Synthesis and biological activity of progesterone derivatives as 5α-reductase inhibitors,and their effect on hamster prostate weight

In this study, we report the synthesis and biological evaluation of four 6- and 17-substituted progesterone derivatives (7–10). These compounds were prepared from the commercially available 17α-acetoxyprogesterone. The biological effect of these steroids was demonstrated in in vivo as well as in vitro experiments. In the in vivo experiments, we measured the activity of 6–10 on the weight of the prostate glands of gonadectomized hamsters treated with testosterone (T). For the studies in vitro, we determined the IC₅₀ value by measuring the concentration of steroidal derivative that inhibited 50% of the activity of 5α-reductase present in the human prostate. The results from this work indicated that compounds 6–9 significantly decreased the weight of the prostate as compared to testosterone-treated animals and this reduction of prostate weight was comparable to that produced by finasteride. Steroid 8 was the most effective of the tested compounds. However, compound 10 did not exhibit this capacity. On the other hand, 6–9 exhibited a high inhibitory activity for the human 5α-reductase enzyme with IC₅₀ values of 10, 70, 22, and 19?nM, respectively. However, 10 was not effective for the inhibition of 5α-reductase activity. In conclusion, the compounds that contained the acetate ester moiety in the molecule (6, 7, 8, and 9) inhibited the activity of 5α-reductase and decreased the weight of the prostate. Nevertheless, the double bond in ring B seems to diminish the inhibitory potency (7 and 9), since 6, which does not possess a double bond at C-6, had the highest inhibitory activity (the lowest IC₅₀ value).     

Bacterial Calcium Carbonate Precipitation in Cave Environments: A Function of Calcium Homeostasis

To determine if microbial species play an active role in the development of calcium carbonate (CaCO ₃ ) deposits (speleothems) in cave environments, we isolated 51 culturable bacteria from a coralloid speleothem and tested their ability to dissolve and precipitate CaCO ₃ . The majority of these isolates could precipitate CaCO ₃ minerals; scanning electron microscopy and X-ray diffractrometry demonstrated that aragonite, calcite and vaterite were produced in this process. Due to the inability of dead cells to precipitate these minerals, this suggested that calcification requires metabolic activity. Given growth of these species on calcium acetate, but the toxicity of Ca ²⁺ ions to bacteria, we created a loss-of-function gene knock-out in the Ca ²⁺ ion efflux protein ChaA. The loss of this protein inhibited growth on media containing calcium, suggesting that the need to remove Ca ²⁺ ions from the cell may drive calcification. With no carbonate in the media used in the calcification studies, we used stable isotope probing with C ¹³ O ₂ to determine whether atmospheric CO ₂ could be the source of these ions. The resultant crystals were significantly enriched in this heavy isotope, suggesting that extracellular CO ₂ does indeed contribute to the mineral structure. The physiological adaptation of removing toxic Ca ²⁺ ions by calcification, while useful in numerous environments, would be particularly beneficial to bacteria in Ca ²⁺ -rich cave environments. Such activity may also create the initial crystal nucleation sites that contribute to the formation of secondary CaCO ₃ deposits within caves.     

Tyrosinase inhibitory activities of the compounds isolated from Neolitsea aciculata (Blume) Koidz.

This study was designed to investigate the mushroom tyrosinase inhibitory activity for the constituents isolated from Neolitsea aciculata. The stems of N. aciculata was extracted with aqueous ethanol and subjected to chromatographic separation, which led to the isolation of 11 compounds: methyl linoleate (1), catechin (2), epicatechin (3), afzelin-7-O-glucopyranoside (4), 2′,3′-di-(p-coumaroyl)afzelin (5), 2′-p-coumaroylafzelin (6), feruloyl tyramine (7), β-sitosterol (8), daucosterol (9), oleic acid (10), and trilaurin (11). Their structures were elucidated on the basis of spectroscopic studies as well as by comparison with the data available in the literature. Among these isolates, compounds 5 and 6 were identified as potent mushroom tyrosinase inhibitors with IC₅₀ values of 0.067 and 0.080 mM, respectively. The inhibition kinetics, analysed by Lineweaver–Burk plots, indicated that compounds 5 and 6 are competitive tyrosinase inhibitors when using l-tyrosine as a substrate. Notably, compounds 1–11 were isolated for the first time from this plant. These results provide evidence that this plant might be a potential source of anti-melanogenesis agents.     

Aromatic esters of progesterone as 5α-reductase and prostate growth inhibitors

The aim of this study was to determine the biological activity of 4 steroidal derivatives (9a, 9b and 10a, 10b) prepared from the commercially available 17α acetoxyprogesterone, where 9a, 9b, have the Δ⁴-3-oxo structure and 10a and 10b an epoxy group at C-4 and C-5.

