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1.
J Biochem Mol Toxicol ; 33(12): e22406, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31593353

RESUMO

Soybean Bowman-Birk protease inhibitor (BBI) and genistein, two biological compounds from soybean, are well-known for their anti-inflammatory, antioxidant, and anticancer activities. The aim of this study was designing a BBI-genistein conjugate and then investigating its protective effect on lipopolysaccharide (LPS)-induced inflammation in BALB/c mice, compared with the effects of combination of BBI and genistein. BBI was purified from soybean and the BBI-genistein conjugate was synthesized. The BALB/c mice were intraperitoneally treated 2 hours before LPS induction. Our results showed that treatment with the combination of BBI and genistein greatly led to more reduced serum levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ compared with the treatments of BBI alone, the BBI-genistein conjugate, and genistein alone, respectively. Moreover, the expression of TNF-α and IFN-γ in the splenocytes was significantly downregulated along with improving host survival against the LPS-induced lethal endotoxemia in the same way. Our data support a new combined therapy using BBI and genistein, as natural anti-inflammatory agents, to develop a new drug for inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Endotoxemia/tratamento farmacológico , Genisteína/uso terapêutico , Extratos Vegetais/uso terapêutico , Soja/química , Inibidor da Tripsina de Soja de Bowman-Birk/uso terapêutico , Animais , Combinação de Medicamentos , Endotoxemia/induzido quimicamente , Genisteína/administração & dosagem , Inflamação/metabolismo , Injeções Intraperitoneais , Interferon gama/antagonistas & inibidores , Interferon gama/sangue , Estimativa de Kaplan-Meier , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/antagonistas & inibidores , Baço/patologia , Taxa de Sobrevida , Resultado do Tratamento , Inibidor da Tripsina de Soja de Bowman-Birk/administração & dosagem , Inibidor da Tripsina de Soja de Bowman-Birk/isolamento & purificação , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue
2.
Gen Physiol Biophys ; 38(5): 389-397, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31595881

RESUMO

Stroke is a leading cause of disability and death in the worldwide. Therefore, prevention of stroke is critically important. Genistein, a natural phytoestrogen extracted from soybeans, has been found to be a potential neuroprotective agent for stroke prevention. However, the role of genistein and its underlying mechanism in ovariectomized rats has been rarely evaluated. In this study, ovariectomized rats were treated with genistein (10 mg/kg) or vehicle daily for two weeks before they received middle cerebral artery occlusion (MCAO) and reperfusion. Seventy-two hours after reperfusion, the neurological function was evaluated by Garcia test, infarct volumes were detected by 2,3,5-triphenyltetrazolium chloride staining; and neuronal damage and cell apoptosis were detected by Nissl and Tunel staining in the ischemic penumbra, respectively. In addition, Western blotting was used to detect the activity of PI3K-Akt-mTOR signal pathway in the ischemic penumbra in different groups. And we found that genistein treatment in ovariectomized rats significantly improved neurological outcomes, reduced infarct volumes, decreased neuronal damage and cell apoptosis, and increased the activity of PI3K-Akt-mTOR signal pathway. Our findings indicated that treatment genistein could alleviate neuronal apoptosis induced by cerebral ischemia in ovariectomized rats via promoting the activity of PI3K-Akt-mTOR signal pathway, which provides a new molecular mechanism for the neuroprotective effects of genistein against stroke.


Assuntos
Genisteína/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Animais , Feminino , Infarto da Artéria Cerebral Média/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Ovariectomia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Discov Med ; 27(149): 177-188, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31361980

RESUMO

Genistein is an isoflavone derived from soy-rich products, which is known to exhibit several beneficial biological effects, such as anti-tumor activity, improvement of glucose metabolism, and reduction of the frequency of peri-menopausal hot flashes, and thus has potential for clinical application. Certain limitations and side effects, such as low bioavailability, biological estrogenic activity, and detrimental effects on thyroid function, have restricted its clinical applications to some extent. Recently, it has been reported that fermentation, use of micromicelles, and modification of its chemical structure can enhance the bioavailability of genistein. Moreover, the modification of its molecular structure may also eliminate its biological estrogenic activity and adverse effects on thyroid function. In this review, we summarize the clinical application prospects and limitations of genistein, as well as the plausible solutions to overcome its low bioavailability, phytoestrogenic activity, and adverse effects on thyroid function.


