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1.
Life Sci ; 254: 117782, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407847

RESUMO

AIMS: This study assessed the prophylactic or therapeutic effects of taurine (TR) and/or hesperidin (HES) on carbon tetrachloride (CCl4) induced acute kidney and testicular injury in rats. MAIN METHODS: Rats were randomly divided into nine experimental groups including control; corn oil; CCl4; HES/CCl4; TR/CCl4; HES + TR/CCl4; CCl4/HES; CCl4/TR; and CCl4/HES + TR groups. CCl4 was intraperitoneally injected with a single dose of 2 ml /kg b.w. HES and TR were orally gavaged twice weekly 100 mg/kg b.w. for four weeks. Kidney function, inflammatory response, sexual hormones, and oxidative stress indicators were assessed. Histomorphological and immune-histochemical studies of the inflammatory marker nuclear factor kappa (NF-κB) in renal and testicular tissues were performed. KEY FINDINGS: The results showed that the TR and/or HES treatment significantly suppressed CCl4 induced rise of urea, uric acid, potassium, and follicle-stimulating hormone levels. However, significant restoration of sodium, testosterone, and luteinizing hormone was apparent in CCl4 exposed rats received HES and/or TR. Also, the HES and/or TR treatment significantly rescues CCl4 induced oxidative stress and inflammation. Moreover, the HES and/or TR dosing significantly repaired the CCl4 evoked altered renal and testicular architecture and suppressed NF-κB immunoexpression. Notably, alleviating CCl4 induced renal and testicular damage was more effective in the prophylactic groups than the therapeutic groups. Also, most of the estimated parameters of the HES + TR group did not significantly vary from those of single TR or HES. SIGNIFICANCE: In conclusion, HES or TR could efficiently guard against CCl4 nephro-and reprotoxic effects, but both bioactive combinations afford only a limited synergistic outcome.


Assuntos
Hesperidina/farmacologia , Inflamação/prevenção & controle , Rim/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Taurina/farmacologia , Testículo/metabolismo , Animais , Tetracloreto de Carbono , Sinergismo Farmacológico , Hormônio Foliculoestimulante/metabolismo , Rim/patologia , Hormônio Luteinizante/metabolismo , Masculino , NF-kappa B/metabolismo , Potássio/metabolismo , Ratos , Sódio/metabolismo , Testículo/patologia , Testosterona/metabolismo , Ureia/metabolismo , Ácido Úrico/metabolismo
2.
J Photochem Photobiol B ; 204: 111767, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006893

RESUMO

Colon carcinoma is a recurring type of cancer that affects the intestine epithelial with a poor survival rate. It was already proven the anticancer property of hesperidin in various cancers but the bioavailability hesperidin is poor, which hinders the hesperidin usage. In this investigation we synthesized hesperidin loaded Zn2+@ SA/PCT nanocomposites and assessed its anticancer potential against colon cancer (HCT116) cells. Hesperidin loaded Zn2+@ SA/PCT nanocomposites were characterized using Fourier transform infrared (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis. The drug releasing capacity and cytotoxic property was assessed via drug releasing assay, MTT assay with HCT116 cells. The anticancer potency of hesperidin nanocomposites were evaluated with TUNEL, DAPI staining, reactive oxygen species (ROS) generation assay and it is confirmed with flow cytometry analysis of MMP disruption in colon cancer (HCT116) cell line. Further the immunoblotting analysis of cysteine proteases Caspases 3, 9, PARP, proapoptotic protein Bax and antiapoptotic protein Bcl2 were performed. The results of FTIR, XRD and electroscopic analyses confirmed the synthesized hesperidin nanocomposites accomplish the properties of potent nanodrug and the MTT assay authentically confirmed that the synthesized hesperidin nanocomposite inhibited the HCT116 cell growth, and the results of fluorescent staining proved that the hesperidin nanocomposite induced the apoptotic mediated cell necrosis via promoting the expression of apoptotic proteins thereby induced the apoptosis in colon cancer (HCT116) cells. Hence, it was concluded that the, hesperidin loaded nanocomposites persuasively inhibited proliferation of colon carcinoma cell and induced apoptosis in in vitro condition.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Hesperidina/química , Nanocompostos/química , Alginatos/química , Antineoplásicos Fitogênicos/química , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Células HCT116 , Hesperidina/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pectinas/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Zinco/química
3.
Toxicology ; 433-434: 152406, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32050098

