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1.
Wei Sheng Yan Jiu ; 49(5): 780-784, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070824

RESUMO

OBJECTIVE: Investigate the estrogen receptor expression in human thyroid squamous cell carcinoma SW579 and the effects of genistein on the apoptosis and cycle of SW579 and its mechnism. METHODS: The real-time PCR was applied to detect the expression of estrogen receptor(ER)α、ERß and G protein-coupled receptor(GPR)30 in human thyroid squamous cell line SW579; MTT was used to test the effect of genistein on cell proliferation in the SW579 cells before and after blocking GPR30; flow cytometry was explorited to measure the effect of genistein on the cell cycle and apoptosis in the SW579 was detected before and after blocking GPR30. RESULTS: The high concentration of genistein promoted the expression of ERß and GPR30 in the SW579 cells, but ERα was not expressed. The specific blocking of GPR30, the cell proliferation was aboviously inhibited by genistein in the SW579 cells and the cell apoptosis was markedly promoted after the GPR30 was blocked; The cell cycle was mainly blocked in G_2/M phase. CONCLUSION: Genistein can obiviously promote the cell proliferation in the SW579 cells, which may be related to the action of GPR30.


Assuntos
Genisteína , Neoplasias da Glândula Tireoide , Apoptose , Ciclo Celular , Divisão Celular , Linhagem Celular Tumoral , Células Epiteliais , Genisteína/farmacologia , Humanos
2.
Ecotoxicol Environ Saf ; 205: 111344, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32977283

RESUMO

Rotenone is an insecticide that generates oxidative stress in the CNS and induces locomotor dysfunction and neurodegeneration in rodents. Biochanin A [BioA] is an isoflavone with antioxidant and anti-inflammatory actions. The antioxidant and the modulatory action of BioA on PI3K/Akt/mTOR signaling and autophagy were tested in rotenone-Parkinsonian mice. Mice were allocated into; Group I: oil control group, Group II: rotenone group [1-mg/kg/48h, subcutaneously], group III: rotenone and BioA [10-mg/kg]. Rotenone injection resulted in locomotor disturbances in mice, degeneration in dopaminergic neurons [tyrosine hydroxylase-immunoreactive cells], low striatal dopamine, increased malondialdehyde and decreased level of glutathione. Neuroinflammation was evidenced by upregulation of astrocytes [glia fibrillary acidic protein, GFAP] and elevated levels of cytokines. The phosphorylation of PI3K/Akt/mTOR and the autophagy-related protein, beclin-1, were decreased significantly as indicated by Western blot analysis. BioA treatment enhanced locomotor activity and afforded nigral neuroprotection. The mechanism by which BioA produced this effect includes increased antioxidant defenses, lessened proinflammatory cytokines, increased phosphorylation of PI3K/Akt/mTOR proteins and upregulated beclin-1. Importantly, BioA suppressed the striatal astrocyte marker [GFAP]. Overall, the currents study highlighted that BioA activates PI3K/Akt/mTOR signaling and enhances beclin-1 leading to neuroprotection for nigral dopaminergic neurons.


Assuntos
Genisteína/farmacologia , Inseticidas/toxicidade , Fármacos Neuroprotetores/farmacologia , Rotenona/toxicidade , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Citocinas/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Camundongos , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
3.
Toxicol Lett ; 333: 222-231, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798538

RESUMO

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 µg/mouse for PND 240 and 290, and 50 µg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.


Assuntos
Envelhecimento/imunologia , Genisteína/farmacologia , Pulmão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Envelhecimento/sangue , Alérgenos/imunologia , Animais , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Feminino , Genisteína/administração & dosagem , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Pulmão/embriologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia
5.
Gene ; 753: 144789, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32442578

