Beyond the Brain: a Study of α-synuclein\u27s Role in Bone and Adipose Tissue

α-Synuclein is a polypeptide encoded by the Snca gene, highly expressed in neurons, but it is also found in bones and adipose tissue. Co-expression analysis showed that Snca regulates skeletal homeostasis, and its deletion reduced estrogen deficiency-induced bone loss and weight gain. It is a major component of Lewy bodies (LB) in Parkinson’s disease (PD), leading to progressive immobilization and a range of nonmotor symptoms, including osteopenia, body composition alterations and insulin resistance. This thesis aimed to determine α-Synuclein’s intrinsic role in bone and adipose homeostasis. We discussed the PD pathophysiology emphasizing aspects of bone health and metabolism. By using in vivo models we showed conditional deletion of Snca in osteoblasts is insufficient to reduce bone loss after estrogen deficiency, however, sufficient to reduce weight gain and decrease marrow adipocyte expansion. Prrx1Cre off-target effects led to decreased in α-Synuclein expression in the brain, decreased serum catecholamines, and behavioral phenotypes. Mutant mice experienced a mild improvement in bone microarchitecture. Although not protected from diet-induced obesity, mutants showed smaller adipocytes in the inguinal fat, decreased adipogenesis and higher oxidative capacity, however, decreased insulin sensitivity. Interestingly, AdipoCre;Sncafl/fl mice showed no significant increase in inguinal adipose accrual, decreased weight gain and increased insulin sensitivity. In vitro models of loss of α-Synuclein led to fragmented mitochondria, decreased adipogenesis, and pAKT and, increased levels of AKT, pIRβ and pSHC. Mutated α-Synuclein overexpression (A53Ttg/tg) led to higher adipogenesis, mitochondria size and increased levels of pAKT/AKT. There was no change in colocalization of α-Synuclein to mitochondria in cells with differential α-Synuclein expression. After insulin treatment, α-Synuclein relocated to the nuclei in controls, however, this response was not seen in A53Ttg/tg. This work showed α-Synuclein regulates adipose tissue cell autonomously and it does affect, mildly, bone microarchitecture through its actions on osteoblasts. Moreover, we showed α-Synuclein regulates insulin response by affecting the levels of pAKT/AKT and phosphorylated insulin receptor β. Future research is essential to understand the local and systemic effects of α-Synuclein signaling on bone remodeling and adipose metabolism to shed light into possible treatment targets for osteoporosis and insulin resistance in PD patients

The genus Podaxis in arid regions of Mexico: preliminary ITS phylogeny and ethnomycological use

Identification of Podaxis species to species-level based on morphology alone is problematic. Thus, species of the genus Podaxis are in dire need of taxonomic and phylogenetic evaluations using molecular data to develop a consensus between morphological taxonomy and more robust molecular analyses. In Mexico, most of the collected specimens of Podaxis have been morphologically identified as Podaxis pistillaris sensu lato and are locally used for its culinary value. In this study, the internal transcribed spacer region of Podaxisspecimens from the MEXU fungarium collected between 1948 and 2014 from arid regions of Mexico were sequenced and these collections placed into a molecular phylogenetic framework using Maximum Likelihood analysis. In addition, the ethnomycological use of Podaxis in Mexico (utility, traditional handling, economic importance, etc.) is described by observations, interviews, and sampling of Podaxis species with local people from three areas of the region of the Cañada of Oaxaca, which belongs to the Tehuacán-Cuicatlán Biosphere Reserve. These results indicate that the Mexican Podaxis were divided into two clades. Specimens collected in the northern region showed phylogenetic affinities to clade D, while specimens from the south of Mexico clustered within clade E. Morphological data, such as spore length and width, showed significant differences between the two phylogenetic clades, implying that these clades represent different species. None of the Mexican specimens were found in association with termite mounds, which might indicate an adaptation to desert-like regions. This study provides the first ethnomycological use of Podaxis from Mexico