RESUMO

Recently, oxidative stress was implicated in the environmental contaminant Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity, however the mechanism is unclear. We investigated the role of oxidative stress-responsive microRNAs in DEHP-induced aberrations and the protective effect of the citrus flavonoid, hesperidin (HSP). Male Wistar rats were randomly allocated into four groups as vehicle-treated control, DEHP-alone group (500 mg/kg/day) for 30 days, and HSP (25 or 50 mg/kg) for 60 days; testicular damage was triggered by oral administration of DEHP (500 mg/kg/day) after thirty days of oral administration of HSP (25 or 50 mg/kg). DEHP administration reduced testis weight coefficient, serum testosterone, testicular 3ß-hydroxysteroid dehydrogenase and antioxidant enzyme activities, and elevated serum fatty acid-binding protein-9, testicular malondialdehyde, and Bax/Bcl2 ratio. Aberrant testicular miR-126-3p and miR-181a expression was observed, along with decreased expression of sirtuin1 (SIRT1) and its targets; nuclear factor-erythroid 2-related factor2, haeme oxygenase-1, and superoxide dismutase2. HSP administration significantly ameliorated these changes and restored testicular function in a dose-dependent manner. We highlight a novel role of oxidative stress-miR-126/miR-181a-SIRT1 network in mediating DEHP-induced changes which were reversed by the antioxidant HSP.


Assuntos
Dietilexilftalato/toxicidade , Hesperidina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Relação Dose-Resposta a Droga , Hesperidina/administração & dosagem , Masculino , Malondialdeído/metabolismo , MicroRNAs/genética , Plastificantes/toxicidade , Ratos , Ratos Wistar , Sirtuína 1/metabolismo , Testículo/patologia , Fatores de Tempo
4.
PLoS One ; 15(1): e0227637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929574

RESUMO

Leptin resistance and co-existing insulin resistance is considered as hallmark of diet-induced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Fármacos Antiobesidade/farmacologia , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Resistência à Insulina , Obesidade/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Fármacos Antiobesidade/química , Dieta Hiperlipídica , Modelos Animais de Doenças , Quimioterapia Combinada , Hesperidina/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Inflamação/metabolismo , Inflamação/patologia , Leptina/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Obesidade/metabolismo , Obesidade/patologia , Orlistate/química , Orlistate/farmacologia , Ratos Wistar
5.
Scand J Immunol ; 91(4): e12867, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31975405

RESUMO

Hesperetin (HES) is a dihydroflavone with the molecular formula of C16H14O6. It has been reported that Hesperetin has antioxidant and anticancer effects. Recent studies showed that it can also regulate immune responses. To assess its potential function as a vaccine adjuvant, we formulated HES with inactivated B16F10 melanoma cells and determined whether it would enhance the activation of antigen-presenting cells by experiments in vivo and in vitro. We found that HES activated the PI3K-Akt signalling pathway in antigen-presenting cells (APCs), enhanced cytotoxic T lymphocyte (CTL) responses and deactivated tolerogenic T cells. We also observed that inactivated B16F10 cells in combination with HES vaccine inhibited the growth of mice tumours, resulting in improved overall survival compared to the effects of inactivated B16F10 cell vaccine. To verify that CD8+ T cells play a key role in inhibiting the development of melanoma, we transferred the sorted CD8+ T cells from immunized mice to B16F10 challenged models and found that the survival rate of tumour-bearing mice was significantly prolonged. Taken together, these results suggest that hesperetin can be used as a potential adjuvant to improve tumour immune responses and antigen immunogenicity.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Hesperidina/farmacologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Antineoplásicos/farmacologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7
6.
Arch Biochem Biophys ; 679: 108204, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31758928