Assuntos
Antineoplásicos Fitogênicos , Estrogênios , Genisteína , Fogachos/tratamento farmacológico , Menopausa/metabolismo , Glândula Tireoide/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Estrogênios/farmacocinética , Estrogênios/uso terapêutico , Feminino , Genisteína/farmacocinética , Genisteína/uso terapêutico , Fogachos/metabolismo , Fogachos/patologia , Humanos , Micelas
4.
Biomed Pharmacother ; 117: 109047, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176163

RESUMO

NAFLD is a vital health problem worldwide; however, no effective treatment is currently available for NAFLD. Intensive studies have indicated the efficacy of genistein (GE), a bioactive isoflavone extracted from soy, in treating NAFLD. In addition to its oestrogen-like effects, GE is known to have multiple molecular effects, for instance, lipid and glucose metabolism-promoting effects and activities against lipid peroxidation, inflammation, fibrosis, and NAFLD-related tumours. Here, this review summarizes the potential role of GE in the treatment and prevention of NAFLD and some of the currently known targets and signalling pathways of GE in NAFLD.


Assuntos
Genisteína/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Ensaios Clínicos como Assunto , Genisteína/química , Genisteína/farmacologia , Humanos , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia
5.
Int J Radiat Oncol Biol Phys ; 105(2): 400-409, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175904

RESUMO

PURPOSE: To assess whether BIO 300, a synthetic genistein nanosuspension, improves the therapeutic index in prostate cancer treatment by preventing radiation-induced erectile dysfunction (ED) without reducing tumor radiosensitivity. METHODS AND MATERIALS: Male Sprague-Dawley rats were exposed to 25 Gy of 220-kV prostate-confined x-rays. Animals were randomized to receive sham radiation therapy (RT), RT alone, RT with daily BIO 300 at 2 experimental dosing regimens, or RT with daily genistein. Erectile response was evaluated over time. Penile shaft tissue was harvested for histologic analyses. Murine xenograft studies using prostate cancer cell lines determined the effects of BIO 300 dosing on RT efficacy. RESULTS: Prostate-confined RT significantly decreased apomorphine-induced erectile response (P < .05 vs sham RT). Erection frequency in animals receiving prophylactic treatment with BIO 300 starting 3 days before RT was similar to sham controls after RT. Treatment with synthetic genistein did not mitigate loss in erectile frequency. At week 14, post-RT treatment with BIO 300 resulted in significantly higher quality of erectile function compared with both the RT arm and the RT arm receiving genistein starting 3 days before irradiation (P < .05). In hormone-sensitive and insensitive prostate tumor-bearing mice, BIO 300 administration did not negatively affect radiation-induced tumor growth delay. CONCLUSIONS: BIO 300 prevents radiation-induced ED, measured by erection frequency, erectile function, and erection quality, when administered 3 days before RT and continued daily for up to 14 weeks. Data also suggest that BIO 300 administered starting 2 hours after RT mitigates radiation-induced ED. Data provide strong nonclinical evidence to support clinical translation of BIO 300 for mitigation of ED while maintaining treatment response to RT.


Assuntos
Disfunção Erétil/prevenção & controle , Genisteína/uso terapêutico , Nanopartículas/uso terapêutico , Ereção Peniana/efeitos dos fármacos , Lesões Experimentais por Radiação/complicações , Protetores contra Radiação/uso terapêutico , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Drogas em Investigação/uso terapêutico , Disfunção Erétil/etiologia , Fibrose , Masculino , Camundongos , Camundongos Nus , Ereção Peniana/efeitos da radiação , Pênis/irrigação sanguínea , Pênis/patologia , Próstata/efeitos da radiação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Suspensões/uso terapêutico , Transplante Heterólogo
6.
Food Funct ; 10(7): 4153-4165, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241065