Additional alpha-glucosidase inhibitors from Malbranchea flavorosea (Leotiomycetes, Ascomycota)

From the rice-based culture of Malbranchea flavorosea, three new compounds namely flavoroseoside B (5-desoxy-5-chloro-flavoroseoside) (2), 4-hydroxy-2-O-a-ribofuranosyl-5-methylacetophenone (3), and (S)-3,4-dihydro-3-(1H-indol-3-ylmethyl)-4-methyl-1H-1,4-benzodiazepine-2,5-dione (4), along with three known compounds, rosigenin (5), massarilactone B (6), and riboxylarinol B (7) were obtained. The structures were determined by spectroscopic methods. Compound 4 and its synthetic analog 3,4-dihydro-3-(1H-indol-3-ylmethyl)-1-methyl-1H-1,4-benzodiazepine-2,5-dione (9) inhibited the activity of Ruminococus obeum a-glucosidase enzyme. Molecular docking and dynamic studies revealed that compounds 4 and 9 might bind to this a-glucosidase at the catalytic center. Phylogenetic analysis using internal transcribed spacer region revealed that Malbranchea flavorosea ATCC 34529 is related to Myxotrichum spp

Dioxomorpholines and Derivatives from a Marine-Facultative Aspergillus Species

[The original abstract for this article contains (characters/images) that cannot be displayed here. Please click on the link below to read the full abstract and article.]]]> 2017 English http://libres.uncg.edu/ir/uncg/f/H_Raja_Dioxomorpholines_2017.pdf oai:libres.uncg.edu/25231 2019-02-27T14:41:40Z UNCG Fungal Planet description sheets: 785–867 NC DOCKS at The University of North Carolina at Greensboro Raja, Huzefa A. <![CDATA[Novel species of fungi described in this study include those from various countries as follows: Angola, Gnomoniopsis angolensis and Pseudopithomyces angolensis on unknown host plants. Australia, Dothiora corymbiae on Corymbia citriodora, Neoeucasphaeria eucalypti (incl. Neoeucasphaeria gen. nov.) on Eucalyptussp., Fumagopsis stellae on Eucalyptus sp., Fusculina eucalyptorum (incl. Fusculinaceae fam. nov.) on Eucalyptus socialis, Harknessia corymbiicola on Corymbia maculata, Neocelosporium eucalypti (incl. Neocelosporium gen. nov., Neocelosporiaceae fam. nov. and Neocelosporiales ord. nov.) on Eucalyptus cyanophylla, Neophaeomoniella corymbiae on Corymbia citriodora, Neophaeomoniella eucalyptigena on Eucalyptus pilularis, Pseudoplagiostoma corymbiicola on Corymbia citriodora, Teratosphaeria gracilis on Eucalyptus gracilis, Zasmidium corymbiae on Corymbia citriodora. Brazil, Calonectria hemileiae on pustules of Hemileia vastatrixformed on leaves of Coffea arabica, Calvatia caatinguensis on soil, Cercospora solani-betacei on Solanum betaceum, Clathrus natalensis on soil, Diaporthe poincianellae on Poincianella pyramidalis, Geastrum piquiriunense on soil, Geosmithia carolliae on wing of Carollia perspicillata, Henningsia resupinata on wood, Penicillium guaibinense from soil, Periconia caespitosa from leaf litter, Pseudocercospora styracina on Styraxsp., Simplicillium filiforme as endophyte from Citrullus lanatus, Thozetella pindobacuensis on leaf litter, Xenosonderhenia coussapoae on Coussapoa floccosa. Canary