红树林来源耐酸真菌Aspergillus fumigatus OUCMDZ5210次生代谢产物的研究

目的 对源自泰国红树林底泥中的耐酸真菌Aspergillus fumigatus OUCMDZ 5210的次生代谢产物进行化学成分和生物活性的研究。方法 综合利用硅胶柱色谱、凝胶柱色谱和半制备高效液相色谱等多种方法对耐酸真菌Aspergillus fumigatus OUCMDZ5210的次生代谢产物进行分离;采用核磁共振谱（NMR）、质谱（MS）、紫外光谱（UV）等现代波谱学技术对分离得到的化合物进行结构鉴定;以人慢性髓性白血病细胞K562及人结肠癌细胞HCT116两株肿瘤细胞为研究模型,采用MTT法和CCK-8法对所分离的化合物进行细胞毒活性评价。结果 从耐酸真菌Aspergillus fumigatus OUCMDZ5210的次级代谢产物中分离得到6个吲哚二酮哌嗪类生物碱：tryprostatins B(1),fumitremorgin C(2),spirotryprostatin A(3), spirotryprostatin.B(4), 6-methoxyspirotryprostatin B (5), 8,9-dihydroxyspirotrypr-ostatin A(6)以及1个酰胺类化合物cephalimysin B(7)。结论 生物活性初步评价结果显示,化合物3和6对人结肠癌细胞HCT116以及人慢性髓性白血病细胞K562具有不同程度的抑制活性。     

一株西沙来源软珊瑚共附生真菌Penicillium citrinum（15XS112ZM-18）次级代谢产物及其活性研究

目的 研究1株中国西沙群岛永兴岛海域短指软珊瑚Sinularia cf. molesta共附生真菌Penicillium citrinum (15XS112ZM-18)的次级代谢产物及其生物活性。方法 利用TLC、硅胶柱层析、Sephadex LH-20凝胶柱层析、MPLC、半制备HPLC等方法,对菌株代谢物进行分离纯化;通过1H NMR及13C NMR等波谱学方法,结合相关文献数据,鉴定化合物结构;通过细胞毒活性模型评价化合物抗肿瘤活性。结果 从真菌P. citrinum (15XS112ZM-18)代谢产物中分离得到8个化合物,分别为：penicillenol A1 (1),penicillenol A2 (2),penicillenol B1 (3),penicillenol B2 (4),sorbicillin (5),2",3"-dihydrosorbicillin (6),ergosterol (7)和25–Hydroxyergosta-4,6,8(14),22-tetraen-3-one (8),其中化合物4在30 μmol L-1浓度下对HL-60细胞的抑制率达到100%,其IC50值为22.97 μmol L-1。     

真菌Aspergillus sp.YN-3的次级代谢产物研究

目的研究真菌Aspergillus sp.YN-3次级代谢产物的化学成分。方法采用硅胶柱色谱法、制备薄层色谱法、Sephadex LH-20凝胶柱色谱法和HPLC法等方法进行对真菌Aspergillus sp.YN-3发酵产物的分离纯化,根据理化性质、NMR、MS等波谱数据鉴定化合物的结构,并采用台盼蓝法对化合物1~3进行了人早幼粒白血病细胞株HL-60的生长抑制实验。结果分离得到10个化合物,分别鉴定为:chrodrimanin E(1)、thailandolide B(2)、thailandolide A(3)、3-(3-羟基-5-甲基苯氧基)-5-甲基苯酚[3-(3-hydroxy-5-methylphenoxy)-5-methylphenol,4]、2,3-二羟基苯甲酸(2,3-dihydroxybenzoic acid,5)、3-羟基-2-甲基苯甲酸(3-hydroxy-2-methylbenzoic acid,6)、环(色-苯丙)二肽[cyclo(Trp-Phe),7]、环(色-亮)二肽[cyclo(Trp-Leu),8]、(22E,24R)-麦角甾-5,7,22-三烯-3β-醇[(22E,24R)-ergosta-5,7,22-trien-3β-ol,9]和3-乙酰氨基-5-乙酰呋喃(3-acetamido-5-acetylfuran,10)。结论化合物1~3从该属真菌中首次分离得到,化合物10为一新天然产物;化合物1~3对于HL-60细胞株显示了较弱的生长抑制活性。     

1株海洋真菌Aspergillus sp. WHUF0313次级代谢产物及其活性研究

摘要：目的 研究1株深海来源曲霉属真菌Aspergillus sp. WHUF0313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葡聚糖凝胶柱层析和半制备高效液相色谱等技术对该菌株的次级代谢产物分离纯化,并通过核磁共振 波谱(NMR)、质谱(MS)等方法,结合相关文献对比鉴定化合物结构;分别采用肉汤微量稀释检测法和MTS细胞增殖与毒性检 测法对化合物进行抗菌和肿瘤细胞毒活性测试。结果 从Aspergillus sp. WHUF0313的发酵产物共分离得到9个化合物,分别 为asperophiobolin G(1)、asperophiobolin F(2)、ophiobolin Q(3)、asperophiobolin H(4)、6-epi-ophiobolin G(5)、ophiobolin H(6)、 6-epi-ophiobolin K(7)、6-epi-21,21-O-dihydroophiobolin G(8)和asperophiobolin J(9)。结论 海洋真菌Aspergillus sp. WHUF0313能 产生多种活性次级代谢产物,化合物4对小鼠黑色素瘤B16有一定的细胞毒活性,化合物6和7具有较强的抗多重耐药幽门螺杆菌 和抗金黄色葡萄球菌活性,因此该菌具有开发为微生物源药物的潜在研究价值。     