RESUMO

This study aimed to explore a novel strategy for the simultaneous consumption of soluble soybean polysaccharides (SSPS) and insoluble genistein to improve the bioavailability of genistein and its prevention against obesity and metabolic syndrome in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed a normal diet and HFD supplemented or not (n = 8) with SSPS (2.5%), genistein (0.5%) and their mixture (S + G) for 12 weeks. The UPLC-qTOP/MS assay showed that SSPS observably enhanced the urinary concentration of genistein and its metabolites compared to that of single genistein in mice. Supplementation of SSPS, genistein or their combination prevented HFD-induced gain weight, dyslipidemia, oxidative stress and inflammation in obese mice. Interestingly, the combined S + G ingestion exhibited more effective alleviation of dyslipidemia by modulating hepatic FAS, ACC, SREBP-1C and ADRP expressions relative to that of individual SSPS or genistein. Furthermore, S + G activated the energy metabolism pathway AMPK in the liver, and the hepatic PPAR-α/PPAR-γ pathways were doubly activated to alleviate lipogenesis, inflammation, obesity and metabolic syndrome. Moreover, S + G supplementation dramatically modified the gut microbial species at the phylum level with a decrease in Firmicutes and increase in Bacteroidetes. These findings support that the combined supplementation of SSPS and genistein is a novel couple to prevent obesity and metabolic syndrome.


Assuntos
Disponibilidade Biológica , Genisteína/farmacologia , Síndrome Metabólica/prevenção & controle , Obesidade/prevenção & controle , Polissacarídeos/farmacologia , Soja/química , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Dislipidemias/metabolismo , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Genisteína/uso terapêutico , Inflamação , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Estresse Oxidativo , PPAR alfa/metabolismo , PPAR gama/metabolismo , Perilipina-2/metabolismo , Extratos Vegetais/farmacologia , Polissacarídeos/uso terapêutico , RNA Ribossômico 16S/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Ganho de Peso/efeitos dos fármacos , Receptor fas/metabolismo
7.
Chem Biol Interact ; 310: 108665, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125535

RESUMO

Diabetes mellitus (DM) is metabolism related problems that share the phenotype of hyperglycemia, which is triggered by a complicated interaction of hereditary and environmental elements. It is the main reason for end-stage renal disease (ESRD), amputations of the traumatic lower extremity, and grown-up visual impairment. It additionally inclines to neurodegenerative and cardiovascular sicknesses. With an expanding rate around the world, DM may be the main motive of morbidity and mortality within the foreseeable future. The objective of treatment for DM is to inhibit mortality and difficulties through normalizing blood glucose stage. Genistein, a naturally available soy isoflavone, is accounted for to have various medical advantages credited to numerous natural capacities. In the course of recent years, various examinations have shown that genistein has hostile to diabetic impacts, specifically, direct consequences for ß-cell expansion, glucose-triggered insulin discharge, and safety towards apoptosis, unbiased of its functions as an estrogen receptor agonist, cancer prevention agent, or tyrosine kinase inhibitor. The present evaluation emphases on the promising molecular and biochemical paths associated with DM complications and, specifically, the multi-target method of genistein in diminishing diabetic neuropathy, nephropathy, and retinopathy.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Genisteína/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Genisteína/farmacologia , Humanos
8.
J Radiat Res ; 60(3): 308-317, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31038675

RESUMO

There are no FDA-approved drugs that can be administered prior to ionizing radiation exposure to prevent hematopoietic-acute radiation syndrome (H-ARS). A suspension of synthetic genistein nanoparticles was previously shown to be an effective radioprotectant against H-ARS when administered prior to exposure to a lethal dose of total body radiation. Here we aimed to determine the time to protection and the duration of protection when the genistein nanosuspension was administered by intramuscular injection, and we also investigated the drug's mechanism of action. A single intramuscular injection of the genistein nanosuspension was an effective radioprotectant when given prophylactically 48 h to 12 h before irradiation, with maximum effectiveness occurring when administered 24 h before. No survival advantage was observed in animals administered only a single dose of drug after irradiation. The dose reduction factor of the genistein nanosuspension was determined by comparing the survival of treated and untreated animals following different doses of total body irradiation. As genistein is a selective estrogen receptor beta agonist, we also explored whether this was a central component of its radioprotective mechanism of action. Mice that received an intramuscular injection of an estrogen receptor antagonist (ICI 182,780) prior to administration of the genistein nanosuspension had significantly lower survival following total body irradiation compared with animals only receiving the nanosuspension (P < 0.01). These data define the time to and duration of radioprotection following a single intramuscular injection of the genistein nanosuspension and identify its likely mechanism of action.


Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Genisteína/uso terapêutico , Hematopoese , Nanopartículas/química , Protetores contra Radiação/uso terapêutico , Animais , Relação Dose-Resposta à Radiação , Genisteína/administração & dosagem , Hematopoese/efeitos dos fármacos , Injeções Intramusculares , Masculino , Camundongos , Exposição à Radiação , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Suspensões
9.
Biomed Pharmacother ; 115: 108975, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100537

RESUMO

In our previous works, we highlight nine candidates (Cathepsin D, Lamp1, Tpi1, Fgb, FVII, Mst4, CDK4, Hdgf and Glud1) that might be key proteins of combination therapy anti-fibrosis in rats. In this research, in order to verify the function of candidates, gene or protein expression of the nine candidates was verified by Western blot and RT-qPCR, and enzyme-linked immunosorbent assay in vitro and vivo. The expression of Fgb, Tpi1, CDK4, Mst4 and FVII significantly changed and matched with previous results after combination treating fibrosis rats or hepatic stellate cells (HSCs). These proteins may play crucial roles in anti-fibrosis. In particular, FVII take on pivotal role in combination therapy against liver fibrosis. The viability and cycle of HSCs was determined using CCK8 assay and Flow Cytometry, respectively. The results indicate that an overexpression of FVII could accelerate HSC proliferation and reduce the pharmacologic sensitivity. Combination therapy may inhibit HSC proliferation by blocking cell cycle in S phase. Although further studies are necessary to determine the precise protein functions, this research provides the possible molecular mechanisms and signaling pathways of combination therapy against liver fibrosis.


Assuntos
Catequina/análogos & derivados , Fator VII/metabolismo , Genisteína/uso terapêutico , Cirrose Hepática Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Taurina/uso terapêutico , Animais , Catequina/administração & dosagem , Catequina/uso terapêutico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Genisteína/administração & dosagem , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Testes de Função Hepática , Ratos Sprague-Dawley , Taurina/administração & dosagem
10.
Int Immunopharmacol ; 71: 144-154, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901677

RESUMO

NLRP3 inflammasome has been reported to be associated with inflammatory bowel disease including colitis due to its potential ability to induce IL-1ß secretion. Emerging studies have demonstrated that Genistein, a major isoflavone, has potential anti-inflammatory effects in murine model colitis. However, its anti-inflammatory mechanism remains unclear. The effects of Genistein in dextran sulfate sodium (DSS)-induced murine colitis via targeting NLRP3 inflammasome was investigated in this study. Also, the mechanisms of protective action of Genistein in DSS-induced colitis may relate to TGR5 signaling. Genistein treatment not only remarkably attenuated loss of body weight and shortening of colon length but also significantly reduced inflammatory cells infiltration and pro-inflammatory mediator production in serum and colon. Moreover, Genistein treatment down-regulated production of caspase-1 and IL-1ß and increased intracellular cAMP level, which were similar to the treatment for INT-777, a semi-synthetic TGR5 agonist, in phorbol myristate acetate (PMA)-differentiated monocytic THP-1 cells and U937 cells. These protective effects of Genistein might be attributed by ubiquination of NLRP3 which was induced due to interaction of cAMP with NLRP3. Furthermore, the effects of Genistein on NLRP3 inflammasome disappeared in TGR5-silenced U937 cells. In conclusion, our study unveils that Genistein was able to inhibit NLRP3 inflammasome via TGR5-cAMP signaling in macrophages. It therefore might be a potential effective drug for inflammatory bowel diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , AMP Cíclico/metabolismo , Genisteína/uso terapêutico , Inflamassomos/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Colite/induzido quimicamente , Modelos Animais de Doenças , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Células THP-1 , Células U937
11.
Int Immunopharmacol ; 69: 270-278, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30743203

