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1.
Phytother Res ; 33(11): 2849-2861, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31407422

RESUMO

Silymarin is a complex extract isolated from the plant Silybum marianum, widely known for its prominent antioxidant and hepatoprotective effects, although increasing evidences have reported extraordinary antiproliferative and apoptotic abilities. As a result, several signaling pathways involved in cell cycle control, cell proliferation, and cell death have been deconvoluted as critical mechanisms. In this regard, cyclin and cyclin-dependent pathways have been the most studied ones. Following that, apoptotic pathways, such as p53, Akt, STAT-3, Ras, and caspases pathways, have been extensively studied, although other mechanisms involved in inflammation and angiogenesis have also been highlighted as silymarin-likely targets in cancer therapy. Therefore, the main challenge of this review is to discuss the diverse molecular mechanisms for silymarin antiproliferative and apoptotic effects; most of them largely studied in various types of cancers so far. Clinical trials and combination therapies related to silymarin application in cancer prevention and treatment are presented as well.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias/patologia , Silimarina/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Cardo Mariano/química , Neoplasias/classificação , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Silimarina/uso terapêutico
2.
Gene ; 712: 143966, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279711

RESUMO

BACKGROUND: Acute paracetamol (PCM) toxicity is a clinical problem; can result in a serious liver injury that finally may progress to acute liver failure. Curcumin (CUR) is a prevalent natural compound that can maintain prooxidant/antioxidant balance and thus can help in liver protection; also, Silymarin (SL) is a traditional antioxidant herb, used to treat liver disorders through scavenging free radicals. This study aimed to illustrate the histological, biochemical and molecular changes induced by acute PCM overdose on rats' liver to elucidate the effectiveness of CUR compared to SL in alleviating such changes. MATERIALS AND METHODS: Male Wister Albino rats were divided into 6 groups each comprising 23 rats: control group, curcumin (CUR) treated group received (100 mg CUR/ kg), silymarin treated group received (100 mg SL/kg) for 7 successive days. Paracetamol (PCM) exposed group administered a single dose of PCM (200 mg/kg orally on 8th day). PCM + CUR group and PCM + SL group pretreated with CUR and SL respectively for 7 days then received single PCM dose (200 mg/kg) on the 8th day. Blood and liver tissues were collected for biochemical, histopathological and immunohistochemical analyses using anti-p53 antibody. In addition, real time polymerase chain reaction (RT- PCR) was used to measure Bax, bcl2 and Peroxisome proliferator-activated receptor-gamma (PPAR γ) mRNA expression levels. RESULTS: In the paracetamol overdose group, the liver architecture showed necrotic changes, hydropic degeneration, congestion and dilatation of central veins. This hepatocellular damage was confirmed by a significant increase of AST, ALT levels and by an apparent increase in the number of p53 stained cells. PCM toxicity showed significant elevation of total oxidant status (TOS), oxidant status index (OSI) and decreased total antioxidant capacity (TAC) compared to controls (p < 0.001). Gene expression analysis showed that PCM caused an elevation of bcl2 and a reduction of both Bax and PPARγ mRNA expression. The histological alternation in the liver architecture was markedly improved in (PCM + CUR) group compared to (PCM+ SL) group, with an obvious decrease in the number of P53 stained cells. CUR pretreatment inhibited the elevation of TOS and OSI as well as the reduction of TAC caused by PCM toxicity compared to (PCM + SL) group. CONCLUSION: Both SL and CUR pretreatment prevented the toxic effects of PCM, but CUR is more effective than SL in ameliorating acute PCM induced hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Curcumina/farmacologia , Falência Hepática Aguda/induzido quimicamente , Fígado/efeitos dos fármacos , Silimarina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Apoptose , Sinergismo Farmacológico , Imuno-Histoquímica , Masculino , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo
3.
Phytother Res ; 33(7): 1770-1783, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155811

