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1.
Int J Mol Sci ; 24(6)2023 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-36982372

RESUMEN

9'-cis-norbixin (norbixin/BIO201) protects RPE cells against phototoxicity induced by blue light and N-retinylidene-N-retinylethanolamine (A2E) in vitro and preserves visual functions in animal models of age-related macular degeneration (AMD) in vivo. The purpose of this study was to examine the mode of action and the in vitro and in vivo effects of BIO203, a novel norbixin amide conjugate. Compared to norbixin, BIO203 displays improved stability at all temperatures tested for up to 18 months. In vitro, BIO203 and norbixin share a similar mode of action involving the inhibition of PPARs, NF-κB, and AP-1 transactivations. The two compounds also reduce IL-6, IL-8, and VEGF expression induced by A2E. In vivo, ocular maximal concentration and BIO203 plasma exposure are increased compared to those of norbixin. Moreover, BIO203 administered systemically protects visual functions and retinal structure in albino rats subjected to blue-light illumination and in the retinal degeneration model of Abca4-/- Rdh8-/- double knock-out mice following 6 months of oral complementation. In conclusion, we report here that BIO203 and norbixin share similar modes of action and protective effects in vitro and in vivo. BIO203, with its improved pharmacokinetic and stability properties, could be developed for the treatment of retinal degenerative diseases such as AMD.


Asunto(s)
Degeneración Macular , Degeneración Retiniana , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Carotenoides/metabolismo , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Degeneración Retiniana/tratamiento farmacológico , Degeneración Retiniana/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Retinoides/farmacología , Ratas
2.
Magn Reson Chem ; 60(5): 504-514, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35075680

RESUMEN

We report the analysis of complex samples obtained during the microwave irradiation/heating of norbixin, which has been identified as a potential therapeutic target for age-related macular degeneration (AMD). In this context, identifying the different isomers that are obtained during its degradation is of primary importance. However, this characterization is challenging because, on the one hand, some of these isomers are unstable, and on the other hand, the 1 H spectra of these isomeric mixtures are poorly resolved. We could successfully apply 1D pure shift experiments to obtain ultrahigh-resolution 1 H nuclear magnetic resonance (NMR) spectra of the norbixin isomer samples and exploit their information content to analyze complementary 2D NMR data and describe accurately their isomeric composition.


Asunto(s)
Imagen por Resonancia Magnética , Carotenoides , Isomerismo , Espectroscopía de Resonancia Magnética
3.
J Mol Endocrinol ; 68(2): 77-87, 2021 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-34825653

RESUMEN

20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysteroid receptors (EcR/RXR complex) and at least one membrane GPCR receptor (DopEcR). It also displays numerous pharmacological effects in mammals, where its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERß receptor. The goal of this study was to better understand 20E mechanism of action in mammals. A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) were used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with angiotensin(1-7), the endogenous ligand of MAS. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using siRNA or pharmacological inhibitors. 17ß-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin(1-7) antagonists. A mechanism involving cooperation between the MAS receptor and a membrane-bound palmitoylated estrogen receptor is proposed. The possibility to activate the MAS receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and, indeed, the proposed mechanism may explain the close similarity between the effects of angiotensin(1-7) and 20E. Our findings open up many possible therapeutic developments involving stimulation of the protective arm of the renin-angiotensin-aldosterone system (RAAS) with 20E.


