human breast tissue. Tissues were exposed to 1α,25(OH)(2)D(3) (1,25D; active metabolite) and 25(OH)D (25D; pre-metabolite). Changes in mRNA expression and protein expression after vitamin D exposure were analysed. Results indicate that while responses in normal and non-malignant breast tissues are similar between individuals, different tumour tissues are highly variable with regards to their gene expression and biological response. Collectively, malignant breast tissue responds well to active 1,25D, but not to the inactive pre-metabolite 25D. This may have consequences for the recommendation of vitamin D supplementation in breast cancer patients.