RESUMO

BACKGROUND: This study determined the possible anti-inflammatory and antioxidant renal protective effect of genistein, a soy isoflavone, against kidney damage and functional disorders following renal ischemia/reperfusion (I/R) in male rats. MATERIALS AND METHODS: The animals were dedicated to five groups (n = 7 per group): Sham, Sham + Geni (genistein, 15 mg/kg in 1 ml 1% DMSO, i.p.), Sham + DMSO (1 ml 1% DMSO, i.p.), I/R (bilateral renal ischemia for 45 min followed by 24 h reperfusion), I/R + Geni (genistein, 15 mg/kg). 24-h urine samples, blood and tissue samples of the kidney were collected at the end of 24 h reperfusion period. RESULTS: Compared to sham, sham + Geni and sham + DMSO groups, IR injury (IRI) ended in kidney dysfunction (decreased creatinine clearance, and increased fractional excretion of sodium), increased levels of malondialdehyde, decreased activities of antioxidant enzymes (superoxide dismutase, gluthatione peroxidase, and catalase), increased gene expression levels of TLR4 (Toll-like receptor 4) and TNF-α (tumor necrosis factor-alpha), as well as histological damages in kidney tissue. Genistein administration decreased all the changes. Therefore, genistein apparently protects the kidney against IRI by mitigating both oxidative stress and inflammation. The antioxidant and anti-inflammatory properties of genistein probably exert important roles in improving functional disorders and offer renal protection against IRI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Genisteína/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/metabolismo , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Genisteína/metabolismo , Inflamação/metabolismo , Isquemia/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Res Vet Sci ; 131: 206-214, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32408231

RESUMO

Flavonoids have shown beneficial effects in various disease conditions as reported by various previous studies. Biochanin-A is a flavonoid present in various plants in nature. Present investigation was done to assess the vasorelaxant potential of biochanin-A on isolated coronary artery of goat and its possible mechanism of action. Vascular reactivity experiments were done on circumflex coronary artery of goats using the tension experiments. Goat coronary arterial rings were relaxed with biochanin-A in concentration (0.1-100 µM)-dependent manner. Endothelium had no effect on biochanin-A-induced relaxation. Maximum relaxation induced by biochanin-A was 116.54 ± 12.21% in endothelium-intact artery and it was not significantly different with maximal relaxation (108.22 ± 1.88%) of endothelium-denuded vessel. L-NAME (100 µM) did not show any effect on biochanin-A-induced relaxation. TEA (BKCa channel blocker), and BaCl2 (KIR blocker) had no effect on biochanin-A-induced relaxation. However, biochanin-A-induced maximal relaxation (71.72 ± 4.50%) was reduced significantly (P < .001) in the presence of 4-aminopyridine (KV channel blocker, 3 mM) in comparison with control (114.07 ± 4.33%). Glibenclaminde (KATP channel blocker), H89 (PKA inhibitor), ICI182780 (estrogen receptor antagonist) showed partial attenuation in the biochanin-A-induced relaxation. ODQ (sGC blocker) and HC067047 (TRPV4 channel blocker) had no effect on biochanin-A-induced relaxation. In K+-depolarized endothelium-denuded arterial rings, biochanin-A (30 µM) significantly (P < .05; P < .001) decreased CaCl2-induced contractions (0.02 ± 0.01 g vs. control 0.73 ± 0.30 g). Biochanin-A did not influence the fasudil (rho kinase inhibitor) and SNP (NO-donor)-induced relaxation in this vessel. Biochanin-A showed relaxation in goat coronary artery in endothelium-independent pathways and showed the partial involvement of KATP, protein kinase A and estrogen receptors and full involvement of Cav1.2 channels.


Assuntos
Vasos Coronários/efeitos dos fármacos , Genisteína/farmacologia , Cabras , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Masculino
7.
Res Vet Sci ; 131: 87-91, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32311590

RESUMO

Isoflavones, such as genistein, have been proposed to have beneficial effects on health, including preventive or therapeutic actions in carcinogenesis. Their structural similarity to oestrogens allows them to bind at the cellular level with oestrogen receptors. Therefore, this study attempted to determine the antitumoural effects of genistein administered in a canine inflammatory mammary cancer xenograft model, in terms of tumour proliferation, appearance of metastases and steroid hormone regulation. Using histology and immunohistochemical analyses as well as the EIA technique for hormonal determinations, the antitumoural effects of genistein on an inflammatory mammary cancer xenograft model were assessed for 3 weeks. Mice treated with genistein showed higher Ki-67 levels than the control group. There were significantly more distant metastases in the genistein-treated xenografts versus the control group. Intratumoural and serum progesterone, androstenedione and oestrogen levels in treated mice were elevated, whereas intratumoural testosterone levels were decreased compared to the control group. These results revealed that genistein ingestion promotes tumour proliferation and elevates metastatic rates by increasing intratumoural and circulating oestrogen levels in a mammary cancer xenograft model.


