RESUMO
CONTEXT: Xiaoyaosan decoction (XYS), a classical Traditional Chinese Medicine (TCM) formula is used to treat liver fibrosis in clinics. OBJECTIVE: This study explores defined compound combinations from XYS decoction to treat liver fibrosis. MATERIALS AND METHODS: Network pharmacology combined with transcriptomics analysis was used to analyze the XYS decoction and liver depression and spleen deficiency syndrome liver fibrosis. From the constructed XYS-Syndrome-liver fibrosis network, the top 10 active formulas were developed by topological analysis according to network stability. The most active formula was determined by in vitro study. The anti-fibrosis effect was evaluated by in vitro and in vivo studies. RESULTS: According to the network XYS-Syndrome-liver fibrosis network, 8 key compounds and 255 combinations were predicted from in XYS. Luteolin, licochalcone A, aloe-emodin and acacetin formula (LLAAF) had a synergistic effect on the proliferation inhibition of hepatic stellate cells compared to individual compounds alone. The treatment of XYS and LLAAF showed a similar anti-liver fibrotic effect that reduced histopathological changes of liver fibrosis, Hyp content and levels of α-SMA and collagen I in CCl4-induced liver fibrosis in rats. Transcriptomics analysis revealed LLAAF regulated PI3K-Akt, AMPK, FoxO, Jak-STAT3, P53, cell cycle, focal adhesion, and PPAR signalling. Furthermore, LLAAF was confirmed to regulate Jak-STAT and PI3K-Akt-FoxO signalling in vitro and in vivo. CONCLUSIONS: This study developed a novel anti-liver formula LLAAF from XYS, and demonstrated its anti-liver fibrotic activity which may be involved in the regulation of Jak-STAT and PI3K-Akt-FoxO signalling.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Animais , Antraquinonas/administração & dosagem , Antraquinonas/farmacologia , Linhagem Celular , Chalconas/administração & dosagem , Chalconas/farmacologia , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Flavonas/administração & dosagem , Flavonas/farmacologia , Células Estreladas do Fígado/patologia , Humanos , Luteolina/administração & dosagem , Luteolina/farmacologia , Masculino , Farmacologia em Rede , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , TranscriptomaRESUMO
BACKGROUND: Blue light can directly penetrate the lens and reach the retina to induce retinal damage, causing dry age-related macular degeneration (dAMD). Cynaroside (Cyn), a flavonoid glycoside, was proved to alleviate the oxidative damage of retinal cells in vitro. However, whether or not Cyn also exerts protective effect on blue light-induced retinal degeneration and its mechanisms of action are unclear. PURPOSE: This study aims to evaluate the protective effects of Cyn against blue-light induced retinal degeneration and its underlying mechanisms in vitro and in vivo. STUDY DESIGN/METHODS: Blue light-induced N-retinylidene-N-retinylethanolamine (A2E)-laden adult retinal pigment epithelial-19 (ARPE-19) cell damage and retinal damage in SD rats were respectively used to evaluate the protective effects of Cyn on retinal degeneration in vitro and in vivo. MTT assay and AnnexinV-PI double staining assay were used to evaluate the in vitro efficacy. Histological analysis, TUNEL assay, and fundus imaging were conducted to evaluate the in vivo efficacy. ELISA assay, western blot, and immunostaining were performed to investigate the mechanisms of action of Cyn. RESULTS: Cyn decreased the blue light-induced A2E-laden ARPE-19 cell damage and oxidative stress. Intravitreal injection of Cyn (2, 4 µg/eye) reversed the retinal degeneration induced by blue light in SD rats. Furthermore, Cyn inhibited the nuclear translocation of NF-κB and induced autophagy, which led to the clearance of overactivated pyrin domain containing 3 (NLRP3) inflammasome in vitro and in vivo. CONCLUSION: Cyn protects against blue light-induced retinal degeneration by modulating autophagy and decreasing the NLRP3 inflammasome.
