RESUMO
Asthma is a chronic disease with increasing prevalence and incidence, manifested by allergic inflammatory reactions, and is life-threatening for patients with severe disease. Repetitive challenges with the allergens and limitation of treatment efficacy greatly dampens successful management of asthma. The adverse events related to several drugs currently used, such as corticosteroids and ß-agonists, and the low rigorous adherence to preconized protocols likely compromises a more assertive therapy. Flavonoids represent a class of natural compounds with extraordinary antioxidant and anti-inflammatory properties, with their potential benefits already demonstrated for several diseases, including asthma. Advanced technology has been used in the pharmaceutical field to improve the efficacy and safety of drugs. Notably, there is also an increasing interest for the application of these techniques using natural products as active molecules. Flavones, flavonols, flavanones, and chalcones are examples of flavonoid compounds that were tested in controlled delivery systems for asthma treatment, and which achieved better treatment results in comparison to their free forms. This review aims to provide a comprehensive understanding of the development of novel controlled delivery systems to enhance the therapeutic potential of flavonoids as active molecules for asthma treatment.
RESUMO
Ultraviolet B (UVB) irradiation causes free radical production, increase inflammation and oxidative stress, thus, supporting the use of antioxidants by topical administration as therapeutic approaches. Quercetin (QC) is a flavonoid with antioxidant activity, however, high liposolubility makes it difficult to remain in the viable skin layer. Thus, this study evaluated whether microencapsulation of QC would enhance its activity in comparison with the same dose of free QC (non-active dose) and unloaded-microcapsules added in formulation for topical administration in a mouse model of UVB irradiation targeting the skin. Topical formulation containing Quercetin-loaded microcapsules (TFcQCMC) presents physico-chemical (colour, consistence, phase separation and pH) and functional antioxidant stability at 4 °C, room temperature and 40 °C for 6 months. TFcQCMC inhibited the UVB-triggered depletion of antioxidants observed by GSH (reduced glutathione), ability to reduce iron, ability to scavenge 2,2'-azinobis radical and catalase activity. TFcQCMC also inhibited markers of oxidation (lipid hydroperoxides and superoxide anion production). Concerning inflammation, TFcQCMC reduced the production of inflammatory cytokines, matrix metalloproteinase-9 activity, skin edoema, collagen fibre damage, myeloperoxidase activity/neutrophil recruitment, mast cell and sunburn cell counts. The pharmacological activity of TFcQCMC was not shared by the same pharmaceutical form containing the same dose of free QC or unloaded control microcapsules.
Assuntos
Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Cápsulas , Modelos Animais de Doenças , Feminino , Inflamação/etiologia , Masculino , Camundongos , Camundongos Pelados , Quercetina/administração & dosagem , Pele/patologia , Raios Ultravioleta/efeitos adversosRESUMO
The skin is the largest human organ and an important topical route. Even with some challenges, it is an important ally in medication administration, mainly because it is painless and easy-to-apply. Semisolid formulations are the most used dosage forms for drug administration via this delivery route and can be optimized when transformed into a film, favoring on-site maintenance, and promoting drug permeation. However, in situ film-forming systems are difficult to assess and characterize using Franz-type diffusion cells once this apparatus is ideal to formulations without transition phases. The present study proposed a different method to characterize these formulations and provide complementary data on drug and penetration enhancer behaviors, as close as possible to real application conditions. This characterization method allowed us to analyze drug concentration on three necessary occasions: remaining in the polymer film, stratum corneum using adhesive tape, and skin to check where drugs will have a desirable effect. As a proof-of-concept, the proposed ex vivo permeation method was used to evaluate a film-forming system containing lidocaine and prilocaine. We could also evaluate transition phases of drug compositions and quantify drugs at key times after application. Hence, the developed method may be used to provide complementary data to the Franz diffusion cell method, in terms of drug and penetration enhancer behaviors incorporated into film-forming delivery systems.
