CATALPOL AND METHYLCATALPOL: NATURALLY OCCURRING GLYCOSIDES IN PLANTAGO AND BUDDLEIA SPECIES.
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ABSTRACT: 1. A glycoside of the aucubin type has been isolated in crystalline form from Plantago and Buddleia species, and has been shown to be identical with catalpol (Lunn, Edward & Edward, 1962). Catalpol has not been found in the free state before, but occurs as its p-hydroxybenzoyl ester, catalposide, in the genus Catalpa. 2. A second glycoside of this type has been obtained in crystalline form from Buddleia, and has been shown to be a mono-O-methyl derivative of catalpol, for which the name ;methylcatalpol' is proposed. 3. Both Plantago and Buddleia species are known to contain aucubin. The concentrations of this glycoside and catalpol are comparable in Plantago. In Buddleia methylcatalpol predominates somewhat over catalpol. Yields of the individual glycosides were about 0.1% of the fresh weight of the leaves. 4. Bobbitt, Spiggle, Mahboob, Philipsborn & Schmid (1962) have suggested structures for catalposide and catalpol based on chemical and physical evidence, in particular on n.m.r. spectra. Reappraisal of this evidence and additional measurements have now confirmed these structures and show that the Buddleia glycoside is the 6-O-methyl derivative of catalpol.
Project description:Influenza remains one of the most widespread infections, causing an annual illness in adults and children. Therefore, the search for new antiviral drugs is one of the priorities of practical health care. Eight isorhamnetin glycosides were purified from Persicaria species, characterized by nuclear magnetic resonance spectroscopy and mass spectrometry and then evaluated as potential agents against influenza virus. A comprehensive in vitro and in vivo assessment of the compounds revealed that compound 5 displayed the most potent inhibitory activity with an EC50 value of 1.2-1.3 μM, better than standard drugs (isorhamnetin 28.0-56.0 μM and oseltamivir 1.3-9.1 μM). Molecular docking results also revealed that compound 5 has the lowest binding energy (-10.7 kcal/mol) among the tested compounds and isorhamnetin (-8.1 kcal/mol). The ability of the isorhamnetin glycosides to suppress the reproduction of the influenza virus was studied on a model of a cell culture and chicken embryos. The ability of active compounds to influence the structure of the virion, as well as the activity of hemagglutinin and neuraminidase, has been demonstrated. Compound 1, 5, and 6 demonstrated the most effective inhibition of virus replication for all tested viruses. Molecular dynamics simulation techniques were run for 100 ns for compound 5 with two protein receptors Hem (1RUY) and Neu (3BEQ). These results revealed that the Hem-complex system acquired a relatively more stable conformation and even better descriptors than the other Neu-complex studied systems, suggesting that it can be an effective inhibiting drug toward hemagglutinin than neuraminidase inhibition. Based on the reported results, compound 5 can be a good candidate to be evaluated for effectiveness in preclinical testing.
Project description:Many glycosylated natural products display biological activity and are deglycosylated by the metabolic processes of the body. Although unnatural CF2-glycosides have been proposed as nonhydrolyzable analogues, CF2-derivatives of natural products are exceedingly challenging to synthesize and few examples exist. These difluorinated molecules may have unique conformational behavior as a consequence of changing the glycosidic linkage. In this study, we performed conformational searches using MacroModel followed by molecular dynamics simulations to investigate the conformational behavior of the glycosidic bonds in flavonoid-O-glycosides and in corresponding CF2-glycosylated derivatives. Compared to their O-glycosylated analogues, flavonoid-3-CF2-glycosides and flavonoid-5-CF2-glycosides showed conformational bias, whereas flavonoid-7-CF2-glycosides showed more flexibility. Flavonoid-5-CF2-glycosides were the least flexible compared to all others. Our results show that the site of the glycosylation and the substitution pattern on the flavonoid determine the conformational properties of these molecules. These two factors influence the steric destabilization and/or stereoelectronic stabilization which govern the conformational behavior of the flavonoid glycosides. Moreover, a docking study of quercitrin and its CF2-analogue into murine ribosomal kinase RSK2 demonstrated the potential for flavonoid-CF2-glycosides to retain a similar binding pose as the parent O-glycoside. These findings will assist in designing stable flavonoid-CF2-glycosides for carbohydrate research.