RESUMO

Crystallin proteins undergo various posttranslational modifications with aging of eye lens. Oxidation of tryptophan (Trp) residues of a major γ-crystallin namely human γD-crystallin (HGD) was found to be inhibited by a naturally occurring flavonoid hesperetin at relatively low concentration mostly due to its antioxidant activity. Further the molecular interactions between HGD and hesperetin were elucidated on the basis of the quenching of Trp fluorescence of the protein by the flavonoid. Ground state complexation between HGD and hesperetin caused static quenching of the Trp fluorescence of HGD. Binding and quenching constants were in the order of (103- 104 M-1). Energy transfer from protein to hesperetin was suggested by FRET calculations. Thermodynamic parameters reveal significant hydrophobic association between the protein and hesperetin. Synchronous fluorescence and CD spectroscopic results had ruled out conformational changes in the protein due to binding of hesperetin. Docking studies suggested the proximity of hesperetin with Trp 42, which largely corroborates our experimental findings.


Assuntos
Hesperidina/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Triptofano/metabolismo , gama-Cristalinas/química , gama-Cristalinas/metabolismo , Humanos , Modelos Moleculares , Oxirredução/efeitos dos fármacos , Conformação Proteica
7.
Arch Pharm Res ; 42(12): 1063-1070, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31802426

RESUMO

Hesperetin, a major bioflavonoid in sweet oranges and lemons, exerts an anti-inflammatory effect in pulmonary diseases; however, its effect on lipopolysaccharide (LPS)-induced acute lung injury is unclear. This study investigated the effect of hesperetin on LPS-induced lung inflammatory response. Mice were intratracheally instilled with 5 mg/kg body weight LPS, and then were given hesperetin orally (10, 20, and 30 mg/kg body weight) 1 h later. Hesperetin dramatically suppressed the levels of interleukin-6 and tumor necrosis factor-α, as well as the number of inflammatory cells in bronchoalveolar lavage fluid. Besides, it reduced lung injury, wet weight/dry weight ratio, and myeloperoxidase and lactate dehydrogenase activities, and enhanced superoxide dismutase activity. In addition, hesperetin significantly downregulated the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) protein expression and suppressed nuclear factor-kappa B (NF-κB) activation in lung tissue. Together, these results indicated that the anti-inflammatory effect of hesperetin is associated with the TLR4-MyD88-NF-κB pathway, and that hesperetin shows therapeutic potential for LPS-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Hesperidina/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Receptor 4 Toll-Like/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Relação Dose-Resposta a Droga , Hesperidina/administração & dosagem , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Molecules ; 24(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766122

RESUMO

The anti-aging activity of many plant flavonoids, as well as their mechanisms of action, have been explored in the current literature. However, the studies on the synergistic effects between the different flavonoid compounds were quite limited in previous reports. In this study, by using a high throughput assay, we tested the synergistic effects between different citrus flavonoids throughout the yeast's chronological lifespan (CLS). We studied the effect of four flavonoid compounds including naringin, hesperedin, hesperitin, neohesperidin, as well as their different combinations on the CLS of the yeast strain BY4742. Their ROS scavenging ability, in vitro antioxidant activity and the influence on the extracellular pH were also tested. The results showed that neohesperidin extended the yeast's CLS in a concentration-dependent manner. Especially, we found that neohesperidin showed great potential in extending CLS of budding yeast individually or synergistically with hesperetin. The neohesperidin exhibited the strongest function in decreasing the reactive oxygen species (ROS) accumulation in yeast. These findings clearly indicated that neohesperidin is potentially an anti-aging citrus flavonoid, and its synergistic effect with other flavonoids on yeast's CLS will be an interesting subject for future research of the anti-aging function of citrus fruits.


Assuntos
Citrus/química , Flavonoides/química , Flavonoides/farmacologia , Hesperidina/análogos & derivados , Saccharomyces cerevisiae/efeitos dos fármacos , Antioxidantes/química , Antioxidantes/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Hesperidina/química , Hesperidina/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/metabolismo
9.
Environ Sci Pollut Res Int ; 26(34): 35151-35162, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31686333

