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1.
Medicina (Kaunas) ; 57(9)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34577802

RESUMO

Background and Objectives: Malignant glioblastoma (GBM) is caused by abnormal proliferation of glial cells, which are found in the brain. The therapeutic effects of surgical treatment, radiation therapy, and chemo-therapy against GBM are relatively poor compared with their effects against other tumors. Luteolin is abundant in peanut shells and is also found in herbs and other plants, such as thyme, green pepper, and celery. Luteolin is known to be effective against obesity and metabolic syndrome. The anti-inflammatory, and anti-cancer activities of luteolin have been investigated. Most studies have focused on the antioxidant and anti-inflammatory effects of luteolin, which is a natural flavonoid. However, the association between the induction of apoptosis by luteolin in GBM and autophagy has not yet been investigated. This study thus aimed to confirm the occurrence of luteolin-induced apoptosis and autophagy in GBM cells and to assess their relationship. Materials and Methods: A172 and U-373MG glioblastoma cell lines were used for this experiment. We confirmed the apoptosis effect of Luteolin on GBM cells using methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunofluorescence, Flow cytometry (FACS) western blot, and real-time quantitative PCR (qPCR). Results: In the luteolin-treated A172 and U-373MG cells, cell viability decreased in a concentration- and time-dependent manner. In addition, in A172 and U-373MG cells treated with luteolin at concentrations greater than 100 µM, nuclear fragmentation, which is a typical morphological change characterizing apoptosis, as well as fragmentation of caspase-3 and Poly (ADP-ribose) polymerase (PARP), which are apoptosis-related factors, were observed. Autophagy was induced after treatment with at least 50 µM luteolin. Inhibition of autophagy using 3MA allowed for a low concentration of luteolin to more effectively induce apoptosis in A172 and U-373MG cells. Conclusions: Results showed that luteolin induces apoptosis and autophagy and that the luteolin-induced autophagy promotes cell survival. Therefore, an appropriate combination therapy involving luteolin and an autophagy inhibitor is expected to improve the prognosis of GBM treatment.


Assuntos
Glioblastoma , Luteolina , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Glioblastoma/tratamento farmacológico , Humanos , Luteolina/farmacologia , Luteolina/uso terapêutico
2.
Int J Mol Sci ; 22(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34502488

RESUMO

The current study was undertaken to unveil the protective effects of Luteolin, a natural flavonoid, against amyloid-beta (Aß1-42)-induced neuroinflammation, amyloidogenesis, and synaptic dysfunction in mice. For the development of an AD mouse model, amyloid-beta (Aß1-42, 5 µL/5 min/mouse) oligomers were injected intracerebroventricularly (i.c.v.) into mice's brain by using a stereotaxic frame. After that, the mice were treated with Luteolin for two weeks at a dose of 80 mg/kg/day. To monitor the biochemical changes, we conducted western blotting and immunofluorescence analysis. According to our findings, the infusion of amyloid-beta activated c-Jun N-terminal kinases (p-JNK), p38 mitogen-activated protein kinases, glial fibrillary acidic protein (GFAP), and ionized calcium adaptor molecule 1 (Iba-1) in the cortex and hippocampus of the experimental mice; these changes were significantly inhibited in Aß1-42 + Luteolin-treated mice. Likewise, we also checked the expression of inflammatory markers, such as p-nuclear factor-kB p65 (p-NF-kB p65 (Ser536), tissue necrosis factor (TNF-α), and Interleukin1-ß (IL-1ß), in Aß1-42-injected mice brain, which was attenuated in Aß1-42 + Luteolin-treated mice brains. Further, we investigated the expression of pro- and anti-apoptotic cell death markers such as Bax, Bcl-2, Caspase-3, and Cox-2, which was significantly reduced in Aß1-42 + Lut-treated mice brains compared to the brains of the Aß-injected group. The results also indicated that with the administration of Aß1-42, the expression levels of ß-site amyloid precursor protein cleaving enzyme (BACE-1) and amyloid-beta (Aß1-42) were significantly enhanced, while they were reduced in Aß1-42 + Luteolin-treated mice. We also checked the expression of synaptic markers such as PSD-95 and SNAP-25, which was significantly enhanced in Aß1-42 + Lut-treated mice. To unveil the underlying factors responsible for the protective effects of Luteolin against AD, we used a specific JNK inhibitor, which suggested that Luteolin reduced Aß-associated neuroinflammation and neurodegeneration via inhibition of JNK. Collectively, our results indicate that Luteolin could serve as a novel therapeutic agent against AD-like pathological changes in mice.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/toxicidade , Encéfalo/metabolismo , Luteolina/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos
3.
Biomed Res Int ; 2021: 2252705, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368345

