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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 study the cyclic peptides from sponge Reniochalina sp. under the guidance of mass spectrometry. Methods Mass spectrometry-guided procedural separation methods were used to track and isolate the cyclic peptides from the sponge genus Reniochalina. The structures of compounds were elucidated by the determination of physicochemical parameters and comparison of spectroscopic data. The preliminary cytotoxic activity of compounds was assessed by the Cell Counting Kit-8 (CCK-8) method. Results Three cyclic peptides were isolated from the sponge Reniochalina sp. and identified as stylopeptide 1 (1), hymenamide D (2) and axinastatin 2 (3). Compound 1 exhibited cytotoxicity against six human cancer cell lines with IC50 values ranging from 6.09 to 17.26 μmol/L. Conclusion Compound 1 - 3 were isolated from Reniochalina sp. for the first time, and compound 1 was a cytotoxic cyclic heptapeptide.
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SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.
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Objective To study the chemical constituents of Aspergillus terreus from sponge epiphytic fungal. Methods Sephadex LH-20 column chromatography, silica gel column chromatography and high performance liquid chroma-tography were used to separate and purify the compounds. The structures of compounds were identified by spectroscopic data. The α-glucosidase inhibitory activity and antioxidant activity of the compounds were tested by PNPG and DPPH methods, respectively. Results Eight compounds were isolated from Aspergillus terreus and identified as methyl-3,4,5-trimethoxy-2-(2-(nicotinamido) benzamido) benzoate (1), terrelumamide A (2), emeheterone (3), (8R,9S)-dihydroisoflavipucine (4), (8S,9S)-dihydroisoflavipucine (5), cyclo(S-Pro-S-Phe) (6), brevianamide F (7), terrein (8). Compound 3 showed strong inhibitory activity against α-glucosidase and the IC50 value was 14.28 μmol/L. Conclusion Compounds 3, 4, 5, and 7 were obtained from Aspergillus terreus for the first time.
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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.
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Objective To investigate the chemical constituents of the marine sponge Theonella swinhoei collected from the Xisha Islands in the South China Sea .Methods The petroleum ether and dichloromethane extract of the marine sponge T . swinhoei were purified by solvent extraction and chromatographic methods including vacuum liquid chromatography (VLC) , medium pressureliquidchromatography(MPLC),thinlayerchromatography(TLC)onsilicagel,highperformanceliquidchro-matography(HPLC) ,and Sephadex LH-20 .The chemical structures were determined by spectroscopic analysis and comparison with the reported data .Results Eight compounds were isolated and their structures were determined as cholest-7-ene-3β,5α, 6β-triol (1) ,ergosta-7 ,22-diene-3β,5α,6β-triol (2) ,25-norcycloartane-3β,6α,16β,24-tetraol (3) ,sinuflexibilin D (4) ,14-de-oxycrassin (5) ,N-(2-phenylethyl)-(9Z)-tetradecanamide(6) ,N-(2-phenylethyl)-tetradecanamide (7) ,7 ,8-dimethyl-isoallox-azine (8) .Conclusion Compounds 1～ 7 were isolated from the sponge of genus Theonella for the first time .
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Objective To investigate the chemical constituents in the marine sponge, Spongia sp., collected from the Xisha Islands.Methods The pure chemical components from the petroleum ether extract of Spongia sp.were obtained by repeated column chromatography on silica gel,ODS,Sephadex LH-20 and semi-preparative HPLC.Their structures were determined by spectroscopic analysis and comparison with the reported data.The antifungal activity of those compounds was evaluated by dilution method.Results 9 compounds were isolated and identified,including smenodiol(1),smenospongorine(2),5-epi-smenospongorine(3),dictyoceratin C(4),epi-smenospongidine(5),dictyoceratin A(6),stigmasta-4,6,8(14),22-tetraen-3-one(7),3-oxo-4,6,8(14)-triunsaturated steroids(8),ergosta-4,6,8(14),22-tetraen-3-one(9).Conclusion Compounds 1~9 were isolated from the sponge of genus spongia for the first time.Compound 2、3、5 and 9 exhibited antifungal activities against Candida albicans,Trichophyton mentaqrophytes and Trichophyton rubrum with the MIC values of 12.5~25 μg/ml.
