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1.
Int J Mol Sci ; 24(3)2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36768783

RESUMO

Age-related macular degeneration (AMD) is an eye disease associated with aging. Development of AMD is related to degeneration and dysfunction of the retinal pigment epithelium (RPE) caused by low-grade chronic inflammation in aged RPE cells leading to visual loss and blindness. Sweet corn is a good source of lutein and zeaxanthin, which were reported to exert various biological activities, including anti-inflammatory activity. The present study aims to investigate the anti-inflammatory activity and mechanisms of SCE to inhibit the production of inflammatory biomarkers related to AMD development. Cells were pretreated with SCE for 1 h followed by stimulation with IL-1ß for another 24 h. The results demonstrated that SCE attenuated IL-1ß-induced production of IL-6, IL-8, and MCP-1 and the expression of ICAM-1 and iNOS in a dose-dependent manner. In addition, SCE suppressed the phosphorylation of ERK1/2, SAPK/JNK, p38, and NF-κB (p65) in IL-1ß-stimulated ARPE-19 cells. These results proved that SCE protected ARPE-19 cells from IL-1ß-induced inflammation by inhibiting inflammatory markers partly via suppressing the activation of MAPK and NF-κB signaling pathways. Overall, SCE is a potential agent for the prevention of AMD development, which should be further evaluated in animals.


Assuntos
Degeneração Macular , NF-kappa B , Animais , Humanos , Idoso , NF-kappa B/metabolismo , Zea mays/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Inflamação/metabolismo , Anti-Inflamatórios/metabolismo , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Células Epiteliais/metabolismo , Pigmentos da Retina/metabolismo
2.
Molecules ; 27(12)2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35745046

RESUMO

Oxyresveratrol (OXY) has been reported for its anti-inflammatory activity; however, the pharmaceutical applications of this compound are limited by its physicochemical properties and poor pharmacokinetic profiles. The use of an ester prodrug is a promising strategy to overcome these obstacles. In previous researches, several carboxylate esters of OXY were synthesized and oxyresveratrol tetraacetate (OXY-TAc) was reported to possess anti-melanogenic and anti-skin-aging properties. In this study, in addition to OXY-TAc, two novel ester prodrugs of OXY, oxyresveratrol tetrapropionate (OXY-TPr), and oxyresveratrol tetrabutyrate (OXY-TBu), were synthesized. Results from the Caco-2-permeation assay suggested that synthesized ester prodrugs can improve the membrane-permeation ability of OXY. The OXY-TAc exhibited the most significant profile, then this prodrug was chosen to observe anti-inflammatory activities with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results showed that OXY-Tac significantly alleviated secretion of several pro-inflammatory mediators (nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), mitigated expression of enzyme-regulated inflammation (inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)), and suppressed the MAPK cascades. Interestingly, the observed anti-inflammatory activities of OXY-TAc were more remarkable than those of its parent compound OXY. Taken together, we demonstrated that OXY-TAc improved physicochemical and pharmacokinetic profiles and enhanced the pharmacological effects of OXY. Hence, the results in the present study would strongly support the clinical utilities of OXY-TAc for the treatment of inflammation-related disorders.


Assuntos
Lipopolissacarídeos , Pró-Fármacos , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Células CACO-2 , Ciclo-Oxigenase 2/metabolismo , Ésteres/metabolismo , Ésteres/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Células RAW 264.7 , Estilbenos
3.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946898

RESUMO

Oxidative stress-induced cell damage and death of the retinal pigmented epithelium (RPE), a polarized monolayer that maintains retinal health and homeostasis, lead to the development of age-related macular degeneration (AMD). Several studies show that the naturally occurring antioxidant Lutein (Lut) can protect RPE cells from oxidative stress. However, the poor solubility and low oral bioavailability limit the potential of Lut as a therapeutic agent. In this study, lutein diglutaric acid (Lut-DG), a prodrug of Lut, was synthesized and its ability to protect human ARPE-19 cells from oxidative stress was tested compared to Lut. Both Lut and Lut-DG significantly decreased H2O2-induced reactive oxygen species (ROS) production and protected RPE cells from oxidative stress-induced death. Moreover, the immunoblotting analysis indicated that both drugs exerted their protective effects by modulating phosphorylated MAPKs (p38, ERK1/2 and SAPK/JNK) and downstream molecules Bax, Bcl-2 and Cytochrome c. In addition, the enzymatic antioxidants glutathione peroxidase (GPx) and catalase (CAT) and non-enzymatic antioxidant glutathione (GSH) were enhanced in cells treated with Lut and Lut-DG. In all cases, Lut-DG was more effective than its parent drug against oxidative stress-induced damage to RPE cells. These findings highlight Lut-DG as a more potent compound than Lut with the protective effects against oxidative stress in RPE cells through the modulation of key MAPKs, apoptotic and antioxidant molecular pathways.