RESUMO

To observe the effects of luteolin on galactosamine (D-Gal)/lipopolysaccharide (LPS) induced liver injury in mice. Male C57BL/6 mice were randomly divided into 4 groups: normal control group, D-GaI/LPS group, D-GaI/LPS + luteolin (Lu, 20 mg/kg), and D-GaI/LPS + luteolin (Lu, 40 mg/kg). Mice in the normal control group and D-GaI/LPS group were given distilled water while other groups were given drugs in 7 days by gavage. 4 hours after the continuous administration, Gal (700 mg/kg) and LPS (10 mg/kg) were injected intraperitoneally. Mice in the normal control group were given the same volume of vegetable oil solution. 24 h after the establishment of the mice model, blood and liver samples were collected. Hematoxylin (HE) staining was used to observe the changes of hepatic histopathology. Alanine aminotransferase (ALT) and glutamic oxalacetic transaminase (AST) in serum, interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor (TNF-α) were measured by related kits. Western blotting was used to demonstrate the expression levels of related inflammation proteins. Lu significantly reduced levels of proinflammatory cytokines including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) in serum and liver. Lu restored the pathological changes after galactosamine (D-Gal)/lipopolysaccharide (LPS) treatment. In addition, Lu regulated proteins levels of the NLRP3/NF-κB pathway in liver. Lu exhibited therapeutical effects on D-GaI/LPS induced liver injury in mice which might be related to the regulation of the NLRP3/NF-κB pathway.


Assuntos
Fígado/lesões , Fígado/patologia , Luteolina/farmacologia , Substâncias Protetoras/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Citocinas/sangue , Galactosamina , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Transcrição RelA/metabolismo
4.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445417

RESUMO

This study aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®), composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in vivo model of traumatic brain injury (TBI) and patients affected by moderate TBI. An increase in neurogenesis was seen in the mice at 72 h and 7 d after TBI. The co-ultra PEALut treatment helped the neuronal reconstitution process to restore the basal level of both novel and mature neurons; moreover, it induced a significant upregulation of the neurotrophic factors, which ultimately led to progress in terms of memory recall during behavioral testing. Moreover, our preliminary findings in a clinical trial suggested that Glialia® treatment facilitated neural recovery on working memory. Thus, co-ultra PEALut (Glialia®) could represent a valuable therapeutic agent for intensifying the endogenous repair response in order to better treat TBI.


Assuntos
Amidas/administração & dosagem , Lesões Encefálicas Traumáticas/tratamento farmacológico , Etanolaminas/administração & dosagem , Luteolina/administração & dosagem , Neurogênese/efeitos dos fármacos , Ácidos Palmíticos/administração & dosagem , Administração Oral , Adulto , Idoso , Amidas/farmacologia , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/psicologia , Modelos Animais de Doenças , Quimioterapia Combinada , Etanolaminas/farmacologia , Feminino , Humanos , Luteolina/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Distribuição Aleatória , Aprendizagem Espacial/efeitos dos fármacos , Resultado do Tratamento
5.
ACS Chem Neurosci ; 12(18): 3314-3322, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34445868