RESUMO

N-acetyl-p-benzoquinoneimine (NAPQI) is toxic metabolite of paracetamol formed primarily by cytochrome P4502E1 (CYP2E1) metabolic pathway when administered at therapeutic doses or overdose. The influence of quercetin (flavonoid) on the bioactivation of paracetamol to NAPQI was investigated using rat liver microsomes and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known inhibitor of CYP2E1, CYP3A4 and quercetin (10 and 20 mg/kg) to rats for 15 consecutive days. Area under the plasma concentration-time curve (AUC0-∞ ) and the peakplasma concentration (Cmax ) of paracetamol were dose-dependently increased with quercetin (10 and 20 mg/kg) compared to paracetamol control group (p < 0.001). On the other hand, the AUC0-∞ and Cmax of NAPQI were decreased significantly with quercetin. The same results were observed with silymarin also. The elevated liver and kidney functional enzymes/compounds were significantly reduced by quercetin and silymarin compared to paracetamol control group. The formation of NAPQI was reduced in the incubation samples in presence of quercetin in experiment using isolated rat hepatocytes. The presentstudy results revealed that quercetin might be inhibited the CYP2E1-mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.


Assuntos
Acetaminofen/farmacocinética , Benzoquinonas/metabolismo , Hepatócitos/efeitos dos fármacos , Iminas/metabolismo , Quercetina/farmacologia , Acetaminofen/sangue , Animais , Células Cultivadas , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Hepatócitos/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Ratos Wistar , Silimarina/farmacologia
4.
Pharmacol Rep ; 71(4): 703-712, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207432

RESUMO

BACKGROUND: Silymarin, a known hepatoprotectant, owing to its poor oral bioavailability, has limited pharmacological effects. The present study was designed to improve its in vitro and in vivo hepatoprotection and increase its oral bioavailability against alcohol intoxication by formulating it in four different liposomal formulations namely conventional, dicetyl phosphate, stearyl amine and PEGylated liposomes. METHOD: The liposomes were prepared using phosphatidylcholine, cholesterol, and silymarin in addition to dicetyl phosphate, stearyl amine and DSPE mPEG 2000 by film hydration method with 5% sucrose as a cryo-protectant. The optimized formulations were studied for their release profile at pH 1.2 and 6.8. Liposomes were studied for in vitro protection on Chang liver cells and efficacious liposomes were selected for in vivo hepatoprotection study. Further, conventional liposomes were studied for bioavailability in alcohol intoxicated Wistar rats. RESULTS: The conventional liposomes increased in vitro release profile at pH 1.2 and 6.8 and also showed better in vitro protection compared to silymarin alone. Conventional and PEGylated liposomes showed better improvement in liver function, better efficacy in combating inflammatory conditions, better improvement in antioxidant levels and reversal of histological changes compared to silymarin alone. Conventional also showed an almost fourfold increase in area under the curve compared to silymarin suspension. CONCLUSION: Conventional and PEGylated liposomes of silymarin were found to be more efficacious as hepatoprotective against alcohol-induced hepatotoxicity by its free radical scavenging and anti-inflammatory effects. Conventional liposomes showed enhanced bioavailability compared to silymarin alone.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Etanol/toxicidade , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Silimarina/farmacologia , Animais , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Lipossomos , Fígado/metabolismo , Fígado/patologia , Masculino , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Wistar , Silimarina/administração & dosagem , Silimarina/farmacocinética
5.
BMC Vet Res ; 15(1): 127, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039823