Assuntos
Antioxidantes/farmacologia , Células Epiteliais/efeitos dos fármacos , Luteína/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Pró-Fármacos/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Catalase/biossíntese , Catalase/genética , Linhagem Celular , Citocromos c/biossíntese , Citocromos c/genética , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/biossíntese , Glutationa/genética , Glutationa Peroxidase/biossíntese , Glutationa Peroxidase/genética , Humanos , Peróxido de Hidrogênio/toxicidade , Luteína/química , Luteína/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Degeneração Macular/tratamento farmacológico , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia
4.
Int J Mol Sci ; 21(16)2020 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784830

RESUMO

Curcumin diglutaric acid (CurDG), an ester prodrug of curcumin, has the potential to be developed as an anti-inflammatory agent due to its improved solubility and stability. In this study, the anti-inflammatory effects of CurDG were evaluated. The effects of CurDG on inflammatory mediators were evaluated in LPS-stimulated RAW 264.7 macrophage cells. CurDG reduced the increased levels of NO, IL-6, and TNF- α, as well as iNOS and COX-2 expression in cells to a greater extent than those of curcumin, along with the potent inhibition of MAPK (ERK1/2, JNK, and p38) activity. The anti-inflammatory effects were assessed in vivo by employing a carrageenan-induced mouse paw edema model. Oral administration of CurDG demonstrated significant anti-inflammatory effects in a dose-dependent manner in mice. The effects were significantly higher compared to those of curcumin at the corresponding doses (p < 0.05). Moreover, 25 mg/kg curcumin did not exert a significant anti-inflammatory effect for the overall time course as indicated by the area under the curve data, while the equimolar dose of CurDG produced significant anti-inflammatory effects comparable with 50, 100, and 200 mg/kg curcumin (p < 0.05). Similarly, CurDG significantly reduced the proinflammatory cytokine expression in paw edema tissues compared to curcumin (p < 0.05). These results provide the first experimental evidence for CurDG as a promising anti-inflammatory agent.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Ésteres/farmacologia , Pró-Fármacos/farmacologia , Animais , Anti-Inflamatórios/química , Carragenina , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Edema/prevenção & controle , Membro Posterior , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pró-Fármacos/química , Células RAW 264.7
5.
Antioxidants (Basel) ; 12(3)2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36978871

RESUMO

Oxidative stress is a significant factor in the development of age-related macular degeneration (AMD), which results from cell damage, dysfunction, and death in the retinal pigmented epithelium (RPE). The use of natural compounds with antioxidant properties to protect RPE cells from oxidative stress has been explored in Dendrobium, a genus of orchid plants belonging to the family Orchidaceae. Two new compounds and seven known compounds from the MeOH extract of the whole plant of Dendrobium virgineum were successfully isolated and structurally characterized. Out of all the compounds isolated, 2-methoxy-9,10-dihydrophenanthrene-4,5-diol (3) showed the highest protective effect against hydrogen peroxide (H2O2)-induced oxidative stress in human retinal pigment epithelial (ARPE-19) cells. Therefore, it was selected to evaluate its protective effect and mechanism on oxidative-stress-induced ARPE-19 cells. Cells were pre-treated with compound 3 at 25, 50, and 100 µg/mL for 24 h and then induced with 400 µM H2O2 for 1 h. The results demonstrated that compound 3 significantly (p < 0.05) increased cell viability by 10-35%, decreased ROS production by 10-30%, and reduced phosphorylation of p38, ERK1/2, and SAPK/JNK by 20-70% in a dose-dependent manner without toxicity. Furthermore, compound 3 significantly (p < 0.05) modulated the expression of apoptosis pathway proteins (cytochrome c, Bax and Bcl-2) by 20-80%, and enhanced SOD, CAT, and GPX activities, and GSH levels in a dose-dependent manner. These results suggest that compound 3 protects ARPE-19 cells against oxidative stress through MAPKs and apoptosis pathways, including the antioxidant system. Thus, compound 3 could be considered as an antioxidant agent for preventing AMD development by protecting RPE cells from oxidative stress and maintaining the retina. These findings open up new possibilities for the use of natural compounds in the treatment of AMD and other oxidative-stress-related conditions.

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