These steroids were tested as inhibitors of 5α-reductase enzyme, which is present in androgen-dependent tissues and converts testosterone to its more active reduced metabolite dihydrotestosterone.

The pharmacological effect of these steroids was demonstrated by the significant decrease of the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with steroids 10a and 10b. For the studies in vitro the IC₅₀ values were determined by measuring the steroid concentration that inhibits 50% of the activity of-5α-reductase. In this study we also determined the capacity of these steroids to bind to the androgen receptor present in the rat prostate cytosol.

The results from this work indicated that compounds 9a, 9b, 10a, and 10b inhibited the 5α reductase activity with IC₅₀ values of 360, 370, 13 and 4.9 nM respectively. However these steroids did not bind to the androgen receptors since none competed with labeled mibolerone. Steroid 10b, an epoxy steroidal derivative containing bromine atom in the ester moiety, was the most active inhibitor of 5α-reductase enzyme, present in human prostate homogenates with an IC₅₀ value of 4.9 nM and also showed in vivo pharmacological activity since it decreased the weight of the prostate from hamsters treated with testosterone in a similar way as finasteride.     

A DNA fragment fromStreptomyces fradiae increases the production of a metalloprotease inStreptomyces lividans

Streptomyces fradiae produces several extracellular proteases and many of these are inducible. An 8.8 kb DNA fragment of Streptomyces fradiae cloned on pIJ699 caused increased protease activity in Streptomyces lividans.Clones carrying this recombinant plasmid showed a significant delay in sporulation. A protein of 18 kDa was purified from the extracellular proteins secreted by the host carrying the recombinant plasmid. Further characterization showed that this protease is a metalloprotease.     

Phenols displaying tyrosinase inhibition from Humulus lupulus

Tyrosinase is the rate-limiting enzyme for the production of melanin and other pigments via the oxidation of l-tyrosine. The methanol extract from Humulus lupulus showed potent inhibition against mushroom tyrosinase. The bioactivity-guided fractionation of this methanol extract resulted in the isolation of seven flavonoids (1–7), identified as xanthohumol (1), 4′-O-methylxanthohumol (2), xanthohumol C (3), flavokawain C (4), xanthoumol B (5), 6-prenylnaringenin (6) and isoxanthohumol (7). All isolated flavonoids (1–7) effectively inhibited the monophenolase (IC₅₀s?=?15.4–58.4?µM) and diphenolase (IC₅₀s?=?27.1–117.4?µM) activities of tyrosinase. Kinetic studies using Lineweaver–Burk and Dixon-plots revealed that chalcones (1–5) were competitive inhibitors, whereas flavanones (6 and 7) exhibited both mixed and non-competitive inhibitory characteristics. In conclusion, this study is the first to demonstrate that the phenolic phytochemicals of H. lupulus display potent inhibitory activities against tyrosinase.     

Insect Antifeedants,Pterocarpans and Pterocarpol,in Heartwood of Pterocarpus macrocarpus Kruz.

The insect antifeedant activities of pterocarpans and a sesquiterpene alcohol from the dichloromethane extract of Pterocarpus macrocarpus Kruz. (Leguminosae) were evaluated against the common cutworm, Spodoptera litura F. (Noctuidae), and the subterranean termite, Reticulitermes speratus (Kolbe)(Rhinotermitidae). Three pterocarpans, (?)-homopterocarpin (1), (?)-pterocarpin (2), and (?)-hydroxyhomopterocarpin (3) and the sesquiterpene alcohol, (+)-pterocarpol (5), were isolated from the dichloromethane extract of the heartwood of P. macrocarpus under guidance by a biological assay. Among these natural products, the most active insect antifeedant against both S. litura and R. speratus was 1. On the other hand, sesquiterpene alcohol 5 showed less insect antifeedant activity than the other pterocarpans against both insect species. While its methylated derivative, (?)-methoxyhomopterocarpin (4), showed high biological activity, 3 showed less insect antifeedant activity in this study. Interestingly, racemic 1 did not show insect antifeedant activity against S. litura. However, all of the test pterocarpans and isoflavones showed antifeedant activity against the test termites. Additionally, since these compounds were major constituents of P. macrocarpus, these antifeedant phenolics may act as chemical defense factors in this tree. In Thailand, lumber made from this tree is used to make furniture and in building construction due to its resistance to termite attack.     

Karyology of a few species of south Indian acridids. II Male germ line karyotypic instability inGastrimargus

Gastrimargus africanus orientalis,an acridid grasshopper has revealed the existence of karyotypic mosaicism in the male germ line cells of a few individuals with 2 n = 23, 19, 21, 25 and 27 chromosomes. Details of this chromosomal instability are presented in this paper. We dedicate this paper to our teacher Prof. L Siddaveere Gowda on the eve of his 60th birthday.     