RESUMO

Luteolin is a flavone compound occurring in a variety of medicinal plants, which is reported to have neuroprotective properties. In this study, we aimed to explore the effects of luteolin in alleviating sevoflurane-induced neurotoxicity. GeneCards and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform were employed to screen luteolin, sevoflurane, and neurotoxicity-related genes. Subsequently, we isolated primary neurons from the hippocampus of 1-day-old C57BL/6J mice and tested for cytotoxicity after treatment of different concentrations of luteolin. Next, we measured the expression of apoptosis by flow cytometry and assessed inflammation-related factors, including heme oxygenase-1 expression detected by immunohistochemical staining and neuronal apoptosis. Finally, water maze, open field, and fear conditioning tests were conducted to observe the interaction between luteolin and sevoflurane in cognitive impairment of mice. Luteolin had the lowest cytotoxicity at concentrations of 30 or 60 µg/mL; we selected 30 µg/mL for drug administration experiments in vitro. Luteolin inhibited sevoflurane-induced neuronal apoptosis and inflammatory responses through the autophagic pathway and thus ameliorated sevoflurane-induced cognitive impairment in mice. Mechanistically, luteolin up-regulated heme oxygenase-1 expression, which activated the autophagy pathway in vitro. This was confirmed by subsequent histological experiments in mice and behavioral results showing rescue cognitive impairment. Our findings uncovered an inhibitory role of luteolin in sevoflurane-induced neuronal apoptosis and inflammatory response through activation of autophagy arising from up-regulation of heme oxygenase-1, thereby alleviating sevoflurane-induced cognitive impairment in mice.


Assuntos
Heme Oxigenase-1 , Luteolina , Animais , Apoptose , Autofagia , Hipocampo , Luteolina/farmacologia , Aprendizagem em Labirinto , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Sevoflurano/toxicidade
6.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361729

RESUMO

Tyrosinase (TYR) is a type III copper oxidase present in fungi, plants and animals. The inhibitor of human TYR plays a vital role in pharmaceutical and cosmetic fields by preventing synthesis of melanin in the skin. To search for an effective TYR inhibitor from various plant extracts, a kinetic study of TYR inhibition was performed with mushroom TYR. Among Panax ginseng, Alpinia galanga, Vitis vinifera and Moringa oleifera, the extracts of V. vinifera seed, A. galanga rhizome and M. oleifera leaf reversibly inhibited TYR diphenolase activity with IC50 values of 94.8 ± 0.2 µg/mL, 105.4 ± 0.2 µg/mL and 121.3 ± 0.4 µg/mL, respectively. Under the same conditions, the IC50 values of the representative TYR inhibitors of ascorbic acid and kojic acid were found at 235.7 ± 1.0 and 192.3 ± 0.4 µg/mL, respectively. An inhibition kinetics study demonstrated mixed-type inhibition of TYR diphenolase by A. galanga and V. vinifera, whereas a rare uncompetitive inhibition pattern was found from M. oleifera with an inhibition constant of Kii 73 µg/mL. Phytochemical investigation by HPLC-MS proposed luteolin as a specific TYR diphenolase ES complex inhibitor, which was confirmed by the inhibition kinetics of luteolin. The results clearly showed that studying TYR inhibition kinetics with plant extract mixtures can be utilized for the screening of specific TYR inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Luteolina/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Moringa oleifera/química , Agaricales/química , Agaricales/enzimologia , Alpinia/química , Ácido Ascórbico/química , Ácido Ascórbico/isolamento & purificação , Ácido Ascórbico/farmacologia , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Proteínas Fúngicas/isolamento & purificação , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Cinética , Luteolina/química , Luteolina/isolamento & purificação , Monofenol Mono-Oxigenase/isolamento & purificação , Panax/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Pironas/química , Pironas/isolamento & purificação , Pironas/farmacologia , Rizoma/química , Sementes/química , Vitis/química
7.
J Mol Model ; 27(8): 221, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236507