RESUMO

Psoriasis is a chronic recurrent skin inflammatory disease, and inhibition of inflammation may be an effective means of treating psoriasis. The flavonoid genistein has a clear anti-inflammatory effect. However, the anti-psoriatic effects of genistein and their underlying mechanisms remain unclear. In this study, we investigated the effects of genistein on imiquimod (IMQ)-induced psoriasis-like skin lesions in vivo and explored the mechanisms underlying those effects in vitro. It was found that genistein can significantly improve IMQ-induced pathological scores of cutaneous skin lesions in mice, reduce epidermal thickness, and inhibit the expression of inflammatory factors,including interleukin (IL)-1ß, IL-6, tumour necrosis factor-alpha (TNF-α), chemokine ligand 2 (CCL2), IL-17 and IL-23. In vitro studies, genistein inhibited the proliferation of human keratinocyte HaCaT cells and inhibited the expression of inflammatory factors in a dose-dependent manner which induced by TNFα. Further researches showed that genistein could also significantly inhibit phosphorylated STAT3 (pSAT3) expression in IMQ mice dorsal skin and in TNF-α-induced HaCaT cells. The inhibitory effect of genistein on the expression of IL-6, IL-23 and TNF-α was weakened after Stat3 siRNA in HaCaT cells. Genistein could also significantly inhibit TNF-α induced the nuclear translocation of NF-κB, and inhibit the phosphorylation of I-kBα (pI-kBα). After combining with NF-κB blocker BAY 11-7082, the effect of genistein down-regulate the expression of TNF-α and VEGFA was attenuated in HaCaT cells. The results suggest that genistein may be developed for the treatment of psoriasis lesions.


Assuntos
Anti-Inflamatórios/uso terapêutico , Genisteína/uso terapêutico , Queratinócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Psoríase/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Heme/análogos & derivados , Humanos , Imiquimode , Mediadores da Inflamação/metabolismo , Queratinócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Transcrição STAT3/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Environ Toxicol ; 34(5): 645-651, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30734460

RESUMO

Doxorubicin (DOX)-induced cardiomyopathy is a lethal disease. DOX-induced cardiotoxic effects are attributed towards increased redox status and apoptotic signaling. In this study, we show that genistein offers protection against DOX-induced cardio toxicity in the mice model. DOX-mediated increase in serum cardiac troponin and redox markers (ROS, LPO, 4-hydroxynonenal-protein adducts [HNE] levels) was significantly reduced by genistein treatment. Significantly increased TNF-α, IL-6, IL-8 expressions during DOX-induced inflammatory responses were down regulated by genistein treatment. Further, we found that genistein regulated antioxidant response through increased Nrf-2, HO-1, NQO1 protein expressions. In addition, DOX downregulated survival proteins (p-Akt, Bcl-2) with concomitant upregulation in Erk (1/2), Bax and cleaved caspase-3 expressions. The apoptotic activation was significantly downregulated by genistein treatment through suppression of apoptosis. Altogether, these findings show that genistein protects against DOX-induced cardiotoxic effects through activation of Nrf-2/HO-1 signaling.


Assuntos
Antioxidantes/uso terapêutico , Cardiomiopatias/prevenção & controle , Doxorrubicina/toxicidade , Genisteína/uso terapêutico , Coração/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/induzido quimicamente , Cardiotoxicidade/prevenção & controle , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Heme Oxigenase-1/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
13.
Biomed Pharmacother ; 112: 108670, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784939