油榄仁果实化学成分的研究

为了解油榄仁(Terminalia bellirica Roxb.)的化学成分,从油榄仁果实的乙酸乙酯提取物中分离得到11个化合物,通过波谱分析,分别鉴定为:表松脂酚(1)、(–)-芝麻素(2)、麻醉椒苦素(3)、二氢醉椒素(4)、异香兰素(5)、3,4-二羟基苯甲酸(6)、没食子酸(7)、没食子酸甲酯(8)、没食子酸乙酯(9)、3,4,8,9,10-五羟基二苯骈[b,d]吡喃-6-酮(10)、polystachyol(11),其中化合物1~6、10和11为首次从油榄仁果实中分离得到。     

Design of potent fluoro-substituted chalcones as antimicrobial agents

Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9–15, and 20–23) using a structure–activity relationship approach. Target compounds were evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3, 9, and 10) displayed significant antitubercular activity with IC₅₀ values of ≤16,760. Compounds derived from trimethoxy substituent scaffolds with monofluoro substitution on the B ring of the chalcone structure exhibited superior inhibition activity compared to corresponding hydroxy analogs. In terms of antimicrobial activity, most compounds (3, 9, 12–14, and 23) exhibited moderate to potent activity against the bacteria, and the antifungal activities of compounds 3, 13, 15, 20, and 22 were comparable to those of reference drugs ampicillin and fluconazole.     

南美蟛蜞菊中的酚酸类化学成分

为了解南美蟛蜞菊[Wedelia trilobata (L.) Hitchc.]的化学成分, 从其全株中分离得到9 个酚酸类化合物。经光谱分析, 分别鉴定为6-乙酰基-7-羟基-2,3-二甲基色原酮 (1)、七叶内酯 (2)、丁香醛 (3)、5-羟甲基糠醛 (4)、对羟基苯甲酸 (5)、水杨酸 (6)、反式对羟基桂皮酸 (7)、咖啡酸甲酯 (8) 和反式咖啡酸 (9)。化合物1~8 为首次从该植物中分离得到。     

An interaction between human Sec63 and nucleoredoxin may provide the missing link between the SEC63 gene and polycystic liver disease

The formation of multiple cysts in one or several organs is a characteristic of several human inherited diseases. Recent research suggests that problems in planar cell polarity may be the common denominator in polycystic diseases. Mutations in at least two genes are linked to autosomal dominant polycystic liver disease (PCLD), PRKCSH and SEC63. A recent study linked PRKCSH to the signaling- and cytoskeletal adaptor-component β-catenin. In a yeast two hybrid screen we identified the cytosolic protein nucleoredoxin (NRX) as an interaction partner of human Sec63. Since NRX is involved in the Wnt signaling pathways, we characterized this interaction. Thus, Sec63 is linked to the Wnt signaling pathways and this interaction may be the reason why mutations in SEC63 can lead to PCLD.

Structured summary

Sec63physically interacts with NRX by two hybrid(View interaction)NRXbinds to Sec63 by peptide array (View Interaction 1, 2)Sec63binds to NRX by pull down(View interaction)Sec63binds to NRX by peptide array (View Interaction 1, 2, 3)     

Conferin,potent antioxidant and anti-inflammatory isoflavone from Caragana conferta Benth

Conferin (1), a new isoflavone, has been isolated from the ethyl acetate soluble fraction of Caragana conferta Benth. along with seven known compounds, namely biochanin A (2), p-hydroxybenzoic acid (3), 3,5- dimethoxybenzoic acid (4), ursolic acid (5), erythrodiol (6), pinoresinol (7), and syringresinol (8), reported for the first time from this species. The structure of the new isoflavone was deduced on the basis of spectroscopic studies. Compounds 1 and 2 were investigated for biological activities and showed significant anti-inflammatory activity in carrageenan induced paw edema of rats. Evaluation of antioxidant activity by the radical scavenging method indicated that compound 1 is a potent antioxidant while 2 is moderately active. It was also shown that the reducing capability of compound 2 was remarkably increased in a concentration dependent manner as compared to 1. Compound 1 showed moderate inhibitory activity against the enzyme lipoxygenase, while 2 showed weak activity.     