RESUMO

Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Luteolina/farmacologia , Simulação de Dinâmica Molecular , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/isolamento & purificação , Antivirais/metabolismo , Sítios de Ligação , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Cinética , Lamiaceae/química , Luteolina/isolamento & purificação , Luteolina/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Ligação Proteica , Conformação Proteica , Receptores Virais/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo
8.
Chem Biol Interact ; 345: 109573, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34217685

RESUMO

Pyroptosis plays an important role in the pathogenesis of numerous infectious, autoimmune, and inflammatory diseases, which makes it a promising target for intervention. In this study, the effect of luteolin on pyroptosis and the underlying mechanism were investigated using the canonical NLRP3 inflammasome in THP-1 macrophages induced by LPS/ATP. The results showed that luteolin exhibited a potent preventive effect on THP-1 macrophage pyroptosis, as evidenced by the increase in cell viability and the decrease in LDH release. Moreover, luteolin was found to significantly reduce the expression of NLRP3, pro-CASP-1 and CASP-1, which are the key components of NLRP3 inflammasome, as well as the expression of N-GSDMD and IL-1ß, and we proved that the inhibition of luteolin on NLRP3 inflammasome activation is ROS-dependent. Furthermore, it was demonstrated that luteolin promoted Nrf2 nuclear translocation, thereby increasing the expression of HO-1 that reduces ROS production, while the anti-pyroptotic effect of luteolin was reversed by a specific Nrf2 inhibitor. Additionally, luteolin inhibited NF-κB p65 phosphorylation and nuclear translocation. In summary, we conclude that luteolin prevents THP-1 macrophage pyroptosis by suppressing ROS production via Nrf2 activation as well as NF-κB inactivation. These results support luteolin as a potential bioactive chemical against pyroptosis-related inflammatory diseases.


Assuntos
Luteolina/farmacologia , Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
9.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299354

RESUMO

The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3',4'-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.


Assuntos
Endonucleases/antagonistas & inibidores , Luteolina/síntese química , Luteolina/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Antivirais/síntese química , Antivirais/farmacologia , Domínio Catalítico/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores
10.
Sci Rep ; 11(1): 12595, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131251

RESUMO

Luteolin is a flavonoid found in a wide range of plant materials, including commonly eaten fruits and vegetables. It displays a wide range of biological activities but is known to have poor bioavailability. In this study, ten different mono-acyl (nine 5-O-acyl and one 7-O-acyl) derivatives of luteolin were synthesised for the purpose of improving bioactivity and bioavailability, and therefore enhance their therapeutic potential. The antiproliferative activity of these derivatives was assessed against the HCT116 colon cancer and MDA-MB-231 breast cancer cell lines using a 3[H] thymidine incorporation assay. The radical scavenging activity of these derivatives against 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical using Trolox as a standard, was also assessed. Some of these derivatives were found to have improved antiproliferative activity with comparable radical scavenging activity compared to luteolin. Increased lipophilicity has been shown to increase the bioavailability of flavonoids implying these analogues will also have increased bioavailability.


Assuntos
Antioxidantes/farmacologia , Disponibilidade Biológica , Sequestradores de Radicais Livres/farmacologia , Luteolina/farmacologia , Antioxidantes/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Feminino , Sequestradores de Radicais Livres/química , Células HCT116 , Humanos , Luteolina/síntese química
11.
Phytomedicine ; 88: 153604, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130054

RESUMO

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/patologia
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(5): 729-735, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34134961