RESUMO

Glucagon-like peptide-1 (GLP-1) an incretin hormone, is known to regulate the glucose-mediated insulin secretion. However, reduction in the level of GLP-1 is considered to be a major cause for the reduction of GLP-1-dependent insulin secretory response. Genistein an isoflavone, is an important polyphenol and has wide range of therapeutic potentials, but its therapeutic effects alone and/or in combination with metformin on GLP-1 secretion have not been investigated yet. Hence, we aimed to investigate the stimulatory action of genistein in combination with metformin on GLP-1 via downregulation of inflammatory mediators, hyperlipidemia and hyperglycemia in alloxan-induced diabetic rats. Diabetes was induced in experimental rats by single administration of alloxan intraperitoneally. Metformin (50 mg/kg/day), genistein (20 mg/kg/day) and combination of genistein and metformin was administered in alloxan-induced diabetic rats. We found that genistein alone and/or in combination with metformin significantly increased the serum level (P < 0.01) and tissue content (P < 0.05) of GLP-1 in intestine when compared with that of metformin-treated animals. Similarly, genistein alone and/or in combination with metformin also resulted in normoglycemia (P < 0.001), glucose tolerance (P < 0.01), insulin sensitivity (P < 0.0001), hyperlipidemia (P < 0.01), liver and kidney function biomarkers (P < 0.01) as compared to that of metformin-treated experimental animals. Moreover, genistein alone and/or in combination with metformin also downregulated the inflammatory responses by decreasing the levels of interleuin-6, tumor necrosis factor-α and C-reactive protein in serum (P < 0.05) and intestine (P < 0.001) more efficiently as compared to that of metformin-treated experimental animals. The downregulation of inflammatory responses in intestine, was positively associated with increased secretion of GLP-1 from intestine. Histopathology of pancreas and intestine also showed that genistein significantly improved the deleterious effects of alloxan on pancreas and intestine. Hence, our work provides new insights on the synergistic effects of genistein and metformin on GLP-1 secretion. This may significantly improve the perception for proposing new GLP-1-based synergistic approaches for the treatment of diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo/efeitos dos fármacos , Genisteína/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Mediadores da Inflamação/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Regulação para Baixo/fisiologia , Genisteína/farmacologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Resistência à Insulina/fisiologia , Ratos
14.
Biomed Pharmacother ; 112: 108618, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798118

RESUMO

Cardiomyocyte hypertrophy, a prevalent clinical condition is deeply associated with many physiological factors. The underlying mechanisms of cardiomyocyte hypertrophy are not yet fully understood. In this study, H9C2 cells were treated with genistein, miR-451 mimic, miR-451 inhibitor and isoproterenol for 24 h, to study the effect of genistein on isoproterenol-induced myocardial hypertrophy in vitro. Simultaneously, ICR mice were treated with genistein for 21 days to evaluate the effects of the phytochemical on isoproterenol-induced myocardial hypertrophy in vivo. Results showed that isoproterenol induced cardiac hypertrophy and down-regulated the expression of miR-451 and up-regulated miR-451's target gene TIMP2. Genistein increased the expression of miR-451 and inhibited the isoproterenol-induced cardiac hypertrophy. This study explored the function of genistein from the epigenetic level, suggesting that miR-451 may play a significant role in the genistein-assisted amelioration of isoproterenol-induced cardiac hypertrophy both in vitro and in vivo.


Assuntos
Cardiomegalia/metabolismo , Genisteína/uso terapêutico , Isoproterenol/toxicidade , MicroRNAs/biossíntese , Inibidores de Proteínas Quinases/uso terapêutico , Inibidor Tecidual de Metaloproteinase-2/biossíntese , Agonistas Adrenérgicos beta/toxicidade , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Feminino , Genisteína/farmacologia , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos ICR , MicroRNAs/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Inibidor Tecidual de Metaloproteinase-2/antagonistas & inibidores
15.
Drug Res (Stuttg) ; 69(6): 305-313, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30517965

