Non-small-cell-lung-cancer (NSCLC) is a prevalent lung malignancy among humans. UBE2C is a critical component of the ubiquitin–proteasome system, and its expression level is significantly associated with cancer development and cell proliferation. Nevertheless, the mechanisms of UBE2C in NSCLC remain unclear. We aimed to investigate the role of MMP9 in UBE2C-overexpressed NSCLC progression. The GEPIA database and Kaplan–Meier curves were used to determine UBE2C expression in human tumors and survival in NSCLC. CCK8, colony formation, and Transwell® assays were employed to assess the function of UBE2C in vitro. Western blotting, immunofluorescence assay, and RT-qPCR were utilized to determine protein and mRNA expression levels. CHX chase and co-immunoprecipitation assays were used to elucidate the regulatory mechanism. This research proved that UBE2C expression was related to patient overall survival, cell proliferation and migration. Furthermore, overexpressed UBE2C could promote the protein stability of Matrix metalloproteinase-9 (MMP9) to upregulate its protein level in NSCLC cells. Meanwhile, UBE2C upregulation promoted lung carcinoma progression by modulating MMP9 expression. Our findings indicate that UBE2C may be a therapeutic and prognostic target for lung carcinoma.

Our previous research has confirmed that the Leptopus genus plants possess significant anti-tumor and hepatoprotective effects, and over 50 triterpenoids were isolated from these plants. In the present work, the anti-inflammatory activities of four Leptopus genus plants were evaluated before phytochemical experiments. Subsequently, eight flavonoids (1-8) including two previously undescribed prenylated flavonoids (1-2) were isolated from the whole plants of Leptopus clarkei. The structures of these new compounds were unequivocally elucidated by high-resolution electrospray ionization mass spectrometry and one-/two-dimensional nuclear magnetic resonance data. Additionally, all isolates were evaluated for their anti-inflammatory activities. Among these compounds, 1 exhibited moderate anti-inflammatory activity with a minimum inhibitory concentration value of 26.5 ± 1.2 µM on nitric oxide production in lipopolysaccharide-induced RAW264.7 cells.

Saline-tolerant medicinal plants possess novel chemical constituents with high bioactivity because of their unique secondary metabolic pathways.

The Yellow River Delta possesses lots of characteristic medicinal plants due to its high salinity and high alkaline environment and Limonium sinense is an iconic plant. However, there are very few studies on L. sinense and its chemical constituents have not been investigated in recent ten years. In the present study, the chemical constituents and bioactivities of L. sinense were fully studied for the first time. UPLC-MS/MS method combined with database comparison identified 109 compounds mainly including flavonoids, alkaloids and polyphenols. In addition, the potential bioactivities of L. sinense were considerated as anti-inflammatory, anti-oxidative, anti-tumor, hepatoprotective and hpyerglycemic activities based on these identified compounds and their related literature. Furthermore, four derivatives of 12-oxo-phytodienoic acid and butenolide including two new ones (1 and 2) were isolated from the whole plants of L. sinense. Their structures, including the absolute configurations, were determined by the analysis of comprehensive spectroscopic data. All isolates were evaluated for their anti-inflammatory activity. Compound 1 exhibited moderate anti-inflammatory activity with IC50 value of 37.5±1.2 μM on NO production level.

Medicinal plants in the high salinity and high alkaline environment might possess some special chemical constituents with new skeleton and high bioactivity. In this work, the main chemical constituents of Limonium sinense, namely flavonoids, were comprehensively studied for the first time. A new flavonoid together with five known compounds were isolated from the whole plants of L. sinense. Their structures were determined by the analysis of comprehensive spectroscopic data. All isolates were evaluated for their anti-inflammatory activity. Compound 1 exhibited moderate anti-inflammatory activity on NO production with IC50 value of 20.5 ± 1.3 μM. In addition, 38 flavonoids were identified by UPLC-MS/MS method and 18 reported flavonoids were summarised.

Front Cover. Two new naphthyridine compounds, 4-methoxycarbonyl-5-oxo-1,6-naphthyridine (1) and 5-methoxycarbonyl-4-oxo-1,6-naphthyridine (2), were isolated from the MeOH extracts of sponge, Aaptos suberitoides, collected in South Sea, China. Their structures were determined by spectroscopic methods. And the structure of compound 1 was further confirmed via single crystal X-ray diffraction analysis. This is the first report of an anti-inflammatory compound isolated from the sponge genus Aaptos. Biological assays and mechanism research have found that compound 1 can significantly inhibited the production of NO in RAW264.7 cells stimulated by LPS, and exerted anti-inflammatory effects by activating Nrf2/HO-1 and inhibiting MAPK signaling pathways as presented by Meng-Shan Liu et al. in their research article at 10.1002/cbdv.202300410. 2023 VOLUME 20 NO. 6 Front Cover Meng-Shan Liu, Zhen Zhang, Qian-Qian He, Shi-Zhou Qi, Kun-Lai Sun, Shuang Miao, Yan Wu, Kai-Kai Gong, Chem. Biodiversity 2023, 20, e2300410. Anti-Inflammatory Effects of New Naphthyridine from Sponge Aaptos suberitoides in LPS-Stimulated RAW 264.7 Macrophages via Regulation of MAPK and Nrf2 Signaling Pathways.