Assuntos
Anticarcinógenos/uso terapêutico , Doenças do Cão/metabolismo , Estrogênios/metabolismo , Genisteína/uso terapêutico , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Animais , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Genisteína/farmacologia , Inflamação/metabolismo , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos
8.
Cell Physiol Biochem ; 54(3): 401-416, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32330379

RESUMO

BACKGROUND/AIMS: Oxidative stress and mitochondria dysfunction could be involved in the onset of non-alcoholic fatty liver disease (NAFLD) and in its progression to non-alcoholic steatohepatitis (NASH). Estrogens/phytoestrogens could counteract liver fat deposition with beneficial effects against NAFLD by unclear mechanisms. We aimed to analyze the protective effects elicited by genistein/estradiol in hepatocytes cultured in NAFLD-like medium on cell viability, triglycerides accumulation, mitochondrial function and oxidative stress and the role of NLRP3 inflammasome, toll like receptors 4 (TLR4), Akt and 5' AMP-activated protein kinase (AMPK)α1/2. METHODS: Human primary hepatocytes/hepatoma cell line (Huh7.5 cells) were incubated with a 2 mM mixture of oleate/palmitate in presence/absence of genistein/17ß-estradiol. In some experiments, Huh7.5 cells were exposed to various inhibitors of the above pathways and estrogenic receptors (ERs) and G protein-coupled estrogen receptor (GPER) blockers, before genistein/17ß-estradiol. Cell viability, mitochondrial membrane potential, reactive oxygen species and triglycerides content were examined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT), 5,51,6,61-tetrachloro-1,11,3,31 tetraethylbenzimidazolyl carbocyanine iodide (JC-1), 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) and the Triglyceride Colorimetric Assay. The expression/activation of kinases was analyzed by means of Western blot. RESULTS: Genistein/17ß-estradiol protected hepatocytes against NAFLD-like medium, by preventing the loss of cell viability and mitochondrial function, triglycerides accumulation and peroxidation. The blocking of kinases, ERs and GPER was able to reduce the above effects, which were potentiated by NLRP3 inflammasome. CONCLUSION: Our findings suggest novel mechanisms underlying the protective effects elicited by phytoestrogens/estrogens against NAFLD/NASH and open novel therapeutic perspectives in the management of NAFLD in postmenopausal women.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Estradiol/farmacologia , Genisteína/farmacologia , Hepatócitos/efeitos dos fármacos , Inflamassomos/metabolismo , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Linhagem Celular , Hepatócitos/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fitoestrógenos/farmacologia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Estrogênicos/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Triglicerídeos/metabolismo
9.
Sci Total Environ ; 722: 137907, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32208265

RESUMO

Natural products (NPs) will continue to serve humans as matchless source of novel drug leads and an inspiration for the synthesis of non-natural drugs. As our scientific understanding of 'nature' is rapidly expanding, it would be worthwhile to illuminate the pharmacological distinctions of NPs to the scientific community and the public. Flavonoids have long fascinated scientists with their remarkable structural diversity as well as biological functions. Consequently, this review aims to shed light on the sources and pharmacological significance of a dietary isoflavone, biochanin A, which has been recently emerged as a multitargeted and multifunctional guardian of human health. Biochanin A possesses anti-inflammatory, anticancer, neuroprotective, antioxidant, anti-microbial, and hepatoprotective properties. It combats cancer development by inducing apoptosis, inhibition of metastasis and arresting cell cycle via targeting several deregulated signaling pathways of cancer. It fights inflammation by blocking the expression and activity of pro-inflammatory cytokines via modulation of NF-κB and MAPKs. Biochanin A acts as a neuroprotective agent by inhibiting microglial activation and apoptosis of neurons. As biochanin A has potential to modulate several biological networks, thus, it can be anticipated that this therapeutically potent compound might serve as a novel lead for drug development in the near future.