RESUMO

BACKGROUND: Laminitis is considered as one of the most important causes of hoof lameness in dairy cows, which can lead to enormous economic losses. However, the etiology and pathogenesis of laminitis have not been clarified yet. Besides, it is of great significant to find alternative herbs for the prevention and treatment of dairy hooves to avoid the antibiotic abuse. In this study, the primary hoof dermal cells of dairy cows were isolated, the inflammatory model was induced by LPS, and treated with silymarin to find whether silymarin has protective effect on the inflammatory dermal cells. The viability of dermal cells, the levels of IL-1ß and TNF-α, the degree of p65 NF-κB and p38 MAPK phosphorylation, the expressions of CYP3A4 and CYP1A1 were measured. RESULTS: Hoof dermal cells of dairy cows were successfully isolated and cultured by tissue adherent culture method. Certain concentrations of LPS can increase the levels of IL-1ß and TNF-α, promote the phosphorylation of p65 NF-κB and p38 MAPK, and inhibit the mRNA expressions of CYP3A4 and CYP1A1. The optimal concentration for LPS to establish a hoof dermal cells inflammatory model was 10 µg/mL. Certain concentrations of silymarin can markedly decrease the secretions of IL-1ß and TNF-α, inhibit the phosphorylation of p65 NF-κB and p38 MAPK, and promote the mRNA expressions of CYP3A4 and CYP1A1 in LPS-induced dermal inflammatory model. CONCLUSIONS: LPS can be used for inducing the hoof dermal cells inflammatory model of dairy cows. Silymarin has protective effects on the LPS-induced inflammatory model.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Casco e Garras/citologia , Silimarina/farmacologia , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Derme/citologia , Derme/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Casco e Garras/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Fosforilação , Fator de Transcrição RelA/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética
6.
Molecules ; 24(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035343

RESUMO

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC-MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0-12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0-12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.


Assuntos
Interações de Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Metabolômica , Silimarina/farmacologia , Sinvastatina/farmacocinética , Animais , Metabolômica/métodos , Estrutura Molecular , Ratos
7.
Molecules ; 24(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035502

RESUMO

The application of natural plant extracts in UV-protection is popular and intensively studied. Silymarin (from Silibum marianum), a naturally occurring polyphenol, has recently received attention due to its antioxidant, anti-inflammatory and anti-apoptotic effects. However, its role in the UV-mediated keratinocyte cell response is still controversial. In this study, we investigated the effects of Silibum marianum extracts with different origins and formulations on UVA-exposed HaCaT keratinocytes in vitro. Our results show, that silymarin treatment caused an inverse dose-dependent photosensitivity relationship (at higher doses, a decrease in cell viability and ROS production) after UVA exposure. The attenuation of the UVA-induced ROS generation after silymarin treatment was also observed. Moreover, silymarin pre-treatment increased the cyclobutane pyrimidine dimer photolesions in keratinocytes after UVA exposure. These results indicated the dual role of silymarin in UVA-exposed keratinocytes. It scavenges ROS but still induces phototoxicity. Based on our results dermatological applications of silymarin and related compounds should be considered very carefully.


Assuntos
Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Silimarina/química , Silimarina/farmacologia , Raios Ultravioleta , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Raios Ultravioleta/efeitos adversos
8.
Molecules ; 24(9)2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31064071

RESUMO

As a longstanding problem, Alzheimer's disease (AD) has stymied researchers in the medical field with its increasing incidence and enormous treatment difficulty. Silymarin has always been valued by researchers for its good efficacy and safety in treating liver disease. Recent studies have shown that silymarin also has good pharmacological activity in the nervous system, especially for the treatment of AD. Silymarin can control the production of Aß by inhibiting the precursor substance of Aß (ß-amyloid precursor protein), and it can inhibit the polymerization of Aß. Silymarin can also increase the acetylcholine content in the nervous system by inhibiting cholinesterase activity. At the same time, it also has the effect of resisting oxidative stress and the inflammatory response of the nervous system. These pharmacological activities contribute to the inhibition of the onset of AD. The good efficacy of silymarin on AD and its high safety and availability give it huge potential for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Silimarina/uso terapêutico , Acetilcolina/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Humanos , Estrutura Molecular , Sistema Nervoso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Silimarina/farmacologia
9.
Arch Dermatol Res ; 311(6): 477-490, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31079190