RESUMO

OBJECTIVE: To investigate the protective effect of luteolin against cadmium (Cd)-induced injury in human lung epithelial Beas-2B cells. OBJECTIVE: Beas-2B cells were treated with different concentrations of luteolin (0-160 µmol/L) or Cd (0-40 µmol/L) for 24 h, and the cell viability was examined using MTT assay. After treatment with luteolin (0.25, 0.5 and 0.75 µmol/L) with or without Cd (5 µmol/L) for 24 h, the cells were examined for viability, lactate dehydrogenase (LDH) activity and morphological changes of the cell nuclei using Hoechst fluorescent staining. The levels of ROS, SOD, GSH and MDA in the treated cells were detected, and the expression levels of Akt, p-Akt and nuclear factor E2-related factor 2 (Nrf2) proteins were determined using Western blotting. OBJECTIVE: Luteolin within the concentration range of 0-80 µmol/L did not significantly affect the survival rate of Beas-2B cells (P>0.05), but Cd at 5 µmol/L significantly decreased the cell viability (P < 0.05) with an IC50 of 24.6 µmol/L. In Cd-treated cells, treatment with luteolin significantly mitigated the decrease of cell viability, reduced LDH release and cell apoptosis, enhanced SOD activity and GSH content, and inhibited the production of MDA and ROS (all P < 0.05). Luteolin also significantly up-regulated the expression levels of p-Akt and Nrf2 protein in Cd-treated Beas-2B cells (P < 0.05). OBJECTIVE: Luteolin has a significant protective effect against Cd-induced injury in Beas-2B cells, and the effects are probably mediated, at least in part, by promoting the activation of Akt and Nrf2.


Assuntos
Cádmio , Luteolina , Apoptose , Cádmio/toxicidade , Células Epiteliais/metabolismo , Humanos , Pulmão/metabolismo , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo
13.
J Biomed Nanotechnol ; 17(6): 1229-1241, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34167635

RESUMO

The effective therapy for lung infectious diseases became more and more difficult since the severe antibiotic resistance of pathogenic microorganisms, it is urgent to develop new antimicrobial agents. Luteolin has been reported to play a crucial part in host immune responses. However, the clinical use of luteolin is impeded due to its hydrophobicity and low oral bioavailability. In this study, we formulated luteolin-loaded Methoxy poly(ethylene glycol)-poly(lactide) micelles (luteolin/MPEG-PLA), to improve the bioavailability of luteolin in lung infectious diseases. The results showed that luteolin/MPEG-PLA treatment could reduce the adhesion of Klebsiella pneumoniae (K. pneumoniae) to lung epithelial cells and enhance the germicidal ability of macrophages against K. pneumoniae compared to untreated group. Meanwhile, luteolin/MPEG-PLA showed stronger adhesion resistance of epithelial cells and germicidal ability of macrophages compared with free luteolin. In vivo study, luteolin/MPEG-PLA administration significantly promoted the clearance of bacteria and reduced inflammatory infiltration of lung tissue in K. pneumoniae induced lung infectious mice model. Further studies showed that treatment with luteolin/MPEG-PLA reduced the mRNA expression of LPS-induced inflammatory cytokines and chemokines in macrophages significantly. In general, luteolin/MPEG-PLA can enhance the anti-bacterial ability of lung epithelial cells and macrophages, and has a stronger therapeutic effect than free luteolin in bacterial-induced lung infection. Luteolin/MPEG-PLA may be an excellent potential drug for bacterial-induced lung infectious diseases treatment.


Assuntos
Luteolina , Micelas , Animais , Anti-Inflamatórios , Bactérias , Portadores de Fármacos , Pulmão , Luteolina/farmacologia , Camundongos , Poliésteres , Polietilenoglicóis
14.
J Cell Mol Med ; 25(12): 5560-5571, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33982869