Assuntos
Apoptose/efeitos dos fármacos , Glucosídeos/farmacologia , Luteolina/farmacologia , Substâncias Protetoras/farmacologia , Degeneração Retiniana/tratamento farmacológico , Animais , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Linhagem Celular , Glucosídeos/administração & dosagem , Humanos , Inflamassomos/metabolismo , Injeções Intravítreas , Luz/efeitos adversos , Luteolina/administração & dosagem , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Ratos Sprague-Dawley , Degeneração Retiniana/etiologia , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologiaRESUMO
Xuebijing Injection have been found to improve the clinical symptoms of COVID-19 and alleviate disease severity, but the mechanisms are currently unclear. This study aimed to investigate the potential molecular targets and mechanisms of the Xuebijing injection in treating COVID-19 via network pharmacology and molecular docking analysis. The main active ingredients and therapeutic targets of the Xuebijing injection, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, and GeneCard databases. According to the 'Drug-Ingredients-Targets-Disease' network built by STRING and Cytoscape, AKT1 was identified as the core target, and baicalein, luteolin, and quercetin were identified as the active ingredients of the Xuebijing injection in connection with AKT1. R language was used for enrichment analysis that predict the mechanisms by which the Xuebijing injection may inhibit lipopolysaccharide-mediated inflammatory response, modulate NOS activity, and regulate the TNF signal pathway by affecting the role of AKT1. Based on the results of network pharmacology, a molecular docking was performed with AKT1 and the three active ingredients, the results indicated that all three active ingredients could stably bind with AKT1. These findings identify potential molecular mechanisms by which Xuebijing Injection inhibit COVID-19 by acting on AKT1.
Assuntos
Antivirais/administração & dosagem , Tratamento Farmacológico da COVID-19 , COVID-19/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , SARS-CoV-2 , Antivirais/farmacocinética , Antivirais/farmacologia , Engenharia Biomédica , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/administração & dosagem , Humanos , Injeções , Luteolina/administração & dosagem , Simulação de Acoplamento Molecular , Pandemias , Ligação Proteica , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/química , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/administração & dosagem , Transdução de Sinais/efeitos dos fármacosRESUMO
Increasing intestinal barrier function is one of the basic methods to suppress inflammation in the progression from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). Luteolin exists widely in vegetables, fruits and natural herbs and has various biological activities, including benefits on nonalcoholic fatty liver disease (NAFLD). However, its regulatory effects on the gut microbiota and involvement in its biological activities remain to be investigated. We fed rats a high-fat diet containing 0.5% luteolin for 12 weeks and determined the effects of luteolin on lipid metabolism, inflammation, and the gut microbiota. Supplementation with luteolin for 12 weeks significantly reduced blood lipids and hepatic lipid levels and improved liver fat accumulation and inflammation. Moreover, supplementation with luteolin led to the significant enrichment of more than 10% of gut bacterial species, which contributed to increase the abundance of ZO-1, reduce intestinal permeability, reduce plasma lipopolysaccharide, and inhibit the TLR4/NF-κB pathway. In summary, the anti-inflammatory effect of luteolin might be related to changes in the gut microbiota and contribute to preventing the progression from SS to NASH. Our research provides new insights into the anti-inflammatory mechanism of luteolin and supports its use as a dietary supplement for NAFLD patients.
Assuntos
Anti-Inflamatórios/farmacologia , Fígado Gorduroso/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Luteolina/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Fígado Gorduroso/patologia , Luteolina/administração & dosagem , Luteolina/química , Estrutura Molecular , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Bisphenol A (BPA) is an industrial chemical used in the production of various plastic materials. It is associated with reproductive, immunological and neurological disorders. Luteolin, a flavonoid found in fruits and vegetables, possesses anti-oxidative, anti-inflammatory and free radical scavenging properties. Here, we carried out studies to ascertain if Luteolin would ameliorate BPA-induced toxicity in Drosophila melanogaster. Firstly, flies were treated separately with Luteolin (0, 50, 100, 150 and 300 mg/kg diet) and BPA (0, 0.01, 0.05 and 0.1 mM) for 28 days survival assessments. Consequently, Luteolin (150 and 300 mg/kg diet) and/or BPA (0.05 mM) were exposed to D. melanogaster for 7 days for the evaluation of nitric oxide level, eclosion rate, viability assay, histology of fat body, antioxidant (Glutathione-S-transferase, catalase and total thiol), oxidative stress (hydrogen peroxide) and behavioural (negative geotaxis and acetylcholinesterase) markers. The results showed that BPA induced antioxidant-oxidative stress imbalance and behavioural deficit in flies. Luteolin increased survival rate and augmented antioxidant markers in flies. Importantly, Luteolin ameliorated BPA-induced degeneration in the fat body around the rostral, thorax and abdominal regions, oxidative stress, behavioural deficit, reduction in cell viability and eclosion rate of D. melanogaster (p < 0.05). Overall, this study offered further insights on the antioxidative and chemopreventive properties of Luteolin against BPA-induced toxicity.