Asunto(s)
Ecdisterona/metabolismo , Proto-Oncogenes Mas/metabolismo , Sistema Renina-Angiotensina , Animales , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Ecdisterona/química , Ecdisterona/farmacología , Metabolismo Energético/efectos de los fármacos , Regulación de la Expresión Génica , Ratones , Músculos/efectos de los fármacos , Músculos/metabolismo , Unión Proteica , Proto-Oncogenes Mas/agonistas , Proto-Oncogenes Mas/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Esteroides/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos
4.
Aging (Albany NY) ; 13(18): 22040-22058, 2021 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-34544906

RESUMEN

N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing angiogenesis and inflammation. A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-α. Here we show that A2E binds and transactivates also peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR). 9'-cis-norbixin, a di-apocarotenoid is also a ligand of these nuclear receptors (NR). Norbixin inhibits PPAR and RXR transactivation induced by A2E. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-κB and AP-1 transactivation and mRNA expression of the inflammatory interleukins (IL) -6 and -8 and of vascular endothelial growth factor (VEGF) enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression in response to A2E. Selective PPAR-α, -ß/δ and -γ antagonists inhibit the expression of IL-6 and IL-8 while only the antagonist of PPAR-γ inhibits the transactivation of NF-κB following A2E exposure. In addition, a cocktail of all three PPARs antagonists and also HX531, an antagonist of RXR reproduce norbixin effects on inflammation. Altogether, A2E's deleterious biological effects could be inhibited through PPAR and RXR regulation. Moreover, the modulation of these NR by norbixin may open new avenues for the treatment of AMD.


Asunto(s)
Carotenoides/administración & dosificación , Degeneración Macular/tratamiento farmacológico , PPAR alfa/inmunología , PPAR delta/inmunología , PPAR gamma/inmunología , PPAR-beta/inmunología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Retinoides/inmunología , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Humanos , Degeneración Macular/inducido químicamente , Degeneración Macular/genética , Degeneración Macular/inmunología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/etiología , Neovascularización Patológica/genética , Neovascularización Patológica/inmunología , PPAR alfa/genética , PPAR delta/genética , PPAR gamma/genética , PPAR-beta/genética , Epitelio Pigmentado de la Retina/inmunología , Receptores X Retinoide/agonistas , Receptores X Retinoide/genética , Receptores X Retinoide/inmunología , Retinoides/efectos adversos , Porcinos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/inmunología
5.
J Steroid Biochem Mol Biol ; 212: 105897, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33862260

RESUMEN

Ecdysteroids are not endogenous to mammals, but are normal components of the food intake of many mammalian species consuming phytoecdysteroid-containing plants. The most frequently encountered phytoecdysteroid is 20-hydroxyecdysone (20E). Several pharmaceutical effects have been observed after ecdysteroid injection or ingestion, but it is not clear to what extent metabolites generated in the mammalian body contribute to these effects. The C21-ecdysteroid poststerone (Post) is a metabolite of 20E in rodents. Post analogues are key intermediates in the metabolism of exogenous ecdysteroids possessing a C20/22-diol. The pharmacokinetics, bioavailability and metabolism of Post have been assessed in male rats after ingestion and injection. The bioavailability of Post is significantly greater than that of 20E and the presence of an efficient entero-hepatic cycle allows Post to be effectively metabolised to a wide range of metabolites which are excreted mainly in the faeces, but also to some extent in the urine. Several of the major metabolites in the bile have been identified unambiguously as 3-epi-poststerone, 16α-hydroxypoststerone, 21-hydroxypoststerone and 3-epi-21-hydroxypoststerone. Conjugates are also present. Parallels are drawn to the metabolism of endogenous vertebrate steroid hormones, to which Post bears more similarity than 20E.


Asunto(s)
Ecdisterona/farmacocinética , Animales , Bilis/metabolismo , Disponibilidad Biológica , Ecdisterona/sangre , Heces/química , Masculino , Ratas Wistar
6.
Aging (Albany NY) ; 12(7): 6151-6171, 2020 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-32255762

