RESUMEN
A methanol extract of rhizomes of Picrorhiza kurroa Royle ex Benth. (Plantaginaceae) showed hepatoprotective effects against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. We had previously isolated 46 compounds, including several types of iridoid glycosides, phenylethanoid glycosides, and aromatics, etc., from the extract. Among them, picroside II, androsin, and 4-hydroxy-3-methoxyacetophenone exhibited active hepatoprotective effects at doses of 50-100 mg/kg, per os (p.o.) To characterize the mechanisms of action of these isolates and to clarify the structural requirements of phenylethanoid glycosides for their hepatoprotective effects, their effects were assessed in in vitro studies on (i) D-GalN-induced cytotoxicity in mouse primary hepatocytes, (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages, and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. These isolates decreased the cytotoxicity caused by D-GalN without inhibiting LPS-induced macrophage activation and also reduced the sensitivity of hepatocytes to TNF-α. In addition, the structural requirements of phenylethanoids for the protective effects of D-GalN-induced cytotoxicity in mouse primary hepatocytes were evaluated.
Asunto(s)
Picrorhiza , Rizoma , Ratones , Animales , Rizoma/química , Picrorhiza/química , Lipopolisacáridos/toxicidad , Factor de Necrosis Tumoral alfa , Glicósidos Iridoides/análisis , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Extractos Vegetales/análisis , Galactosamina/toxicidadRESUMEN
Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy-resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis-inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system Xc - that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis-inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.
Asunto(s)
Ferroptosis , Neoplasias , Humanos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Oxidación-Reducción , Hierro/metabolismoRESUMEN
Polybrominated diphenyl ethers (PBDEs) are more frequently suspected with the induction of toxicity via signal transduction pathway of cytosolic aryl hydrocarbon receptor (AhR), the initial binding to which is assumed to be an essential prerequisite during the ligand-dependent activation. However, the AhR binding property and associated toxicity of PBDEs is yet to be clearly known for lacking insights into the structural requirements at molecular level. To understand the AhR binding property of PBDEs, the ligand binding domain (LBD) of AhR was simulatively developed on homologous protein after basic validation of geometrical rationality and the binding interaction profile was visually described using molecular docking approach. For AhR binding, the offset or edge-on π-π stackings with aromatic motifs including Phe289, Phe345 and His285 were shown to be structurally required whereas the electrostatic attraction validated for AhR binding to dioxins might be less effective for 2,2',3,4,4'-pentabromodiphenyl ether (BDE-85). Besides the demands of less steric hindrance from alanines and weak formulation of hydrogen bonds, the dispersion force through large contact and polarization of S-π electrons seemed to be impactful when BDE-85 were closer to Cys327, Met334 or Met342. With theoretical computation of AhR binding energies, the more significant correlativity with bioassays was derived especially for the lowly/moderately brominated congeners, and could be used to predict the AhR binding affinity on certain degree. The informative results would thus not only help well understand the molecular basis of AhR-mediated toxicity but give an approach for accelerative evaluation of AhR binding and toxicity of PBDEs.
Asunto(s)
Contaminantes Ambientales/toxicidad , Éteres Difenilos Halogenados/toxicidad , Receptores de Hidrocarburo de Aril/metabolismo , Bioensayo , Éteres Difenilos Halogenados/metabolismo , Humanos , Enlace de Hidrógeno , Ligandos , Simulación del Acoplamiento Molecular , Bifenilos Polibrominados/farmacología , Unión Proteica , Transducción de Señal/efectos de los fármacosRESUMEN
l-Ascorbic acid has multifunctional benefits on skin aesthetics, including inhibition of melanin production, and is widely used in cosmetics. It, however, has low stability and poor skin penetration. We hypothesize that alkylglyceryl-l-ascorbic acid derivatives, highly stable vitamin C-alkylglycerol conjugates, would have similar anti-melanogenic activity with better stability and penetration. We test 28 alkylglyceryl-l-ascorbic acid derivatives (1-28) on theophylline-stimulated B16 melanoma 4A5 cells to determine if they inhibit melanogenesis and establish any structure-function relationships. Although not the most potent inhibitors, 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-l-ascorbic acid (6, IC50 = 81.4 µM) and 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-l-ascorbic acid (20, IC50 = 117 µM) are deemed the best candidate derivatives based on their inhibitory activities and low toxicities. These derivatives are also found to be more stable than l-ascorbic acid and to have favorable characteristics for skin penetration. The following structural requirements for inhibitory activity of alkylglyceryl-l-ascorbic acid derivatives are also determined: (i) alkylation of glyceryl-l-ascorbic acid is essential for inhibitory activity; (ii) the 3-O-alkyl-derivatives (2-14) exhibit stronger inhibitory activity than the corresponding 2-O-alkyl-derivatives (16-28); and (iii) derivatives with longer alkyl chains have stronger inhibitory activities. Mechanistically, our studies suggest that l-ascorbic acid derivatives exert their effects by suppressing the mRNA expression of tyrosinase and tyrosine-related protein-1.