Assuntos
Compostos Benzidrílicos/toxicidade , Suplementos Nutricionais , Disruptores Endócrinos/toxicidade , Luteolina/administração & dosagem , Fenóis/toxicidade , Acetilcolinesterase/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Drosophila melanogaster , Locomoção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
The objective was to evaluate the effects of 6 months of supplementation with Altilix®, containing chlorogenic acid and its derivatives, and luteolin and its derivatives, on cardiovascular risk and hepatic markers in subjects with metabolic syndrome (MetS). A randomized, double-blind, placebo-controlled study was performed in 100 subjects with MetS with a follow-up period of 6 months; 50 subjects were randomized to Altilix® (26 men and 24 women, mean age 63 ± 8 years) and the other 50 to placebo (28 men and 22 women, mean age 63 ± 11 years). Anthropometric, cardiometabolic, and hepatic parameters were assessed at baseline and at the end of follow-up. Carotid intima-media thickness and endothelial function were assessed by doppler ultrasound and by flow-mediated dilation of the brachial artery, respectively. The presence and degree of non-alcoholic fatty liver disease (NAFLD) was assessed by the fatty liver index (FLI), and subjects were divided into three subgroups: (1) without NAFLD; (2) with borderline NAFLD; and (3) with NAFLD. After 6 months of Altilix® supplementation, we found a significant improvement vs. placebo in most of the evaluated parameters, including body weight (-2.40% (95% CI -3.79, -1.01); p < 0.001), waist circumference (-2.76% (95% CI -4.55, -0.96); p = 0.003), HbA1c (-0.95% (95% CI -1.22, -0.67); p < 0.001), plasma lipids, FLI (-21.83% (95% CI -27.39, -16.27); p < 0.001), hepatic transaminases, flow-mediated dilation (10.56% (95% CI 5.00, 16.12); p < 0.001), and carotid intima-media thickness (-39.48% (95% CI -47.98, -30.97); p < 0.001). Further, the improvement in cardiometabolic variables was independent of the degree of hepatic steatosis. Altilix® supplementation improved hepatic and cardio-metabolic parameters in MetS subjects. Altilix® supplementation was a beneficial approach in the management of hepatic and cardiometabolic alterations in MetS subjects.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Ácido Clorogênico/administração & dosagem , Suplementos Nutricionais , Luteolina/administração & dosagem , Síndrome Metabólica/terapia , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Método Duplo-Cego , Feminino , Humanos , Fígado/metabolismo , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Breast cancer is worldwide commonly found malignancy in women and effective treatment is regarded as a huge clinical challenge even in the presence of several options. Extensive literature is available that demonstrating polyphenols, the richly introduce phytopharmaceuticals as anticancer agents. Among these polyphenols, resveratrol, silibinin, quercetin, genistein, curcumin reported to have an awesome potential against breast cancer. However, till now no comprehensive survey found about the anticarcinogenic properties of luteolin against breast cancer. SCOPE AND APPROACH: This review targeted the available literature on luteolin in the treatment of breast cancer, effects in combination with other anticancer drugs with possible mechanisms. KEY FINDINGS AND CONCLUSION: An outstanding therapeutic potential of luteolin in the treatment of breast cancer has been recorded not just as a chemopreventive and chemotherapeutic agent yet complemented by its synergistic effects with other anticancer therapies such as cyclophosphamide, doxorubicin, and NSAID such as celecoxib, and possible underlying mechanisms. Ideally, this review will open new dimensions for luteolin as an effective and safe therapeutic agent in diminishing breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Luteolina/farmacologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Celecoxib/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Luteolina/administração & dosagem , Luteolina/químicaRESUMO
The natural polyphenols mangiferin and luteolin have free radical-scavenging properties, induce the antioxidant gene program and down-regulate the expression of superoxide-producing enzymes. However, the effects of these two polyphenols on exercise capacity remains mostly unknown. To determine whether a combination of luteolin (peanut husk extract containing 95% luteolin, PHE) and mangiferin (mango leave extract (MLE), Zynamite®) at low (PHE: 50 mg/day; and 140 mg/day of MLE containing 100 mg of mangiferin; L) and high doses (PHE: 100 mg/day; MLE: 420 mg/day; H) may enhance exercise performance, twelve physically active men performed incremental exercise to exhaustion, followed by sprint and endurance exercise after 48 h (acute effects) and 15 days of supplementation (prolonged effects) with polyphenols or placebo, following a double-blind crossover design. During sprint exercise, mangiferin + luteolin supplementation enhanced exercise performance, facilitated muscle oxygen extraction, and improved brain oxygenation, without increasing the VO2. Compared to placebo, mangiferin + luteolin increased muscle O2 extraction during post-exercise ischemia, and improved sprint performance after ischemia-reperfusion likely by increasing glycolytic energy production, as reflected by higher blood lactate concentrations after the sprints. Similar responses were elicited by the two doses tested. In conclusion, acute and prolonged supplementation with mangiferin combined with luteolin enhances performance, muscle O2 extraction, and brain oxygenation during sprint exercise, at high and low doses.