Assuntos
Genisteína/farmacologia , Anti-Inflamatórios , Apoptose , Humanos , NF-kappa B
10.
Phytother Res ; 34(4): 846-858, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32115816

RESUMO

Sleep deprivation has been widely reported to cause cognitive dysfunction, and elevation in oxidative stress and inflammation in the body, including the brain, have been suggested as the main factors. Genistein (GE) is an isoflavone widely present in leguminous plants, and it was found to exert a wide spectrum of biological activities, including antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, and antimetastatic effects. In this study, the protective effect of GE on chronic sleep deprivation (CSD)-induced cognitive dysfunction was investigated. The mice were subjected to the sleep interruption apparatus and continuously sleep deprived for 25 days. GE was orally administrated (10, 20, and 40 mg/kg) during the sleep deprivation process totally for 25 days. Cognitive behavioral tests were conducted to study the learning and memory using the object location recognition (OLR) task, novel object recognition (NOR) test, and the Morris water maze (MWM) task. Additionally, the cortex and hippocampus were dissected to measure the oxidative stress markers and the antioxidant element nuclear erythroid-2-related factor 2 (Nrf2) and its downstream targets, including glutamate cysteine ligase catalytic, glutamate cysteine ligase modifier, heme oxygenase 1, and quinone oxidoreductase 1, as well as nuclear factor kappa B (NF-κB) p65, nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) protein expression. Moreover, the pro-inflammatory cytokines (TNF-α, interleukin [IL]-6, and IL-1ß) level was examined in the serum. The current results showed that GE could dose-dependently ameliorate the cognitive deficits of CSD-treated mice in the OLR, NOR, and MWM tasks. In addition, GE treatment significantly elevated the activities of total antioxidant capacity and superoxide dismutase and the level of glutathione and lowered the content of malondialdehyde in the cortex and hippocampus of CSD-treated mice. Furthermore, GE administration effectively activated the antioxidant element Nrf2 and its downstream targets in the cortex and hippocampus of CSD-treated mice. Moreover, GE treatment significantly suppressed CSD-induced NF-κB p65, iNOS, and COX-2 activation in the cortex and hippocampus, as well as inhibited CSD-induced pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) release in the serum. Taken together, all these results suggested that GE has substantial potential as a therapeutic intervention for the alleviation of CSD-induced deleterious effects.


Assuntos
Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Genisteína/farmacologia , Fármacos Neuroprotetores/farmacologia , Privação do Sono/complicações , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Doença Crônica , Disfunção Cognitiva/tratamento farmacológico , Genisteína/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Privação do Sono/tratamento farmacológico , Privação do Sono/psicologia
11.
Biol Pharm Bull ; 43(3): 550-553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115514

RESUMO

Equol, an intestinal metabolite of daidzein, inhibited more potently mushroom tyrosinase in vitro than other inhibitors, genistein and kojic acid. We investigated the mechanism underlying tyrosinase inhibition by equol. Treating racemic equol with tyrosinase produced 3'-hydroxyequol. Because the optical activity of the product showed <25% enantiomeric excess, the reaction was not highly stereospecific. Using enzyme-linked immunosorbent assays with an anti-equol monoclonal antibody, we observed that equol bound to pre-coated tyrosinase in a dose-dependent manner. Our results suggested the formation of a stable equol-tyrosinase complex.


Assuntos
Agaricales , Equol/química , Equol/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Genisteína/farmacologia , Pironas/farmacologia
12.
J Cardiovasc Pharmacol ; 75(5): 460-474, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32195757