Islands (Spain), Orbilia amarilla on Euphorbia canariensis. Cape Verde Islands, Xylodon jacobaeus on Eucalyptus camaldulensis. Chile, Colletotrichum arboricola on Fuchsia magellanica. Costa Rica, Lasiosphaeria miniovina on tree branch. Ecuador, Ganoderma chocoense on tree trunk. France, Neofitzroyomyces nerii (incl. Neofitzroyomyces gen. nov.) on Nerium oleander. Ghana, Castanediella tereticornis on Eucalyptus tereticornis, Falcocladium africanum on Eucalyptus brassiana, Rachicladosporium corymbiae on Corymbia citriodora. Hungary, Entoloma silvae-frondosae in Carpinus betulus-Pinus sylvestris mixed forest. Iran, Pseudopyricularia persiana on Cyperus sp.Italy, Inocybe roseascens on soil in mixed forest. Laos, Ophiocordyceps houaynhangensis on Coleoptera larva. Malaysia, Monilochaetes melastomae on Melastoma sp. Mexico, Absidia terrestris from soil. Netherlands, Acaulium pannemaniae, Conioscypha boutwelliae, Fusicolla septimanifiniscientiae, Gibellulopsis simonii, Lasionectria hilhorstii, Lectera nordwiniana, Leptodiscella rintelii, Parasarocladium debruynii and Sarocladium dejongiae (incl. Sarocladiaceae fam. nov.) from soil. New Zealand, Gnomoniopsis rosae on Rosa sp. and Neodevriesia metrosideri on Metrosideros sp. Puerto Rico, Neodevriesia coccolobae on Coccoloba uvifera, Neodevriesia tabebuiae and Alfaria tabebuiae on Tabebuia chrysantha. Russia, Amanita paludosa on bogged soil in mixed deciduous forest, Entoloma tiliae in forest of Tilia × europaea, Kwoniella endophytica on Pyrus communis. South Africa, Coniella diospyri on Diospyros mespiliformis, Neomelanconiella combreti (incl. Neomelanconiellaceae fam. nov. and Neomelanconiella gen. nov.) on Combretum sp., Polyphialoseptoria natalensis on unidentified plant host, Pseudorobillarda bolusanthi on Bolusanthus speciosus, Thelonectria pelargonii on Pelargonium sp. Spain, Vermiculariopsiella lauracearum and Anungitopsis lauri on Laurus novocanariensis, Geosmithia xerotolerans from a darkened wall of a house, Pseudopenidiella gallaica on leaf litter. Thailand, Corynespora thailandica on wood, Lareunionomyces loeiensis on leaf litter, Neocochlearomyces chromolaenae (incl. Neocochlearomyces gen. nov.) on Chromolaena odorata, Neomyrmecridium septatum (incl. Neomyrmecridium gen. nov.), Pararamichloridium caricicola on Carex sp., Xenodactylaria thailandica (incl. Xenodactylariaceae fam. nov. and Xenodactylaria gen. nov.), Neomyrmecridium asiaticum and Cymostachys thailandica from unidentified vine. USA, Carolinigaster bonitoi(incl. Carolinigaster gen. nov.) from soil, Penicillium fortuitum from house dust, Phaeotheca shathenatiana(incl. Phaeothecaceae fam. nov.) from twig and cone litter, Pythium wohlseniorum from stream water, Superstratomyces tardicrescens from human eye, Talaromyces iowaense from office air. Vietnam, Fistulinella olivaceoalba on soil. Morphological and culture characteristics along with DNA barcodes are provided

Freshwater Ascomycetes: Minutisphaera (Dothideomycetes) revisited, including one new species from Japan