Project description:Breast cancer is second most prevalent cancer in women, and the second only to lung cancer in cancer-related deaths. It is a heterogeneous disease and has several subtypes based on the presence or absence of hormone receptors and/or human epidermal growth factor receptor 2 (HER2). Hormone receptor-positive and HER2-enriched cancers can be targeted using hormone and HER2-targeting therapies such as trastuzumab or lapatinib. However, triple-negative breast cancers (TNBCs) do not express any of the receptors and therefore are resistant to most targeted therapies, and cytotoxic chemotherapies are the only viable option available for the treatment of TNBCs. Recently, cardiac glycosides (CGs) have emerged as potential anticancer agents that impart their antiproliferative effect by targeting multiple pathways. In this study our aim was to evaluate anticancer effects of two naturally occurring CGs, Convallatoxin (CT) and Peruvoside (PS), on ER+ and TNBCs cells. CT and PS demonstrated dose- and time-dependent cytotoxic effect on MCF-7 cells, which was further supported by loss of colony formation on drug treatment. CT and PS arrested MCF-7 cells in the G0/G1 phase and reduced the viability of MCF-7-derived mammospheres (MMs). Interestingly, while CT and PS imparted cell death in TNBCs cells from both Caucasians (MDA-MB-231 cells) and African Americans (MDA-MB-468 cells) in a dose- and time-dependent manner, the drugs were much more potent in MDA-MB-468 as compared with TNBC MDA-MB-231 cells. Both drugs significantly inhibited migration and invasion of both MCF-7 and MDA-MB-468 cells. An assessment of intracellular pathways indicated that both drugs were able to modulate several key cellular pathways such as EMT, cell cycle, proliferation and cell death in both cell types. Our data suggest a promising role for CGs in breast cancer treatment specifically in targeting TNBCs derived from African Americans, and provides impetus for further investigation of the anticancer potential of this class of drugs.
Project description:Fusarium head blight (FHB) can lead to dramatic yield losses and mycotoxin contamination in small grain cereals in Canada. To assess the extent and severity of FHB in oat, samples collected from 168 commercial oat fields in the province of Manitoba, Canada, during 2016-2018 were analyzed for the occurrence of Fusarium head blight and associated mycotoxins. Through morphological and molecular analysis, F. poae was found to be the predominant Fusarium species affecting oat, followed by F. graminearum, F. sporotrichioides, F. avenaceum, and F. culmorum. Deoxynivalenol (DON) and nivalenol (NIV), type B trichothecenes, were the two most abundant Fusarium mycotoxins detected in oat. Beauvericin (BEA) was also frequently detected, though at lower concentrations. Close clustering of F. poae and NIV/BEA, F. graminearum and DON, and F. sporotrichioides and HT2/T2 (type A trichothecenes) was detected in the principal component analysis. Sampling location and crop rotation significantly impacted the concentrations of Fusarium mycotoxins in oat. A phylogenetic analysis of 95 F. poae strains from Manitoba was conducted using the concatenated nucleotide sequences of Tef-1α, Tri1, and Tri8 genes. The results indicated that all F. poae strains belong to a monophyletic lineage. Four subgroups of F. poae strains were identified; however, no correlations were observed between the grouping of F. poae strains and sample locations/crop rotations.
Project description:Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described.
Project description:The chemical identity of RNA molecules beyond the four standard ribonucleosides has fascinated scientists since pseudouridine was characterized as the "fifth" ribonucleotide in 1951. Since then, the ever-increasing number and complexity of modified ribonucleosides have been found in viruses and throughout all three domains of life. Such modifications can be as simple as methylations, hydroxylations, or thiolations, complex as ring closures, glycosylations, acylations, or aminoacylations, or unusual as the incorporation of selenium. While initially found in transfer and ribosomal RNAs, modifications also exist in messenger RNAs and noncoding RNAs. Modifications have profound cellular outcomes at various levels, such as altering RNA structure or being essential for cell survival or organism viability. The aberrant presence or absence of RNA modifications can lead to human disease, ranging from cancer to various metabolic and developmental illnesses such as Hoyeraal-Hreidarsson syndrome, Bowen-Conradi syndrome, or Williams-Beuren syndrome. In this review article, we summarize the characterization of all 143 currently known modified ribonucleosides by describing their taxonomic distributions, the enzymes that generate the modifications, and any implications in cellular processes, RNA structure, and disease. We also highlight areas of active research, such as specific RNAs that contain a particular type of modification as well as methodologies used to identify novel RNA modifications. This article is categorized under: RNA Processing > RNA Editing and Modification.