RESUMO

Genistein is the natural isoflavone and a phytoestrogen with a broad range of pharmacological properties, such as tyrosine and topoisomerase inhibition. It also induces apoptosis and cell proliferation inhibition, differentiates cancer cells. Added health benefits include the reduction of osteoporosis by suppressing osteoclasts and lymphocyte functions, decreased the risk of cardiovascular attacks and relieved postmenopausal problems. Genistein traditionally used in Chinese and Ayurvedic medicine and are found to be associated with lower risk of breast, prostate and lung cancer. Numerous factors comprising genetic, epigenetic and transcriptomic alterations are evidenced to be responsible for breast, prostate and lung cancer. In present review, an overview on genistein, the various analytical methods and drug delivery approaches to determine genistein in the formulations are discussed. It may help to develop novel formulations with better solubility and bioavailability of genistein. The tumor cell scan may be targeted to form a stable genistein formulation.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Genisteína/farmacologia , Neoplasias/tratamento farmacológico , Fitoestrógenos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Disponibilidade Biológica , Genisteína/uso terapêutico , Humanos , Medicina Ayurvédica/métodos , Medicina Tradicional Chinesa/métodos , Fitoestrógenos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Solubilidade
16.
Chem Biol Drug Des ; 93(2): 188-200, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30299583

RESUMO

A series of genistein derivatives were synthesized and evaluated as multifunctional anti-Alzheimer agents. The results showed that these derivatives had significant acetylcholinesterase (AChE) inhibitory activity; compound 5a exhibited the strongest inhibition to AChE with an IC50 value (0.034 µM) much lower than that of rivastigmine (6.53 µM). A Lineweaver-Burk plot and molecular modeling study showed that compound 5a targeted both the catalytic active site and the peripheral anionic site of AChE. These compounds also showed potent peroxy scavenging activity and metal-chelating ability. The compounds did not show obvious effect on HepG2 and PC12 cell viability at the concentration of 100 µM. Therefore, these genistein derivatives can be utilized as multifunctional agents for the treatment of AD.


Assuntos
Inibidores da Colinesterase/síntese química , Genisteína/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Aminas/química , Animais , Antioxidantes/química , Sítios de Ligação , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Genisteína/metabolismo , Genisteína/farmacologia , Genisteína/uso terapêutico , Células Hep G2 , Humanos , Cinética , Simulação de Acoplamento Molecular , Células PC12 , Ratos , Relação Estrutura-Atividade
17.
Toxicol Appl Pharmacol ; 363: 98-110, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30468814

RESUMO

One of the major female sex hormones, estrogen, can influence a variety of mental states. Individuals with multiple sclerosis (MS) often suffer from mental health issues, which are correlated with the pathology of gray matter. In this study, we aimed to elucidate the validity of phytoestrogen genistein (GEN) for treating the gray matter lesions in MS using the mouse model of cuprizone (CPZ)-induced demyelination. First, we confirmed that 5-week 0.2% CPZ intoxication induced demyelination in the hippocampus, and that myelination was successfully recovered by GEN. Loss of mature oligodendrocytes following CPZ intoxication was counteracted by GEN. Neither CPZ nor GEN affected the densities of oligodendrocyte precursor cells and astrocytes. CPZ-induced activation and proliferation of microglia were not inhibited by GEN. Upregulation of gene expression of the pro-inflammatory cytokine, interleukin-1ß, in sorted microglia by CPZ was not inhibited by GEN either. However, the expression levels of genes related to phagocytosis, such as cluster of differentiation 68 and lysosomal-associated membrane protein 1, in sorted microglia were elevated by CPZ but lowered by GEN. Notably, physical contact of microglia with myelin was increased by CPZ but decreased by GEN. The expression levels of myelin-related genes, such as myelin basic protein and myelin oligodendrocyte glycoprotein, in the whole hippocampal tissue were decreased by CPZ but recovered by GEN. These results show that GEN may act on mature oligodendrocytes in the hippocampus by promoting their survival and myelin formation, and suggest the therapeutic potential of phytoestrogens for treating MS patients suffering from mental health issues.