Asunto(s)
Ácido Ascórbico/análogos & derivados , Melaninas/biosíntesis , Melanocitos/efectos de los fármacos , Preparaciones para Aclaramiento de la Piel/síntesis química , Animales , Línea Celular , Línea Celular Tumoral , Humanos , Melanocitos/metabolismo , Ratones , Relación Estructura-Actividad Cuantitativa , Preparaciones para Aclaramiento de la Piel/química , Preparaciones para Aclaramiento de la Piel/farmacologíaRESUMEN
Three gedunin-type limonoids, gedunin (1), 6α-acetoxygedunin (2), and 7-deacetoxy-7-oxogedunin (3), which were isolated from the seed and flower oils of andiroba (Carapa guianensis Aublet, Meliaceae), exhibited hepatoprotective effects at doses of 25 mg/kg, p.o. against d-galactosamine (d-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. To characterize the mechanisms of action of 1-3 and clarify the structural requirements for their hepatoprotective effects, 17 related limonoids (1-17) isolated from the seed and/or flower oils of C. guianensis were examined in in vitro studies assessing their effects on (i) d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes, (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages, and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. The mechanisms of action of 1-3 are likely to involve the inhibition of LPS-induced macrophage activation and reduced sensitivity of hepatocytes to TNF-α; however, these compounds did not decrease the cytotoxicity caused by d-GalN. In addition, the structural requirements of limonoids (1-17) for inhibition of LPS-induced NO production in mouse peritoneal macrophages and TNF-α-induced cytotoxicity in L929 cells were evaluated.
Asunto(s)
Hepatocitos/efectos de los fármacos , Limoninas/farmacología , Meliaceae/química , Animales , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Flores/química , Limoninas/química , Limoninas/aislamiento & purificación , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Óxido Nítrico/metabolismo , Semillas/químicaRESUMEN
We previously demonstrated that cannabidiol (CBD) was a potent mechanism-based inhibitor of human cytochrome P450 1A1 (CYP1A1). However, the moiety of CBD that contributes to the potent mechanism-based inhibition of human CYP1A1 remains unknown. Thus, the effects of compounds structurally related to CBD on CYP1A1 activity were examined with recombinant human CYP1A1 in order to characterize the structural requirements for potent inactivation by CBD. When preincubated in the presence of NADPH for 20min, olivetol, which corresponds to the pentylresorcinol moiety of CBD, enhanced the inhibition of the 7-ethoxyresorufin O-deethylase activity of CYP1A1. In contrast, d-limonene, which corresponds to the terpene moiety of CBD, failed to inhibit CYP1A1 activity in a metabolism-dependent manner. Pentylbenzene, which lacks two free phenolic hydroxyl groups, also did not enhance CYP1A1 inhibition. On the other hand, preincubation of the CBD-2'-monomethyl ether (CBDM) and CBD-2',6'-dimethyl ether (CBDD) enhanced the inhibition of CYP1A1 activity. Inhibition by cannabidivarin (CBDV), which possessed a propyl side chain, was strongly potentiated by its preincubation. Orcinol, which has a methyl group, augmented CYP1A1 inhibition, whereas its derivative without an alkyl side chain, resorcinol, did not exhibit any metabolism-dependent inhibition. The preincubation of CBD-hydroxyquinone did not markedly enhance CYP1A1 inhibition. We further confirmed that olivetol, CBDM, CBDD, CBDV, and orcinol, as well as CBD (kinact=0.215min(-1)), inactivated CYP1A1 activity; their kinact values were 0.154, 0.0638, 0.0643, 0.226, and 0.0353min(-1), respectively. These results suggest that the methylresorcinol structure in CBD may have structurally important roles in the inactivation of CYP1A1.