A large number of extracts of medicinal plants or natural products shows beneficial to combat obesity. In the present work, a new flavonoid named (2S,1 '' R,2 '' R)-4 '-hydroxy-7-methoxy-6-(1,2,3-trihydroxy-3-methyl-butyl)-flavanone (1), along with seven known compounds (2-8) were isolated from the seeds of Cullen corylifolium. Their structures, including the absolute configurations, were determined by the analysis of comprehensive spectroscopic data and computational calculation methods. All isolates were evaluated for their diacylglycerol acyltransferase (DGAT) inhibitory activity. Compounds 1-4 exhibited different level of DGAT1 inhibitory activity with IC50 values ranging from 28.2 +/- 1.1 to 127.3 +/- 1.9 mu M. In addition, 45 flavonoids which be evaluated for DGAT inhibitory activity were summarised and potential structure-activity relationships were discussed.

目的 研究1株黄河三角洲盐碱地曲霉属真菌A.versicolor BHT-72的次级代谢产物及其生物活性.方法 采用硅胶柱层析、Sephadex LH-20葡聚糖凝胶柱层析、ODS柱层析、高效液相(HPLC)等色谱方法对该菌株的次级代谢产物分离纯化,并通过核磁共振(NMR)、质谱(MS)等方法,结合相关文献对比鉴定化合物结构;分别采用CCK8法和改良的Ellman法对化合物进行抗肿瘤和抗乙酰胆碱酯酶抑制活性的测试.结果 从A.versi-color BHT-72的大米发酵产物中共分离得到10个单体化合物,分别为diorcinol(1)、12-O-acetyl-sydowinin A(2)、sydowinin A(3)、13-O-acetylsydowinin B(4)、sydoxanthone(5)、3-formylindole(6)、尿苷(7)、zarzissine(8)、6-氨基嘌呤核苷(9)、6-氨基嘌吟脱氧核苷(10).细胞毒活性测定结果显示,化合物1在质量浓度为30 μg/mL时,对鼻咽癌细胞CNE-2的抑制率为65.0％,对非小细胞肺癌H1299和H520的抑制率分别为81.3％和87.0％.化合物2在质量浓度为30 μg/mL时对H1299细胞的抑制率为49.8％.在质量浓度为100μg/mL时,化合物1～5对乙酰胆碱酯酶具有一定的抑制活性,抑制率分别为59.4％、60.0％、54.6％、40.0％和66.6％.结论 黄河三角洲盐碱地真菌A.versicolor BHT-72能产生结构多样的活性次级代谢产物,化合物1和2对鼻咽癌细胞CNE-2、非小细胞肺癌H1299和H520具有一定的细胞毒活性,化合物1～5具有一定的乙酰胆碱酯酶抑制活性.

Two new naphthyridine compounds, 4-methoxycarbonyl-5-oxo-1,6-naphthyridine (1) and 5-methoxycarbonyl-4-oxo-1,6-naphthyridine (2) were obtained from the MeOH extracts of sponge Aaptos suberitoides. Their structures were determined by spectroscopic methods, including HR-ESI-MS, 1D-NMR (1 H-NMR, 13 C-NMR), 2D-NMR (COSY, HSQC, HMBC). The structure of compound 1 was further confirmed via single crystal X-ray diffraction analysis. Compound 1 was found to reduce NO production in LPS-induced RAW 264.7 macrophages with IC50 value of 0.15 mM. In addition, it decreased the mRNA expression levels of pro-inflammatory mediators, such as the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) in LPS-induced macrophages. It also decreased the protein expression of iNOS and COX-2 in LPS-induced macrophages. Mechanistic studies further revealed that compound 1 inhibited the mitogen-activated protein kinase (MAPK), and activated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathways in LPS-induced RAW 264.7 macrophages.