Assuntos
Antioxidantes/administração & dosagem , Suplementos Nutricionais , Exercício Físico/fisiologia , Luteolina/administração & dosagem , Desempenho Físico Funcional , Xantonas/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Ácido Láctico/sangue , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Resistência Física/efeitos dos fármacos , Esforço Físico/efeitos dos fármacos , Corrida/fisiologia , Adulto JovemRESUMO
OBJECTIVE: To focus a new chemoprevention approach that uses nanotechnology to deliver luteolin to human breast cancer cells (MCF-7), and its underlying mechanism. METHODS: Water-soluble copolymer-encapsulated nanoparticle-luteolin (CENL) was formulated using the hydrophobic drug luteolin. The ability to load and release he anticancer drug into/from the synthesized hyperbranched polyester was evaluated by high-performance liquid chromatography. The successful synthesis of CENL was supported by analytical techniques including fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, gel permeation chromatography, and dynamic light scattering. Cell viability was measured using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide color method. Reactive oxygen species (ROS) were measured using a dichlorofluorescein probe and intracellular calcium (Cai2+) was evaluated with a flu3-AM probe. RESULTS: The results showed that the drug delivery system is stable and that the loading capacity is high. Treatment with nanoparticles containing luteolin and free luteolin resulted in cell death in breast cancer cells at high concentrations [IC50 (33 ± 4) and (48 ± 6) µM, respectively]. At high concentrations, CENL reduced cell viability and increased ROS and Cai2+ production. CONCLUSION: Our results demonstrate that CENL has potential for human breast cancer treatment.
Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/síntese química , Luteolina/química , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Luteolina/administração & dosagem , Nanopartículas/química , Polímeros/síntese química , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
OBJECTIVES: Herein, we propose combined aromatase inhibitor and herbal therapy of breast cancer as a synergistic therapeutic modality. METHODS: Zein nanospheres were prepared by phase separation for co-delivery of exemestane and luteolin. To enhance their tumor-targeting capability, the nanospheres were coated with PEGylated phospholipids and lactoferrin for passive and active targeting, respectively. RESULTS: The developed nanospheres demonstrated a small particle size and controlled drug release. In addition, the nanospheres revealed high serum stability, acceptable hemocompatibility, and good physical stability. Moreover, a 5-fold scale-up of zein nanospheres could be enabled followed by spray-drying using 2.5% mannitol as a drying adjuvant. PEGylated and lactoferrin-targeted nanospheres showed enhanced cytotoxicity against MCF-7 and 4T1 breast cancer cells with higher selectivity to cancer cells rather than normal fibroblasts. The in-vivo pharmacokinetics and anti-tumor efficacy confirmed the superiority of zein nanospheres particularly after PEGylation compared to free drug(s). The enhanced anti-cancer activity of nanocarriers was revealed as prolonged circulation half-life, lower % change in tumor volume, reduced expression of aromatase, Cyclin D1 and VEGF markers as well as amplified apoptosis and necrosis. CONCLUSION: Overall, combined delivery of aromatase inhibitors and herbal drugs via tumor-targeted zein nanospheres could serve as a promising strategy for breast cancer therapy.