RESUMO

Acrylamide (AA) is a heat-induced toxin formed during thermal processing of many commonly consumed foods, including meat products, French fries, potato crisps, bread, cereals, cookies, and coffee. There is thus potentially high dietary exposure of humans to AA, which can induce significant oxidative stress. Hesperidin (HS) and diosmin (DS) are flavone glycosides that have antioxidant properties. The aim of this study was to investigate the protective effects of HS and DS against AA toxicity. Fifty-six adult male Wistar albino rats were divided into seven groups. The first group was orally administered 0.5% (w/v) dimethyl sulfoxide (DMSO) and considered as the control group. The second and third groups were orally administered 10 mg/kg/day of HS or DS, respectively. The fourth group received 20 mg/kg/day of AA orally for 14 days. The fifth and sixth groups were given 10 mg/kg/day of HS or DS, respectively, followed by AA. The seventh group was given both HS and DS after AA administration. AA intoxication significantly (p ≤ 0.05) increased serum levels of liver function enzymes (ALT, AST, and ALP), kidney function products (urea and creatinine), oxidative DNA damage marker (OHdG), proinflammatory markers (TNF-α, IL-1ß, and IL-6), lipid peroxidation marker (malondialdehyde), and nitric oxide (NO). On the other hand, it significantly (p ≤ 0.05) decreased levels of reduced glutathione (GSH) in the liver, kidney, and brain. The activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) in the liver, kidney, and brain tissues were also reduced. HS and DS supplementation prevented lipid peroxidation, normalized the serum parameters altered by AA, and enhanced the tissue concentrations and activities of antioxidant biomarkers. It could be concluded that HS and DS have potent protective effects against oxidative stress, lipid peroxidation, and DNA damage induced by AA toxicity in rats.


Assuntos
Acrilamida/toxicidade , Diosmina/farmacologia , Substâncias Perigosas/toxicidade , Hesperidina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Catalase/metabolismo , Creatinina/metabolismo , Dano ao DNA/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
10.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614601

RESUMO

To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 µM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) than indomethacin and celecoxib at 10 µM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.


Assuntos
Hesperidina/química , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Óxido Nítrico/biossíntese , Animais , Celecoxib/farmacologia , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hesperidina/síntese química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Indometacina/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Camundongos , NF-kappa B/genética , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética
11.
Eur J Pharmacol ; 864: 172712, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586469

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal growing problem, with limited therapeutic options. Transforming growth factor beta 1 (TGF-ß1) plays a critical role in many pathological processes that characterize pulmonary fibrosis. Effective and well-tolerated antifibrotic agents that interfere with TGF-ß1 signaling would be an ideal treatment but no such treatments are available. In this study, we identified that the natural compound, neohesperidin, antagonizes TGF-ß1/Smad3 signaling. We found that neohesperidin not only inhibited the TGF-ß1-induced injury to alveolar epithelial cells but also decreased the TGF-ß1-induced myofibroblast differentiation, extracellular matrix production, and fibroblast migration. Furthermore, we obtained in vivo evidence that neohesperidin treatment inhibited bleomycin-induced lung injuries and even attenuated established pulmonary fibrosis in mice. Our data suggest that neohesperidin can target the critical signaling pathway and profibrogenic responses in progressive pulmonary fibrosis and may have a potential use in treatment.


Assuntos
Bleomicina/efeitos adversos , Hesperidina/análogos & derivados , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Animais , Hesperidina/farmacologia , Hesperidina/uso terapêutico , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Células NIH 3T3 , Fibrose Pulmonar/patologia
12.
Int Immunopharmacol ; 76: 105838, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473406

RESUMO

Hepatic fibrosis, a common pathological feature and leading cause of various chronic liver diseases, still lacks effective therapy. Hesperetin derivative (HD) is a derivative of Traditional Chinese Medicine monomer isolated from the fruit peel of Citrusaurantium L. (Rutaceae). In the present study, we revealed the anti-fibrotic effects of HD in CCl4-induced mouse hepatic fibrosis model and in TGF-ß1-activated LX-2 cells, in vivo and in vitro. Results showed that HD prevented CCl4-induced liver injury and histological damage. Consistently, HD inhibited the up-regulation of liver fibrogenesis markers α-SMA, Col1α1, Col3α1 and TIMP-1 in primary hepatic stellate cells (HSCs) and suppressed inflammatory responses in primary liver macrophages from hepatic fibrosis mice. Furthermore, HD promoted the apoptosis of activated HSCs, a key step in the onset of fibrosis regression. Mechanistically, the Hedgehog pathway was involved in HD-treated hepatic fibrosis, and HD specifically contributed to attenuate the aberrant expression of Glioma associated oncogene-1 (Gli-1). Interestingly, blockade of Gli-1 removed the inhibitory effect of HD on activated HSCs, indicating that Gli-1 may play a pivotal role in mediating the anti-fibrotic effect of HD in hepatic fibrosis. Collectively, our results suggest that HD may be a potential anti-fibrotic Traditional Chinese Medicine monomer for the treatment of hepatic fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hesperidina/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Citocinas/genética , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Hesperidina/farmacologia , Humanos , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Fator de Crescimento Transformador beta1/farmacologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
13.
Mater Sci Eng C Mater Biol Appl ; 105: 110099, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546395