During investigations of freshwater ascomycetes we found one interesting taxon from Aomori (Japan), as well as three additional taxa from North Carolina (USA), which were morphologically similar to Minutisphaera, a recently described freshwater fungus in the Dothideomycetes. The ascomata of all the collections bore dark hair-like structures around the ostiolar region, obovoid to obclavate bitunicate asci, and one to three septate hyaline to brown ascospores with a sheath (in material from Japan), and with both sheath and appendages (in material from the USA). The apothecial ascomata of these taxa, however, differ from those of the type species of the genus, which are perithecial. Two collections of Minutisphaera-like fungi from the USA were morphologically quite similar but differed in ascospore size. To assess the phylogenetic affinities of Minutisphaeralike taxa with the type species, M. fimbriatispora, we sequenced 18S and 28S nrDNA of five newly collected strains of Minutisphaera. We also sequenced the nrDNA for the entire internal transcribed spacer region of 10 strains to assess interspecific and intraspecific variation with M. fimbriatispora. Additionally we examined the secondary metabolite profiles of two strains from USA. Based on maximum likelihood and Bayesian analyses of combined 18S and 28S, and separate ITS sequences, as well as examination of morphology, we describe and illustrate a new species, M. japonica. One collection from North Carolina is confirmed as M. fimbriatispora, while two other collections are Minutisphaera-like fungi that had a number of similar diagnostic morphological characters but differed only slightly in ascospore sizes. The phylogeny inferred from the internal transcribed spacer region suggested that two out of the three North Carolina collections may be novel and perhaps cryptic species within Minutisphaera. Organic extracts of Minutisphaera from USA, M. fimbriatispora (G155-1) and Minutisphaera-like taxon (G156-1), revealed the presence of palmitic acid and (E)-hexadec-9-en-1-ol as major chemical constituents. We discuss the placement of the Minutisphaera clade within the Dothideomycetes. The description of the genus Minutisphaera is emended to accommodate M. japonica within Minutisphaera

Isochromenones, isobenzofuranone, and tetrahydronaphthalenes produced by Paraphoma radicina, a fungus isolated from a freshwater habitat

Six isochromenones (1–6), clearanols F (5) and G (6), one isobenzofuranone (7), and two tetrahydronaphthalene derivatives (8 and radinaphthalenone (9)), were isolated and identified from a culture of the fungus Paraphoma radicina, which was isolated from submerged wood in a freshwater lake. Compounds 5, 6 and 9 were previously unknown. The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds 5 and 6 were determined by comparison of their experimental ECD measurements with values predicted by TDDFT calculations. Compounds 1–9 were evaluated for antimicrobial activity against an array of bacteria and fungi. The inhibitory activity of compound 4 against Staphylococcus aureus biofilm formation was evaluated.Abbreviations: BLAST, basic local alignment search tool; CHCl3, chloroform; CH3CN, acetonitrile; COSMO, conductor-like screening model; DFT, density functional theory; ECD, electronic circular dichroism; HPLC, high performance liquid chromatography; HRESIMS, high-resolution electrospray ionization mass spectrometry; ITS, internal transcribed spacer; LS, large scale; LSU, large subunit; MeOH, methanol; MICs, minimal inhibitory concentrations; NMR, nuclear magnetic resonance; nrDNA, nuclear ribosomal deoxyribonucleic acid; PDA, potato dextrose agar; rRNA, ribosomal ribonucleic acid; SCRF, self-consistent reaction field; TDDFT, time-dependent density functional theory; UPLC, ultra-performance liquid chromatography; UV, ultraviolet; UV–Vis, ultraviolet/visibl

Peptaibols, Tetramic Acid Derivatives, Isocoumarins, and Sesquiterpenes from a Bionectria sp. (MSX 47401)

An extract of the filamentous fungus Bionectria sp. (MSX 47401) showed both promising cytotoxic activity (&gt;90% inhibition of H460 cell growth at 20 µg/mL) and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). A bioactivity-directed fractionation study yielded one new peptaibol (1) and one new tetramic acid derivative (2), and the fungus biosynthesized diverse secondary metabolites with mannose-derived units. Five known compounds were also isolated: clonostachin (3), virgineone (4), virgineone aglycone (5), AGI-7 (6), and 5,6-dihydroxybisabolol (7). Compounds 5 and 7 have not been described previously from natural sources. Compound 1 represents the second member of the peptaibol structural class that contains an ester-linked sugar alcohol (mannitol) instead of an amide-linked amino alcohol, and peptaibols and tetramic acid derivatives have not been isolated previously from the same fungus. The structures of the new compounds were elucidated primarily by high-field NMR (950 and 700 MHz), HRESIMS/MS, and chemical degradations (Marfey’s analysis). All compounds (except 6) were examined for antibacterial and antifungal activities. Compounds 2, 4, and 5 showed antimicrobial activity against S. aureus and several MRSA isolates