Assuntos
Androstadienos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Lactoferrina/química , Zeína/química , Animais , Inibidores da Aromatase/administração & dosagem , Portadores de Fármacos/química , Feminino , Humanos , Luteolina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Nanosferas , Tamanho da Partícula , Fosfolipídeos/química , Polietilenoglicóis/química , Ratos , Ratos Sprague-DawleyRESUMO
Chronic pharyngitis is characterized as a common inflammation of the pharyngeal mucosa, and anti-inflammatory medications are the common treatment to relieve it. Polysacharides of Citrus grandis L. Osbeck (PCG) and luteolin have been reported to have anti-inflammatory activities. In this study, the protective effects of PCG and luteolin on chronic pharyngitis are evaluated and the underlying mechanisms are explored. PCG and luteolin are administrated to animal models with granuloma, ear edema and chronic pharyngitis and the effects of PCG and luteolin on disease severity are evaluated. We also evaluate the effects of PCG and luteolin on inflammatory cytokine production in macrophages stimulated with lipopolysaccharides (LPS)/interferon-gamma (IFN-γ) and detect the effects of PCG and luteolin on macrophage polarization. Finally, we evaluate the effects of PCG and luteolin on activations of LPS-induced downstream signaling pathways. PCG and luteolin alleviate the disease severity of granuloma, ear edema and chronic pharyngitis. PCG and luteolin suppress the productions of pro-inflammatory cytokines interlukin-6 (IL-6), interlukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) in macrophages. Luteolin promotes macrophage M2 polarization by enhancing expressions of arginase (Arg1) and mannose receptor C type 1 (Mrc1). PCG and luteolin suppress nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and interferon regulatory factor 1 (IRF1), interferon regulatory factor 5 (IRF5) expression. PCG together with luteolin relieves chronic pharyngitis by anti-inflammatory via suppressing NF-κB pathway and the polarization of M1 macrophage.
Assuntos
Anti-Inflamatórios/uso terapêutico , Citrus/química , Luteolina/uso terapêutico , Macrófagos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Faringite/tratamento farmacológico , Polissacarídeos/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/imunologia , Granuloma/tratamento farmacológico , Granuloma/imunologia , Luteolina/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Faringite/imunologia , Polissacarídeos/administração & dosagem , Polissacarídeos/isolamento & purificação , Coelhos , Ratos Wistar , Mucosa RespiratóriaRESUMO
Luteolin (LU) is a widely distributed flavonoid with multitarget effects. The objective of this study was to determine whether LU could reduce the ischemia-reperfusion injury of the spinal cord (SCII) in a rat model. Forty-eight rats were divided into four groups: sham, SCII, SCII+L-LU (50 mg/kg), and SCII+H-LU (100 mg/kg). Abdominal aortic occlusion was carried out for 40 min in all groups. Hindlimb motor functions were evaluated using the Tarlov scoring system. Nissl and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) staining were used to detect cell survival and apoptosis in the spinal cord. Spinal cord samples were taken for determination of malondialdehyde, xanthine oxidase, superoxide dismutase, and glutathione peroxidase activities. The levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-18 were assessed using ELISA kits to examine the inflammatory responses in the spinal cord. Western blot analysis was used to examine the expression of nuclear factor erythroid 2-related factor (Nrf2) and nod-like receptor pyrin domain-containing 3 protein (NLRP3) levels. We found that LU pretreatment significantly improved the locomotor function of rats after SCII, increased neuron survival, and inhibited apoptosis in the spinal cord. Furthermore, the oxidative stress and inflammatory response were significantly suppressed upon treatment with LU. Finally, LU upregulated Nrf2 levels and downregulated NLRP3 protein expression in SCII tissues. Thus, LU exhibited a neuroprotective effect following SCII by alleviating oxidative stress and inhibiting inflammatory responses and cell apoptosis. The possible mechanism may be related to the activation of Nrf2 and inhibition of NLRP3 inflammasome pathway.
