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Desensitization of G protein-coupled receptors (GPCRs) represents a gradual attenuation of receptor responsiveness by continuous or repeated exposure to agonists. The most widely accepted molecular mechanism responsible for desensitization is that of GRK2-mediated receptor phosphorylation followed by association with β-arrestins. However, in most cases, this mechanism cannot explain the desensitization of GPCRs. In this study, we investigated whether there exists a direct correlation between desensitization and certain cellular events that commonly observed with desensitizing receptors. Our study showed that constitutive ubiquitination of β-arrestin, accompanied by nuclear to cytoplasmic translocation of Mdm2, was observed in cells expressing desensitizing GPCRs (dopamine D3 receptor, K149C-dopamine D2 receptor, β2 adrenoceptor, and lysophosphatidic acid receptor 1). In contrast, Mdm2 was observed in the nucleus in cells expressing non-desensitizing GPCRs (dopamine D2 receptor, C147K-dopamine D3 receptor, and dopamine D4 receptor). Molecular manipulation to convert the characteristics of the dopamine D4 receptor from non-desensitizing to desensitizing changed the status of subcellular localization of Mdm2 from nuclear to cytoplasmic. With repeated agonist treatments of desensitizing receptors, Mdm2 translocated from cytoplasm to nucleus, resulting in the deubiquitination of β-arrestins. This study suggests that the property of a receptor that causes a change in subcellular localization of Mdm2, from the nuclear to cytoplasmic, could be used as a biomarker to predict the desensitization of a receptor.We investigated the impact of human demineralized bone matrix (hDBM) plus adipose-derived stem cells (hADS) plus photobiomodulation (PBM) on a critical-sized femoral defect (CSFD) in ovariectomy induced osteoporosis in rats. There were 6 groups as follows. In group 1 (control, C), only CSFDs were created. Groups 2-6 were implanted with DBM into the CSFD (DBM-CSFD). In group 2 (S), only DBM was transplanted into the CSFD. In group 3 (S + PBM), the DBM-CSFDs were treated with PBM. In group 4, the DBM-CSFDs were treated with alendronate (S + ALN). In group 5, ADSs were seeded into DBM-CSFD (S + ADS). In group 6, ADSs were seeded into DBM-CSFD and the CSFDs were treated with PBM (S + PBM + ADS). At week eight (catabolic phase of bone repair), the S + ALN, S + PBM + ADS, S + PBM, and S + ADS groups all had significantly increased bone strength than the S group (ANOVA, p = 0.000). The S + PBM, S + PBM + ADS, and S + ADS groups had significantly increased Hounsfield unit than the S group (ANOVA, p = 0.000). ALN, ADS, and PBM significantly increased healed bone strength in an experimental model of DBM-treated CSFD in the catabolic phase of bone healing in osteoporotic rats. However, ALN alone and PBM plus ADS were superior to the other protocols.It is hard to explain the decrease in mechanosensitivity of osteocytes under microgravity. Primary cilia are essential mechanosensor for osteocytes. [https://www.selleckchem.com/products/blu-451.html selleck chemicals] The cilia become shorter under the simulated microgravity (SMG) environment. The cilia change may be the reason for the mechanosensitivity decrease of osteocytes under SMG. To reveal the role of primary cilia in weightless-induced osteocyte dysfunction, we investigate intraflagellar transport (IFT) to understand the mechanism of the decreased cilia length of osteocytes when subjected to SMG. We measure the number of anterograde IFT particles with GFPIFT88 and retrograde IFT particles with OFPIFT43 that occur at a particular transverse plane of the cilia. We also measure the expression of IFT88 and IFT43 and the size of IFT particles under SMG. Herein, the ratio of anterograde/retrograde particle number and the ratio of protein expression of IFT88/IFT43 increase under SMG. The size of anterograde IFT particles with GFPIFT88 gets a significant decrease under SMG. Fundamentally, SMG has broken the balanced operating state of IFT and makes the IFT particles smaller. The phenomenon under SMG is intriguing.Rosiglitazone is a ligand of peroxisome proliferation-activated receptor gamma (PPARγ). However, it exerts biological activities and therapeutic effects through both PPARγ-dependent and independent mechanisms. In this study, we defined that rosiglitazone was also a ligand of retinoid X receptor alpha (RXRα) and displayed RXRα-dependent activities. We found that rosiglitazone directly bound to the ligand binding domain (LBD) of RXRα and induced RXRα/LBD tetramerization. Rosiglitazone inhibited the agonist-induced transcriptional activity of RXRα homodimers and heterodimers likely through inhibiting RXRα homo- and hetero-dimerization. In acute promyelocytic leukemia (APL) NB4 cells, rosiglitazone inhibited cell proliferation and induced cell differentiation, resulting from inhibiting RXRα/PML-RARα complex formation and down-regulating PML-RARα. Together, our study identified RXRα as a novel target of rosiglitazone and RXRα mediating the anti-APL activity of rosiglitazone.Flavonoids are generally glycosylated, and the glycan moieties of flavonoid glycosides are known to greatly affect their physicochemical and biological properties. Thus, the development of a variety of tools for glycan remodeling of flavonoid glycosides is highly desired. An endo-β-N-acetylglucosaminidase mutant Endo-CC N180H, which is developed as an excellent chemoenzymatic tool for creating sialylglycoproteins, was employed for the glycosylation of flavonoids. Endo-CC N180H transferred the sialyl biantennary glycans from the sialylglyco peptide to pNP-GlcNAc and narigenin-7-O-glucoside. The kinetic parameters of Endo-CC N180H towards SGP and pNP-GlcNAc were determined. Flavonoid glucosides harboring a 1,3-diol structure in the glucose moieties acted as substrates of Endo-CC N180H. We proposed that the sialyl biantennary glycan transfer to the flavonoid by Endo-CC N180H could pave the way for the improvement of the inherent biological functions of the flavonoids and creation of novel flavonoid glycoside derivatives for future human health benefits including foods and drugs.Type 2 diabetes mellitus (DM)-induced cardiomyopathy is a multifactorial and complex disease involving oxidative stress, lipids, and fibrosis. It is based on metabolic disorders and microvascular disease and causes extensive focal necrosis of the heart muscle. Curcumin (CUR) is a natural polyphenol isolated from turmeric rhizomes and plays an important role in the antioxidant, anti-apoptotic and anti-inflammatory effects of diabetes. Therefore, we established a mouse model of diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice in our study. We divided the experiment into three groups the control group, DM group and DM + CUR group.We performed cardiac dissection on mice treated in different conditions and conducted special pathological staining on isolated cardiac tissue. We were surprised to find that a high glucose environment can promote cardiomyocyte apoptosis by TUNEL assay. In addition, after detecting dihydroethiidine (DHE), hematoxylin-eosin (H&amp;E) and Oil Red O staining, we unexpectedly found that CUR can inhibit the production of reactive oxygen species (ROS), reduce myocardial apoptosis, and myocardial lipid accumulation.