Reaction of Astaxanthin with Peroxynitrite

The in vitro reactivities of astaxanthin toward peroxynitrite were investigated and the reaction products after scavenging with peroxynitrite were analyzed in order to determine the complete mechanism of this reaction. A series of carotenoids, 13-apo-astaxanthinone (1), 12′-apo-15′-nitroastaxanthinal (2), 12′-apo-astaxanthinal (3), 10′-apo-astaxanthinal (4), 9-cis-14′-s-cis-15′-nitroastaxanthin (5), 14′-s-cis-15′-nitroastaxanthin (6), 13-cis-14′-s-cis-15′-nitroastaxanthin (7), 10′-s-cis-11′-cis-11′-nitroastaxanthin (8), 13,15,13′-tri-cis-15′-nitroastaxanthin (9), 9-cis-astaxanthin (10), and 13-cis-astaxanthin (11), were isolated from the reaction products of carotenoids with peroxynitrite. Our previous studies achieved for the first time the isolation of nitro derivatives from the reaction of astaxanthin with peroxynitrite. Here we identify the major remaining reaction products of this reaction and investigate the stabilities of the nitro astaxanthins.     

Genome analysis of species in the genus Hystrix (Triticeae; Poaceae)

Genomic in situ hybridisation (GISH) and Southern genomic hybridisation were applied in order to gain further knowledge regarding generic delimitation of the genus Hystrix as well as to clarify the genomes of the Hystrix species H. patula, H. longearistata, H. coreana, H. duthiei and H. komarovii. The hybridisation intensity of different genomic probes was compared among the Hystrix species and with other Triticeae species. The Southern- and GISH results confirm that H. patula contains the StH genome and show that H. komarovii most likely has a variant of this StH genome. The other Hystrix species under study, i.e. H. longearistata, H. coreana and H. duthiei, contain an Ns basic genome, and most probably two variants of this basic genome, Ns ¹ Ns ² . The genus Hystrix is thus not a monophyletic group of species.     

广东省县级公立医院改革试点医院效率分析

目的 评价县级公立医院综合改革试点医院服务体系运营效率。方法 以广东省第一批县级公立医院综合改革试点医院为研究对象,运用DEA-Malmquist指数法分析其全要素生产率及其分解因素的变化趋势。结果 2012—2015年广东第一批县级公立医院改革试点医院全要素生产率平均下降1.6%,技术进步下降2.4%,技术效率增长0.8%。纯技术效率和规模效率年平均增长率分别为0.5%和0.2%;跨年度全要素生产率由0.951上,升到1.004。结论 广东省县级公立医院全要素生产率有待提高,需补足技术短板,从而提高整体运营效率。     

Revision of the genus Adorodocia Brenske 1893 (Coleoptera: Scarabaeoidea: Rutelinae: Adoretini) endemic to Madagascar

Summary. The Adoretini of the Malagasy endemic genus Adorodocia Brenske 1893 is revised. Fourteen new species and one new subspecies are described and compared with their most closely related species: A. constricta n. sp., A. cuccodoroi n. sp., A. flava n. sp., A. liliae n. sp., A. marginata n. sp., A. peyrierasi n. sp., A. pseudoconstricta n. sp., A. pseudoflava n. sp., A. pseudostrigata n. sp., A. recta n. sp., A. robusta n. sp., A. sogai n. sp., A. vadoni n. sp., A. viettei n. sp. and A. vittaticollis flavipes n. ssp. The synonymy between Adoretus strigatus Waterhouse 1878, and Pseudadorodocia aenigma Arrow 1901, is confirmed. Thus, based on the results of this study, the genus Adorodocia includes 16 species, and one of them is represented by two subspecies. Diagnostic characters to separate the species in the genus deal mostly with the shape of parameres, color of body and legs, shape of pronotum and female eighth tergite, setation of pronotum and elytra. Key to species, diagnoses and distribution for each species are provided. Endophallus and female genitalia are illustrated for the first time for this genus.     

Serum levels of glial fibrillary acidic protein and Nogo-A in children with autism spectrum disorders

Context: Improved biomarkers would facilitate the diagnosis and treatment of autism spectrum disorders (ASD).

Objective: Our objective was to examine the levels of Nogo-A and glial fibrillary acidic protein (GFAP) in children with ASD.

Materials and methods: Serum concentrations of GFAP and Nogo-A were determined by enzyme-linked immunosorbent assay.

Results: In this preliminary study, we found that serum Nogo-A was not found significantly different between groups, while serum levels of GFAP were significantly lower in ASD than controls.

Discussion and conclusions: It will be of great interest to determine other potential causes of elevated serum levels of GFAP, and whether this elevation has any phenotypic effect.     

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by ¹H NMR, ¹³CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1–S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1–S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with K_is in the range of 1.79?±?0.22–2.73?±?0.08?nM against hCA I and in the range of 1.72?±?0.58–11.64?±?5.21?nM against hCA II, respectively.