Assuntos
Apoptose/efeitos dos fármacos , Luteolina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Isquemia do Cordão Espinal/tratamento farmacológico , Animais , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2 , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Isquemia do Cordão Espinal/metabolismo , Isquemia do Cordão Espinal/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Mercury exposure is a common cause of metal poisoning which is biotransformed to highly toxic metabolites thus eliciting biochemical alterations and oxidative stress. Luteolin, a phenolic compound found in many natural products, has multiple biological functions. Our study was aimed to explore the biological effects of luteolin in a liver injury model induced in rats by mercuric chloride (HgCl2). Criteria for injury included liver enzyme, glutathione and malondialdehyde levels, histopathology, TUNEL assay, hepatocyte viability and reactive oxygen species levels. The results showed that luteolin protected against HgCl2-induced liver injury. Luteolin increased total nuclear factor-erythroid-2-related factor 2 (Nrf2) levels in the presence of HgCl2. Upregulation of its downstream factors, heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1, was also observed. This suggested that protection by luteolin against HgCl2-induced liver injury involved Nrf2 pathway activation. Luteolin also decreased expression of nuclear factor-κB (NF-κB) and P53. HgCl2 exposure led to increased Bcl-associated X protein (Bax), and decreased Bcl-2-related protein long form of Bcl-x (Bcl-xL) and B-cell leukemia/lymphoma-2 (Bcl-2) expression, leading to an increased Bax/Bcl-2 ratio. Taken together, our data suggested that decreasing oxidative stress is a protective mechanism of luteolin against development of HgCl2-induced liver injury, through the Nrf2/NF-κB/P53 signaling pathway in rats.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Crônica , Suplementos Nutricionais , Heme Oxigenase-1/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Luteolina/administração & dosagem , Cloreto de Mercúrio/toxicidade , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos WistarRESUMO
In many countries afflicted with dengue fever, traditional medicines are widely used as panaceas for illness, and here we describe the systematic evaluation of a widely known natural product, luteolin, originating from the "heat clearing" class of herbs. We show that luteolin inhibits the replication of all four serotypes of dengue virus, but the selectivity of the inhibition was weak. In addition, ADE-mediated dengue virus infection of human cell lines and primary PBMCs was inhibited. In a time-of-drug-addition study, luteolin was found to reduce infectious virus particle formation, but not viral RNA synthesis, in Huh-7 cells. During the virus life cycle, the host protease furin cleaves the pr moiety from prM protein of immature virus particles in the trans-Golgi network to produce mature virions. Analysis of virus particles from luteolin-treated cells revealed that prM was not cleaved efficiently. Biochemical interrogation of human furin showed that luteolin inhibited the enzyme activity in an uncompetitive manner, with Ki value of 58.6 µM, suggesting that treatment may restrict the virion maturation process. Luteolin also exhibited in vivo antiviral activity in mice infected with DENV, causing reduced viremia. Given the mode of action of luteolin and its widespread source, it is possible that it can be tested in combination with other dengue virus inhibitors.
Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Furina/metabolismo , Luteolina/antagonistas & inibidores , Pró-Proteína Convertases/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Células A549 , Animais , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Replicação do DNA/efeitos dos fármacos , Dengue/tratamento farmacológico , Dengue/virologia , Vírus da Dengue/classificação , Vírus da Dengue/genética , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Cinética , Luteolina/administração & dosagem , Luteolina/química , Masculino , Camundongos , Pró-Proteína Convertases/metabolismo , RNA Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Vírion/efeitos dos fármacos , Rede trans-Golgi/efeitos dos fármacosRESUMO
BACKGROUND: Two brown-like adipocytes, including classical brown adipocytes from brown adipose tissues and beige cells from white adipose tissues, regulate thermogenesis. The developmental and functional induction of brown-like cells provides a defense against obesity and associated metabolic diseases. Our previous study suggests dietary luteolin can improve diet-induced obesity and insulin resistance in mice. Here we further elucidated the action of the natural flavonoid on energy expenditure and adaptive thermogenesis. METHODS: Five-week-old male C57BL/6 mice were fed low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with 0.01% luteolin. After 12 weeks, their energy expenditure were detected using a combined indirect calorimetry system. Moreover, thermogenic program and associated molecular regulators were assessed in adipose tissues. In another independent study, even-aged mice were fed LFD and luteolin-containing LFD for 12 weeks, and their energy expenditure and thermogenic program were also investigated. Finally, differentiated primary brown and subcutaneous adipocytes were used to identify the critical participation of AMPK/PGC1α signaling in luteolin-regulated browning and thermogenesis. RESULTS: In mice fed either HFD or LFD, dietary luteolin supplement increased oxygen consumption, carbon dioxide production and respiratory exchange ratio. The enhancement in energy expenditure was accompanied by the upregulation of thermogenic genes in brown and subcutaneous adipose tissues. Meanwhile, several important AMPK/PGC1α signaling molecules were activated by dietary luteolin in the tissues. Further, luteolin treatment directly elevated thermogenic gene expressions and activated AMPK/PGC1α signaling in differentiated primary brown and subcutaneous adipocytes, whereas AMPK inhibitor Compound C reversed the efficiencies. CONCLUSIONS: Dietary luteolin activated browning and thermogenesis through an AMPK/PGC1α pathway-mediated mechanism.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/patologia , Luteolina/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Obesidade/metabolismo , Termogênese/fisiologia , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Suplementos Nutricionais , Modelos Animais de Doenças , Metabolismo Energético , Regulação da Expressão Gênica , Resistência à Insulina , Luteolina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Termogênese/efeitos dos fármacosRESUMO