Assuntos
Administração Tópica , Absorção Cutânea , Adesivos/metabolismo , Administração Cutânea , Animais , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Lidocaína/administração & dosagem , Permeabilidade/efeitos dos fármacos , Polímeros/metabolismo , Pele/metabolismoRESUMO
Evidence demonstrates the pronounced anti-inflammatory activity of a beetroot (Beta vulgaris) dye enriched in betalains obtained using precipitation with ethanol. Herein, we expand upon our previous observations and demonstrate the analgesic and antioxidant effect of betalains. Betalains [10-1000 mg/kg; intraperitoneal route (i.p.)] diminished acetic acid- and PBQ-induced abdominal contortions, and the overt pain-like behaviour induced by complete Freund`s adjuvant (CFA) and formalin (intraplantar; i.pl.) injection. Moreover, betalains (100 mg/kg) administered by various routes [i.p. or subcutaneous (s.c.)] or as a post-treatment reduced carrageenin- or CFA-induced hyperalgesia. Mechanistically, betalains mitigated carrageenin-induced tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, superoxide anion levels, and lipid peroxidation. Betalains also stopped the depletion of reduced glutathione (GSH) levels and ferric reducing ability produced by carrageenin, as well as upregulated Nrf2 and Ho1 transcript expression in the plantar tissue of mice. Furthermore, betalains showed hydroxyl radical, 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulphonic acid) radical (ABTS+), and 2,2-diphenyl-1-picryl-hydrazyl radical (DPPHâ¢) scavenging ability and iron-chelating activity (bathophenantroline assay), and inhibited iron-independent and iron-dependent lipid peroxidation (LPO) in vitro. Finally, betalains-treated bone marrow-derived macrophages exhibited lower levels of cytokines (TNF-α and IL-1ß), and superoxide anion levels and nuclear factor kappa B (NF-κB) activation following lipopolysaccharide (LPS) stimulation. Therefore, this betalain-rich dye extracted using a novel precipitation approach presents prominent analgesic effect in varied models of pain by mechanisms targeting cytokines and oxidative stress.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Beta vulgaris/química , Betalaínas/farmacologia , Inflamação/tratamento farmacológico , Animais , Carragenina/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Dor/induzido quimicamente , Dor/metabolismo , Superóxidos/metabolismoRESUMO
OBJECTIVES: To evaluate the effects of a topical emulsion containing pyrrolidine dithiocarbamate (PDTC) (EcPDTC) in skin oxidative stress and inflammation triggered by ultraviolet B (UVB) irradiation (dose of 4.14 J/cm2 ). METHODS: Hairless mouse received treatment with 0.5 g of EcPDTC or control emulsion (CTRLE) on the dorsal surface skin 12 h, 6 h and 5 min before and 6 h after the irradiation. Oxidative stress was evaluated by ferric reducing antioxidant power (FRAP), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS) scavenging capacity, reduced glutathione quantitation, catalase activity, superoxide anion production and lipid peroxidation products. Inflammation parameters were as follows: skin oedema, myeloperoxidase activity (neutrophil marker), matrix metalloproteinase-9 activity, collagen fibre damage, mast cell and sunburn cell counts, and cytokine production. KEY FINDINGS: Topical treatment with EcPDTC protected from UVB-induced skin injury by maintaining the antioxidant capacity levels similar to non-irradiated control group. Furthermore, EcPDTC inhibited UVB irradiation-induced superoxide anion production, lipid peroxidation and reduced skin inflammation by inhibiting skin oedema, neutrophil recruitment, metalloproteinase-9 activity, collagen fibre damage, mast cell and sunburn cell counts, and cytokine (TNF-α and IL-1ß) production. CONCLUSIONS: Topical treatment with EcPDTC improves antioxidant systems and inhibits inflammation, protecting the skin from the damaging effects of UVB irradiation.
Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Pirrolidinas/administração & dosagem , Pele/efeitos dos fármacos , Queimadura Solar/prevenção & controle , Tiocarbamatos/administração & dosagem , Raios Ultravioleta , Administração Cutânea , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Citocinas/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Emulsões , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos Pelados , Estresse Oxidativo/efeitos dos fármacos , Pirrolidinas/química , Pele/metabolismo , Pele/patologia , Queimadura Solar/metabolismo , Queimadura Solar/patologia , Tiocarbamatos/químicaRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular lesions, recruitment of inflammatory cells and increased levels of pro-inflammatory cytokine. The intra-articular administration of zymosan is an experimental model that promotes inflammatory parameters resembling RA. Therefore, this model was used to investigate the efficacy of quercetin as a treatment of articular inflammation. Treatment with quercetin dose-dependently reduced zymosan-induced hyperalgesia, articular edema and the recruitment of neutrophils to the knee joint cavity. Histological analysis confirmed that quercetin inhibited zymosan-induced arthritis. The treatment with quercetin also inhibited zymosan-induced depletion of reduced glutathione (GSH) levels, TNFα and IL-1ß production, and gp91phox, prepro-endothelin-1 (preproET-1), and cyclooxygenase-2 mRNA expression. These molecular effects of quercetin were related to the inhibition of the nuclear factor kappa-B and induction of Nuclear factor erythroid 2- related factor (Nrf2)/home oxygenase (HO-1) pathway. Thus, quercetin exerted anti-inflammatory, analgesic and antioxidant effects in experimental arthritis, suggesting quercetin is a possible candidate for arthritis treatment.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Quercetina/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Relação Dose-Resposta a Droga , Heme Oxigenase-1/biossíntese , Masculino , Proteínas de Membrana/biossíntese , Camundongos , Fator 2 Relacionado a NF-E2/biossíntese , Quercetina/administração & dosagem , Transdução de Sinais , ZimosanRESUMO
Trans-chalcone (TC) is a common precursor of flavonoids. However, the pharmacological properties of TC remain to be fully understood. The present study investigated whether topical formulation containing TC (TFcTC) presents therapeutic effect in UVB radiation-induced skin damage using disease, enzyme activity, antioxidant activity, protein and mRNA parameters. Control topical formulation (CTF) and TFcTC were applied in hairless mice before and after exposure to UVB radiation. Dorsal skin samples were collected after UVB exposure to evaluate: i) skin edema (weight) was measured by punch biopsy; ii) spectrophotometric assays were used to measure myeloperoxidase (MPO) and catalase activities, ferric (FRAP) and ABTS cation reducing antioxidant power, superoxide anion production and levels of reduced glutathione (GSH); iii) enzymography was used to measure matrix metalloproteinase-9 (MMP-9) activity; iv) chemiluminescence was used to measure the lipid peroxidation (LPO); v) enzyme-linked immunosorbent assay (ELISA) was used to measure tumor necrosis factor alpha (TNF-α) levels; vi) reverse transcription quantitative PCR (RT-qPCR) was used to measure cyclooxygenase-2 (COX-2), gp91phox (NADPH oxidase sub-unity), glutathione peroxidase-1 (Gpx1), glutathione reductase (Gr), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) mRNA expression. TFcTC inhibited UVB-induced skin edema, MPO activity, MMP-9 activity, TNF-α production, and COX-2 mRNA expression. TFcTC inhibited UVB-induced LPO, down-regulated superoxide anion levels and gp91phox mRNA expression, and improved antioxidant potential and GSH skin levels. The mRNA expression of detoxification systems such as Nrf2, HO-1, Gpx1 and Gr, and catalase activity were also enhanced by treatment with TFcTC. In conclusion, TFcTC protects mice skin from UVB radiation by inhibiting inflammation, and improving antioxidant and detoxification systems. Therefore, topical treatment with TC is a novel therapeutic approach for the treatment of UVB radiation skin damages, which merits further pre-clinical and clinical investigation.