Polyhydroxyanthraquinones as Quorum Sensing Inhibitors from the Guttates of Penicillium restrictum and Their Analysis by Desorption Electrospray Ionization Mass Spectrometry

The endophytic fungus Penicillium restrictum was isolated from the stems of a milk thistle (Silybum marianum) plant. In culture, the fungus produced distinct red guttates, which have been virtually uninvestigated, particularly from the standpoint of chemistry. Hence, this study examined the chemical mycology of P. restrictum and, in doing so, uncovered a series of both known and new polyhydroxyanthraquinones (1–9). These compounds were quorum sensing inhibitors in a clinical isolate of methicillin-resistant Staphylococcus aureus (MRSA), with IC50 values ranging from 8 to 120 µM, suggesting antivirulence potential for the compounds. Moreover, the spatial and temporal distribution of the polyhydroxyanthraquinones was examined in situ via desorption electrospray ionization–mass spectrometry (DESI-MS) imaging, demonstrating the first application of this technique to a guttate-forming fungus and revealing both the concentration of secondary metabolites at the ventral surface of the fungus and their variance in colonies of differing ages

w-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

Antibiotic-resistant pathogens are a global health threat. Small molecules that inhibit bacterial virulence have been suggested as alternatives or adjuncts to conventional antibiotics, as they may limit pathogenesis and increase bacterial susceptibility to host killing. Staphylococcus aureus is a major cause of invasive skin and soft tissue infections (SSTIs) in both the hospital and community settings, and it is also becoming increasingly antibiotic resistant. Quorum sensing (QS) mediated by the accessory gene regulator (agr) controls virulence factor production essential for causing SSTIs. We recently identified ?-hydroxyemodin (OHM), a polyhydroxyanthraquinone isolated from solid-phase cultures of Penicillium restrictum, as a suppressor of QS and a compound sought for the further characterization of the mechanism of action. At concentrations that are nontoxic to eukaryotic cells and subinhibitory to bacterial growth, OHM prevented agr signaling by all four S. aureus agr alleles. OHM inhibited QS by direct binding to AgrA, the response regulator encoded by the agr operon, preventing the interaction of AgrA with the agr P2 promoter. Importantly, OHM was efficacious in a mouse model of S. aureus SSTI. Decreased dermonecrosis with OHM treatment was associated with enhanced bacterial clearance and reductions in inflammatory cytokine transcription and expression at the site of infection. Furthermore, OHM treatment enhanced the immune cell killing of S. aureus in vitro in an agr-dependent manner. These data suggest that bacterial disarmament through the suppression of S. aureus QS may bolster the host innate immune response and limit inflammation

Benzoquinones and Terphenyl Compounds As Phosphodiesterase-4B Inhibitors from a Fungus of the Order Chaetothyriales (MSX 47445)

Three bioactive compounds were isolated from an organic extract of an ascomycete fungus of the order Chaetothyriales (MSX 47445) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, two were benzoquinones [betulinan A (1) and betulinan C (3)], and the third was a terphenyl compound, BTH-II0204-207:A (2). The structures were elucidated using a set of spectroscopic and spectrometric techniques; the structure of the new compound (3) was confirmed via single-crystal X-ray diffraction. Compounds 1–3 were evaluated for cytotoxicity against a human cancer cell panel, for antimicrobial activity against Staphylococcus aureus and Candida albicans, and for phosphodiesterase (PDE4B2) inhibitory activities. The putative binding mode of 1–3 with PDE4B2 was examined using a validated docking protocol, and the binding and enzyme inhibitory activities were correlated