RESUMO

The exposure of naked unprotected skin to solar radiation may result in numerous acute and chronic undesirable effects. Evidence suggests that silymarin, a standardized extract from Silybum marianum (L.) Gaertn. seeds, and its major component silybin suppress UVB-induced skin damage. Here, we aimed to investigate the UVA-protective effects of silymarin's less abundant flavonolignans, specifically isosilybin (ISB), silychristin (SC), silydianin (SD), and 2,3-dehydrosilybin (DHSB). Normal human dermal fibroblasts (NHDF) pre-treated for 1 h with flavonolignans were then exposed to UVA light using a solar simulator. Their effects on reactive oxygen species (ROS), carbonylated proteins and glutathione (GSH) level, caspase-3 activity, single-strand breaks' (SSBs) formation and protein level of matrix metalloproteinase-1 (MMP-1), heme oxygenase-1 (HO-1), and heat shock protein (HSP70) were evaluated. The most pronounced preventative potential was found for DHSB, a minor component of silymarin, and SC, the second most abundant flavonolignan in silymarin. They had significant effects on most of the studied parameters. Meanwhile, a photoprotective effect of SC was mostly found at double the concentration of DHSB. ISB and SD protected against GSH depletion, the generation of ROS, carbonylated proteins and SSBs, and caspase-3 activation, but had no significant effect on MMP-1, HO-1, or HSP70. In summary, DHSB and to a lesser extent other silymarin flavonolignans are potent UVA-protective compounds. However, due to the in vitro phototoxic potential of DHSB published elsewhere, further studies are needed to exclude phototoxicity for humans as well as to confirm our results on human skin ex vivo and in vivo.


Assuntos
Citoproteção/efeitos dos fármacos , Silimarina/análogos & derivados , Protetores Solares/farmacologia , Raios Ultravioleta/efeitos adversos , Caspase 3/metabolismo , Células Cultivadas , Quebras de DNA de Cadeia Simples/efeitos da radiação , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Glutationa/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Carbonilação Proteica/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Silimarina/farmacologia , Pele/efeitos da radiação
10.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010179

RESUMO

Silymarin flavonolignans are well-known agents that typically possess antioxidative, anti-inflammatory, and hepatoprotective functions. Recent studies have also documented the antiviral activities of silymarin and its derivatives against several viruses, including the flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunya virus and Mayaro virus), influenza virus, human immunodeficiency virus, and hepatitis B virus. This review will describe some of the latest preclinical and clinical studies detailing the antiviral profiles of silymarin and its derivatives, and discuss their relevance for antiviral drug development.


Assuntos
Antivirais/farmacologia , Flavonolignanos/farmacologia , Silimarina/farmacologia , Antivirais/química , Vírus Chikungunya/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Flavivirus/efeitos dos fármacos , Flavonolignanos/química , HIV/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Silimarina/química , Togaviridae/efeitos dos fármacos
11.
In Vitro Cell Dev Biol Anim ; 55(5): 368-375, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025252

RESUMO

Ketosis is a condition where ketone bodies are produced as an alternative energy source, due to insufficient glucose for energy production so that the body switches from carbohydrate metabolism to mostly fat metabolism. In this study, we examined the anti-ketosis effects of silibinin, a major active component of silymarin. We induced ketosis in FL83B mouse hepatocytes in vitro by culturing in low glucose media and compared results to hepatocytes maintained in high-glucose conditions. We quantified ß-hydroxybutyrate (BHB) levels with a colorimetric assay. In low-glucose conditions, silibinin reduced the amount of BHB produced, compared to high-glucose conditions; thus, silibinin exhibited an anti-ketotic effect. Ketone body formation during beta oxidation is mediated by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) regulates the transcription of HMGCS2, and plays a vital role in BHB levels. We showed that silibinin inhibited the expression of HMGCS2 and NF-kB at transcriptional and translational levels. Silibinin also inhibited the nuclear translocation of NF-kB and its DNA binding activity. To elucidate the relationship between HMGCS2 and NF-kB, we tested inhibited and over-expressed NF-kB. We found that NF-kB acted as a positive regulator for HMGCS2 under ketosis treatment conditions.


