Decreased sarcoplasmic reticulum phospholipids in human skeletal muscle are associated with metabolic syndrome.

Metabolic syndrome affects more than one in three adults and is associated with increased risk of diabetes, cardiovascular disease, and all-cause mortality. Muscle insulin resistance is a major contributor to the development of the metabolic syndrome. Studies in mice have linked skeletal muscle sarcoplasmic reticulum (SR) phospholipid composition to sarcoplasmic/endoplasmic reticulum Ca2+-ATPase activity and insulin sensitivity. To determine if the presence of metabolic syndrome alters specific phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species in human SR, we compared SR phospholipid composition in skeletal muscle from sedentary subjects with metabolic syndrome and sedentary control subjects without metabolic syndrome. Both total PC and total PE were significantly decreased in skeletal muscle SR of sedentary metabolic syndrome patients compared with sedentary controls, particularly in female participants, but there was no difference in the PC:PE ratio between groups. Total SR PC levels, but not total SR PE levels or PC:PE ratio, were significantly negatively correlated with BMI, waist circumference, total fat, visceral adipose tissue, triglycerides, fasting insulin, and homeostatic model assessment for insulin resistance. These findings are consistent with the existence of a relationship between skeletal muscle SR PC content and insulin resistance in humans.

Association Between the Fatigue and Sleep Quality of Kidney Transplant Recipients: The Mediating Role of Rumination.

ABSTRACT: Sleep disorders persist in renal transplant patients. Previous studies have showed that fatigue and rumination are an important determinant of sleep quality. However, very few studies have explored the mediating role of rumination in the relationship between fatigue and sleep quality in kidney transplant recipients. A descriptive cross-sectional research design was implemented, and 192 kidney transplant patients completed the short questionnaire about their recent experiences of fatigue, rumination, and sleep quality. The prevalence of sleep disorders among kidney transplant recipients was 19.3%. With rumination as a partial mediator, fatigue indirectly affected the patients' sleep quality. This indirect effect was 0.10 (95% confidence interval, 0.154-0.419). Our results indicate that the incidence of sleep disorders after renal transplantation was high, and the more tired kidney transplant recipients become, the more likely they are to ruminate, which leads to a decline in sleep quality.

Depression mediates the relationship between social capital and health-related quality of life among Chinese older adults in the context of the COVID-19 pandemic: A cross-sectional study.

AIM: To explore the association between social capital and health-related quality of life (HRQoL) and to determine whether depression mediates the association among Chinese older adults in the context of the COVID-19 pandemic. DESIGN: A descriptive cross-sectional research design. METHODS: The Geriatric Depression Scale-15, Social Capital Questionnaire and 12-item Short-Form Health Survey were used to investigate 1201 older adults selected from Jinan, Shandong Province, China, using a multistage stratified cluster random sampling method. RESULTS: Pearson's correlation analysis revealed a significant positive correlation between social capital and HRQoL (r = 0.269, p < 0.01). Multivariate linear regression analyses demonstrated that social capital was significantly negatively associated with depression (ß = -0.072, p < 0.001) and that depression was associated with HRQoL (ß = -1.031, p < 0.001). The mediation analyses showed that depression mediated the association between social capital and HRQoL, and the indirect effect size was 0.073 (95% confidence interval: 0.050, 0.100).