RESUMEN

Atrophic A\age-related macular degeneration (AMD) and Stargardt disease (STGD) are major blinding diseases affecting millions of patients worldwide, but no treatment is available. In dry AMD and STGD oxidative stress and subretinal accumulation of N-retinylidene-N-retinylethanolamine (A2E), a toxic by-product of the visual cycle, causes retinal pigment epithelium (RPE) and photoreceptor degeneration leading to visual impairment. Acute and chronic retinal degeneration following blue light damage (BLD) in BALB/c mice and aging of Abca4-/- Rdh8-/- mice, respectively, reproduce features of AMD and STGD. Efficacy of systemic administrations of 9'-cis-norbixin (norbixin), a natural di-apocarotenoid, prepared from Bixa orellana seeds with anti-oxidative properties, was evaluated during BLD in BALB/c mice, and in Abca4-/- Rdh8-/- mice of different ages, following three experimental designs: "preventive", "early curative" and "late curative" supplementations. Norbixin injected intraperitoneally in BALB/c mice, maintained scotopic and photopic electroretinogram amplitude and was neuroprotective. Norbixin chronic oral administration for 6 months in Abca4-/- Rdh8-/- mice following the "early curative" supplementation showed optimal neuroprotection and maintenance of photoreceptor function and reduced ocular A2E accumulation. Thus, norbixin appears promising as a systemic drug candidate for both AMD and STGD treatment.


Asunto(s)
Carotenoides/farmacología , Degeneración Macular , Células Fotorreceptoras de Vertebrados , Retinoides , Enfermedad de Stargardt , Animales , Monitoreo de Drogas/métodos , Electrorretinografía/métodos , Inyecciones Intraperitoneales , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Degeneración Macular/prevención & control , Ratones , Fármacos Neuroprotectores/farmacología , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/metabolismo , Retinoides/antagonistas & inhibidores , Retinoides/metabolismo , Enfermedad de Stargardt/tratamiento farmacológico , Enfermedad de Stargardt/metabolismo , Enfermedad de Stargardt/prevención & control , Resultado del Tratamiento
7.
Phytochem Anal ; 31(5): 643-661, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32182633

RESUMEN

INTRODUCTION: Phytoecdysteroids are analogues of arthropod steroids occurring in plants. They contribute to invertebrate deterrence. A wide diversity of ecdysteroids occurs in phytoecdysteroid-containing plant species, sometimes in high amounts. Ecdysteroids demonstrate potentially useful pharmaceutical actions in mammals. OBJECTIVES: Establish reversed-phase high-performance liquid chromatography with tandem mass spectrometry (RP-HPLC-MS/MS) and RP-HPLC-DAD-MS (diode array detector mass spectrometry) methods for the separation, identification and quantification of ecdysteroids to screen for species containing significant amounts of 20-hydroxyecdysone (20E) and other useful ecdysteroids. MATERIALS AND METHODS: Micro-extracts of seed samples (ca. 30 mg) in 50% ethanol were subjected to RP-SPE (solid-phase extraction) purification prior to analysis by RP-HPLC-MS/MS and RP-HPLC-DAD-MS. The method was initially applied to genera (Amaranthus, Centaurea, Lychnis, Ourisia, Serratula, Silene and Trollius) where high-accumulating species had been previously encountered. Seeds of 160 randomly selected species, many of which have not previously been assessed, were then analysed. HPLC-MS/MS with a short analysis time initially identifies ecdysteroid-positive extracts and quantifies 20E. The positive extracts (20 ng 20E) are then analysed by HPLC-MS/MS with a longer analysis time to identify and quantify 17 common phytoecdysteroids and, finally, HPLC-DAD-MS (0.1-0.25 µg 20E) is used to obtain UV- and MS-spectra to confirm identifications or as a basis for characterisation of partially identified or novel analogues. RESULTS: Lychnis coronaria, Silene fimbriata and Silene hookeri ecdysteroids are characterised for the first time and those of Cucubalus baccifer and Ipheion uniflorum are more extensively characterised. CONCLUSIONS: The procedure provides a rapid/sensitive method for screening small plant samples for the presence, quantification and identification of ecdysteroids. It permits ready dereplication of samples, identifying extracts containing large amounts or novel analogues.


