Cilostazol suppresses β‐amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1‐coupled retinoic acid receptor‐β

The accumulation of plaques of β‐amyloid (Aβ) peptides, a hallmark of Alzheimer's disease, results from the sequential cleavage of amyloid precursor protein (APP) by activation of β‐ and γ‐secretases. However, the production of Aβ can be avoided by alternate cleavage of APP by α‐and γ‐secretases. We hypothesized that cilostazol attenuates Aβ production by increasing a disintegrin and metalloproteinase 10 (ADAM10)/α‐secretase activity via SIRT1‐coupled retinoic acid receptor‐β (RARβ) activation in N2a cells expressing human APP Swedish mutation (N2aSwe). To evoke endogenous Aβ overproduction, the culture medium was switched from medium containing 10% fetal bovine serum (FBS) to medium containing 1% FBS, and cells were cultured for 3～24 hr. After depletion of FBS in media, N2aSwe cells showed increased accumulations of full‐length APP (FL‐APP) and Aβ in a time‐dependent manner (3–24 hr) in association with decreased ADAM10 protein expression. When pretreated with cilostazol (10–30 μM), FL‐APP and Aβ levels were significantly reduced, and ADAM10 and α‐secretase activities were restored. Furthermore, the effect of cilostazol on ADAM10 expression was antagonized by pretreating Rp‐cAMPS and sirtinol and by SIRT1‐gene silencing. In the N2aSwe cells overexpressing the SIRT1 gene, ADAM10, and sAPPα levels were significantly elevated. In addition, like all‐trans retinoic acid, cilostazol enhanced the protein expressions of RARβ and ADAM10, and the cilostazol‐stimulated ADAM10 elevation was significantly attenuated by LE135 (a RARβ inhibitor), sirtinol, and RARβ‐gene silencing. In conclusion, cilostazol suppresses the accumulations of FL‐APP and Aβ by activating ADAM10 via the upregulation of SIRT1‐coupled RARβ. © 2014 Wiley Periodicals, Inc.     

Peptidoglycan recognition protein genes and risk of Parkinson's disease

Increased gut permeability, inflammation, and colonic α‐synuclein pathology are present in early Parkinson's disease (PD) and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. Peptidoglycan recognition proteins (PGRPs) maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that variants in genes that encode PGRPs are associated with PD risk. Participants in two independent case‐control studies were genotyped for 30 single‐nucleotide polymorphisms (SNPs) in the four PGLYRP genes. Using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounding variables, we conducted analyses in each study, separately and pooled. One SNP failed the assay, and three had little to no variation. The ORs were similar in both study populations. In pooled analyses, three of seven PGLYRP2 SNPs (rs3813135, rs733731, rs892145), one of five PGLYRP3 SNPs (rs2987763), and six of nine PGLYRP4 SNPs (rs10888557, rs12063091, rs3006440, rs3006448, rs3006458, and rs3014864) were significantly associated with PD risk. Association was strongest for PGLYRP4 5'untranslated region (UTR) SNP rs10888557 (GG reference, CG OR 0.6 [95%CI 0.4‐0.9], CC OR 0.15 [95%CI 0.04‐0.6]; log‐additive P‐trend, 0.0004). Common variants in PGLYRP genes are associated with PD risk in two independent studies. These results require replication, but they are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD. © 2014 International Parkinson and Movement Disorder Society     

Pain Hypervigilance is Associated with Greater Clinical Pain Severity and Enhanced Experimental Pain Sensitivity Among Adults with Symptomatic Knee Osteoarthritis

Background

Pain hypervigilance is an important aspect of the fear-avoidance model of pain that may help explain individual differences in pain sensitivity among persons with knee osteoarthritis (OA).

Purpose

The purpose of this study was to examine the contribution of pain hypervigilance to clinical pain severity and experimental pain sensitivity in persons with symptomatic knee OA.

Methods

We analyzed cross-sectional data from 168 adults with symptomatic knee OA. Quantitative sensory testing was used to measure sensitivity to heat pain, pressure pain, and cold pain, as well as temporal summation of heat pain, a marker of central sensitization.

Results

Pain hypervigilance was associated with greater clinical pain severity, as well as greater pressure pain. Pain hypervigilance was also a significant predictor of temporal summation of heat pain.

Conclusions

Pain hypervigilance may be an important contributor to pain reports and experimental pain sensitivity among persons with knee OA.     

Clinical Outcomes in Patients with Non-Diagnostic Thyroid Fine Needle Aspiration Cytology: Usefulness of the Thyroid Core Needle Biopsy

Background

Patients with non-diagnostic thyroid fine needle aspiration cytology (FNAC) results undergo repeat FNAC or core needle biopsy (CNB) for definite diagnosis or surgical resection, or are followed up by clinical and ultrasound surveillance. We aimed at evaluating the risk of malignancy in patients with non-diagnostic FNACs and their clinical outcomes according to the follow-up modality.

Methods

We retrospectively reviewed 1,496 (8.8 %) cases with a non-diagnostic result on a first aspiration among 17,045 thyroid FNACs performed between October 2008 and August 2012. Of the non-diagnostic FNACs, 389 patients underwent a second FNAC; 125, CNB; and 89, thyroidectomy by clinical indication. The remaining patients were clinically followed up.

