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Stephen R Brand, Thorsten P Degenhardt, Karen Person, Jack D Sobel, Paul Nyirjesy, Robert J Schotzinger, Amir Tavakkol
BACKGROUND: Lanosterol demethylase (CYP51), is an enzyme essential for fungal growth, and catalyzes an early step in the biosynthetic pathway of ergosterol, a sterol required for fungal cell membrane formation and integrity. CYP51 is the molecular target of the class of drugs referred to as 'azole antifungals.' VT-1161 is a novel, oral, selective inhibitor of fungal CYP51, and is being developed for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared to placebo in women with recurrent vulvovaginal candidiasis, defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period...
March 10, 2018: American Journal of Obstetrics and Gynecology
Kristina Beijer, Maria Jönsson, Siraz Shaik, Daphné Behrens, Björn Brunström, Ingvar Brandt
Antifungal azoles are widely used in medicine, agriculture, and material protection and several antifungal azoles have been found in environmental samples. Although these compounds were designed to inhibit fungal enzymes such as lanosterol-14-demethylase (cytochrome P450 (CYP) 51), it is well established that the inhibitory actions of azoles are not specific for fungal CYP isozymes. We refined a gill filament assay to determine the inhibition of CYP1, measured as reduced 7-ethoxyresorufin-O-deethylase (EROD) activity, in rainbow trout (Oncorhynchus mykiss) gill tissue ex vivo...
February 21, 2018: Aquatic Toxicology
Omar Gómez-García, Dulce Andrade-Pavón, Elena Campos-Aldrete, Ricardo Ballinas-Indilí, Alfonso Méndez-Tenorio, Lourdes Villa-Tanaca, Cecilio Álvarez-Toledano
A series of 3-benzoyl imidazo[1,2- a ]pyrimidines, obtained from N -heteroarylformamidines in good yields, was tested in silico and in vitro for binding and inhibition of seven Candida species ( Candida albicans (ATCC 10231), Candida dubliniensis (CD36), Candida glabrata (CBS138), Candida guilliermondii (ATCC 6260), Candida kefyr , Candida krusei (ATCC 6358) and Candida tropicalis (MYA-3404)). To predict binding mode and energy, each compound was docked in the active site of the lanosterol 14α-demethylase enzyme (CYP51), essential for fungal growth of Candida species...
March 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Wen-Fang Wang, Han Xiao, Jian-Jiang Zhong
Ganoderic acid (GA), a triterpenoid from the traditional Chinese medicinal higher fungus Ganoderma lucidum, possesses antitumor and other significant pharmacological activities. Owing to the notorious difficulty and immaturity in genetic manipulation of higher fungi as well as their slow growth, biosynthesis of GAs in a heterologous host is an attractive alternative for their efficient bioproduction. In this study, using Saccharomyces cerevisiae as a host, we did a systematic screening of 72 candidates of cytochrome P450 monooxygenase (CYP450) genes from G...
February 24, 2018: Biotechnology and Bioengineering
Gabriel Marc, Anca Stana, Adrian Pîrnău, Laurian Vlase, Dan C Vodnar, Mihaela Duma, Brînduşa Tiperciuc, Ovidiu Oniga
A series of 12 new thiazolidine-2,4-dione derivatives were obtained by microwave-assisted synthesis. All compounds were physicochemically characterized by quantitative elemental C, H, N, S analysis and spectral data (mass spectrometry [MS], infrared [IR], and nuclear magnetic resonance [NMR]), with the results being in agreement with the expected data. An in vitro screening performed on Candida albicans ATCC 10231 showed their moderate antifungal activity, which was further investigated by determining the minimum inhibitory concentration and minimum fungicidal concentration values for the most active compounds on four strains of Candida...
February 1, 2018: SLAS Discovery
Ana Lis Moyano, Jeffrey Steplowski, Haibo Wang, Kyung-No Son, Diana I Rapolti, Jeffrey Marshall, Vince Elackattu, Michael S Marshall, Amy K Hebert, Cory R Reiter, Viviana Ulloa, Katarzyna C Pituch, Maria I Givogri, Q Richard Lu, Howard L Lipton, Ernesto R Bongarzone
Analysis of microRNA (miR) expression in the central nervous system white matter of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) revealed a significant reduction of miR-219, a critical regulator of myelin assembly and repair. Restoration of miR-219 expression by intranasal administration of a synthetic miR-219 mimic before disease onset ameliorates clinical disease, reduces neurogliosis, and partially recovers motor and sensorimotor function by negatively regulating proinflammatory cytokines and virus RNA replication...
January 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
William J Griffiths, Yuqin Wang
Oxysterols are oxidised derivatives of cholesterol or its precursors post lanosterol. They are intermediates in the biosynthesis of bile acids, steroid hormones and 1,25-dihydroxyvitamin D3. Although often considered as metabolic intermediates there is a growing body of evidence that many oxysterols are bioactive and their absence or excess may be part of the cause of a disease phenotype. Using global lipidomics approaches oxysterols are underrepresented encouraging the development of targeted approaches. In this article, we discuss recent discoveries important in oxysterol biochemistry and some of the targeted lipidomic approaches used to make these discoveries...