Uropathogenic Escherichia coli (UPEC), the primary uropathogen, adhere to and invade bladder epithelial cells (BECs) to establish a successful urinary tract infection (UTI). Emerging antibiotic resistance requires novel nonantibiotic strategies. Our previous study indicated that luteolin attenuated adhesive and invasive abilities as well as cytotoxicity of UPEC on T24 BECs through down-regulating UPEC virulence factors. The aims of this study were to investigate the possible function of the flavonoid luteolin and the mechanisms by which luteolin functions in UPEC-induced bladder infection. Firstly, obvious reduction of UPEC invasion but not adhesion were observed in luteolin-pretreated 5637 and T24 BECs sa well as mice bladder via colony counting. The luteolin-mediated suppression of UPEC invasion was linked to elevated levels of intracellular cAMP induced by inhibiting the activity of cAMP-phosphodiesterases (cAMP-PDEs), which resulting activation of protein kinase A, thereby negatively regulating Rac1-GTPase-mediated actin polymerization. Furthermore, p38 MAPK was primarily and ERK1/2 was partially involved in luteolin-mediated suppression of UPEC invasion and actin polymerization, as confirmed with chemical activators of p38 MAPK and ERK1/2. These data suggest that luteolin can protect bladder epithelial cells against UPEC invasion. Therefore, luteolin or luteolin-rich products as dietary supplement may be beneficial to control the UPEC-related bladder infections, and cAMP-PDEs may be a therapy target for UTIs treatment. © 2016 BioFactors, 42(6):674-685, 2016.
Assuntos
Antibacterianos/administração & dosagem , Luteolina/administração & dosagem , Infecções Urinárias/prevenção & controle , Escherichia coli Uropatogênica/efeitos dos fármacos , Actinas/metabolismo , Administração Oral , Animais , Aderência Bacteriana/efeitos dos fármacos , Suplementos Nutricionais , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Neuropeptídeos/metabolismo , Multimerização Proteica , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Luteolin is a common dietary flavonoid present in Chinese herbal medicines that has been reported to have important anti-inflammatory properties. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-virus inflammatory capacity of luteolin and its molecular mechanisms of action were analyzed. The cytotoxic effects of luteolin were assessed in the presence or absence of pseudorabies virus (PRV) via LDH and MTT assays. The results showed that luteolin (<10µM) had no toxic effects and there were tendencies toward higher cell survival. In PRV-infected RAW264.7 cells, luteolin potently inhibited the production of NO, iNOS, COX-2 and inflammatory cytokine production. Luteolin did not inhibit the phosphorylation of ERK 1/2, p38, and JNK 1/2 either. We found that PRV-induced NF-κB activation is regulated through inhibition of STAT1and STAT3 phosphorylation in response to luteolin. Additionally, luteolin caused the induction of HO-1 via upregulation of Nrf2, both of which are involved in the secretion of proinflammatory mediators. The blockade of HO-1 expression with SnPP, a HO-1 inhibitor, attenuated HO-1 induction by luteolin and thus mitigated its anti-inflammatory effects during PRV-infected RAW264.7 cells. Taken together, our data indicate that luteolin diminishes the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2, in PRV-infected RAW264.7 cells by inhibiting STAT1/3 dependent NF-κB activation and inducing Nrf2mediated HO-1 expression.
Assuntos
Heme Oxigenase-1/genética , Inflamação/tratamento farmacológico , Luteolina/administração & dosagem , Proteínas de Membrana/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Animais , Antioxidantes/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Herpesvirus Suídeo 1/patogenicidade , Inflamação/genética , Inflamação/virologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Fosforilação/efeitos dos fármacos , Células RAW 264.7RESUMO
Luteolin, a flavonoid present in leaves and stems of many plants finds mention in literature for beneficial effects on eyes. Presently, no reports are available on the in vivo anticataractogenic effect of luteolin. The current study was designed to evaluate the efficacy of luteolin on selenite-induced cataract models in vivo. The study consisted of three groups of Sprague Dawley rat pups 8-10â d old (Groupâ I (Normal), Groupâ II (Cataract induced), and Groupâ III (Treatment)). Cataract was induced in Groupâ II and Groupâ III by a subcutaneous injection of sodium selenite (4â µg/g body weight) on the 10th day. Luteolin was administered orally from 8th day up to 12th day at a concentration of 1â µg/g body weight in Groupâ III. After 30â d, lenses of treated animals showed normal morphology. Activities of antioxidant enzymes were increased and levels of reactive oxygen species were decreased in the luteolin-treated group when compared to the cataract-induced group. Increased Ca(2+) ATPase activity and lowered calcium level, caspase 3 activity and down-regulation of caspase 3 expression were seen in the treatment group when compared to the selenite group. Luteolin enhances the antioxidant potential and thereby lowers the oxidative damages to the lens. It also stabilizes the membrane integrity of the lens and maintains the ionic balance.
