RESUMEN
We investigated whether a cholic acid (CA)-supplemented diet and marginal iron deficiency (MID) diet influence hepatic lipid accumulation and iron balance in rats for 2 weeks. The CA diet enhanced hepatic lipid accumulation and modulated iron metabolism such as enhancement of fecal iron excretion, reduction in iron absorption, and no alteration in plasma iron levels. The MID diet did not alter hepatic lipid concentrations with reduced iron concentration in the liver and plasma. In combination, influence of the CA supplementation on the hepatic iron concentration was opposite between iron-sufficient and MID conditions. In the liver, the CA diet enhanced lipocalin 2 expression, whereas the MID diet enhanced transferrin receptor 1 expression and reduced hepcidin expression. This study revealed an involvement of 12-hydroxylated bile acids in regulation of hepatic iron concentration under MID condition.
Asunto(s)
Deficiencias de Hierro , Hierro , Ratas , Animales , Ácido Cólico , Hierro/metabolismo , Hígado/metabolismo , Suplementos Dietéticos , LípidosRESUMEN
Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson's disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.
Asunto(s)
Astrocitos/efectos de los fármacos , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Mirtazapina/farmacología , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Antioxidantes/farmacología , Astrocitos/metabolismo , Células Cultivadas , Neuronas Dopaminérgicas/metabolismo , Femenino , Masculino , Metalotioneína/metabolismo , Ratones , Ratones Endogámicos ICR , Estrés Oxidativo/efectos de los fármacos , Oxidopamina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Embarazo , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
Despite the existing treatment options for onychomycosis, there remains a strong demand for potent topical medications. ME1111 is a novel antifungal agent that is active against dermatophytes, has an excellent ability to penetrate human nails, and is being developed as a topical agent for onychomycosis. In the present study, we investigated its mechanism of action. Trichophyton mentagrophytes mutants with reduced susceptibility to ME1111 were selected in our laboratory, and genome sequences were determined for 3 resistant mutants. The inhibitory effect on a candidate target was evaluated by a spectrophotometric enzyme assay using mitochondrial fractions. Point mutations were introduced into candidate genes by a reverse genetics approach. Whole-genome analysis of the 3 selected mutants revealed point mutations in the structural regions of genes encoding subunits of succinate dehydrogenase (complex II). All of the laboratory-generated resistant mutants tested harbored a mutation in one of the subunits of succinate dehydrogenase (SdhB, SdhC, or SdhD). Most of the mutants showed cross-resistance to carboxin and boscalid, which are succinate dehydrogenase inhibitors. ME1111 strongly inhibited the succinate-2,6-dichlorophenolindophenol reductase reaction in Trichophyton rubrum and T. mentagrophytes (50% inhibitory concentrations [IC50s] of 0.029 and 0.025 µg/ml, respectively) but demonstrated only moderate inhibition of the same reaction in human cell lines. Furthermore, the target protein of ME1111 was confirmed by the introduction of point mutations causing the amino acid substitutions in SdhB, SdhC, and SdhD found in the laboratory-generated resistant mutants, which resulted in reduced susceptibility to ME1111. Thus, ME1111 is a novel inhibitor of the succinate dehydrogenase of Trichophyton species, and its mechanism of action indicates its selective profile.
Asunto(s)
Antifúngicos/farmacología , Farmacorresistencia Fúngica/genética , Onicomicosis/tratamiento farmacológico , Fenoles/farmacología , Pirazoles/farmacología , Succinato Deshidrogenasa/genética , Trichophyton/efectos de los fármacos , Trichophyton/genética , Administración Tópica , Sustitución de Aminoácidos/genética , Arthrodermataceae/efectos de los fármacos , Secuencia de Bases , Línea Celular , ADN de Hongos/genética , Humanos , Datos de Secuencia Molecular , Onicomicosis/microbiología , Análisis de Secuencia de ADNRESUMEN
Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation.
Asunto(s)
Antifúngicos/farmacología , Uñas/efectos de los fármacos , Uñas/microbiología , Onicomicosis/tratamiento farmacológico , Fenoles/farmacología , Pirazoles/farmacología , Trichophyton/efectos de los fármacos , Administración Tópica , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Línea Celular , Proliferación Celular/efectos de los fármacos , Humanos , Japón , Queratinas/metabolismo , Pruebas de Sensibilidad Microbiana , Fenoles/administración & dosificación , Pirazoles/administración & dosificación , Trichophyton/aislamiento & purificaciónRESUMEN
Two new beta-hydroxy acetamides, BE-52211 B and BE-52211 C, which were structural analogues of BE-52211, were obtained as an inseparable mixture from an actinomycete, Streptomyces sp. Their structures were elucidated on the basis of spectroscopic data. They inhibited cell division of starfish embryos at a concentration of 2.5 microg/mL or greater.
Asunto(s)
Acetamidas/aislamiento & purificación , Citotoxinas/aislamiento & purificación , Streptomyces/química , Acetamidas/química , Acetamidas/farmacología , Animales , División Celular/efectos de los fármacos , Citotoxinas/química , Citotoxinas/farmacología , Embrión no Mamífero/efectos de los fármacos , Indonesia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Estrellas de Mar/efectos de los fármacos , EstereoisomerismoRESUMEN
Piericidins C5 (1) and C6 (2), two new members of the piericidin family, were isolated from a Streptomyces sp. and a Nocardioides sp., together with known piericidins C1 (3), C2 (4), C3 (5), C4 (6), D1 (7), and A3 (8). The structures were determined on the basis of their spectroscopic data. Both new compounds inhibited cell division of fertilized starfish (Asterina pectinifera) eggs at the minimum inhibitory concentration of 0.09 microg/mL.