February 5, 2018: Biochemical and Biophysical Research Communications
Masashi Inafuku, Mohammad Basyuni, Hirosuke Oku
This study examined the effect of triterpenoid on the salt tolerance of lanosterol synthase deficient yeast mutant GIL77. The expression of the triterpenoid synthase gene under GAL1 promoter in GIL77 increased the triterpenoid concentration of both whole cell and plasma membrane fractions. Without the induction of the genes, the growth curve of BgbAS or RsM1 transformant depicted patterns similar to control cells in both the presence and absence of salt with growth inhibition at 500 mM NaCl. The induction of BgbAS and RsM1 gene expression slightly repressed growth compared with control cells in the absence of NaCl...
January 2018: Saudi Journal of Biological Sciences
Humberto F Freitas, Acássia Benjamim Leal Pires, Marcelo S Castilho
Leishmaniasis, a neglected tropical disease, is a major cause of morbidity and mortality worldwide. Of the three main clinical forms, cutaneous leishmaniasis (CL) is the most common and 40 million people are at risk in the endemic areas. Currently, the available drugs to fight leishmaniasis have high toxicity and poor efficiency. Then, it is very important to search for effective and safe drugs that would target essential enzymes from the parasite, such as lanosterol 14-alpha demethylase (CYP51, EC 1.14.13...
January 23, 2018: Molecular Biology Reports
Dieter Lütjohann, Milka Marinova, Karsten Wolter, Winfried Willinek, Norman Bitterlich, Martin Coenen, Christoph Coch, Frans Stellaard
Chitosan treatment results in significantly lower serum low density lipoprotein (LDL) cholesterol concentrations. To assess the working mechanisms of chitosan, we measured serum surrogate markers of cholesterol absorption (campesterol, sitosterol, cholestanol), synthesis (lathosterol, lanosterol, desmosterol), and degradation to bile acids (7α-hydroxy-cholesterol, 27-hydroxy-cholesterol), corrected for cholesterol concentration (R_sterols). Over 12 weeks, 116 obese subjects (Body Mass Index, BMI 31.7, range 28...
January 11, 2018: Nutrients
Mercy A Ezeokonkwo, Onyinyechi N Ogbonna, Sunday N Okafor, Evelyn U Godwin-Nwakwasi, Fidelia N Ibeanu, Uchechukwu C Okoro
The reaction of diaza-5H-benzo[a]phenoxazin-5-one and 5H-benzo[a]phenoxazin-5-one with various phenols catalyzed by Pd/t-BuXPhos/K3PO4 system gave previously unknown ether derivatives (7a-f and 8a-f) in good yields. UV-visible, FTIR, and 1H NMR data were used to confirm structures of the synthesized compounds. The parent compounds and the derivatives were screened in-silico for their drug-likeness and binding affinities to the microbial targets through molecular docking. Molinspiration software and AutoDock were used for the drug-likeness and docking studies, respectively...
2017: Frontiers in Chemistry
Aldo Almeida, Lemeng Dong, Bekzod Khakimov, Jean-Etienne Bassard, Tessa Moses, Frederic Lota, Alain Goossens, Giovanni Appendino, Søren Bak
8,14- seco -Triterpenoids are characterized by their unusual open C-ring. Their distribution in nature is rare and scattered in taxonomically unrelated plants. The 8,14- seco -triterpenoid α-onocerin is only known from the evolutionarily distant clubmoss genus Lycopodium and the leguminous genus Ononis , which makes the biosynthesis of this seco -triterpenoid intriguing from an evolutionary standpoint. In our experiments with Ononis spinosa, α-onocerin was detected only in the roots. Through transcriptome analysis of the roots, an oxidosqualene cyclase, OsONS1, was identified that produces α-onocerin from squalene-2,3;22,23-dioxide when transiently expressed in Nicotiana bethamiana In contrast, in Lycopodium clavatum , two sequential cyclases, LcLCC and LcLCD, are required to produce α-onocerin in the N...
February 2018: Plant Physiology
Abraham M Vidal-Limon, Oscar Daniel Luna-Martinez, Fausto Rojas-Durán, Thuluz Meza-Menchaca, Maria Elena Hernández-Aguilar, Angel Trigos, Jorge Suárez-Medellín
Male sex hormones such as testosterone and dihydrotestosterone play important roles in several physiological and pathological processes. The biological activities of the aforementioned metabolites are mediated by the multidomain androgen receptor (AR), which is therefore a well-studied drug target. Ganoderma mushroom lanostanoid extracts have previously been shown to exert antiandrogenic activity; therefore, this work aims to identify which lanostane derivatives might act as selective ligands for AR. Because protein flexibility is of paramount importance for ligand binding, different conformations of AR were sampled to account for binding modes within a ligand binding site, then subjected to virtual screening against a metabolite library...