RESUMO

Estrogenic deficiency is considered a risk of coronary disease in women. The phytoestrogen genistein could be a safe preventive strategy. The first aim of this work was to validate a model of cardiac stunning in which natural estrogenic deficiency rats, ie, adult young male (YM) and aged female (AgF), are compared with young female rats (YF). The second aim was to study whether the in vivo administration of genistein prevents the stunning in estrogenic deficiency rats. The third aim was to evaluate whether in our estrogenic deficiency model exists a synergy between genistein and estradiol. The fourth aim was to characterize the underlying mechanisms of genistein. Stunning was induced by ischemia/reperfusion (I/R) in isolated hearts inside a calorimeter. The left ventricular pressure (P) and total heat rate (Ht) were simultaneously measured, while diastolic contracture and muscle economy (P/Ht) were calculated. During R, P/Ht and P recovered less in AgF and YM than in YF rat hearts. Genistein through i.p. (GST-ip) improved P and P/Ht in AgF and YM, but not in YF. In YM, the cardioprotections of GST-ip and estradiol were synergistic. After ischemia, GST-ip increased SR Ca leak causing diastolic contracture. The GST-ip cardioprotection neither was affected by blockade of PI3K-Akt, NO synthases, or phosphatases, but it was sensitive to blockade of protein-kinase C and mKATP channels. Results suggest that (1) estrogenic deficiency worsens cardiac stunning, (2) GST-ip was more cardioprotective in estrogenic deficiency and synergistic with estradiol, and (3) cardioprotection of GST-ip depends on the protein-kinase C and mKATP channel pathway activation.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Genisteína/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio Atordoado/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Fitoestrógenos/farmacologia , Canais de Potássio/metabolismo , Fatores Etários , Animais , Sinalização do Cálcio , Modelos Animais de Doenças , Estradiol/farmacologia , Feminino , Preparação de Coração Isolado , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/enzimologia , Miocárdio Atordoado/patologia , Miocárdio Atordoado/fisiopatologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Proteína Quinase C/metabolismo , Ratos Sprague-Dawley , Fatores Sexuais , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos
13.
Radiat Res ; 193(3): 286-300, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32017668

RESUMO

New radiosensitizers are urgently needed for radiation therapy patients with localized hepatocellular carcinoma (HCC) that is refractory to radical surgery. We previously found that genistein, a major soy isoflavone, exerts radioprotective effects on L-02 normal liver cells at low concentrations. Here, we report that 5 µM genistein shows less harm to L-02 cells than HCC cells and that it significantly enhances the radiosensitivity of HCC cells by enhancing DNA damage, chromosomal aberrations and cell cycle arrest at G2/M phase and by exacerbating apoptosis. Mechanistically, genistein aggravates X-ray-induced decreases in the levels of phospho-Bad (Ser136) but enhances the levels of phospho-Chk2 (Thr68), phospho-ATM (Ser1981) and γ-H2AX. Micro-array analysis indicated that downregulation of POU6F and CCNE2 expression and upregulation of FBXO32 and cyclin B1 expression might play vital roles in genistein-induced radiosensitivity. These findings suggest genistein as an interesting candidate for adjuvant radiotherapy for HCC and indicate that genistein causes less harm to normal cells than HCC cells by inducing G2/M arrest and apoptosis.


Assuntos
Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Divisão Celular/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Genisteína/farmacologia , Neoplasias Hepáticas/patologia , Tolerância a Radiação/efeitos dos fármacos , Animais , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Camundongos , Raios X
14.
Phytomedicine ; 68: 153168, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982837

RESUMO

BACKGROUND: Cancer is hyper-proliferative, multi-factorial and multi-step, heterogeneous group of molecular disorders. It is the second most reported disease after heart diseases. Breast carcinoma is the foremost death causing disease in female population worldwide. Cancer can be controlled by regulating the gene expression. Current therapeutic options are associated with severe side effects and are expensive for the people living in under-developed countries. Plant derived substances have potential application against different diseases like cancer, inflammation and viral infections. HYPOTHESIS: The mechanism of action of the medicinal plants is largely unknown. Targeting gene network and miRNA using medicinal plants could help in improving the therapeutic options against cancer. METHODS: The literature from 135 articles was reviewed by using PubMed, google scholar, Science direct to find out the plants and plant-based compounds against breast cancer and also the studies reporting their mechanistic route of action both at coding and noncoding RNA levels. RESULTS: Natural products act as selective inhibitors of the cancerous cells by targeting oncogenes and tumor suppressor genes or altering miRNA expression. Natural compounds like EGCG from tea, Genistein from fava beans, curcumin from turmeric, DIM found in cruciferous, Resveratrol a polyphenol and Quercetin a flavonoid is found in various plants have been studied for their anticancer activity. The EGCG was found to inhibit proliferative activity by modulating miR-16 and miR-21. Similarly, DIM was found to down regulate miR-92a which results to modulate NFkB and stops cancer development. Another plant-based compound Glyceollins found to upregulate miR-181c and miR-181d having role in tumor suppression. It also found to regulate miR-22, 29b and c, miR-30d, 34a and 195. Quercetin having anti-cancer activity induce the apoptosis through regulating miR-16, 26b, 34a, let-7g, 125a and miR-605 and reduce the miRNA expression like miR-146a/b, 503 and 194 which are involved in metastasis. CONCLUSION: Targeting miRNA expression using natural plant extracts can have a reverse effect on cell proliferation; turning on and off tumor-inducing and suppressing genes. It can be efficiently adopted as an adjuvant with the conventional form of therapies to increase their efficacy against cancer progression.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Curcumina/farmacologia , Feminino , Genisteína/farmacologia , Humanos , Resveratrol/farmacologia
15.
Cell Physiol Biochem ; 54(1): 53-70, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31961100