Results

The rate of a second non-diagnostic result was significantly higher on repeat FNAC than on CNB (33.2 vs. 2.4 %; p < 0.001). There was no significant difference in the malignancy risk among patients initially non-diagnostic, twice non-diagnostic, and thrice or more non-diagnostic, nor did this differ from the rate following CNB. No further malignancy was found in cases with ≥2 non-diagnostic CNBs. The malignancy risk was 51 % in those who underwent thyroidectomy. The sensitivity for detecting malignancy was 65 and 70 % for repeat FNACs and first CNBs, respectively, with no false positives seen in either test.

Conclusions

Approximately one-third of repeat FNACs after an initial non-diagnostic aspirate are non-diagnostic on repeat examination, and the malignancy risk may not reduce following repetitively non-diagnostic FNACs. However, a single CNB may be enough to exclude malignancy risk for patients with a non-diagnostic aspirate.     

Effect of body mass index on the outcomes of patients with upper and lower urinary tract cancers treated by radical surgery: Results from a Canadian multicenter collaboration

ObjectiveTo evaluate the effect of body mass index (BMI) on the outcomes of patients with urinary tract carcinoma treated with radical surgery.Materials and methodsData were collected from 10 Canadian centers on patients who underwent radical cystectomy (RC) (1998–2008) or radical nephroureterectomy (RNU) (1990–2010). Various parameters among subsets of patients (BMI<25, 25≤BMI<30, and BMI≥30 kg/m²) were analyzed. Kaplan-Meier and multivariate analyses were performed to assess the effect of BMI on overall survival, disease-specific survival, and recurrence-free survival (RFS).ResultsAmong the 847 RC and 664 RNU patients, there was no difference in histology, stage, grade, and margin status among the 3 patient subsets undergoing either surgery. However, RC patients with lower BMIs (<25 kg/m²) were significantly older (P = 0.004), had more nodal metastasis (P = 0.03), and trended toward higher stage (P = 0.052). RNU patients with lower BMIs (<25 kg/m²) were significantly older (P = 0.0004) and fewer received adjuvant chemotherapy (P = 0.04) compared with those with BMI≥30 kg/m²; however, there was no difference in tumor location (P = 0.20), stage (P = 0.48), and management of distal ureter among the groups (P = 0.30). On multivariate analysis, BMI was not prognostic for overall survival, disease-specific survival, and RFS in the RC group. However, BMI≥30 kg/m² was associated with more bladder cancer recurrences and worse RFS in the RNU group (HR = 1.588; 95% CI: 1.148–2.196; P = 0.0052).ConclusionsIncreased BMI did not influence survival among RC patients. BMI≥30 kg/m² is associated with worse bladder cancer recurrences among RNU patients; whether this is related to difficulty in obtaining adequate bladder cuff in patients with obesity requires further evaluation.     

Myriocin induces apoptotic lung cancer cell death via activation of DR4 pathway

It has been known that myriocin inhibits melanoma growth. However, the effects and action mechanisms of myriocin on lung cancer cell growth have not been reported. In this study, we examined whether myriocin isolated from Mycelia sterilia inhibits cell growth of lung cancer cells (A549 and NCI-H460) as well as possible signaling pathways involved in cell growth inhibition. Different concentrations of myriocin inhibited the growth of lung cancer cells through the induction of apoptotic cell death. Consistent with cancer cell growth inhibition, myriocin induced the expression of death receptors (DRs) as well as p-JNK and p-p38 in both cell lines. Moreover, the combination of myriocin with DR4 ligand TRAIL, and other well known anti-tumor drugs (docetaxel and cisplatin) synergistically inhibited cancer cell growth, and induced DR4 expression. These results showed that myriocin inhibits lung cancer cells growth through apoptosis via the activation of DR4 pathways, and enhanced anti-cancer effects with well known drugs. Thus, our study indicates that myriocin could be effective for lung cancer cells as an anti-cancer drug and/or a conjunction agent with well known anti-cancers.     

Quercetin-3-O-β-d-glucuronide isolated from Polygonum aviculare inhibits cellular senescence in human primary cells

Cellular senescence is known to contribute to tissue aging, a variety of age-related diseases, tissue regeneration, and cancer. Therefore, aging intervention might be useful for prevention of aging as well as age-related disease. In this study, we investigated compounds from Polygonum aviculare to determine if they inhibited cellular senescence in human primary cells, human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs). Ten compounds from P. aviculare were purified and their inhibitory effects on adriamycin-induced cellular senescence were measured by observing senescence-associated β-galactosidase (SA-β-gal) activity and reactive oxygen species. Among them, compound 9 (quercetin-3-O-β-d-glucuronide) showed inhibitory effects against cellular senescence in HDFs and HUVECs treated with adriamycin. Additionally, compound 9 rescued replicative senescence in HDFs and HUVECs. These data imply that compound 9 represses cellular senescence in human primary cells and might be useful for the development of dietary supplements or cosmetics that ameliorate tissue aging or aging-associated diseases.