2017: International Journal of Medicinal Mushrooms
Lucía Baila-Rueda, Ana Cenarro, Itziar Lamiquiz-Moneo, Sofía Perez-Calahorra, Ana M Bea, Victoria Marco-Benedí, Estíbaliz Jarauta, Rocío Mateo-Gallego, Fernando Civeira
Primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH), and familial combined hyperlipidemia (FCHL) are polygenic genetic diseases that occur with hypercholesterolemia, and both share a very high cardiovascular risk. In order to better characterize the metabolic abnormalities associated with these primary hypercholesterolemias, we used noncholesterol sterols, as markers of cholesterol metabolism, to determine their potential differences. Hepatic cholesterol synthesis markers (desmosterol and lanosterol) and intestinal cholesterol absorption markers (sitosterol and campesterol) were determined in non-FH GH (n=200), FCHL (n=100) and genetically defined heterozygous familial hypercholesterolemia subjects (FH) (n=100) and in normolipidemic controls (n=100)...
March 2018: Journal of Nutritional Biochemistry
Rui Kano
 Canine and feline upper respiratory tract (URT) infection due to Aspergillus spp. is considered an emerging disease, with the number of reported cases continuing to rise in Japan. Aspergillus fumigatus has been the most frequently reported etiologic agent of sino-orbital aspergillosis in dogs and cats; the other Aspergillus species, Aspergillus felis, Aspergillus fischeri, Aspergillus udagawae, Aspergillus viridinutans, and A. fumigatus, have also been implicated in feline cases. The minimum inhibitory concentrations (MICs) of antifungal drugs are elevated for these cryptic species compared with A...
2017: Medical Mycology Journal
Zafer Asım Kaplancıklı, Serkan Levent, Derya Osmaniye, Begüm Nurpelin Sağlık, Ulviye Acar Çevik, Betül Kaya Çavuşoğlu, Yusuf Özkay, Sinem Ilgın
Azole-based antifungal agents constitute one of the important classes of antifungal drugs. Hence, in the present work, 12 new benzimidazole-thiazole derivatives 3a-3l were synthesized to evaluate their anticandidal activity against C.albicans, C.glabrata, C.krusei, and C.parapsilopsis. The structures of the newly synthesized compounds 3a-3l were confirmed by IR, ¹H-NMR, (13)C-NMR, and ESI-MS spectroscopic methods. ADME parameters of synthesized compounds 3a-3l were predicted by an in-slico study and it was determined that all synthesized compounds may have a good pharmacokinetic profile...
November 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Rita Caramalho, Joel D A Tyndall, Brian C Monk, Thomas Larentis, Cornelia Lass-Flörl, Michaela Lackner
Mucormycoses are emerging and potentially lethal infections. An increase of breakthrough infections has been found in cohorts receiving short-tailed azoles prophylaxis (e.g. voriconazole (VCZ)). Although VCZ is ineffective in vitro and in vivo, long-tailed triazoles such as posaconazole remain active against mucormycetes. Our goal was to validate the molecular mechanism of resistance to short-tailed triazoles in Mucorales. The paralogous cytochrome P450 genes (CYP51 F1 and CYP51 F5) of Rhizopus arrhizus, Rhizopus microsporus, and Mucor circinelloides were amplified and sequenced...
November 21, 2017: Scientific Reports
Thomas R Sewell, Nichola J Hawkins, Henrik U Stotz, YongJu Huang, Steven L Kelly, Diane E Kelly, Bart Fraaije, Bruce D L Fitt
Lanosterol 14-α demethylase is a key enzyme intermediating the biosynthesis of ergosterol in fungi, and the target of azole fungicides. Studies have suggested that Leptosphaeria maculans and L. biglobosa, the causal agents of phoma stem canker on oilseed rape, differ in their sensitivity to some azoles, which could be driving pathogen frequency change in crops. Here we used CYP51 protein modelling and heterologous expression to determine whether there are interspecific differences at the target-site level...
November 20, 2017: Scientific Reports
Serkan Levent, Betül Kaya Çavuşoğlu, Begüm Nurpelin Sağlık, Derya Osmaniye, Ulviye Acar Çevik, Özlem Atlı, Yusuf Özkay, Zafer Asım Kaplancıklı
In the field of infection management, it is a major challenge to discover a potent and safe antifungal agent due to the emergence of resistant strains. Hence, the goal of this paper is to design and synthesize novel oxadiazole-thiadiazole hybrid compounds (6a-6s) and evaluate their antifungal activity. The structures of synthesized compounds were elucidated by various methods including FT-IR, ¹H-NMR, (13)C-NMR and HR-MS spectral data. Compounds were tested against four Candida species by broth microdilution assay...
November 18, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Amit Chaudhary, Birendra Singh Yadav, Swati Singh, Pramod Kumar Maurya, Alok Mishra, Shweta Srivastva, Pritish Kumar Varadwaj, Nand Kumar Singh, Ashutosh Mani
Background: Ficus religiosa L. is generally known as Peepal and belongs to family Moraceae. The tree is a source of many compounds having high medicinal value. In gastrointestinal tract, histamine H2 receptors have key role in histamine-stimulated gastric acid secretion. Their over stimulation causes its excessive production which is responsible for gastric ulcer. Objective: This study aims to screen the range of phytochemicals present in F. religiosa for binding with human histamine H2 and identify therapeutics for a gastric ulcer from the plant...
October 2017: Pharmacognosy Magazine
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