一株药用红树内生真菌Talaromyces flavus TGGP34次级代谢产物及其活性研究

目的 研究1株药用红树老鼠簕（Acanthus ilicifolius L.）来源内生真菌篮状菌属的Talaromyces flavus TGGP34的次级代谢产物及其抗菌活性。方法 利用正、反相硅胶柱层析、Sephadex LH-20凝胶柱层析、半制备高效液相色谱（HPLC）等色谱分离方法,对TGGP34发酵产物的乙酸乙酯粗浸膏进行系统分离纯化;利用核磁共振波谱（NMR）、质谱（MS）等方法并结合文献报道数据确定化合物结构,并对其抗菌活性进行测定。结果 从内生真菌T. flavus TGGP34中分离得到9个化合物,包括4个甾醇类化合物β-sitosterol（1）、24-methylcholesta-7,22-diene-3β,5α,6β-triol（2）、3β,15β-dihydroxyl-(22E,24R)-ergosta-5,8(14),22-trien-7-one（3）、ganodermaside B（4）,3个内酯类化合物dehydroisopenicillide（5）、penicillide（6）、purpactin A（7）,2个二酮哌嗪类化合物cyclo-(S-Pro-R-Val)（8）和cyclo-(L-Pro-L-Leu)（9）,其中化合物3对3株致病菌金黄色葡萄球菌（Staphylococcus aureus）、表皮葡萄球菌（Staphylococcus epidermidis）和白色念珠菌（Candida albicans）表现出明显的抑制活性,其MIC值分别为12.5、12.5和6.25 μg/mL。结论 化合物1～4为首次从篮状菌属（Talaromyces sp.）中分离得到;化合物3具有显著的抗菌活性,具有重要的研究和潜在开发价值。     

包瑞弯孢菌C. borreriae HS-FG-237次级代谢产物及其生物活性研究

目的 研究包瑞弯孢菌(Curvularia borreriae)HS-FG-237菌株的次级代谢产物及其生物活性。方法 采用HP-20树脂柱、硅胶柱层析、Sephadex LH-20凝胶柱层析、半制备高效液相分析等色谱分离手段对菌体发酵液进行分离与纯化,同时利用现代波谱分析技术鉴定所得化合物结构;以3种肿瘤细胞A549,K562和MDA-MB-231为供试细胞株,采用CCK-8法对分离得到化合物进行细胞毒性研究。结果 从C. borreriae HS-FG-237菌株发酵液提取物中获得12个代谢产物,分别鉴定为：curvalarol A (1), 3β,12β-dihydroxy-4,4,14α-trimethyl-5α-pregna-7,9(11)-diene-20s-carboxylate (2), curva larol B (3), 3β-Hydroxy-lanost-24-en (4), cyclo-(Gly-Pro) (5), cyclo-(Pho-Thr) (6), cyclo-(Leu-Pro) (7), 4,6,8-Trihydroxy-2,3-dihydro-2H-naphthalen-1-one (8), cyclo-(4-hydroxyl-Pro-Leu) (9), ergosterolperoxide (10), 9-β-D-ribofuranosyl adenine (11), cerebr oside C (12),均为已知化合物;生物活性结果显示化合物1~3和10对3种肿瘤细胞有一定的细胞毒活性。结论 环二肽化合物为C. borreriae HS-FG-237菌株的主要代谢产物,12个化合物均为首次从该菌中分离得到。     

盐碱地真菌棘孢曲霉Aspergillus aculeatus的化学成分研究△﹡

目的 对一株具有抗肿瘤活性的滨州盐碱地真菌棘孢曲霉Aspergillus aculeatus的活性次级代谢产物进行研究。方法 采用硅胶柱层析、LH-20凝胶色谱和半制备高效液相色谱分离纯化代谢产物,通过理化性质、波谱手段结合X-ray单晶衍射技术鉴定化合物,采用MTT法测试所得化合物对肿瘤细胞A549的增殖抑制活性。结果 从棘孢曲霉Aspergillus aculeatus中分离得到8个化合物(1～8),分别鉴定为5-Hydroxymethyl-2-furoic acid (1)、Isorhodoptilometrin (2)、Secalonic acid F (3)、Emodin (4)、Protocatechuic acid (5)、Altechromones B (6)、Cyclo (L-Tyr-L-Leu) (7)和Cyclo (L-Phe-L-Ala) (8)。化合物3对A549细胞具有一定的增殖抑制活性,其IC50值为14.9 μM。结论 首次研究了来源于盐碱地真菌棘孢曲霉Aspergillus aculeatus的活性次级代谢产物,并首次报道secalonic acid F对A549肿瘤细胞增殖抑制活性。     