miR-1293 Suppresses Tumor Malignancy by Targeting Hydrocyanic Oxidase 2: Therapeutic Potential of a miR-1293/Hydrocyanic Oxidase 2 Axis in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is a common cancer, and extensive research suggests that microRNA may play an important role in the progression of RCC. The emphasis of this article was to reveal the function and mechanism of microRNA-1293(miR-1293) in the development of RCC tumors. First, the authors carried out bioinformatics analysis. The differential expression of miR-1293 in RCC tumor and normal cells was analyzed using the data from The Cancer Genome Atlas database, and Kaplan-Meier survival analysis was carried out to test the survival rate. Subsequently, the miR-1293 expression in RCC cell lines was examined by quantitative real-time PCR. Then Cell counting kit-8 and Transwell assays were executed to detect the function of miR-1293 in RCC. Bioinformatics prediction, western blotting, and dual-luciferase reporter assay were set to check the target gene of miR-1293. Finally, they conducted rescue experiments to verify whether the regulation of miR-1293 on the biological function of RCC cells was achieved by regulating hydrocyanic oxidase 2 (HAO2). Bioinformatics results showed that miR-1293 was highly expressed in RCC, and the miR-1293 high-expression group showed a lower survival rate than the miR-1293 low-expression group, which suggested that the high expression of miR-1293 was related to unfavorable prognosis in RCC. Subsequent assays evidenced that upregulation of miR-1293 expression significantly increased the cell viability and promoted cell migration and invasion in RCC. Silencing miR-1293 expression showed opposite results. Furthermore, HAO2 was confirmed to be a direct target gene of miR-1293 by dual-luciferase reporter assay, and miR-1293 negatively regulated the expression of HAO2. Moreover, rescue experiments evidenced that miR-1293 reduced the cell viability, invasion, and migration of RCC by regulating HAO2. In sum, miR-1293 can regulate the viability, invasion, and migration of RCC tumor cells by targeting HAO2, suggesting that miR-1293 can be used as a new biomarker for clinical treatment of RCC.

Predictors and Outcomes Associated With Adherence to Weekly Alendronate in US Military Veterans: Clinical Research Study.

Background: Poor adherence to oral bisphosphonates is a challenge to treatment and prevention of osteoporosis. The Veterans Health Administration (VA) operates the largest integrated health care system in the United States and offers certain advantages to possibly improve medication adherence. We aimed to determine adherence to weekly alendronate for osteoporosis in Veterans, and investigate predictors and outcomes related to adherence. Methods: A retrospective study cohort was generated from VA databases selecting Veterans who were treated with weekly alendronate. Adherence was measured by medication possession ratio (MPR) and persistence. Two groups were defined as low and high adherence based on MPR <80% or ≥80%, respectively. Regression models were used to investigate predictors of adherence and included clinically relevant covariates. Further regressions were used to investigate the impact of adherence on change in bone mineral density measured by dual energy X-ray absorptiometry and incident fracture. Results: In a cohort of 913 (female/male, 207/706) Veterans, 48% had high adherence in year 1. Distribution for gender, race, and age were similar between the 2 groups, MPR <80% or MPR ≥80%. Baseline fracture [odds ratio OR: 0.64, 95%CI: (0.41, 0.98)], alcohol abuse [0.40 (0.21, 0.74)] and tobacco use [0.44 (0.31, 0.63)] were associated with low adherence in the unadjusted analyses, but only tobacco use [0.45 (0.30, 0.67)] was associated with low adherence after adjustment. Among males, tobacco use was associated with low adherence while prostate cancer predicted high adherence in adjusted models. High adherence was associated with a 30% [hazard ratio HR: 0.70, 95% CI: (0.47, 1.03)] decreased risk of incident fracture in the whole cohort, and a 40% [0.60 (0.38, 0.95)] decrease risk in males. Conclusion: Year one adherence to weekly alendronate was a relevant determinant to long-term clinical outcomes including changes in bone mineral density and incident fracture in Veterans.

The E-cadherin gene polymorphism 160C->A and cancer risk: A HuGE review and meta-analysis of 26 case-control studies.

