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b-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that b-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. b-Arrestin-1 (ARRB1) and b-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n ¼ 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, diseasespecific-mortality, and failure to Gemcitabine þ Cisplatin (GþC) chemotherapy; $80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9-mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.

Interaction between parathyroid hormone/parathyroid hormone-related peptide receptor 1 (PTHR1) and low density lipoprotein receptor-related protein 6 (Lrp6) is important for parathyroid hormone (PTH) signaling and anabolic action. Since N-cadherin has been shown to negatively regulate canonical Wnt/β-catenin signaling, we asked whether N-cadherin alters PTH signaling and stimulation of bone formation. Ablation of the N-cadherin gene (Cdh2) in primary osteogenic lineage cells resulted in increased Lrp6/PTHR1 interaction in response to PTH1–34, associated with enhanced PTH-induced PKA signaling and PKA-dependent β-catenin C-terminus phosphorylation, which promotes β-catenin transcriptional activity. β-catenin C-terminus phosphorylation was abolished by Lrp6 knockdown. Accordingly, PTH1–34 stimulation of Tcf/Lef target genes, Lef1 and Axin2, was also significantly enhanced in Cdh2 deficient cells. This enhanced responsiveness to PTH extends to the osteo-anabolic effect of PTH, as mice with a conditional Cdh2 deletion in Osx+ cells treated with intermittent doses of PTH1–34 exhibited significantly larger gains in trabecular bone mass relative to control mice, the result of accentuated osteoblast activity. Therefore, N-cadherin modulates Lrp6/PTHR1 interaction, restraining the intensity of PTH-induced β-catenin signaling, and ultimately influencing bone formation in response to intermittent PTH administration.

The longan industry produces a large amount of byproducts such as pericarp and seed, resulting in environmental pollution and resource wastage. The present study was performed to systematically evaluate functional components, i.e., polyphenols (phenolics and flavonoids) and alkaloids, in longan byproducts and their bioactivities, including antioxidant activities, nitrite scavenging activities in simulated gastric fluid and anti-hyperglycemic activities in vitro. Total phenolic and total flavonoid contents in pericarp were slightly higher than those in seeds, but seeds possessed higher alkaloid content than pericarp. Four polyphenolic substances, i.e., gallic acid, ethyl gallate, corilagin and ellagic acid, were identified and quantified using high-performance liquid chromatography. Among these polyphenolic components, corilagin was the major one in both pericarp and seed. Alkaloid extract in seed showed the highest DPPH radical scavenging activity and oxygen radical absorbance capacity. Nitrite scavenging activities were improved with extract concentration and reaction time increasing. Flavonoids in seed and alkaloids in pericarp had potential to be developed as anti-hyperglycemic agents. The research result was a good reference for exploring longan byproducts into various valuable health-care products.

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