Project description:Fluorescence, the absorption of short-wavelength electromagnetic radiation reemitted at longer wavelengths, has been suggested to play several biological roles in metazoans. This phenomenon is uncommon in tetrapods, being restricted mostly to parrots and marine turtles. We report fluorescence in amphibians, in the tree frog Hypsiboas punctatus, showing that fluorescence in living frogs is produced by a combination of lymph and glandular emission, with pigmentary cell filtering in the skin. The chemical origin of fluorescence was traced to a class of fluorescent compounds derived from dihydroisoquinolinone, here named hyloins. We show that fluorescence contributes 18-29% of the total emerging light under twilight and nocturnal scenarios, largely enhancing brightness of the individuals and matching the sensitivity of night vision in amphibians. These results introduce an unprecedented source of pigmentation in amphibians and highlight the potential relevance of fluorescence in visual perception in terrestrial environments.
Project description:Carbon is one of the most important chemical elements, forming a wide range of important allotropes, ranging from diamond over graphite to nanostructural materials such as graphene, fullerenes, and carbon nanotubes (CNTs). Especially these nanomaterials play an important role in technology and are commonly formed in laborious synthetic processes that often are of high energy demand. Recently, fullerenes and their building blocks (buckybowls) have been found in natural fossil materials formed under geological conditions. The question arises of how diverse nature can be in forming different types of natural allotropes of carbon. This is investigated here, using modern analytical methods such as ultrahigh-resolution mass spectrometry and transmission electron microscopy, which facilitate a detailed understanding of the diversity of natural carbon allotropes. Large fullerenes, fullertubes, graphene sheets, and double- and multiwalled CNTs together with single-walled CNTs were detected in natural heavy fossil materials while theoretical calculations on the B3LYP/6-31G(d) level of theory using the ORCA software package support the findings.
Project description:A comparative phytochemical study on the phenylethanoid glycoside (PhEG) composition of the underground organs of three Plantago species (P. lanceolata, P. major, and P. media) and that of the fruit wall and seed parts of Forsythia suspensa and F. europaea fruits was performed. The leaves of these Forsythia species and six cultivars of the hybrid F. × intermedia were also analyzed, demonstrating the tissue-specific accumulation and decomposition of PhEGs. Our analyses confirmed the significance of selected tissues as new and abundant sources of these valuable natural compounds. The optimized heat treatment of tissues containing high amounts of the PhEG plantamajoside (PM) or forsythoside A (FA), which was performed in distilled water, resulted in their characteristic isomerizations. In addition to PM and FA, high amounts of the isomerization products could also be isolated after heat treatment. The isomerization mechanisms were elucidated by molecular modeling, and the structures of PhEGs were identified by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry (HR-MS) techniques, also confirming the possibility of discriminating regioisomeric PhEGs by tandem MS. The PhEGs showed no cytostatic activity in non-human primate Vero E6 cells, supporting their safe use as natural medicines and allowing their antiviral potency to be tested.
Project description:ObjectiveTo provide an alternative to propensity scoring (PS) for the common situation where there are interacting covariates.SettingWe used 1.3 million assessments of residents of the United States Veterans Affairs nursing homes, collected from January 1, 2000, through October 9, 2012.DesignIn stratified covariate balancing (SCB), data are divided into naturally occurring strata, where each stratum is an observed combination of the covariates. Within each stratum, cases with, and controls without, the target event are counted; controls are weighted to be as frequent as cases. This weighting procedure guarantees that covariates, or combination of covariates, are balanced, meaning they occur at the same rate among cases and controls. Finally, impact of the target event is calculated in the weighted data. We compare the performance of SCB, logistic regression (LR), and propensity scoring (PS) in simulated and real data. We examined the calibration of SCB and PS in predicting 6-month mortality from inability to eat, controlling for age, gender, and nine other disabilities for 296,051 residents in Veterans Affairs nursing homes. We also performed a simulation study, where outcomes were randomly generated from treatment, 10 covariates, and increasing number of covariate interactions. The accuracy of SCB, PS, and LR in recovering the simulated treatment effect was reported.FindingsIn simulated environment, as the number of interactions among the covariates increased, SCB and properly specified LR remained accurate but pairwise LR and pairwise PS, the most common applications of these tools, performed poorly. In real data, application of SCB was practical. SCB was better calibrated than linear PS, the most common method of PS.ConclusionsIn environments where covariates interact, SCB is practical and more accurate than common methods of applying LR and PS.