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Objective To investigate the chemical constituents of marine sponge Mycale sp.collected from the South China Sea.Methods The ethyl acetate extract of the marine sponge Mycale sp.was separated and purified by repeated column chromatography on silica gel, Sephadex LH-20 and reversed-phase high-performance liquid chromatography (RP-HPLC).The structures of these compounds were identified by means of various modern spectroscopic techniques and comparison with their physicochemical properties to reported data.The tumor cell growth inhibitory activities of these compounds against human breast cancer cell lines MCF-7 and human lung cancer cell lines PC9 were tested by Cell Counting Kit-8 (CCK-8) method.Results Ten compounds were isolated and identified as cyclo-(Pro-Ile)(1),cyclo-(Pro-Leu)(2),cyclo-(Ile-Leu)(3),cyclo-(Phe-Pro)(4),cyclo-(Phe-Val)(5),cyclo-(Phe-Leu)(6),cyclo-(Phe-Ile)(7), 2′-deoxythymidine (8), thymine (9), 5-hydroxy-3,4-dimethyl-5-pentyl-2(5H)-furanone (10).These compounds showed weak tumor cell growth inhibitory activities toward cells MCF-7 and PC9 in vitro.Conclusion Compounds 1, 2, 4, 5, 6, 7 and 10 were isolated from the sponge Mycale sp.for the first time.It is the first time to report the antitumor activity evaluation for compounds 1~10.
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Objective To screen the active compounds targeting lung cancer stem cells (LCSCs) from the sponge Aaptos aaptos.Methods The A549-Nanog-GFP model of LCSCs was constructed.Western blot and immunofluorescence were used to examine the expression of pluripotency markers in screening model.The established LCSCs model was used to screen 8 fractions of Aaptos aaptos dichloromethane extract.The active fraction was separated by various chromatographic methods.CCK8 assay was used to screen the compounds for anti-LCSCs activity in vitro.Results LCSCs model with high expression of CD44 and ALDH1A1 protein was successfully constructed.The fraction D6 showed significant inhibitory activity in LCSCs(P<0.01).Four aaptamine alkaloids were isolated from this fraction.Compound AP-1 has good activity against LCSCs(P<0.01)with IC50 value(3.84±0.12) μmol/L.Conclusion AP-1 isolated from the spongeAaptos aaptos exhibited significant activity against LCSCs.
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OBJECTIVE:To evaluate the cost and utility of ivabradine in the treatment of chronic heart failure (CHF) patients in China.METHODS:The cost and utility of standard plan plus ivabradine (called "ivabradine plan" for short) vs.standard plan were evaluated by Markov model,and lifetime total costs and quality adjusted life years (QALYs) were obtained.The clinical parameters were obtained from SHIFT China subgroup study;cost and utility data related to CHF came from domestic published literatures.Single-factor sensitivity analysis and probability sensitivity analysis were performed to test cost-utility analysis.RESULTS:Compared with standard plan,ivabradine plan could increase 0.30 QALYs;at the same time,the total cost increased by 20 153.70 yuan,and the incremental cost-utility ratio was 67 189.50 yuan/QALY.Probability sensitivity analysis showed that the probability of ivabradine plan with cost and utility was 90％ when pay threshold was 3 times GDP per capita (140 000 yuan/QALY).The cardiovascular mortality risk ratio of ivabradine plan to standard plan was most sensitive model parameters.CONCLUSIONS:Compared with standard plan,additional use of ivabradine in the therapy for China CHF patients shows cost and utility.
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Lung cancer is the leading cause of cancer deaths worldwide.Recurrence and metastasis are the primary reasons for its poor prognosis.Growing evidence has proposed that lung cancer may be driven by cancer stem cells (CSCs), which may be responsible for the poor outcome of lung cancer.The resistance mechanisms of cancer stem cells include four aspects: high expression of the chemo-resistant efflux transporter ABC in CSCs populations, over-expression of ALDH, efficient DNA damage repair system, developmental pathway activation.The tolerance mechanism of CSCs was described to provide theoretical basis for clinical treatment and development of new anti-tumor drugs.
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Objective:To establish an HPLC method for the determination of gastrodin in Fufang Zhenma capsules. Methods:A YMC-Pack Pro C18(250 mm ×4.6 mm,5μm)column was used. The mobile phase consisted of acetonitrile-water (2 ∶98). The detec-tion wavelength was 220 nm. The flow rate was 1. 0 ml·min-1 ,the column temperatime was 20℃. the sample size was 25μl. Results:Gastrodin showed a good linear relationship within the range of 3.38-432.80 μg·ml-1(r =0.999 9). The average recovery was 97. 14% (RSD=2. 67%)(n=6). Conclusion:The method is feasible with good specificity and reproducibility, and can be used for the determination of gastrodin in Fufang Zhenma capsules.
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OBJECTIVE:To establish a method for the quality control of Huangmai granules and provide reference for the qual-ity control. METHODS:TLC was conducted to identify the Leguminosae in Huangmai granules and HPLC was used to determine the contents of icariin,hyperin and stilbene glycoside in Huangmai granules. RESULTS:The spots on TLC plates were clear with good reproducibility. The results of HPLC showed that the linear range was 9.969-319.0 μg/ml(r=0.999 9) for icariin , 12.3-196.8 μg/ml(r=0.999 9)for hyperin and 12.64-202.2 μg/ml(r=0.999 8)for stilbene glycoside;RSDs of precision,stability and reproducibility tests were all no more than 2.92%;the average recoveries were respectively 95.44%(RSD=1.46%,n=6), 101.06%(RSD=1.90%,n=6)and 100.51%(RSD=1.73%,n=6). CONCLUSIONS:The method is simple,reproducible,accu-rate and reliable,and can be used for the quality control of Huangmai granules.