RESUMO

BACKGROUND/AIMS: Genistein, a soy isoflavone, has been shown to have anti-cancer effects in various cancers including renal cancer. Long non-coding RNA, HOX transcript antisense RNA (HOTAIR), is involved in cancer progression and metastasis, such as renal cancer. Our aim was to investigate the effects of genistein on HOTAIR chromatin remodeling functions. METHODS: We used MTS assays and Transwell migration assays to study the effects of genistein on cell proliferation and migration respectively in human renal cell carcinoma (RCC) cell lines. We used Western blots to analyze SNAIL and ZO-1 expression. We performed chromatin immunoprecipitation (ChIP) assays to study recruitment of the polycomb repressive complex 2 (PRC2) to the ZO-1 promoter. We performed RNA immunoprecipitation (RIP) assays to study interaction between HOTAIR and PRC2, SMARCB1 or ARID1A. We also performed transfection experiments to overexpress EED, HOTAIR and knockdown SMARCB1. RESULTS: Genistein reduced cell proliferation and migration of human renal cell carcinoma cell lines. ChIP assays indicated that genistein reduces recruitment of the PRC2 to the ZO-1 promoter and increased its expression. RIP assays showed that genistein inhibits HOTAIR interaction with PRC2, leading to tumor suppression. Immunoprecipitation also revealed that genistein reduced EED levels in PRC2, suggesting that decreased EED levels suppress HOTAIR interaction with PRC2. EED overexpression in the presence of genistein restored PRC2 interaction with HOTAIR and reduced ZO-1 transcription, suggesting genistein activates ZO-1 by inhibiting HOTAIR/PRC2 functions. RIP assays also showed that HOTAIR interacts with SMARCB1 and ARID1A, subunits of the human SWI/SNF chromatin remodeling complex and genistein reduces this interaction. Combination of HOTAIR overexpression and SMARCB1 knockdown in the presence of genistein revealed that genistein inhibits SNAIL transcription via the HOTAIR/SMARCB1 pathway. CONCLUSION: Genistein suppresses EED levels in PRC2 and inhibits HOTAIR/PRC2 interaction. Genistein suppresses HOTAIR/PRC2 recruitment to the ZO-1 promoter and enhances ZO-1 transcription. Genistein also inhibits SNAIL transcription via reducing HOTAIR/SMARCB1 interaction. We demonstrate that the reduction of HOTAIR interaction with chromatin remodeling factors by genistein represses HOTAIR/chromatin remodeling pathways to suppress RCC malignancy.


Assuntos
Anticarcinógenos/farmacologia , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Genisteína/farmacologia , Neoplasias Renais/tratamento farmacológico , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle
16.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 7-12, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31950782