A single nucleotide polymorphism, - 160C-->A, has been identified in the promoter region of the E-cadherin gene and has been shown to alter its transcriptional activity. To assess susceptibility of -160A allele carriers to seven types of cancers, the authors conducted a comprehensive meta-analysis, up to November 2006, of 26 case-control studies comprising 7,042 cases and 7,011 controls. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analyses were also performed, which showed that -160A allele carriers, compared with noncarriers, had about a 17-19% increased risk of several invasive/metastatic tumors. Analyses of various types of cancers revealed that, in Europeans, the -160AA homozygote was associated with an increased risk of urothelial cancer, carriers of -160A were at increased risk of lung and prostate cancers, and carriers of -160A with gastric cancer were found to suffer a significantly increased risk, whereas their Asian counterparts seemed to be tolerant. No evidence was found that the -160A allele predisposed its carriers to breast, colorectal, or esophageal cancers. These findings indicate that -160A of the E-cadherin gene is emerging as a low-penetrance tumor susceptibility allele for the development of gastric, lung, prostate, and urothelial cancers.

Comparative proteomics of apoptosis initiation induced by 5-fluorouracil in human gastric cancer.

5-Fluorouracil is the first choice chemotherapeutic drug for patients with gastric cancer, but the mechanism that 5-fluorouracil plays the anti-tumor role remains unclear. The aim of this study was to clarify correlated [corrected] proteins induced by 5-fluorouracil in the apoptosis-initiation of human gastric cancer (MGC-803) cells. The time point of apoptosis-initiation induced by 5-fluorouracil in MGC-803 cells was determinated using 5-fluorouracil-withdrawal. Two-dimensional electrophoreses (2-DE) were employed to compare the differentials of protein expressions of the MGC-803 cells at the apoptosis-initiation phase and those of the MGC-803 cells untreated with 5-fluorouracil. The differential proteins included 14 upregulated proteins and 8 downregulated proteins. They indicated a more-than-doubled alteration. These proteins were digested in gels by trypsin and the mass of generated peptides were measured by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The data obtained from peptide mass fingerprinting (PMF) were searched out using the internet available database mascot (http://www.matrixscience.com). The results showed that proteomics analyses have evidenced that many kinds of proteins are involved in the apoptosis initiation of human gastric cancer MGC-803 cells. These proteins are related to metabolism, oxidation, cytoskeleton and signal transduction and other aspects of cells. In conclusion, the experiment model of apoptosis-initiation of human gastric cancer MGC-803 cells induced by 5-fluorouracil based on proteomic analysis has been established, giving an impetus to researches of the mechanism of apoptosis in human gastric cancer, and laying a foundation for the selection of potential drug precursors specific for inducing apoptosis-initiation in human gastric cancer.

[Differentially expressed genes between a fertile patient and an infertile patient in a large Chinese androgen insensitivity syndrome pedigree].

OBJECTIVE: To screen and identify differentially expressed genes between a fertile patient and another infertile patient who belonged to a large Chinese pedigree affected with androgen insensitivity syndrome (AIS). METHODS: We constructed the forward and reversed subtracted libraries using genital skin fibroblasts (GSF), which were obtained from the fertile patient MJ and infertile patient ZGJ, as tester respectively. Candidate clones were screened with colony in situ hybridization, dot blot, and Southern blot analysis step by step and conformed with Northern blot analysis. The potential positive clones were sequenced and the homology of the sequences was analyzed. RESULTS: The forward and reversed subtracted libraries containing differentially expressed pattern of two GSF cell lines were constructed. Two positive clones identified by Northern blot were obtained in the reversed subtracted library. Eleven candidate clones from the two libraries that failed to hybridize with both RNA populations were obtained simultaneously, which might represent differentially expressed low abundance transcripts. Sequencing results and homology analysis demonstrated that the two positive clones were significantly homologous with the genes of autotaxin-t and calcium binding protein calcyclin (S100A6), respectively. CONCLUSIONS: Two positive clones and eleven clones showing no hybridization signals may represent differentially expressed genes between the two GSFs. This finding may be useful to elucidate the molecular mechanisms leading to phenotypic variation and preserved fertility of the AIS pedigree.

Defective expression of transforming growth factor beta receptor type II is associated with CpG methylated promoter in primary non-small cell lung cancer.