一株红树内生真菌Penicillium sp. JY246次级代谢产物及其活性研究

目的 研究一株红树角果木来源内生真菌Penicillium sp. JY246的次级代谢产物及其生物活性。方法 利用硅胶柱层析、Sephadex LH-20凝胶柱层析、半制备HPLC等方法,对该菌发酵产物的乙酸乙酯浸膏进行分离纯化;利用NMR、MS等波谱解析方法以及与文献数据对照,鉴定化合物的结构;通过抗菌和抗虫活性模型对化合物的生物活性进行评价。结果 从内生真菌Penicillium sp. JY246中分离得到12个化合物,分别为7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone (1),(2′S)-2-(propan-2′-ol)-5-hydroxy-benzopyran-4-one (2),2, 3-dihydro-5-hydroxy-2(S)-methyl-4H-1-benzopyran-4-one (3),(11S)-diaprothin (4),questin (5),4-hydroxy-3-prenylbenzoic acid (6),4-methoxy-6-styryl-pyran-2-one (7),(R) 4-hydroxy-2-oxo-1-pyrrolidineacetamide (8),p-hydroxy-benzaldehyde (9),4-hydroxyacetophenone (10),apocynin (11)和1-(2,6-dihydroxyphenyl) ethan-1-one (12)。结论 从内生真菌Penicillium sp. JY246的次级代谢产物中分离得到12个单体化合物,并对所有化合物进行抗菌和抗虫活性测试。结果表明,化合物1, 2, 4和5显示抗细菌活性;化合物4, 5和8对棉铃虫幼虫显示了生长抑制活性。     

深海真菌Aspergillus tubingensis 的次生代谢产物的研究

目的 对一株来源于深海环境的真菌Aspergillus tubingensis的次生代谢产物及生物活性进行研究。方法 通过初步体外活性筛选,从十株来源于雅浦海沟的真菌中筛选获得一株具有人肿瘤细胞毒和海虾毒性的真菌Aspergillus tubingensis,采用硅胶柱色谱、Sephadex LH-20色谱、半制备HPLC等色谱学方法对菌株发酵提取物的活性部位进行分离纯化;通过NMR、MS、IR等光谱学方法,并结合文献数据对比鉴定了化合物的结构;对分离得到的化合物进行海虾致死及细胞毒活性测试。结果 分离得到了5个单体化合物。结构确定为：malformin C(1)、malformin E(2)、diketopiperazine dimer(3)、cristatumin E(4)、tensidol B(5),其中1、2具有较好的海虾致死活性。细胞毒活性测试结果显示,化合物1、2具有强细胞毒活性,对HepG2肝癌细胞株的IC50值分别为2.42和34.02 μM.L-1。结论 雅浦海沟真菌Aspergillus tubingensis 能够代谢产生具有海虾致死和细胞毒活性的次生代谢产物。     

深海来源的微生物抗肿瘤活性筛选及次级代谢产物的初步研究

目的 对来自深海的海水、海泥样品进行了微生物分离并通过抗肿瘤活性筛选获得活性菌株,并研究活性菌株c2b的次级代谢产物.方法 从样品中选择性分离得到真菌,并采用海虾生物致死法和人体慢性艇性白血病细胞(K562)为筛选模型对分离得到真菌的发酵产物进行抗肿瘤活性筛选;采用溶剂萃取、硅胶柱色谱及制备HPLC等分离手段对c2b菌株发酵产物的活性部位进行了活性追踪分离,通过理化性质及渡谱学手段进行化学结构鉴定,以SRB法评价了化合物的抗肿瘤活性.结果与结论 从深海来源的样品中共分离获得29株真菌,其中7株具有细胞毒活性;从c2b活性菌株的发酵产物中分离得到6个单体化合物(1～6),其化学结构分别鉴定为N-乙酰色氨(1),chrysogine(2),过氧化麦角甾醇(3),5,8-epidioxy-24-methylcholesta-6,22-dien-3β-ol(4),cerevisterol(5)和(4E,8E)-N-[(2'R,3'E)-2'-hydroxy-3'-hexadecenoyl]-1-O-β-D-glycopyranosyl-9-methyl-4,8-sphingadiene(6),其中化合物3,4对小鼠乳腺癌细胞(tsFT210)具有中等强度的细胞毒活性.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Nachweis einiger Heilmittel in der Kniegelenksynovialflüssigkeit

Zusammenfassung Mittels Gaschromatographie und Dünschichtchromatographie wiesen die Autoren 11 Substanzen nach, welche durch Injektion oder nach Verabreichung per os in die Kniegelenksynovialflüssigkeit eindrangen. In ihrer Aufstellung konnten sie eine direkte Beziehung zwischen Struktur sowie chemischphysikalischen Eigenschaften der Substanz und ihrer Fähigkeit, aus dem Blut in die Kniegelenksynovialflüssigkeit einzudringen, nicht nachweisen, außer der Tatsache, daß Substanzen mit starker Affinität zu Eiweißstoffen erst in höheren Dosen nachweisbar waren.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.