目的 制备归桂(即当归-桂枝)自微乳载药系统(AC-SMEDDS),优化其处方并表征所得制剂.方法 以当归和桂枝的混合挥发油(以下简称"归桂混合挥发油")为油相和模型药物,在乳化剂、助乳化剂筛选及两者质量比范围优化的基础上,以油相(归桂混合挥发油)占比、乳化剂与助乳化剂质量比为因素,挥发油含量、粒径、乳化时间的综合评分为指标,采用中心复合设计-效应面法优化处方;对优化后AC-SMEDDS的形态、粒径、载药量和包封率、稳定性等参数进行表征.结果 AC-SMEDDS的最优处方为油相占比30％、乳化剂(EL-40)与助乳化剂(乙醇)质量比9:1.验证实验表明,3批AC-SMEDDS的平均粒径为(148.33±1.53)nm,乳化时间为(18.44±0.11)s;综合评分为0.68,与预测值(0.70)的相对误差为2.86％.按最优处方所制AC-SMEDDS为淡黄色,均匀、澄清液体,透射电镜下可见边缘半透明的球形微粒;以藁本内酯、桂皮醛计,载药量分别为(7.58±0.03)、(4.17±0.01)mg/g,包封率分别为(93.25±0.01)％、(88.89±0.02)％;10000 r/min离心5 min或4、25℃下放置7 d均无分层或沉淀产生,藁本内酯、桂皮醛含量稳定;以水稀释50、100、200倍对粒径均无明显影响.结论 成功制备了AC-SMEDDS并优化了其处方,所得制剂的稳定性良好.

Three new aaptamines (1-3) together with two known derivatives (4-5) were isolated from the South China Sea sponge Aaptos suberitoides. The structures of all compounds were unambiguously elucidated by spectroscopic analyses as well as the comparison with literature data. All the compounds were evaluated for their cytotoxic activities against five human cancer cell lines including H1299, H520, SCG7901, CNE-2 and SW680 cells. As a result, compounds 3-5 showed moderate cytotoxicities against H1299 and H520 cells with IC50 values ranging from 12.9 to 20.6 μg/mL. Besides, compounds 3-5 also showed potent inhibitory activities toward cyclin-dependent kinase-2 (CDK2) with IC50 values of 14.3, 3.0 and 6.0 μg/mL, respectively. In addition, compounds 3-5 significantly induced G1 arrests of H1299 cells at low concentrations. Drug affinity responsive target stability (DARTS) experiments were carried out and further demonstrated that compound 3 could effectively bind with CDK2 protein and protect it from the degradation by pronase.

Chemical investigation of coastal saline soil-derived fungus Aspergillus flavipes RD-13 led to the isolation of two new seco-cytochalasins (1) and (2) along with nine known analogs. Their structures were elucidated by comprehensive spectral analysis, and the absolute configurations of these two new ones were determined through Rh2(OCOCF3)4-induced CD experiment and chemical interconversions. Moreover, the absolute configuration of a known compound named cytochalasins Z18 (3) was also determined for the first time. Structurally, compounds 1, 2 and 3 were the open ring derivatives of compounds 5, 8, and 4, respectively. All compounds were evaluated for their cytotoxic activities on A549, H1299 and H520 cells and 4 exhibited the strongest inhibitory activities towards the above cell lines with IC50 values of 0.15, 0.23 and 0.43 μg/mL, respectively. Preliminary structure-activity relationship analysis suggested the importance of macrocyclic ring in cytochalasins to confer cytotoxicity.

中医药是我国中国传统文化和传统医学的代表,在其不断发展的同时,中药种植的规模也在不断扩大.该研究将在"进一步发展中医药"指导下运用《中医药法》,以滨州市中药经济作物种植模式的主要问题为核心,探究引导更多粮农种植中药的策略方法,创新沿黄流域中药经济作物种植模式,促进粮农转药农转型,为进一步推动滨州市中医药产业健康持续发展提供帮助.

Background The importance of mRNA methylation erased by ALKBH5 in mRNA biogenesis, decay, and translation control is an emerging research focus. Ectopically activated YAP is associated with the development of many human cancers. However, the mechanism whereby ALKBH5 regulates YAP expression and activity to inhibit NSCLC tumor growth and metastasis is not clear. Methods Protein and transcript interactions were analyzed in normal lung cell and NSCLC cells. Gene expression was evaluated by qPCR and reporter assays. Protein levels were determined by immunochemical approaches. Nucleic acid interactions and status were analyzed by immunoprecipitation. Cell behavior was analyzed by standard biochemical tests. The m 6 A modification was analyzed by MeRIP. Results Our results show that YAP expression is negatively correlated with ALKBH5 expression and plays an opposite role in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. ALKBH5 reduced m 6 A modification of YAP . YTHDF3 combined YAP pre-mRNA depending on m 6 A modification. YTHDF1 and YTHDF2 competitively interacted with YTHDF3 in an m 6 A-independent manner to regulate YAP expression. YTHDF2 facilitated YAP mRNA decay via the AGO2 system, whereas YTHDF1 promoted YAP mRNA translation by interacting with eIF3a; both these activities are regulated by m 6 A modification. Furthermore, ALKBH5 decreased YAP activity by regulating miR-107/LATS2 axis in an HuR-dependent manner. Further, ALKBH5 inhibited tumor growth and metastasis in vivo by reducing the expression and activity of YAP. Conclusions The presented findings suggest m 6 A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC. Moreover, effective inhibition of m 6 A modification of ALKBH5 might constitute a potential treatment strategy for lung cancer.