Assuntos
Catarata/prevenção & controle , Suplementos Nutricionais , Luteolina , Ácido Selenioso , Animais , Caspase 3/genética , Catarata/induzido quimicamente , Catarata/fisiopatologia , Regulação da Expressão Gênica , Luteolina/administração & dosagem , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/químicaRESUMO
The purpose of our study was to observe the effects of luteolin on the expression of the genes ICAM-1, LFA-3, and PCNA in H22 hepatoma tissue. Sixty ICR (Institute of Cancer Research) mice with H22 hepatoma were randomly divided into five groups: a normal saline control group, low-, medium-, and high-dose luteolin groups, and a cyclophosphamide group. The mice were euthanized the day after administration withdrawal and subcutaneous tumor tissue was extracted. Quantitative fluorescence RT-PCR was used to detect the expression of ICAM-1, LFA-3, and PCNA in H22 hepatoma tissue in the mice. Luteolin was found to up-regulate the expression of ICAM-1 in H22 hepatoma tissue, of which the middle-dose group had the most obvious effect, showing a significant difference (P < 0.01) as compared to the normal saline group. Each dose group of luteolin significantly down-regulated the expression of LFA-3 in H22 hepatoma tissue, showing significant differences as compared to the saline control group (P < 0.01). The medium- and high-dose luteolin groups significantly reduced the expression of PCNA in H22 hepatoma tissue of ICR mice, where the effect of the high-dose group was the most obvious, and the difference between the two luteolin groups and the normal saline group was statistically significant (P < 0.01). Luteolin may inhibit tumor angiogenesis and tumor cell proliferation by down-regulation of LFA- 3 and PCNA and up-regulation of ICAM-1 in tumor tissue of tumor-bearing mice, thereby achieving its anti-tumor effect.
Assuntos
Antígenos CD58/biossíntese , Carcinoma Hepatocelular/genética , Molécula 1 de Adesão Intercelular/biossíntese , Neoplasias Hepáticas/genética , Neovascularização Patológica/genética , Antígeno Nuclear de Célula em Proliferação/biossíntese , Animais , Antígenos CD58/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Molécula 1 de Adesão Intercelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Luteolina/administração & dosagem , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Antígeno Nuclear de Célula em Proliferação/genéticaRESUMO
OBJECTIVES: The paper describes the flavonoid composition of the aerial parts (young leaves, YL; adult leaves, AL; stems, ST) of Passiflora loefgrenii Vitta, a rare species native to Brazil, where it is traditionally used as food. Antioxidant potential has also been evaluated. To the best of our knowledge, no phytochemical and biological study on this species has been reported previously. METHODS: Compositional data have been acquired combining HPLC-diode array detector (DAD) and Electrospary ionization-tandem mass spectrometry (ESI-MS/MS) analyses. Antioxidant activity has been evaluated by the 2,2'-di-phenyl-1-picrylhydrazyl method. KEY FINDINGS: Glycosylated flavones, with luteolin as the main aglycone, can be regarded as biomarkers for this drug. Qualitative composition of the extracts from YL, AL and ST was similar. The bulk of the constituents was made up by 8-C-ß-glucosyl luteolin (orientin), 7-O-α-rhamnosyl-6-C-ß-glucosyl luteolin and 6-C-α-rhamnosyl luteolin, which totally amounted to 16.57 (73%), 10.77 (74%) and 5.07 (77%) µg/mg in YL, AL and ST, respectively. P. loefgrenii showed a good antioxidant activity (IC50 of 350 µg/ml), higher than generally reported for other passifloras. CONCLUSIONS: P. loefgrenii, rich in luteolin glycosides, can be regarded as a good candidate to be explored for therapeutic properties other than the sedative one since it represents a rich source of valuable flavonoids with antioxidant potential.