Assuntos
Hidroximetilglutaril-CoA Sintase/genética , Cetose/tratamento farmacológico , NF-kappa B/genética , Silibina/farmacologia , Ácido 3-Hidroxibutírico/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colorimetria , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Corpos Cetônicos/biossíntese , Corpos Cetônicos/metabolismo , Cetose/genética , Cetose/metabolismo , Cetose/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Silimarina/química , Silimarina/farmacologia
12.
Immunol Invest ; 48(5): 533-548, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30947570

RESUMO

Background: Immunosuppressive agents are necessary to enhance allograft tolerance after transplantation and the treatment of autoimmune disorders. Regulatory T cells (Tregs) play a pivotal role in improving allograft tolerance and determining the fate of transplanted organs. Therefore, the aim of this study was to investigate the immunomodulatory effects of cyclosporine A (CsA) and silymarin on the proliferation and cytokine production of Tregs. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy voluntaries and Tregs were isolated using an immunomagnetic separation method. The phenotypic characteristics of Tregs were determined by flow cytometry. Tregs were expanded and then cultured with different concentrations of CsA and silymarin. The effects of CsA and silymarin on the viability, proliferation, and transforming growth factor-beta 1 (TGF-ß1) production of Tregs were determined after 3 and 5 days of culture. Results: CsA significantly decreased Treg proliferation in a dose-dependent manner (p < 0.01-0.05). CsA failed to change TGF-ß1 production of Tregs. On the contrary, silymarin significantly increased the proliferation of Tregs (p < 0.01-0.05). A statistically significant increase was also observed in the TGF-ß1 production of Tregs (p < 0.01-0.05). Our data showed that Treg viability was not compromised by CsA and silymarin. Conclusion: Overall, the results of this study for the first time indicate that silymarin, unlike CsA, has the ability to increase the proliferation and TGF-ß1 production of Tregs and may be beneficial in the treatment of autoimmune disorders and improvement of Treg-dependent allograft tolerance after transplantation.


Assuntos
Ciclosporina/farmacologia , Silimarina/farmacologia , Linfócitos T Reguladores/imunologia , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Voluntários Saudáveis , Humanos , Separação Imunomagnética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária , Fator de Crescimento Transformador beta1/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-31017870

RESUMO

Background The objective of this investigation was to examine the impact of silymarin supplementation on locomotion, anxiety-related behavior, learning, and memory via several behavioral tests, such as open field, elevated plus maze, and Morris water maze tests in streptozotocin-induced diabetic rats. Methods The rats were divided into the control, diabetes, silymarin, and diabetes plus silymarin groups. On the 30th-35th days of the study, several behavioral tests were performed and blood and brain tissue samples were taken and brain-derived neurotrophic factor (BDNF) and histone deacetylase 3 (HDAC3) levels were analyzed. Results There was no significant difference in locomotor activity between the groups (p = 0.534). Spatial memory was lower (p = 0.000) but anxiety scores were higher (p = 0.005) in the diabetes group than in the control, silymarin, and diabetes plus silymarin groups. Plasma (p = 0.000) and brain tissue (p = 0.007) BDNF levels were lower in the diabetes group than in the control, silymarin, and diabetes plus silymarin groups; however, plasma (p = 0.432) and brain tissue (p = 0.321) HDAC3 levels did not significantly differ between the groups. Conclusions The findings obtained from this study suggest that silymarin supplementation could improve anxiety-related behavior, and learning and memory in diabetic rats by increasing the BDNF levels.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/complicações , Silimarina/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/metabolismo , Suplementos Nutricionais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos
14.
Oxid Med Cell Longev ; 2019: 6026902, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30891115