RESUMO

Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.


Assuntos
Androstadienos , Antineoplásicos Fitogênicos , Inibidores da Aromatase , Neoplasias da Mama , Hesperidina , Nanocápsulas , Albuminas/química , Albuminas/farmacocinética , Albuminas/farmacologia , Androstadienos/química , Androstadienos/farmacocinética , Androstadienos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Boro/química , Boro/farmacocinética , Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Hesperidina/química , Hesperidina/farmacocinética , Hesperidina/farmacologia , Humanos , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/farmacologia
14.
Life Sci ; 235: 116858, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31505195

RESUMO

AIMS: The current study was conducted to investigate the potential protective effects of hesperidin and its possible mechanisms of action on pancreatic ß-cells in diabetes. MAIN METHODS: Male Sprague Dawley rats were made diabetic using 65 mg/kg intraperitoneal injection of streptozotocin, and then administered daily with 100 mg/kg of hesperidin over 4 weeks. On conclusion of the experiment, blood and pancreatic tissue were collected to determine the function of ß-cells, apoptosis, oxidative stress, ER stress, and inflammation. KEY FINDINGS: Treatment of diabetic rats with hesperidin, significantly decreased fasting blood glucose and food intake, along with increased body weight, serum and pancreatic insulin levels, and pancreatic-duodenal homeobox-1 (PDX-1) protein expression. The beneficial roles of hesperidin on diabetic pancreatic ß-cells exhibited an increment in antioxidant SOD and GPx activities, and a decrement in nitrotyrosine as well as malondialdehyde (MDA) levels. Additionally, the elevated concentration of TNF-α and expressions of ER stress maker GRP78 and CHOP proteins in the pancreas of diabetic rats were significantly diminished by hesperidin treatment. Furthermore, hesperidin effectively modulated expressions of apoptosis-regulatory proteins in diabetic rat pancreas, as revealed by upregulating anti-apoptotic Bcl-xL; with a concomitant downregulating pro-apoptotic Bax, cleaved caspase-3, and inhibiting the activation of DNA repair protein poly (ADP-ribose) polymerase (PARP). SIGNIFICANCE: Collectively, these findings suggest that hesperidin may have the potential to protect pancreatic ß-cells and improve their function by suppressing oxidative and ER stress, along with activating its antioxidant, anti-inflammatory, and anti-apoptotic effects.


Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hesperidina/farmacologia , Células Secretoras de Insulina/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Homeodomínio/biossíntese , Inflamação , Insulina/sangue , Insulina/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Superóxido Dismutase/metabolismo , Transativadores/biossíntese , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
15.
Transplant Proc ; 51(8): 2828-2832, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31493917

RESUMO

OBJECTIVE: Hepatic ischemia and reperfusion (I/R) is a destructive event associated with high rates of liver failure after liver transplantation. Hesperidin significantly contributes to the antioxidant defense system and has been reported to act as a powerful agent against superoxide and hydroxyl radicals. Our objective was to investigate the protective effect of hesperidin against hepatic IR injury in a rat model. METHODS: We fed Sprague-Dawley rats either hesperidin (100 mg/kg/d) or saline. One week later, ischemia was induced by clamping the rats' common hepatic artery and portal vein for 30 minutes. The rats were divided into 3 groups: 1. the sham operated group; 2. the I/R group; and 3. the I/R-hesperidin group. RESULTS: Compared to the sham group, the I/R group had higher expression of serum aspartate aminotransferase and serum alanine aminotransferase and lower expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, nitric oxide, and albumin. Compared to the I/R group, the I/R-hesperidin group had higher expression of catalase, superoxide dismutase, antioxidant and nitric oxide and lower expression of serum aspartate aminotransferase and serum alanine aminotransferase. CONCLUSIONS: Our findings suggest that hesperidin is a potential therapeutic agent for hepatic I/R injury.