RESUMO

Lung cancer is the leading cause of cancer-related deaths. LIM domain kinase (LIMK) 1 is a member of serine/threonine kinase family and highly expressed in various cancers. Luteolin, a polyphenolic plant flavonoid, has been reported to suppress tumour proliferation through inducing apoptosis and autophagy via MAPK activation in glioma. However, the mechanism of luteolin on suppressing lung cancer growth is still unclear. We found that luteolin targeted LIMK1 from the in silico screening and significantly inhibited the LIMK1 kinase activity, which was confirmed with pull-down binding assay and computational docking models. Treatment with luteolin inhibited lung cancer cells anchorage-independent colony growth and induced apoptosis and cell cycle arrest at G1 phase. Luteolin also decreased the expression of cyclin D1 and increased the levels of cleaved caspase-3 by down-regulating LIMK1 signalling related targets, including p-LIMK and p-cofilin. Furthermore, luteolin suppressed the lung cancer patient-derived xenograft tumour growth by decreasing Ki-67, p-LIMK and p-cofilin expression in vivo. Taken together, these results provide insight into the mechanism that underlies the anticancer effects of luteolin on lung cancer, which involved in down-regulation of LIMK1 and its interaction with cofilin. It also provides valuable evidence for translation towards lung cancer clinical trials with luteolin.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinases Lim/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Luteolina/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Técnicas In Vitro , Quinases Lim/genética , Quinases Lim/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Bioorg Chem ; 112: 104966, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33991837

RESUMO

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-Atividade
16.
Fitoterapia ; 152: 104922, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33984439

RESUMO

The treatment of sepsis is still challenging and the liver is an important target of sepsis-related injury. Macrophages are important innate immune cells in liver, and modulation of macrophages M1/M2 polarization may be a promising strategy for septic liver injury treatment. Macrophage polarization and inflammation of liver tissue has been shown regulated by pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis and immune inflammatory pathways. Therefore, modulating PKM2-mediated immunometabolic reprogramming presents a novel strategy for inflammation-associated diseases. In this study, cynaroside, a flavonoid compound, promoted macrophage phenotypic transition from pro-inflammatory M1 to anti-inflammatory M2, and mitigated sepsis-associated liver inflammatory damage. We established that cynaroside reduced binding of PKM2 to hypoxia-inducible factor-1α (HIF-1α) by abolishing translocation of PKM2 to the nucleus and promoting PKM2 tetramer formation, as well as suppressing phosphorylation of PKM2 at Y105 in vivo and in vitro. Moreover, cynaroside restored pyruvate kinase activity, inhibited glycolysis-related proteins including PFKFB3, HK2 and HIF-1α, and inhibited glycolysis-related hyperacetylation of HMGB1 in septic liver. Therefore, this study reports a novel function of cynaroside in hepatic macrophage polarization, and cecum ligation and puncture-induced liver injury in septic mice. The findings provide crucial information with regard to therapeutic efficacy of cynaroside in the treatment of sepsis.


Assuntos
Glucosídeos/farmacologia , Fígado/lesões , Luteolina/farmacologia , Macrófagos/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia , Fígado/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fosforilação , Piruvato Quinase , Células RAW 264.7
17.
Chirurgia (Bucur) ; 116(2): 170-177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33950812

RESUMO

Breast cancer represents one of the three most common gynecological cancers, with each subtype having distinct risk profile and treatment strategies. Optimal therapy for each case depends not only on tumor subtype and cancer stage, but also on patient preferences. Thus, the final therapeutic choice seems complicated to be reached. In addition, frequent relapses and the aesthetic effects have led to the search for more effective and less invasive methods. Surgical interventions have become less complex and new hormonal and chemotherapeutic drugs are established, that promise great results, either combined to surgical treatment or used exclusively. Luteolin is a representative of natural flavonoid that has proven to modulate various signaling pathways involved in cancer development. Recent data demonstrate that luteolin induces apoptotic cell death via antioxidant activity, acting as an anticancer agent against various types of human malignancies including breast cancer. The aim of this review is to summarize latest data considering the therapeutic role of luteolin in breast cancer.