RESUMO

Bilirubin is considered to be one of the most potent endogenous antioxidants in humans. Its serum concentrations are predominantly affected by the activity of hepatic bilirubin UDP-glucuronosyl transferase (UGT1A1). Our objective was to analyze the potential bilirubin-modulating effects of natural polyphenols from milk thistle (Silybum marianum), a hepatoprotective herb. Human hepatoblastoma HepG2 cells were exposed to major polyphenolic compounds isolated from milk thistle. Based on in vitro studies, 2,3-dehydrosilybins A and B were selected as the most efficient compounds and applied either intraperitoneally or orally for seven days to C57BL/6 mice. After, UGT1A1 mRNA expression, serum, intrahepatic bilirubin concentrations, and lipoperoxidation in the liver tissue were analyzed. All natural polyphenols used increased intracellular concentration of bilirubin in HepG2 cells to a similar extent as atazanavir, a known bilirubinemia-enhancing agent. Intraperitoneal application of 2,3-dehydrosilybins A and B (the most efficient flavonoids from in vitro studies) to mice (50 mg/kg) led to a significant downregulation of UGT1A1 mRNA expression (46 ± 3% of controls, p < 0.005) in the liver and also to a significant increase of the intracellular bilirubin concentration (0.98 ± 0.03vs.1.21 ± 0.02 nmol/mg, p < 0.05). Simultaneously, a significant decrease of lipoperoxidation (61 ± 2% of controls, p < 0.005) was detected in the liver tissue of treated animals, and similar results were also observed after oral treatment. Importantly, both application routes also led to a significant elevation of serum bilirubin concentrations (125 ± 3% and 160 ± 22% of the controls after intraperitoneal and oral administration, respectively, p < 0.005 in both cases). In conclusion, polyphenolic compounds contained in silymarin, in particular 2,3-dehydrosilybins A and B, affect hepatic and serum bilirubin concentrations, as well as lipoperoxidation in the liver. This phenomenon might contribute to the hepatoprotective effects of silymarin.


Assuntos
Bilirrubina/metabolismo , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Silimarina/isolamento & purificação , Silimarina/farmacologia , Animais , Flavonoides/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Espaço Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Silibina/administração & dosagem , Silibina/farmacologia
15.
Phytother Res ; 33(4): 871-880, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30834633

RESUMO

Dyslipidemia is a leading cause of endothelial dysfunction and cardiovascular disease. Several studies used silymarin as an herbal supplement in hyperlipidemic subjects. The aim of the present systematic review and meta-analysis was to examine the effect of silymarin supplementation on blood lipids. PubMed, Scopus, Ovid (Cochrane library), ISI Web of Science, and Google Scholar were systematically searched until March 2018 to find intervention studies that examined the impact of silymarin supplementation on blood lipids in adults. Changes in blood lipids and potential sources of between-study variation were extracted. We run a subgroup analysis to determine potential sources of inter-study heterogeneity. Ten clinical trials fulfilled the eligibility criteria. Meta-analysis indicated that silymarin supplementation in combination with other treatments (not silymarin alone) reduced total cholesterol (change: -25.45 mg/dl; 95% confidence interval [CI] [-47.89, -3.01 mg/dl]) and low-density lipoprotein (change: -28.25 mg/dl; 95% CI [-53.09, -3.42 mg/dl]). Also, silymarin increased high-density lipoprotein concentration (change: 4.82 mg/dl; 95% CI [2.01, 7.63 mg/dl]). Blood concentration of triglyceride was significantly after silymarin supplementation in comparison with controls (change: -22.55 mg/dl; 95% CI [-44.32, -0.78 mg/dl]). Present systematic review and meta-analysis revealed that silymarin supplementation in combination with other treatments had a favorable effect on blood lipids.


Assuntos
Suplementos Nutricionais , Lipídeos/sangue , Silimarina/farmacologia , Ensaios Clínicos como Assunto , Humanos , Silimarina/administração & dosagem
16.
Int J Mol Sci ; 20(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823534