Context Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD.Objective To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the in vivo therapeutic effect on AD in a zebrafish model.Materials and methods Aaptamine was isolated from the sponge Aaptos suberitoides Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE in vitro. Zebrafish were divided into six groups: control, model, 8 μM donepezil, 5 , 10 and 20 μM aaptamine. After three days of drug treatment, the behaviour assay was performed.Results The IC50 values of aaptamine towards AChE and BuChE were 16.0 and 4.6 μM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with Ki values of 6.96 ± 0.04 and 6.35 ± 0.02 μM, with Kd values of 87.6 and 10.7 μM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. In vivo studies indicated that the dyskinesia recovery rates of 5 , 10 and 20 μM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%.Discussion and conclusions Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.

目的 了解山东省质子泵抑制剂致新的和严重的药品不良反应(ADR)的发生情况及特点,为临床安全合理用药提供参考.方法 对山东省ADR监测中心2018年1月—2020年9月收集到的质子泵抑制剂致ADR的病例报告进行回顾性分析.结果 共收集到3925例质子泵抑制剂致ADR病例报告,新的和严重的ADR共755例(19.24％),包括严重的ADR 359例(9.15％),新的一般的ADR 396例(10.09％).男性(50.06％)与女性(49.67％)发生率基本接近,65岁以上老年人(40.77％)为高发人群;消化系统疾病(58.01％)为主要原患疾病,用药原因主要为胃炎(22.65％);引发ADR数量最多的药物为奥美拉唑(47.15％),其次为泮托拉唑(31.52％);发生ADR的主要途径是静脉给药(73.38％),ADR多发生于用药后25 min内,主要累及全身损害、皮肤及其附件损害、胃肠损害,若用药疗程7 d以上发生肝胆、血液系统损害等罕见ADR的数量较多,同时也应警惕循环系统、呼吸系统损害等新的ADR的发生.结论 临床应掌握质子泵抑制剂ADR发生特点,加强用药监护,减少ADR对患者造成的损害,保障临床用药安全.

目的 探讨复方延胡索微乳凝胶贴膏中非挥发性组分的最优提取工艺及提取物的镇痛抗炎药效.方法 确定延胡索乙素提取率、延胡索总生物碱提取率、鸡血藤总黄酮提取率、干浸膏得率为考察指标,在单因素试验的基础上,采用模糊层次分析法联合Box-Behnken设计优化提取工艺.采用醋酸致扭体模型、二甲苯致耳肿胀模型观察提取物的镇痛抗炎效果.结果 最优提取工艺为加入21倍68％乙醇,连续回流提取5 h.所得提取物可使扭体反应次数明显减少,耳肿胀程度明显降低.结论 优化后的提取工艺操作简单、稳定可靠,提取物具有良好的镇痛抗炎药效,为复方延胡索微乳凝胶贴膏的制剂开发提供了思路.

Genome mining revealed that the genomes of basidiomycetes may include a considerable number of biosynthetic gene clusters (BGCs), yet numerous clusters remain unidentified. Herein, we report a combination of genome mining with an OSMAC (one strain, many compounds) approach to characterize the spectrum of melleolides produced by Armillaria tabescens CPCC 401429. Using F1 fermentation medium, the metabolic pathway of the gene cluster mel was successfully upregulated. From the extracts of the wild-type strain, two new melleolides (1 and 2), along with five new orsellinic acid-derived lactams (10-14), were isolated, and their structures were elucidated by LC-HR-ESIMS/MS and 2D-NMR. Several melleolides exhibited moderate anti-carcinoma (A549, NCI-H520, and H1299) effects with IC50 values of 4.0-48.8 μM. RNA-sequencing based transcriptomic profiling broadened our knowledge of the genetic background, regulation, and mechanisms of melleolide biosynthesis. These results may promote downstream metabolic engineering studies of melleolides. Our study demonstrates the approach is effective for discovering new secondary metabolites from Armillaria sp. and will facilitate the mining of the unexploited biosynthetic potential in other basidiomycetes.