RESUMO

Objective: To study the effects of genistein (GEN) on reproductive system in prepubertal male rats. Methods: Thirty SPF-rated male SD rats were randomly divided into control group (Con group), low-dose group (G1 group) and high-dose group (G2 group), with 10 rats in each group. Corn oil, 150 mg/kg and 300 mg/kg GEN dissolved in corn oil of equal volume were respectively administered every day and weighed the next day. After 6 weeks, the rats were sacrificed, and the testis, epididymis and prostate were dissected, and organ coefficients were calculated. Histopathological changes of testis was observed. The number of sperm was counted and the rate of sperm malformation was calculated. The concentrations of serum testosterone and estradiol were detected by radioimmunoassay. The protein phosphatase 2, regulatory subunit B, gamma (PPP2R2C) protein expression in testicular tissue was detected by immunofluorescence assay. The mRNA and protein expression levels of PPP2R2C and cyclin dependent protein kinases 2 (CDK2) in rat testis were detected by real-time quantitative fluorescence PCR (RT-qPCR) and Western blot, respectively. The protein phosphatase 2A (PP2A) activity in testicular tissue was detected by immunoprecipitation. Results: There were no statistically significant differences in body mass, sperm number, serum estradiol and PP2A enzyme activity among the groups ( P>0.05). The pathological structure of testicular in G2 group was disordered. Sperm abnormality rate in G1 and G2 groups was higher than that in Con group ( P<0.05). Serum testosterone concentration in G2 group was lower than that in Con group ( P<0.05). The expression of PPP2R2C and CDK2 in G2 group was higher than that in Con group ( P<0.05), but the protein level was lower than that in Con group ( P<0.05). PPP2R2C protein was expressed in testicular tissue in each group. Conclusion: Long-term exposure to high dose (300 mg/kg) GEN during prepuberty may cause adverse effects on reproductive function in adult male rats. Further investigation is needed to determine whether PPP2R2C-PP2A-CDK2 phosphorylation pathway affects reproductive system in rats.


Assuntos
Genisteína , Genitália Masculina , Animais , Estradiol/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Genisteína/farmacologia , Genitália Masculina/efeitos dos fármacos , Masculino , Fitoestrógenos/farmacologia , Ratos , Ratos Sprague-Dawley , Contagem de Espermatozoides , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/enzimologia , Testosterona/sangue
17.
J Physiol Biochem ; 76(1): 99-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31898015

RESUMO

Phytoestrogens have been proposed as a natural therapy for prevention of bone loss. In this work, we studied the mechanism of action of genistein on osteoblast differentiation. Primary cell cultures of calvarial osteoblasts isolated from female Wistar rats were in vitro exposed to genistein. Osteoblast differentiation markers were measured. Genistein stimulated osteoblast migration (71-257% above control). An earlier upregulation of estrogen receptor alpha gene expression and an enhancement of mRNA levels of the Runt-related transcription factor 2 were detected after 3 days of culture. The isoflavone significantly increased osteocalcin expression, extracellular collagen deposition, and alkaline phosphatase activity. The mechanism displayed by genistein involved estrogen receptor and nitric oxide pathway participation, since cell preincubation with the estrogen receptor antagonist ICI 182780, or the nitric oxide synthase inhibitor L-NAME, suppressed the phytoestrogen action. Evidence of MAPK and PI3K transduction systems participation on the stimulatory action of genistein on extracellular collagen deposition and alkaline phosphatase activity was also obtained. Genistein favored monocyte adhesion to osteoblasts (77% above control) in an ER; NOS; and MAPK kinase-dependent and PI3K-dependent manner. Co-cultured osteoblast-monocyte long term exposed (21 days) to genistein exhibited a high number of multinucleated and tartrate-resistant acid phosphatase-positive cells added to osteoblasts, suggesting that the phytoestrogen promotes osteoclast differentiation. In conclusion, genistein promoted osteoblastogenesis through the participation of ER and NOS pathways, and the contribution of ERK or PI3K signal transduction pathways, and also stimulates osteoclast differentiation from its mononuclear progenitor.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Genisteína/farmacologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Fitoestrógenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Feminino , Óxido Nítrico/metabolismo , Osteoblastos/citologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Cultura Primária de Células , Ratos , Ratos Wistar , Receptores Estrogênicos/metabolismo , Crânio/citologia
18.
Food Funct ; 11(1): 860-870, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31942583

