Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching.

BACKGROUND: Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. We aimed to investigate whether Homocysteine-responsive endoplasmic reticulum protein (Herp) was involved in VSMC phenotypic switching and affected atheroprogression. METHODS: To assess the role of Herp in homocysteine (Hcy)-associated atherosclerosis, Herp-/- and LDLR-/- double knockout mice were generated and fed with a high methionine diet (HMD) to induce Hyperhomocysteinemia (HHcy). Atherosclerotic lesions, cholesterol homeostasis, endoplasmic reticulum (ER) stress activation, and the phenotype of VSMCs were assessed in vivo. We used siRNAs to knockdown Herp in cultured VSMCs to further validate our findings in vitro. RESULTS: HMD significantly activated the activating transcription factor 6 (ATF6)/Herp arm of ER stress in LDLR-/- mice, and induced the phenotypic switch of VSMCs, with the loss of contractile proteins (SMA and calponin) and an increase of OPN protein. Herp-/-/LDLR-/- mice developed reduced atherosclerotic lesions in the aortic sinus and the whole aorta when compared with LDLR-/- mice. However, Herp deficiency had no effect on diet-induced HHcy and hyperlipidemia. Inhibition of VSMC phenotypic switching, decreased proliferation and collagen accumulation were observed in Herp-/-/LDLR-/- mice when compared with LDLR-/- mice. In vitro experiments demonstrated that Hcy caused VSMC phenotypic switching, promoted cell proliferation and migration; this was reversed by Herp depletion. We achieved similar results via inhibition of ER stress using 4-phenylbutyric-acid (4-PBA) in Hcy-treated VSMCs. CONCLUSION: Herp deficiency inhibits the phenotypic switch of VSMCs and the development of atherosclerosis, thus providing novel insights into the role of Herp in atherogenesis.

The potential of microRNAs as human prostate cancer biomarkers: A meta-analysis of related studies.

Prostate cancer (PC) is a very important kind of male malignancies. When PC evolves into a stage of hormone resistance or metastasis, the fatality rate is very high. Currently, discoveries and advances in miRNAs as biomarkers have opened the potential for the diagnosis of PC, especially early diagnosis. miRNAs not only can noninvasively or minimally invasively identify PC, but also can provide the data for optimization and personalization of therapy. Moreover, miRNAs have been shown to play an important role to predict prognosis of PC. The purpose of this meta-analysis is to integrate the currently published expression profile data of miRNAs in PC, and evaluate the value of miRNAs as biomarkers for PC. All of relevant records were selected via electronic databases: Pubmed, Embase, Cochrane, and CNKI based on the assessment of title, abstract, and full text. we extracted mean ± SD or fold change of miRNAs expression levels in PC versus BPH or normal controls. Pooled hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS) and recurrence-free survival (RFS), were also calculated to detect the relationship between high miRNAs expression and PC prognosis. Selected 104 articles were published in 2007-2017. According to the inclusion criteria, 104 records were included for this meta-analysis. The pooled or stratified analyze showed 10 up-regulated miRNAs (miR-18a, miR-34a, miR-106b, miR-141, miR-182, miR-183, miR-200a/b, miR-301a, and miR-375) and 14 down-regulated miRNAs (miR-1, miR-23b/27b, miR-30c, miR-99b, miR-139-5p, miR-152, miR-187, miR-204, miR-205, miR-224, miR-452, miR-505, and let-7c) had relatively good diagnostic and predictive potential to discriminate PC from BPH/normal controls. Furthermore, high expression of miR-32 and low expression of let-7c could be used to differentiate metastatic PC from local/primary PC. Additional interesting findings were that the expression profiles of five miRNAs (miR-21, miR-30c, miR-129, miR-145, and let-7c) could predict poor RFS of PC, while the evaluation of miR-375 was associated with worse OS. miRNAs are important regulators in PC progression. Our results indicate that miRNAs are suitable for predicting the different stages of PC. The detection of miRNAs is an effective way to control patient's prognosis and evaluate therapeutic efficacy. However, large-scale detections based on common clinical guidelines are still necessary to further validate our conclusions, due to the bias induced by molecular heterogeneity and differences in study design and detection methods.

Comparison of the hemodynamics and dynamics of fluid shift of Ringer's solution before surgery in children and adults.