PURPOSE: Reduced expression of the transforming growth factor beta receptor type II (TGF beta RII), a key inhibitor of epithelial cell growth and tumor suppressor gene, was reported frequently in many types of tumors including non-small cell lung cancer (NSCLC). This study explored the significance of the TGF beta RII gene in NSCLC carcinogenesis. EXPERIMENTAL DESIGN: With 43 independent pairs of tumor and paracarcinoma tissue samples from patients with primary NSCLC, we carried out PCR-denaturing gradient gel electrophoresis screening for DNA variants over the coding sequence of the TGF beta RII gene, immunohistochemical assay of TGF beta RII expression, methylation-specific PCR analysis, and semiquantitative reverse transcription-PCR. RESULTS: The PCR-denaturing gradient gel electrophoresis did not detect variation in the whole coding sequence of the TGF beta RII gene, but the immunohistochemistry experiment revealed reduced or lost expression of the gene in 44% (19 of 43) of the tumor samples. The methylation analysis on the 19 pairs detected the frequent occurrence of methylated TGF beta RII promoter in tumor tissues, whereas most of the paracarcinoma tissues were free of methylation. The reduced TGF beta RII expression was highly significantly associated with the methylation event (P < 10(-4)). The reverse transcription-PCR analysis demonstrated a clear agreement between reduced TGF beta RII expression and decreased mRNA level of the gene in the tumor tissue samples. CONCLUSIONS: TGF beta RII plays an important role as a tumor suppressor in NSCLC carcinogenesis. The defective expression may serve as one of most important molecular mechanisms in explaining progression of the disease. In particular, aberrant 5' CpG methylation of the gene has explained the down-regulation of the gene at a transcriptional level.

Mutational analysis of the transforming growth factor beta receptor type I gene in primary non-small cell lung cancer.

Transforming growth factor-beta receptor-dependent signals are critical for cell growth and differentiation and are often disrupted during tumorigenesis. The entire coding region of TGFbetaRI and flanking intron sequences from 53 primary non-small cell lung cancer (NSCLC) tissues were examined for alterations using SSCP and direct sequencing. No somatic point mutations other than two silent mutations and a polymorphism were found in the TGFbetaRI gene. The two silent mutations located at codon 344 (AAT to AAC) and codon 406 (TTA to CTA), respectively, and the polymorphism was at the 24th base of intron 7 (G to A). To investigate whether the presence of this polymorphism is associated with NSCLC, we determined its allele distribution in all the 53 carcinomas and 89 normal controls. Interestingly, we found that the subjects with homozygous genotype A/A displayed more than 3-fold increased risk of developing NSCLC than the common wild genotype G/G. As the first report, the present study showed that TGFbetaRI gene is not a frequent site of spontaneous mutational inactivation while the detected polymorphism is frequent in the pathogenesis of NSCLC.

Novel microdeletion in the transforming growth factor beta type II receptor gene is associated with giant and large cell variants of nonsmall cell lung carcinoma.

Mutations in the tumor suppressor gene transforming growth factor beta (TGFB) Type II receptor (TGFBR2) are frequently found in many cancers with microsatellite instability, but are less common in lung cancer. In the present study, we looked for mutations in TGFBR2 in nonsmall cell lung carcinoma (NSCLC) cells and tissues. A novel homozygous microdeletion (c.492_507del) was identified in two cell lines derived from the same giant cell carcinoma (GCC) and was confirmed in the corresponding tumor tissues. Furthermore, a heterozygous c.492_507del was found in the germ-line of one patient, as well as in the other GCC cases and some large cell carcinomas (LCC) but not in other subtypes of NSCLC. The 16 bp-microdeletion introduced a premature stop codon at positions 590-592 of the cDNA, resulting in a truncated TGFBR2 protein with a mutated transmembrane domain and loss of kinase domain. The GCC cells were characterized as being unresponsive to TGFB induction both in growth inhibition and stimulation of extracellular matrix protein. Moreover, after the reconstitution of wild-type TGFBR2 expression, the sensitivity to TGFB was restored. Therefore, mutated TGFBR2 seems to play an important role in the abrogation of TGFB signal transduction in GCC cells.