Assuntos
Antioxidantes/uso terapêutico , Hesperidina/uso terapêutico , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Hesperidina/farmacologia , Hepatopatias/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo
16.
Transplant Proc ; 51(8): 2838-2841, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31493919

RESUMO

OBJECTIVE: Hesperidin is a well-known flavanone glycoside copiously found in sweet orange and lemon, which was recently reported to possess significant anti-inflammatory, analgesic, antifungal, antiviral, antioxidant, and anticancer activities. Ischemia-reperfusion (I/R) injury is a major problem after renal transplantation. Furthermore, inflammatory responses to I/R exacerbate the resultant renal injury. In the present study, we investigated whether hesperidin exhibits renoprotective effects against I/R-induced acute kidney injury in a rat model. METHODS: We fed Sprague-Dawley rats either hesperidin (100 mg/kg/d) or saline. One week later, ischemia was induced by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion. The rats were randomly divided into 3 groups, which were treated as follows: 1. the sham operated group; 2. the I/R group; 3. the I/R-hesperidin group RESULTS: Compared to the sham group, the I/R group had higher expression of blood urea nitrogen and serum creatinine and lower expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidants, and nitric oxide. Compared to the I/R group, the I/R-hesperidin group had higher expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, and nitric oxide and lower expression of blood urea nitrogen and serum creatinine. CONCLUSIONS: Hesperidin improved acute renal I/R injury through its antioxidant effects. These findings suggest that hesperidin is a potential therapeutic agent for acute ischemia-induced renal damage.


Assuntos
Lesão Renal Aguda/prevenção & controle , Antioxidantes/uso terapêutico , Hesperidina/uso terapêutico , Rim/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/metabolismo , Animais , Antioxidantes/farmacologia , Nitrogênio da Ureia Sanguínea , Catalase/metabolismo , Creatinina/sangue , Glutationa Peroxidase/metabolismo , Hesperidina/farmacologia , Rim/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo
17.
Toxicol Mech Methods ; 29(9): 644-653, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31345080

RESUMO

The present study investigated the protective effect of hesperidin on carbohydrate metabolizing enzymes in streptozotocin-induced diabetic rats. Hesperidin was administered to streptozotocin-induced (40 mg/kg b.w.) diabetic rats at different dosages of (25, 50, 100 mg/kg b.w.) respectively for 30 days to evaluate its effect on fasting plasma glucose, insulin, glycosylated hemoglobin, hemoglobin, and carbohydrate metabolic enzymes. The plasma glucose levels were significantly reduced in a dose-dependent manner in hesperdin-treated group of rats when compared to the diabetic control rats. In addition, concomitant increase in hemoglobin and insulin levels and a decrease in glycosylated hemoglobin were observed in treated group of rats. The activities of the hepatic key enzymes of carbohydrate metabolism such as hexokinase and glucose-6-phosphate dehydrogenase were significantly increased, whereas glucose-6-phosphatase and fructose-1,6-bisphosphatase were significantly decreased. Furthermore, hesperidin administration prevented the loss in body weight and improved the glycogen content in the hepatic tissue of diabetic animals by reinstating the activities of glycogen synthase and glycogen phosphorylase. These results showed that hesperidin has potential antihyperglycemic activity in streptozotocin-induced diabetic rats. This was further supported by the histological studies of pancreas and liver.