The present study investigated the hemodynamics, vascular and extravascular volume expansion induced by infusion of lactated Ringer's solution in children and adults before surgery. This was a prospective randomized double-blind study. A total of 28 patients (14 children and 14 adult patients; American Society of Anesthesiology status I) scheduled for similar minor pelvic, anal rectal or lower limb surgery were recruited for the present study. All patients were administered with 10 ml/kg of lactated Ringer's solution at a constant rate over 20 min. After fluid infusion, plasma dilutions were calculated based on the concentration of hemoglobin. Heart rate (HR), mean arterial pressure (MAP) and urine output were measured before anesthesia was administered for surgery. Results demonstrated that the plasma dilution within 90 min of infusion initiation of lactated Ringer's solution was less pronounced in children compared with adult patients (0.07 vs. 0.16; P<0.001). Children also excreted more of the infused fluid through the kidney within 90 min of infusion initiation than the adults (55% vs. 24%; P=0.01). Following completion of fluid infusion, the volume expansion efficiency was higher in adults [0.82 (0.52-1.00)] than in children [0.46 (0.26-0.68)]. The relative changes in HR were significantly greater in children than in adults 15-60 min after infusion initiation (P<0.01). After 60 min, HRs were comparable between the groups; however, MAP declined significantly from 25-90 min after infusion initiation in children (P<0.05), yet remained nearly constant in adults (P>0.05). Simple regression analysis revealed a positive relationship between the relative changes in MAP and the plasma dilution, and the reduction in MAP in children was able to explain 47% of the variation in plasma dilution (R2=0.47; P=0.007). In conclusion, different hemodynamics and dynamics of fluid shift of Ringer's solution prior to surgery in children and adults may provide anesthesiologists with new information of how to administer fluid treatment for each patient.

Poly(glucono-δ-lactone) based nanocarriers as novel biodegradable drug delivery platforms.

Novel biocompatible and biodegradable polymers are highly desirable and crucial in drug delivery applications in order to overcome the technical challenges and problems existing in the traditional method of poly(ethylene glycol) based drug carriers. In this study, ring-opening polymerization of a carbohydrate-derived lactone, glucono-δ-lactone (GDL), generates a new highly branched polymer (PGDL) that can form stable nanoparticles through a w/o emulsification approach. The biodegradable and biocompatible particles can carry anticancer agent 5-fluorouracil (5-FU) effectively. The controlled release of 5-FU from the PGDL particles exhibits a non-Fickian mechanism without an initial burst, with an enhanced release exponent at tumoral pH. Cell viability studies by MTT assays indicate that ovarian carcinoma cells (OVCAR-3) and macrophage cells (raw 264.7) treated with PGDL (2.5mg/ml) show no signs of toxicity in 24h cell incubations. The PGDL particles can interact with the OVCAR-3 cell line efficiently. Therefore, the glucono-δ-lactone based particles represent an effective delivery system for cancer therapy.

Expression profile analysis of microRNAs in prostate cancer by next-generation sequencing.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of tumor mortality among males in western societies. In China, the diagnostic and fatality rate of PCa is increasing yearly. METHODS: To characterize underlying molecular mechanisms, the microRNA (miRNA) profile of high-grade PCa, low-grade PCa, and benign prostate hyperplasia (BPH) were compared using high-throughput Illumina sequencing and quantitative real-time PCR (qRT-PCR) methods. Moreover, a variety of biological information softwares and databases were applied to predict the target genes of miRNA, molecular functions, and signal pathways. RESULTS: Eighteen miRNAs were differentially expressed (fold change ≥ 2, P < 0.05), of which thirteen were upregulated and five were downregulated by sequencing. This was confirmed by qRT-PCR in more clinical tissue samples. In the tumors, miRNAs (miR-125b-5p, miR-126-5p, miR-151a-5p, miR-221-3p, and miR-222-3p) were significantly upregulated with downregulation of miR-486-5p. In addition, 13 novel miRNAs were identified from three prostate tissue libraries, with 12 of them assayed in 21 human normal tissues by qRT-PCR. Multiple databases indicated target genes for these differentially expressed miRNAs. Function annotation of target genes indicated that most of them tend to target genes involved in signal transduction and cell communication, especially cancer-related PI3K-Akt and p53 signaling pathway. CONCLUSIONS: The small RNA transcriptomes obtained in this study uncovers six differentially expressed miRNAs and 12 novel miRNAs, and provides a better understanding of the expression and function of miRNAs in the development of PCa and reveals several miRNAs in PCa that may have biomarker and therapeutic potentials.

Expression status of fatty acid synthase (FAS) but not HER2 is correlated with the differentiation grade and prognosis of esophageal carcinoma.

BACKGROUND/AIMS: Fatty acid synthase (FAS) and human epidermal growth factor receptor 2 (HER2) are overexpressed in a series of cancers. However, few studies have investigated the potential role of FAS and HER2 in esophageal carcinoma. The aim of this study was to evaluate the expression of FAS and HER2 and the possible link between FAS/HER2 expression and the pathological prognostic variables. METHODOLOGY: The frequency of FAS and HER2 expression was determined immunohistochemically. The overall survival rate was analysed by the Kaplan-Meier method and the log-rank test using SPSS 17.0 software. RESULTS: The majority of the cases were esophageal squamous cell carcinomas (n=142). FAS and HER2 overexpression in the studied cases are 73.2% and 14.1%, respectively. There was a significant difference in FAS expression regarding tumor differentiation and FAS overexpression showed its prognostic value for patients with different tumor differentiation. Meanwhile, HER2 overexpression did not significantly relate to the clinicopathological characteristics of the tumors, with the only exception of the surgical margins. CONCLUSIONS: FAS and HER2 overexpression are common in esophageal carcinomas. FAS overexpression showed its prognostic value for esophageal carcinoma patients with different tumor differentiation, which lead us to consider FAS-inhibitors as potential candidates for target-based adjuvant therapies.