RESUMO

Genistein is a major isoflavone with antioxidant and anti-inflammatory activities and hydrophobic features. To increase its bioavailability, researchers supplemented genistein with dietary oils. The present study aims to compare the effectiveness of genistein supplementation with water solution or oils and find the best possible dietary oil for fortification. A total of 135 male Sprague-Dawley rats were randomly assigned to nine groups, including one control group and eight acetic acid-induced colitis groups. The rats in the intervention groups were treated with 5 ml per kg body weight of oral pure and genistein fortified forms of extra virgin olive oil (EVOO), canola oil (CaO), and rice bran oil (RBO); the Genistein group (G) received 100 mg per kg body weight of genistein in aqueous solution orally. The colitis and control groups did not receive any treatment. The levels of colonic MDA (malondialdehyde), MPO (myeloperoxidase) activity, and IL-1ß (interleukin-1ß) were evaluated and a stereological analysis of colonic tissues was performed. All of the dietary oils (EVOO, CaO, and RBO) were effective at ameliorating the rats' oxidative and inflammatory status (p < 0.05); however, EVOO (with or without genistein) prescription resulted in slightly better results, especially with regard to the inflammatory profile. Additionally, delivering genistein via an oil vehicle was more efficient at reducing MDA formation, MPO activity, and IL-1ß concentration than genistein in aqueous solution. The quantitative analysis of colonic tissue was consistent with the biochemical analysis. Our findings suggest that the oral administration of EVOO, canola oil, and rice bran oil can attenuate the elevated IL-1ß levels and oxidative damage in induced colitis. Moreover, genistein fortified oils, especially EVOO, showed more beneficial effects in decreasing these markers in comparison with the pure oils or genistein (aqueous solution).


Assuntos
Colite Ulcerativa/prevenção & controle , Genisteína/farmacologia , Óleos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Ácido Acético , Animais , Colite Ulcerativa/induzido quimicamente , Alimentos Fortificados , Masculino , Azeite de Oliva/química , Azeite de Oliva/farmacologia , Óleos Vegetais/química , Óleo de Brassica napus/química , Óleo de Brassica napus/farmacologia , Ratos , Ratos Sprague-Dawley , Óleo de Farelo de Arroz/química , Óleo de Farelo de Arroz/farmacologia
19.
Biosci Biotechnol Biochem ; 84(3): 544-551, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31791192

RESUMO

Alveolar and bronchial epithelial cells have critical functions in acute respiratory distress syndrome progress. Genistein could protect the lungs from acute lung injury, however, whether genistein protects the alveolar epithelial cells from LPS-induced injury was less studied. Spectrophotometric method 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and enzyme-linked immunosorbent assay (ELISA) were performed to detect cell viability and levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6. Flow cytometry and western blot assay were performed to detect cells apoptosis and protein levels. In LPS-induced model of mouse lung epithelial (MLE)-12 cells, PBEF (proinflammatory cytokine) expression, and cell apoptosis were increased and cell viability was decreased, whereas NF-κB was activated and expression levels of TNF-α, IL-1ß, and IL-6 were increased. However, genistein partly reversed the effect of LPS, and it plays a protective role in lung injury by reducing expression of PBEF, inhibiting the activation of NF-κB and alleviating inflammatory response of cells.


Assuntos
Células Epiteliais/efeitos dos fármacos , Genisteína/farmacologia , Lipopolissacarídeos/toxicidade , Pneumonia/prevenção & controle , Alvéolos Pulmonares/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/metabolismo , Camundongos , NF-kappa B/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia
20.
Int J Mol Sci ; 20(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816816

RESUMO

Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role of miR-451 and the therapeutic effects of genistein in the NASH mouse model. MiR-451 was downregulated in various types of liver inflammation, and subsequent experiments showed that miR-451 regulates liver inflammation via IL1ß. Genistein is a phytoestrogen with anti-inflammatory and anti-oxidant effects. Interestingly, we found that the anti-inflammatory effects of genistein were related to miR-451 and was partially antagonized by the miR-451 inhibitor. MiR-451 overexpression or genistein treatment inhibited IL1ß expression and inflammation. Taken together, this study shows that miR-451 has a protective effect on hepatic inflammation, and genistein can be used as a natural promoter of miR-451 to ameliorate NASH.


Assuntos
Genisteína/uso terapêutico , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Animais , Sequência de Bases , Linhagem Celular , Dieta Hiperlipídica , Regulação para Baixo/genética , Feminino , Genisteína/farmacologia , Humanos , Inflamação/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos Endogâmicos ICR , MicroRNAs/genética
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