Asunto(s)
Semillas , Espectrometría de Masas en Tándem , Animales , Cromatografía Líquida de Alta Presión , Ecdisteroides , Extracción en Fase Sólida
8.
PLoS One ; 11(12): e0167793, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27992460

RESUMEN

The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9'-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin. In Abca4-/- Rdh8-/- mice (a model of dry AMD), intravitreally-injected norbixin maintained the electroretinogram and protected photoreceptors against light damage. In a standard rat blue-light model of photodamage, norbixin was at least equally as active as phenyl-N-tert-butylnitrone, a free radical spin-trap. Chronic experiments performed with Abca4-/- Rdh8-/- mice treated orally for 3 months with norbixin showed a reduced A2E accumulation in the retina. Norbixin appears promising for developing an oral treatment of macular degeneration. A drug candidate (BIO201) with 9'-cis-norbixin as the active principle ingredient is under development, and its potential will be assessed in a forthcoming clinical trial.


Asunto(s)
Carotenoides/administración & dosificación , Degeneración Macular/tratamiento farmacológico , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Retinoides/efectos adversos , Transportadoras de Casetes de Unión a ATP/genética , Oxidorreductasas de Alcohol/genética , Animales , Bixaceae/química , Carotenoides/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Técnicas In Vitro , Inyecciones Intravítreas , Degeneración Macular/inducido químicamente , Degeneración Macular/genética , Degeneración Macular/metabolismo , Ratones , Ratones Noqueados , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Epitelio Pigmentado de la Retina/citología , Porcinos
9.
Phytochem Anal ; 26(5): 293-300, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25953625

RESUMEN

INTRODUCTION: Ajuga turkestanica is a plant used in traditional medicine for its high ecdysteroid content, including the presence of the particularly active turkesterone, which possess efficient anabolic activity. OBJECTIVES: To isolate and identify minor ecdysteroids present in a semi-purified plant fraction containing ca. 70% turkesterone. MATERIAL AND METHODS: Multi-step preparative HPLC (combining RP- and NP-HPLC systems) was used to purify the different components present in the turkesterone fraction. Isolated compounds were identified by high-resolution mass spectrometry and 2D-NMR. RESULTS: Fourteen ecdysteroids (including turkesterone and 20-hydroxyecdysone) were isolated. Seven of these, all bearing an 11α-hydroxy group, were previously unreported. CONCLUSION: Ajuga turkestanica ecdysteroids are characterised by the abundance of 11α-hydroxylated compounds and by the simultaneous presence of 24C, 27C, 28C and 29C ecdysteroids. It is expected that even more ecdysteroids are to be found in this plant since the starting material for this study lacked the less polar ecdysteroids. The simultaneous presence of 20-hydroxyecdysone and turkesterone (its 11α-hydroxy analogue) as the two major ecdysteroids suggests that every ecdysteroid is probably present in both 11α-hydroxy and 11-deoxy forms.


Asunto(s)
Ajuga/química , Ecdisteroides/análisis , Raíces de Plantas/química , Plantas Medicinales/química , Cromatografía Líquida de Alta Presión/métodos , Ecdisteroides/química , Ecdisteroides/aislamiento & purificación , Ecdisterona/análogos & derivados , Ecdisterona/análisis , Ecdisterona/química , Ecdisterona/aislamiento & purificación , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos
10.
Nat Prod Commun ; 9(8): 1069-74, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25233576

RESUMEN

Phytoecdysteroids are plant analogues of insect moulting hormones and are used by plants to repel or disturb phytophagous insects. They are also active on mammals and present in many plants used in traditional medicine. The Ajuga genus contains several such species, which occur in various pharmacopoeias. We report the isolation and identification of major and minor ecdysteroids present in two Ajuga species, A. iva and A. remota, both of which are used as medicinal plants in Africa. Three minor ecdysteroids (abutasterone, ponasterone A and sidisterone) have been found for the first time in the Ajuga genus.


Asunto(s)
Ajuga/química , Ecdisteroides/química , Extractos Vegetales/química , África , Estructura Molecular , Plantas Medicinales/química
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