RESUMO

Paracetamol is responsible for acute liver failure in humans and experimental animals when taken at high doses and transformed into a reactive metabolite by the liver cytochrome P450. On the other hand, nutmeg is rich with many phytochemical ingredients that are known for their ability to inhibit cytochrome P450. Hence, the present experiment was aimed at studying the hepatoprotective effect of Myristica fragrans (nutmeg), kernel extract (MFKE) in respect to paracetamol (acetaminophen; N-acetyl-p-amino-phenol (APAP))-induced hepatotoxicity in rats, focusing on its antioxidant, anti-inflammatory, and anti-apoptotic activities. Liver toxicity was induced in rats by a single oral administration of APAP (2 g/kg). To evaluate the hepatoprotective effect of MFKE against this APAP-induced hepatotoxicity, rats were pre-treated with either oral administration of MFKE at 300 mg/kg daily for seven days or silymarin at 50 mg/kg as a standard hepatoprotective agent. APAP intoxication caused a drastic elevation in liver function markers (transaminases, alkaline phosphatase, and total bilirubin), oxidative stress indicators (lipid peroxidation and nitric oxide), inflammatory biomarkers (tumour necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and nuclear factor ĸB) and the pro-apoptotic BCL2 Associated X (Bax) and caspases-3 genes. Furthermore, analyses of rat liver tissue revealed that APAP significantly depleted glutathione and inhibited the activities of antioxidant enzymes in addition to downregulating two key anti-apoptotic genes: Cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein (c-FLIP) and B-cell lymphoma 2 (Bcl-2). Pre-treatment with MFKE, however, attenuated APAP-induced liver toxicity by reversing all of these toxicity biomarkers. This hepatoprotective effect of MFKE was further confirmed by improvement in histopathological findings. Interestingly, the hepatoprotective effect of MFKE was comparable to that offered by the reference hepatoprotector, silymarin. In conclusion, our results revealed that MFKE had antioxidant, anti-inflammatory, and anti-apoptotic properties, and it is suggested that this hepatoprotective effect could be linked to its ability to promote the nuclear factor erythroid 2⁻related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Myristica/química , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Heme Oxigenase (Desciclizante)/genética , Masculino , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Silimarina/farmacologia , Silimarina/uso terapêutico
17.
Andrologia ; 51(5): e13242, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30729546

RESUMO

Cadmium is known as an oxidative stress-inducing factor. Silymarin extracted from Silybum marianum is regarded as a potent antioxidant. The present study investigated the preventing effects of silymarin on cadmium chloride-induced toxicity in terms of testis histopathology and serum testosterone level as well as oxidative stress indicators in mice. In addition, the activities of antioxidant defence enzymes was evaluated. Adult male mice were divided into four groups (n = 6 in each group): (a) control; (b) cadmium chloride; (c) silymarin + cadmium chloride and (d) Silymarin. In this study, cadmium chloride significantly decreased the diameter and wall thickness of the seminiferous tubule, diameter of the spermatogonia nucleus and serum testosterone levels compared to the control group. Furthermore, in mice treated with this pollutant, a significant increase in malondialdehyde was observed while ferric reducing antioxidant power level, and the activity of catalase, superoxide dismutase and glutathione peroxidase were significantly reduced in the testis. In the silymarin + cadmium chloride group, silymarin could significantly reverse the toxic effects of cadmium chloride. The findings of this study showed that silymarin, as a potent antioxidant, can compensate the adverse effects of cadmium chloride on testis histopathology, testosterone level, oxidative stress indicators and antioxidant defence enzymes in mice.


Assuntos
Antioxidantes/farmacologia , Cloreto de Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Silimarina/farmacologia , Animais , Masculino , Camundongos , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue
18.
Chem Biol Interact ; 302: 123-134, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30794797

RESUMO

Paracetamol (N-acetyl-para amino phenol) is the most commonly used analgesic and antipyretic around the world. Its causes hepatotoxicity and nephrotoxicity at overdose or even at therapeutic doses. It is primarily metabolized by glucuronidation and sulfate conjugation. It is also metabolized by cytochrome-P450 system (CYP2E1, CYP1A2 and CYP 3A4), leading to the formation of N-acetyl-p-benzoquinoneimine (NAPQI). The present study was planned to investigate the influence of chrysin (known CYP2E1 and CYP3A4 inhibitor) on the bioactivation of paracetamol to NAPQI using rat liver microsomes in vitro and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known CYP2E1 inhibitor and chrysin (100 and 200 mg/kg) to rats for 15 consecutive days. The area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of paracetamol were dose-dependently increased with chrysin (100 and 200 mg/kg) compared to paracetamol control group. On the other hand, the AUC0-∞ and Cmax of NAPQI were decreased significantly with chrysin (100 and 200 mg/kg). The elevated liver and kidney function markers were significantly reduced by chrysin and silymarin compared to paracetamol control group (P < 0.01). Histopathological studies of liver and kidney also well correlated with liver and kidney function tests. Chrysin also reduced the formation of NAPQI in the incubation samples of rat hepatocytes. The present study (both in vivo and in vitro) results revealed that chrysin might be inhibited the CYP2E1, CYP1A2 and CYP3A4-mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.


