ABSTRACT
Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APCmin/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.
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@#Objective To investigate the clinical and neuroimaging features of adults with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease at the first attack. Methods We retrospectively analyzed the clinical manifestations,radiological features,laboratory findings,and outcome of 14 adult patients with MOG antibody-associated disease at the first attack who were hospitalized in the departments of neurology of Jiangxi Provincial People's Hospital and Xinyu People's Hospital from January 2018 to January 2022. Results The 14 patients included six males and eight females,with a median age of 29.5 years. The most common initial symptoms were fever and headache (n=5),seizure (n=3),and dizziness (n=3). The supratentorial lesions were located in the thalamus (n=7),subcortical white matter (n=6),cortex (n=5),corpus callosum (n=2), and basal ganglia (n=2). The infratentorial lesions were frequently located in the brainstem:the pons (n=5),middle cerebellar peduncle (n=3),midbrain (n=2), and medulla (n=2). Three patients had spinal cord involvement,with one case of longitudinally extensive transverse myelitis. Thirteen patients had elevated cerebrospinal fluid cell counts,and seven had elevated cerebrospinal fluid protein levels. The serum MOG antibody titer ranged from 1∶3.2 to 1∶512. All the 14 patients received intravenous pulse glucocorticoid therapy. Only one patient had a relapse with optic neuritis. Conclusion In our study,MOG antibody-associated disease showed a slight female predominance and frequently presented as acute disseminated encephalomyelitis. The supratentorial lesions were often located in the thalamus and subcortical white matter,while the infratentorial lesions were frequently in the pons. Intravenous pulse steroid therapy was effecitve in the acute phase. The majority of the patients had a favorable outcome.
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Objective:To explore the mediating effect of self-compassion between family cohesion and loneliness among adolescents.Method:From November to December 2020, a total of 626 adolescents were investigated with the family adaptability and cohesion scale, children loneliness scale and the self-compassion scale short form.Data were analyzed by SPSS 23.0 and PROCESS v 2.16 softwares.The statistical methods included t-test, one-way ANOVA, Pearson correlation analysis and intermediary effect analysis. Results:Compared with girls, boys’ score of family cohesion((63.52±8.47), (65.48±9.07)) was significantly lower but the scores of self-compassion((37.68±5.26), (36.49±5.75)) and loneliness((37.74±10.44), (36.01±10.48)) were significantly higher( t=-2.79, 2.06, 2.70; all P<0.05). There was no significant difference in the scores of family cohesion((63.67±8.71), (64.74±8.85)), self-compassion((37.45±5.71), (36.98±5.49)) and loneliness((36.60±10.52), (36.96±10.49)) between left-behind and non-left-behind children( t=1.29, -0.87, 0.38, all P>0.05). The score of family cohesion of the adolescents from Grade 7 was significantly lower than those of Grade 8, Grade 10 and Grade 11( P<0.01), while the score of self-compassion of the adolescents from Grade 10 was significantly lower than those of Grade 7 and Grade 11(both P<0.01), but the score loneliness of the adolescents from Grade 11 was significantly lower than those of Grade 8 and Grade 10(both P<0.05). Family cohesion(64.50±8.82)was significantly positively associated with self-compassion(37.09±5.54)( r=0.22; P<0.01). Loneliness(36.88±10.49)were significantly negatively associated with self-compassion( r=-0.27, P<0.01) and family cohesion( r=-0.28, P<0.01). The relation between family cohesion and loneliness was partly mediated by self-compassion and the effect of mediation was 20.9%. Conclusion:Family cohesion will not only directly affect the loneliness of adolescents, but also affect loneliness through the mediating effect of self-care.
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Post-stroke insomnia is very common in clinic. Most clinicians regard post-stroke insomnia as common insomnia without considering the particularity of stroke patients. There are many kinds of hypnotics in clinic, and the mechanism and side effects of various hypnotics are different; however, the choice of drugs for post-stroke insomnia is entirely based on experience, and the curative effect is different. This review describes the drug selection of post-stroke insomnia.
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Objective To discover the medicinal active molecules from the fermentation extract of sponge-symbiotic Streptomyces sp. LHW2432. Methods Compounds were isolated and purified from the fermentation extract of LHW2432 by silica gel, ODS chromatographic columns, and HPLC. The structures of the compounds were elucidated based on the analyses of modern spectrum technologies and the related literatures research. Through plate coating method and broth microdilution method, the antimicrobial activities were tested by the indicator strains of Bacillus mycoides, methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium smegmatis, Candida Albicans, and Escherichia coli. Results Five compounds were discovered and their structures were identified as descycloavandulyl-lavanduquinocin (1), N-acetyltyramine (2), phomapyrone C (3), germicidin A (4), and germicidin I (5). Compound 1 showed inhibitory activities against MRSA (MIC, 100 μg/ml) and M. smegmatis (MIC, 64 μg/ml), respectively. Conclusion Five compounds were discovered from LHW2432, among which compound 1 was a new natural product and could be used as a precursor of the tricyclic carbazole alkaloids with neuroprotective activity. Moreover, compound 1 showed weak inhibitory activities against gram-positive pathogenic bacteria.