Assuntos
Glicemia/análise , Metabolismo dos Carboidratos/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Hesperidina/farmacologia , Hipoglicemiantes/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Frutose-Bifosfatase/metabolismo , Teste de Tolerância a Glucose , Glucose-6-Fosfatase/metabolismo , Hemoglobina A Glicada/análise , Hesperidina/uso terapêutico , Hexoquinase/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Masculino , Ratos Wistar , Estreptozocina
18.
Phytother Res ; 33(8): 2118-2125, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31264313

RESUMO

This study aimed to evaluate the effects of hesperidin on nonalcoholic fatty liver disease (NAFLD) characteristics. In this randomized, double-blind, controlled clinical trial, 50 NAFLD patients were supplemented with either 1-g hesperidin capsule or identical placebo capsule for 12 weeks. During the intervention, both groups were advised to follow healthy lifestyle habits including dietary and physical activity recommendations. At the end of the study, hesperidin supplementation, compared with placebo, was associated with a significant reduction in alanine aminotransferase (p = .005), γ-glutamyltransferase (p = .004), total cholesterol (p = .016), triglyceride (p = .049), hepatic steatosis (p = .041), high-sensitivity C-reactive protein (p = .029), tumor necrosis factor-α, and nuclear factor-κB (NF-κB). In conclusion, our results indicate that hesperidin supplementation accompanied with lifestyle modification is superior to lifestyle modification alone in management of NAFLD at least partially through inhibiting NF-κB activation and improving lipid profile. Further studies with higher dose of hesperidin are required to find the optimal dose.


Assuntos
Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Hesperidina/uso terapêutico , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Método Duplo-Cego , Feminino , Hesperidina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia
19.
Nutr Rev ; 77(12): 845-864, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271436

RESUMO

CONTEXT: The cardioprotective effects of the flavonoid hesperidin, which is present in citrus products, are controversial and unclear. This systematic review was conducted in accordance with the PRISMA 2015 guidelines. OBJECTIVE: To evaluate the current evidence from animal and human clinical studies and thus determine whether the consumption of hesperidin exerts beneficial effects on cardiovascular risk factors. DATA SOURCES: PICOS (Population, Intervention, Comparison, Outcome, and Study Design) criteria defined the research question. Searches of the PubMed and Cochrane Plus databases were conducted and studies that met the inclusion criteria and were published in English in the last 15 years were included. DATA EXTRACTION: The first author, year of publication, study design, characteristics of animals and humans, intervention groups, dose of hesperidin, route of administration, duration of the intervention, cardiovascular risk biomarkers assessed, and results observed were extracted from the included articles. RESULTS: A total of 12 animal studies and 11 randomized clinical trials met the inclusion criteria. In the animal studies, the glucose, total and LDL cholesterol, and triglyceride levels decreased with chronic flavonoid consumption. In the human studies, endothelial function improved with flavonoid consumption, whereas no conclusive results were observed for the other biomarkers. CONCLUSIONS: Animal studies have revealed that hesperidin and hesperetin consumption reduces glucose levels and various lipid profile parameters. However, a definitive conclusion cannot be drawn from the existing human clinical trials. Further research is needed to confirm whether the findings observed in animal models can also be observed in humans. SYSTEMATIC REVIEW REGISTRATION: Prospero registration number CRD42018088942.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Hesperidina/farmacologia , Animais , Biomarcadores , Doenças Cardiovasculares , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
20.
Arch Pharm Res ; 42(8): 695-703, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31327152

RESUMO

Neuroinflammation is a specific or nonspecific immunological reaction in the central nervous system that is induced by microglia activation. Appropriate regulation of activated microglial cells is therefore important for inhibiting neuroinflammation. Hesperetin is a natural flavanone and an aglycone of hesperidin that is found in citrus fruits. Hesperetin reportedly possesses anti-inflammatory, anti-cancer, and antioxidant effects. However, the anti-neuroinflammatory effects of hesperetin on microglia are still unknown. Here, we investigated the anti-neuroinflammatory effects of hesperetin on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We found that hesperetin strongly inhibited nitric oxide production and expression of inducible nitric oxide synthase in LPS-stimulated BV-2 microglial cells. Hesperetin also significantly reduced secretion of inflammatory cytokines including interleukin (IL)-1ß and IL-6. Furthermore, hesperetin down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase, exerting anti-inflammatory effects. Hesperetin suppressed astrocyte and microglia activation in the LPS-challenged mouse brain. Collectively, our findings indicate that hesperetin inhibits microglia-mediated neuroinflammation and could be a prophylactic treatment for neurodegenerative diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/antagonistas & inibidores , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/química , Linhagem Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Hesperidina/química , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade
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