Assuntos
Acetaminofen/metabolismo , Benzoquinonas/metabolismo , Flavonoides/farmacologia , Hepatócitos/efeitos dos fármacos , Iminas/metabolismo , Acetaminofen/sangue , Acetaminofen/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Benzoquinonas/sangue , Benzoquinonas/farmacocinética , Cromatografia Líquida de Alta Pressão , Meia-Vida , Hepatócitos/citologia , Hepatócitos/metabolismo , Iminas/sangue , Iminas/farmacocinética , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Curva ROC , Ratos , Ratos Wistar , Silimarina/farmacologia
19.
Biol Pharm Bull ; 42(2): 255-260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713255

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation, which is the most common form of chronic liver disease. Multiple clinical studies using natural compounds such as flavonoids have been conducted to treat NAFLD. In the present study, the pharmacological effect of Citrus aurantium L. (Rutaceae) peel extract (CAE), which contains over 27% of polymethoxyflavone nobiletin, on NAFLD was evaluated using a high-fat diet (HFD) animal model susceptible to developing NAFLD. C57BL/6 mice were fed an HFD (60% kcal of energy derived from fat) for 8 weeks to induce obesity. Obese mice were randomly allocated to four groups of eight mice each (HFD alone, HFD with silymarin, HFD with 50 mg/kg CAE, and HFD with 100 mg/kg CAE). After 8 weeks of treatment, all mice were euthanized, and plasma and liver tissues were analyzed biochemically and histopathologically. The results indicate that CAE treatment significantly reduced HFD-induced NAFLD, as shown by decreased serum lipid index and prevented liver histopathology. The expression of genes involved in lipid synthesis including free fatty acid (FFA), peroxisome-proliferator-activated receptor γ (PPAR-γ), sterol receptor element binding protein 1c (SREBP-1c), and fatty acid synthesis enzyme was suppressed by CAE treatment. Moreover, compared to untreated mice, CAE-treated HFD mice showed decreased pro-inflammatory cytokine expression. These results demonstrated that CAE prevented HFD-induced NAFLD by reducing plasma levels of triglyceride and cholesterol and de novo lipid synthesis.


Assuntos
Citrus/química , Flavonoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR gama/biossíntese , PPAR gama/genética , Extratos Vegetais/farmacologia , Proteínas Quinases/metabolismo , Distribuição Aleatória , Silimarina/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Receptor fas/metabolismo
20.
Inflammation ; 42(4): 1203-1214, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30806958

RESUMO

Dysregulation of the immune system and impairment in the function and number of patient-derived regulatory T cells (Treg) have an important role in multiple sclerosis (MS) pathogenesis. MS patients still receive different medications to overcome the relapses and to slow the disease progression. However, the benefits of these therapies are limited and are accompanied by different side effects. The immunoregulatory effects of Silymarin as a plant-derived flavonoid have shown in studies. In the present study, regulatory T cells (Tregs) were isolated from MS patients who diagnosed as new cases and IFN-ß-treated RRMS patients. Isolated Treg cells were cultured in the presence of different concentrations of Silymarin (50, 100, 150 µM) for 48, 72, and 120 h. Proliferation and activation of Treg cells were assessed by flow cytometry. Also, FOXP3, JAK3, and STAT5 gene expression, IL-10, and TGF-ß production by Tregs were evaluated by real-time PCR and ELISA respectively. The results showed that Silymarin promoted Treg proliferation at 100 µM concentration after 72 h. Additionally, IL-10, TGF-ß levels, and FOXP3, JAK3, and STAT5 gene expression enhanced by Silymarin dose and time dependently. Our preliminary results suggest that the induction and activation of Tregs could be an underlying mechanism of the ancient used herbal medicine Silymarin, providing effective means against autoimmune and inflammatory diseases.


Assuntos
Esclerose Múltipla/tratamento farmacológico , Silimarina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Ativação Linfocitária/efeitos dos fármacos , Esclerose Múltipla/imunologia , Substâncias Protetoras/farmacologia , Silimarina/uso terapêutico , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
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