RESUMEN
Many useful natural products are usually screened based on their biological activities. On the other hand, various natural products can be detected based on their physicochemical properties. We have already reported the isolation and characterization of mangromicins from a cultural broth of Lechevalieria aerocolonigenes K10-0216 using physicochemical screening. In this report, we have conducted the mass spectrometry-based screening of new mangromicin analogs based on the neutral loss pattern originated from the unique cyclopentadecane skeleton of mangromicins. Two novel analogs were detected showing characteristic neutral loss pattern found in eight known mangromicin analogs. We propose the structures of the newly-found analogs based on the mass spectrometric as well as genomic and metabolic pathway data.
Asunto(s)
Productos Biológicos , Espectrometría de Masas en TándemRESUMEN
Trehangelins (THG) are newly identified trehalose compounds derived from broth cultures of an endophytic actinomycete, Polymorphospora rubra. THG are known to suppress Cellular Communication Network factor 1 (CCN1), which regulates collagen homeostasis in the dermis. Although the physical properties of THG suggest a high penetration of the stratum corneum, the effect of THG on the epidermis has not been reported. Here we describe a possible mechanism involved in skin aging focusing on the effect of THG on epidermal CCN1. This study shows that: (1) THG suppress epidermal CCN1 expression by inhibiting the translocation of Yes-Associated Protein (YAP) to nuclei. (2) Epidermal CCN1, localized at the basement membrane, regulates the balance between the growth and differentiation of keratinocytes. (3) Keratinocytes secrete more CCN1 than fibroblasts, which leads to disruption of the basement membrane and extracellular matrix components. (4) The secretion of CCN1 from keratinocytes is increased by ultraviolet B exposure, especially in aged keratinocytes, and deteriorates the elastic fiber structures in the underlying dermis. (5) Topical application of THG ameliorates the structure of the basement membrane in ex vivo human skin explants. Taken together, THG might be a promising treatment for aged skin by suppressing the aberrant YAP-CCN1 axis.
Asunto(s)
Proteína 61 Rica en Cisteína/metabolismo , Queratinocitos/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Trehalosa/análogos & derivados , Adolescente , Anciano , Anciano de 80 o más Años , Células Cultivadas , Niño , Proteína 61 Rica en Cisteína/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Técnicas de Cultivo de Tejidos , Trehalosa/farmacología , Trehalosa/uso terapéutico , Proteínas Señalizadoras YAP/metabolismoAsunto(s)
Actinobacteria/metabolismo , Antioxidantes/aislamiento & purificación , Macrólidos/aislamiento & purificación , Pironas/aislamiento & purificación , Animales , Antioxidantes/química , Antioxidantes/farmacología , Células Cultivadas , Fermentación , Macrólidos/química , Macrólidos/farmacología , Espectroscopía de Resonancia Magnética , Ratones , Pironas/química , Pironas/farmacologíaRESUMEN
We have been continually searching for novel chemical compounds from culture broths of various actinomycetes using a physicochemical screening system. During the course of this program, we have previously reported the discovery of two new natural products, designated mangromicins A and B, discovered in a broth of a rare actinomycete strain, Lechevalieria aerocolonigenes K10-0216. Mangromicins have a unique and rare structure, a cyclopentadecane skeleton with a tetrahydrofuran unit and a 5,6-dihydro-4-hydroxy-2-pyrone moiety. New mangromicin analogs were isolated by using an improved production medium. As a consequence, six analogs, together with mangromicins A and B, were isolated from a cultured broth of L. aerocolonigenes K10-0216. We named them mangromicins D, E, F, G, H and I. All mangromicins showed radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals and nitric oxide generated from LPS-stimulated RAW264.7 cells, a murine macrophage cell line. Among the analogs, mangromicins A and I showed the most potent DPPH radical scavenging activity and nitric oxide scavenging activity, respectively.
Asunto(s)
Actinobacteria/química , Antioxidantes/química , Antioxidantes/farmacología , Depuradores de Radicales Libres/química , Animales , Línea Celular , Depuradores de Radicales Libres/farmacología , Furanos/química , Furanos/aislamiento & purificación , Furanos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Óxido Nítrico/química , Pironas/química , Pironas/aislamiento & purificación , Pironas/farmacologíaRESUMEN
Two new cyclopentadecane antibiotics, named mangromicins A and B, were separated out from the culture broth of Lechevalieria aerocolonigenes K10-0216 by Diaion HP-20, silica gel and ODS column chromatography, and were finally purified by HPLC. The chemical structures of the two novel compounds were elucidated by instrumental analyses, including various NMR, MS and X-ray crystallography. Mangromicins A and B consist of cyclopentadecane skeletons with a tetrahydrofuran unit and a 5,6-dihydro-4-hydroxy-2-pyrone moiety. Mangromicins A and B showed in vitro antitrypanosomal activity with IC50 values of 2.4 and 43.4 µg ml(-1), respectively. The IC50 values of both compounds were lower than those of cytotoxicity against MRC-5 human fetal lung fibroblast cells.
Asunto(s)
Actinomycetales/química , Fibroblastos/efectos de los fármacos , Macrólidos/farmacología , Tripanocidas/farmacología , Cromatografía , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Fibroblastos/metabolismo , Humanos , Concentración 50 Inhibidora , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Macrólidos/química , Macrólidos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Gel de Sílice , Pruebas de Toxicidad , Tripanocidas/química , Tripanocidas/aislamiento & purificaciónRESUMEN
Three new natural products, designated trehangelins A, B and C, were isolated by solvent extraction, silica gel and octadecylsilyl silica gel column chromatographies and subsequent preparative HPLC from the cultured broth of an endophytic actinomycete strain, Polymorphospora rubra K07-0510. The trehangelins consisted of a trehalose moiety and two angelic acid moieties. Trehangelins A (IC50 value, 0.1 mg ml(-1)) and C (IC50 value, 0.4 mg ml(-1)), with symmetric structures, showed potent inhibitory activity against hemolysis of red blood cells induced by light-activated pheophorbide a. However, trehangelin B, with an asymmetric structure, displayed only a slight inhibition (IC50 value, 1.0 mg ml(-1)).