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OBJECTIVE:To demonstrate challenges of pharmacy automation reconstruction so as to set solutions. METHODS:Based on literature review,analysis of pharmacy automation setting and features,this paper gave the suggestions and solutions on construction cost,management model change,equipment maintenance and emergency response,etc. according to the practice of the hospital. RESULTS&CONCLUSIONS:Pharmacy automation construction should be stick to the requirements of new health re-form to lower the cost by using the out resources and interior optimal allocation,to improve efficiency by unified planning and proper design,and to ensure the system running efficiently by sufficient maintenance and contingency plan.
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Objective: To analyze the uncertainty of quercetin concentration determination in Sicao Tongmai capsules by HPLC. Methods: The source of uncertainty was confirmed by analyzing the HPLC determination process. The uncertainty components were quantified by statistics, and the extended uncertainty and confidence level were finally obtained. Results: The extended uncertainty of the measurement results was 0. 19 μg · g-1 . Quercetin concentration in Sicao Tongmai capsules was (353. 65 ± 0. 19)μg·g-1 . Conclusion: The uncertainty analysis method is suitable for the standard limit formulation for Sicao Tongmai capsules, and it is important to establish uncertainty analysis methods for traditional Chinese medicines.
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Five compounds were isolated from marine sponge Aplysinopsis sp.collected from the South China Sea.Their structures were elucidated by ~1H-NMR,~(13)C-NMR and MS as (E)-3'-deimino-3'-oxoaplysinopsin(Ⅰ),(Z)-3'-deimino-3'-oxoaplysinopsin(Ⅱ),3-(2- oxopropyl )- 3-hydroxyind-olin-2-one(Ⅲ),1H-indole-3-carboxaldehyde(Ⅳ),5?,6?-epoxystigmasta -7-en-3?-ol(Ⅴ).CompoundsⅢ,Ⅴwere isolated from Aplysinopsis sp.for the first time.
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Three active compounds were isolated from the marine bryozoan Bugula neritina living in the South China Sea by bioassay-guiding isolation method with a combination of extraction with suitable solvent and multiple column chromatography(Sephadex LH-20, ODS and preparative HPLC). Their structures were assigned as known bryostatin 4, bryostatin 5 and bryostatin 6 by intensive analysis of the data of high resolution 2DNMR(600 MHz,DQF-COSY,TOCSY,HMQC and ROESY). All these compounds were obtained from this bryozoan in the South China Sea for the first time and showed significant antineoplastic activities in vitro.
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Eight active compounds were isolated from Bugula neritina Linnaeus collected off Dapen Bay in Guandong province, guided by P 388 bioassay system by a combination of successive chromatographies and preparative HPLC. By intensive analysis of the data of high resolution 2D NMR spectrum and ESI MS, their structures were elucidated as known bryostatins--bryostatin 4, 5, 6, 8, 10, 11, 16 and 18, among which bryostatin 8 and 16 were for the first time obtained from this animal in South China Sea and they showed significant antineoplastic activities in vitro.
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Two active compounds were isolated from chinese marine mollusc sea hare (Notarchus leachii cirrosus) by bioassay guided method with conidia of Pyricularia oryzae , and by a combination of extraction and purification with suitable solvent as well as multiple column chromatographies. Their structures were elucidated as (7 E) 1 acetoxy 8 chloro 7 (dichloromethyl) 3 methyoct 7 en 4 one (Ⅰ), (7 Z) 1 acetoxy 8 chloro 7 (dichloromethy l) 3 methyoct 7 en 4 one (Ⅱ). All compounds were obtained for the first time from this specimen and showed significant antineoplastic activities in vitro .
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Objective:To screen for the bioactive marine organisms and to study the active constituents from them.Methods:Bioactivities of marine organisms extracts were screened by Pyricularia oryzae bioassay method and the constituents were isolated and identified by a combination of multi chromatography and spectral analysis.Results:Twenty ethanolic extracts and 5 aqueous extracts of the tested marine organisms showed activities causing morphological abnormality of P.oryzae mycelia.Fifty six compounds were obtained and identified from Sargassum carpophyllum,Ishige okamurai and Natarchus leachii freeri ,among which 28 compounds showed activities against P.oryzae and exhibited cytotoxicities on various cultured tumor cell lines,eight compounds showed inhibition effects on Fonsecaea pedrosoi in vitro .Conclusion:The screening data and bioactivity evaluation suggest the P.oryzae bioassay is suitable for preliminary screening of bioactive agents from marine organisms.