An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Protein arginine methylation is a common post-translational modification (PTM) catalyzed by nine protein arginine methyltransferases (PRMTs). As the major symmetric arginine methyltransferase that methylates both histone and non-histone substrates, PRMT5 plays key roles in a number of biological processes critical for development and tumorigenesis. PRMT5 overexpression has been reported in multiple cancer types including prostate cancer (PCa), but the exact biological and mechanistic understanding of PRMT5 in aggressive PCa remains ill-defined. Here, we show that PRMT5 is upregulated in PCa, correlates with worse patient survival, promotes corrupted RNA splicing, and functionally cooperates with an array of pro-tumorigenic pathways to enhance oncogenesis. PRMT5 inhibition via either genetic knockdown or pharmacological inhibition reduces stemness with paralleled differentiation and arrests cell cycle progression without causing appreciable apoptosis. Strikingly, the severity of antitumor effect of PRMT5 inhibition correlates with disease aggressiveness, with AR+ PCa being less affected. Molecular characterization pinpoints MYC, but not (or at least to a lesser degree) AR, as the main partner of PRMT5 to form a positive feedback loop to exacerbate malignancy in both AR+ and AR- PCa cells. Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.
Objective
To investigate the abnormality of intrahepatic biliary epithelial cells autophagy in primary biliary cirrhosis (PBC) mice, and explore the mechanism of UC-Mesenchymal stem cell (MSCs) in treating PBC.
Methods
After establishing the PBC model, we divided them into the PBC model group; the UC-MSCs treatment group and the Stattic group [Signal transducer and activator of transcription 3 (STAT3) inhibitor group]. Six mice were used as the control group. Liver pathology and the serum pyruvate dehydrogenase complex E2 subunit (PDC-E2) antibody titers were detected. Autophagosome of the intrahepatic biliary epithelial cell was observed by electronic microscope. Protein levels of STAT3/pSTAT3, Beclin-1 were detected by western blot. We cultured human intrahepatic biliary epithelial cells in vitro, and down regulated STAT3. After stimulated by GCDC, we co-cultured them with UC-MSCs, and collected the cells in order to detect LC3Ⅱ. The measurement data were compared with t test or single factor analysis of variance.
Results
Compared with the control group, periportal inflammatory cell infiltration and granuloma formation were observed in the PBC group. MSCs treatment decreased the infiltration of inflammatory cells. The level of anti-PDC-E2 of the PBC group (107±18) ng/ml was higher than that of the control group (42±6) ng/ml (q=6.326, P 0.05). Western blot showed that the level of Beclin-1 was higher in PBC group(1.80±0.36) than the control group(0.40±0.20) (q=6.757, P<0.01),MSCs reduced the expression of Beclin-1 (0.86±0.06)(q=4.536, P<0.05) as well as Stattic (0.72±0.03) (q=5.226, P<0.05). PBC group had a higher expression level of STAT3 (1.80±0.42)(q=5.730, P<0.05) and pSTAT3(2.04±0.29)(q=6.492, P<0.01) than the control group(0.50±0.05)(0.91±0.14). MSCs treatment decreased the expression of STAT3(0.51±0.13)(q=5.703, P<0.01) and pSTAT3 (0.76±0.07)(q=7.388, P<0.01) in intrahepatic biliary epithelial cells. After down regulated STAT3 of HiBECs, MSCs reduced the expression of LC3Ⅱ of HiBECs.
Conclusion
The intrahepatic biliary epithelial cells autophage of PBC mice is abnormal, MSCs can alleviate PBC by down regulating the autophage of intrahepatic biliary epithelial cells via STAT3.
Key words:
Mesenchymal stem cell; Primary biliary cirrhosis; Autophagy; Signal transducer and activator of transcription 3
N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure–activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.