Assuntos
Neoplasias da Mama , Luteolina , Apoptose , Neoplasias da Mama/tratamento farmacológico , Humanos , Luteolina/farmacologia , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do Tratamento
18.
Phytomedicine ; 87: 153586, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34044253

RESUMO

BACKGROUND: Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases. PURPOSE: The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis. STUDY DESIGN: Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin. METHODS: Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury. RESULTS: The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1ß (IL-1ß) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro. CONCLUSIONS: These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inflamassomos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Luteolina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Tiorredoxinas/antagonistas & inibidores , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatite/tratamento farmacológico , Hepatite/etiologia , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Inflamassomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
19.
Toxicol Appl Pharmacol ; 424: 115581, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34019859

RESUMO

Oral squamous cell carcinoma (OSCC) is among the most prevalent cancers of the head and neck. This study revealed that isoorientin attenuates OSCC cell stemness and epithelial-mesenchymal transition potential through the inhibition of JAK/signal transducer and activator of transcription 3 (STAT3) and Wnt/ß-catenin signaling in cell lines. Our findings indicated that isoorientin is a potential inhibitor of ß-catenin/STAT3 in vitro and in vivo. We analyzed possible synergism between isoorientin and cisplatin in OSCC. A sulforhodamine B assay, colony formation assay, tumorsphere-formation assay, and Wnt reporter activity assay were used for determining cell invasion, cell migration, drug cytotoxicity, and cell viability with potential molecular mechanisms in vitro. Isoorientin reduced the expression of p-STAT3, ß-catenin, and p-GSK3 as well as downstream effectors TCF1/TCF7 and LEF1 and significantly reduced ß-catenin colocalization in the nucleus. Isoorientin markedly strengthened the cytotoxic effects of cisplatin against SAS and SCC-25. Therefore, combining isoorientin and cisplatin treatments can potentially improve the anticancer effect of cisplatin. Isoorientin inhibited the tumorigenicity and growth of OSCC through the abrogation of Wnt/ß-catenin/STAT3 signaling in vivo. Thus, isoorientin disrupted the ß-catenin signaling pathway through the inactivation of STAT3 signaling. In conclusion, targeting OSCC-SC-mediated stemness with isoorientin to eradicate OSCC-SCs may be an effective strategy for preventing relapse and metastasis of OSCC and providing long-term survival benefits.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Luteolina/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Luteolina/administração & dosagem , Luteolina/química , Camundongos , Estrutura Molecular , Neoplasias Experimentais , Células-Tronco Neoplásicas , Interferência de RNA , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
20.
Molecules ; 26(9)2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946287

RESUMO

Skin moisturization is very crucial for maintaining the flexibility, viscoelasticity, and differentiation of the epidermis and its deprivation causes several diseases from dry skin to dermatitis. Aloe vera, a miracle plant having diverse medicinal properties including skin moisturization effects. This study investigated for the first time the molecular mechanism targeting skin moisturization effects of the Aloe vera flower and its major active constituent. By treating human epidermal keratinocytes (HaCaT cells) with Aloe vera flower water extract (AFWE), we found that AFWE upregulated epidermal involucrin by activating the expression of protein kinase C, p38, and ERK 1/2. Additionally, it modulated filaggrin, increased aquaporin expression, and hyaluronan synthesis via a balanced regulation of HAS1 and HYAL1 protein. Similarly, it was able to protect UVB-induced photodamage. Western blot analysis, ELISA, and qRT- PCR were performed to evaluate various epidermal differentiation markers and moisturization-related factors on human epidermal keratinocytes (HaCaT cells). TLC and HPLC were used to detect and analyze the chemical constituents. Among them, we found that an active component of Aloe vera flower, isoorientin (IO) has a high binding affinity to all of its targeted proteins such as involucrin, PKC, P38, etc. through molecular docking assay. This study indicated that the Aloe vera flower and its active constituent, IO can be used as a prominent ingredient to enhance skin barrier function and improve its related pathologies.


Assuntos
Aloe/química , Flores/química , Regulação da Expressão Gênica/efeitos dos fármacos , Luteolina/química , Luteolina/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Precursores de Proteínas/genética , Biomarcadores , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Relação Estrutura-Atividade
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