Assuntos
Chalcona/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Raios Ultravioleta , Administração Tópica , Animais , Catalase/metabolismo , Chalcona/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Redutase/genética , Glutationa Redutase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Inflamação/prevenção & controle , Isomerismo , Peroxidação de Lipídeos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Pelados , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos da radiação , Peroxidase/genética , Peroxidase/metabolismo , Pele/metabolismo , Pele/efeitos da radiação , Fator de Necrose Tumoral alfa/análise , Glutationa Peroxidase GPX1RESUMO
We investigated the anti-inflammatory and analgesic effects of quercetin in monosodium urate crystals (MSU)-induced gout arthritis, and the sensitivity of quercetin effects to naloxone, an opioid receptor antagonist. Mice were treated with quercetin, and mechanical hyperalgesia was assessed at 1-24 h after MSU injection. In vivo, leukocyte recruitment, cytokine levels, oxidative stress, NFκB activation, and gp91phox and inflammasome components (NLRP3, ASC, Pro-caspase-1, and Pro-IL-1ß) mRNA expression by qPCR were determined in the knee joints at 24 h after MSU injection. Inflammasome activation was determined, in vitro, in lipopolysaccharide-primed macrophages challenged with MSU. Quercetin inhibited MSU-induced mechanical hyperalgesia, leukocyte recruitment, TNFα and IL-1ß production, superoxide anion production, inflammasome activation, decrease of antioxidants levels, NFκB activation, and inflammasome components mRNA expression. Naloxone pre-treatment prevented all the inhibitory effects of quercetin over MSU-induced gout arthritis. These results demonstrate that quercetin exerts analgesic and anti-inflammatory effect in the MSU-induced arthritis in a naloxone-sensitive manner.
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An effective short interfering RNA (siRNA) delivery system protects the siRNA from degradation, facilitates its cellular uptake, and promotes its release into the cytoplasm. Local administration of siRNA presents advantages over systemic administration, such as the possibility to use lower doses and allow local and sustained release. In this context, in situ solidifying organogels based on monoglycerides (MO), polyethylenimine (PEI), propylene glycol (PG) and tris buffer are an attractive strategy for intratumoral delivery of siRNA. In this study, precursor fluid formulation (PFF) composed of MO/PEI/PG/tris buffer at 7.85:0.65:76.5:15 (w/w/w/w) was used to deliver siRNA to tumor cells. The internal structure of the gel obtained from PFF was characterized using small angle X-ray scattering (SAXS). In addition, its ability to complex siRNA, protect it from degradation, and functionally deliver it to tumor cells was investigated. Moreover, in vivo gel formation following intratumoral injection was evaluated. The gel formed in excess water from PFF was found to comprise a mixture of hexagonal and cubic phases. The system was able to complex high amounts of siRNA, protect it from degradation, promote siRNA internalization, and induce gene silencing in vitro in a variety of tumor cell lines. Moreover, a gel formed in situ following intratumoral injection in a murine xenograft model. In conclusion, PFF is a potential delivery system for local and sustained delivery of siRNA to tumor tissue after intratumoral administration.
Assuntos
Inativação Gênica/fisiologia , Cristais Líquidos/química , Monoglicerídeos/química , Polietilenoimina/química , Propilenoglicol/química , RNA Interferente Pequeno/genéticaRESUMO
Naringenin (NGN) exhibits anti-inflammatory and antioxidant activities, but it remains undetermined its topical actions against ultraviolet B (UVB)-induced inflammation and oxidative stress in vivo. The purpose of this study was to evaluate the physicochemical and functional antioxidant stability of NGN containing formulations, and the effects of selected NGN containing formulation on UVB irradiation-induced skin inflammation and oxidative damage in hairless mice. NGN presented ferric reducing power, ability to scavenge 2,2'-azinobis (3-ethylbenzothiazoline- 6-sulfonic acid) (ABTS) and hydroxyl radical, and inhibited iron-independent and dependent lipid peroxidation. Among the three formulations containing NGN, only the F3 kept its physicochemical and functional stability over 180 days. Topical application of F3 in mice protected from UVB-induced skin damage by inhibiting edema and cytokine production (TNF-α, IL-1ß, IL-6, and IL-10). Furthermore, F3 inhibited superoxide anion and lipid hydroperoxides production and maintained ferric reducing and ABTS scavenging abilities, catalase activity, and reduced glutathione levels. In addition, F3 maintained mRNA expression of cellular antioxidants glutathione peroxidase 1, glutathione reductase and transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), and induced mRNA expression of heme oxygenase-1. In conclusion, a formulation containing NGN may be a promising approach to protecting the skin from the deleterious effects of UVB irradiation.