Recent studies strongly suggest that atorvastatin combination therapy with tangeretin could be beneficial in the treatment of hyperlipidemia. This study aimed to investigate the pharmacokinetic interactions among atorvastatin, its active metabolite 2-hydroxy atorvastatin, and tangeretin after oral administration of atorvastatin with tangeretin in rats. A rapid, selective, and sensitive assay was developed and validated based on ultra-high performance supercritical fluid chromatography-tandem mass spectrometry for the simultaneous measurement of atorvastatin, 2-hydroxy atorvastatin, and tangeretin concentrations in rat plasma. Chromatographic separation of the analytes was conducted on an ACQUITY Torus 1-AA column in gradient elution mode. The mass transition ion pairs were m/z 559.0→440.0 for atorvastatin, m/z 575.2→440.0 for 2-hydroxy atorvastatin, m/z 373.0→358.1 for tangeretin, and m/z 254.8→136.7 for daidzein (internal standard). Calibration curves showed good linear correlations at the following concentration range: 1-400 (r = 0.9952), 1-400 (r = 0.9980), and 3-1200 (r = 0.9945) for atorvastatin, 2-hydroxy atorvastatin, and tangeretin, respectively. The method was fully validated and satisfied the acceptance criteria recommended by the United States Food and Drug Administration. Finally, it was successfully applied in a pharmacokinetic study in rats to evaluate the pharmacokinetic behavior of atorvastatin, 2-hydroxy atorvastatin, and tangeretin.
Survivin is a member of the inhibitor of apoptosis protein (IAP) family, which is discovered recently, and it has special structure. It is a bifunctional protein that suppresses apoptosis and regulation of cell division. Survivin is a tumor-specific antiapoptosis factor which is undetectable in adult normal tissues. However, its expression in all the most common human tumors has been associated with increased aggressiveness and decreased patient survival. In this paper, the advances in research of Survivin in oral-maxillofacial epithelial tumors were summarized and the function of survivin in tumors were discussed.
A novel actinomycete, designated strain NEAU-A2T, was isolated from rhizosphere soil of wheat (Triticum aestivum L.) and characterized using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NEAU-A2T should be assigned to the genus Lechevalieria and forms a distinct branch with its closest neighbour Lechevalieria aerocolonigenes DSM 40034T (99.0 %). Moreover, key morphological and chemotaxonomic properties also confirmed the affiliation of strain NEAU-A2T to the genus Lechevalieria . The cell wall contained meso-diaminopimelic acid and the whole-cell hydrolysates were galactose, mannose, rhamnose, glucose and ribose. The polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositolmannoside and two glycolipids. The predominant menaquinones were MK-9(H4) and MK-9(H6). The major fatty acids were iso-C16 : 0, anteiso-C15 : 0, C16 : 1ω7c and anteiso-C17 : 0. The DNA G+C content was 68.2 mol%. The combination of the DNA–DNA hybridization result and some phenotypic characteristics demonstrated that strain NEAU-A2T could be distinguished from its closest relative. Therefore, it is proposed that strain NEAU-A2T represents a novel species of the genus Lechevalieria , for which the name Lechevalieria rhizosphaerae sp. nov. is proposed. The type strain is NEAU-A2T (=CGMCC 4.7405T=DSM 104541T).
It’s essential to know the occurrence of emerging organic contaminants (EOCs) such as pharmaceuticals and personal care products (PPCPs) in ambient environment to clarify the increasing public concerns. However, such analysis is quite challenging due to the normally trace level of such contaminants in water, which therefore requires several liters of water samples. In this study, a large volume solid phase extraction (LV-SPE) device was developed and evaluated for its performance in monitoring PPCPs as an example. Relatively good recovery and reproducibility have been obtained under the operational conditions: volume of water sample <20 L, flow rates <120 mL/min, and methanol elution volumes >30 mL. In addition, the results from the onsite enrichment approach using LV-SPE were compared with conventional approach using normal SPE device in laboratory for real groundwater samples. For eight selected PPCPs (nalidixic acid, carbamazepine, bezafibrate, clofibric acid, sulfadiazine, sulfamethoxypyridazine, sulfamethazine and sulfamonomethoxine), more target compounds can be detected by the LV-SPE approach. Despite of generally comparable detected concentrations, slightly higher concentrations can be found for carbamazepine, clofibric acid, sulfadiazine and sulfamethazine. The developed device provides an alternative approach for trace analysis of PPCPs, also might be applicable for other emerging organic contaminants.
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