Assuntos
Genisteína/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Fitoestrógenos/uso terapêutico , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cuprizona/toxicidade , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Genisteína/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fagocitose/efeitos dos fármacos , Fitoestrógenos/farmacologia , Resultado do Tratamento
18.
J Diet Suppl ; 16(5): 550-563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29969325

RESUMO

Parkinson's disease (PD) is the second-most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress has also been linked with the progression of PD, hence the involvement of a natural plant product could offer neuroprotection. The present study deals with the effect of genistein on the transgenic flies expressing normal human alpha synuclein panneurally. The PD flies were exposed to 10, 20, 30, and 40 µM of genistein (mixed in diet) for 24 days. A significant dose-dependent increase in the life span and delay in the loss of climbing ability were observed in the PD flies exposed to genistein (p < .05). A significant dose-dependent decrease in oxidative stress markers and increase in dopamine content were observed in PD flies exposed to genistein. However, the exposure of genistein did not inhibit the expression of α-synuclein in the brains of PD flies.


Assuntos
Animais Geneticamente Modificados , Drosophila , Genisteína/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Dopamina/análise , Drosophila/genética , Drosophila/metabolismo , Expressão Gênica , Humanos , Locomoção/efeitos dos fármacos , Monoaminoxidase/metabolismo , Neurônios/metabolismo , alfa-Sinucleína/genética
19.
Nutr Neurosci ; 22(6): 375-391, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29063799

RESUMO

Genistein is a plant estrogen promoted as an alternative to post-menopausal hormone therapy because of a good safety profile and its promotion as a natural product. Several preclinical studies of cerebral ischemia and other models of brain injury support a beneficial role for genistein in protecting the brain from injury whether administered chronically or acutely. Like estrogen, genistein is a pleiotropic molecule that engages several different mechanisms to enhance brain health, including reduction of oxidative stress, promotion of growth factor signaling, and immune suppression. These actions occur in endothelial, glial, and neuronal cells to provide a coordinated beneficial action to ischemic challenge. Though many of these protective actions are associated with estrogen-like actions of genistein, additional activities on other receptors and intracellular targets suggest that genistein is more than a mere estrogen-mimic. Importantly, genistein lacks some of the detrimental effects associated with post-menopausal estrogen treatment and may provide an alternative to hormone therapy in those patients at risk for ischemic events.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Genisteína/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Humanos , Receptores Estrogênicos/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismo
20.
Can J Diabetes ; 42(6): 639-644, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30054234

RESUMO

OBJECTIVES: Without proper medication for the treatment of diabetic retinopathy, retinal cells become malnourished and degenerate, which results in damage to vision cells and can lead to blindness. Flavonoids such as biochanin A (BCA) can directly target various facets of angiogenesis. We assessed the effect of administrating BCA on angiogenic and inflammatory markers in the retina of rats with diabetes. METHODS: We randomly selected 2 groups from 30 male Wistar rats. We used 6 rats in each group. We selected 1 control group, Group 1 (which received 0.5% dimethyl sulfoxide), and a second group, Group 2, which received 10 mg/kg body weight (bw) of BCA. Type 1 diabetes was induced in other rats by a single injection of streptozotocin (55 mg/kg bw). Rats with diabetes were randomly divided into 3 groups as follows: Group 3, the control group with diabetes, which received 0.5% dimethyl sulfoxide; and Groups 4 and 5, which received 10 and 15 mg/kg bw of BCA, respectively. The concentration of vascular endothelial growth factor, tumor necrosis factor-alpha and interleukin-1beta were quantified in the retina of rats with diabetes that received BCA for 6 weeks, and the levels were compared to those of control rats. RESULTS: Administration of BCA to rats with diabetes resulted in a significant restoration of fasting blood glucose levels. After administration of BCA, retina concentrations of vascular endothelial growth factor, tumor necrosis factor-alpha and interleukin-1beta decreased in the 2 groups of treated rats with diabetes compared to the control group with diabetes (p<0.05). No significant difference was shown between the 2 doses of BCA. CONCLUSIONS: Administration of BCA can improve and postpone retinopathy by lowering blood sugar, suppressing inflammation via decreasing tumor necrosis factor-alpha and interleukin-1beta, and reducing angiogenesis via decreasing vascular endothelial growth factor in the retinal tissues.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/prevenção & controle , Genisteína/farmacologia , Genisteína/uso terapêutico , Interleucina-1beta/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Glicemia/análise , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/metabolismo , Masculino , Ratos , Ratos Wistar , Retina/patologia
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