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1.
Ecotoxicol Environ Saf ; 190: 110126, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31918251

RESUMO

Tetramethyl thiuram disulfide (thiram) is a dithiocarbamate pesticide used for crop protection and storage. But, it's widespread utilization is associated with deleterious growth plate cartilage disorder in broilers termed as avian tibial dyschondroplasia (TD). TD results in non-mineralized and less vascularized proximal tibial growth plate cartilage causing lameness and poor growth performance. This study investigated the therapeutic potential of puerarin against thiram toxicity in TD affected chickens. One-day-old broiler chickens (n = 240) were alienated into three equal groups i.e. control, TD and puerarin (n = 80) and were offered standard feed. Additionally, TD and puerarin groups were offered thiram at 50 mg/kg of feed from 4 to 7 days for TD induction followed by puerarin therapy at 120 mg/kg to puerarin group only from 8 to 18 days for TD treatment. Thiram feeding to TD and puerarin group chickens caused lameness, mortality, and increased the aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA) levels and growth plate (GP) size and upregulated HIF-1α expression. Besides, the production parameters, alkaline phosphatase (ALP), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels and the expressions of TIMP-3 and BCL-2 were decreased (p < 0.05). Puerarin alleviated lameness, enhanced angiogenesis and growth performance and serum and antioxidant enzymes, decreased apoptosis and recuperated GP width by significantly downregulating HIF-1α and upregulating the TIMP-3 and BCL-2 mRNA and protein expressions in puerarin group chickens (p < 0.05). In conclusion, the toxic effects associated with thiram can be mitigated using puerarin.


Assuntos
Fungicidas Industriais/toxicidade , Isoflavonas/farmacologia , Osteocondrodisplasias/veterinária , Tiram/toxicidade , Vasodilatadores/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas/metabolismo , Glutationa Peroxidase/metabolismo , Lâmina de Crescimento/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Malondialdeído/metabolismo , Neovascularização Patológica/induzido quimicamente , Doenças das Aves Domésticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Tíbia/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-3/metabolismo
2.
Chem Biol Interact ; 315: 108897, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726037

RESUMO

Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF-α, IL-1ß, MDA, and TGF-ß contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.


Assuntos
Fibrose/tratamento farmacológico , Interleucina-33/metabolismo , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Interleucina-1/metabolismo , Animais , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fibrose/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
3.
J Biochem Mol Toxicol ; 34(2): e22431, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833131

RESUMO

Cisplatin-induced nephrotoxicity persists as a clinical problem despite several supportive measures to alleviate renal damage. Daidzein (DZ), a dietary isoflavone having antioxidant and anti-inflammatory activity, is investigated in this study for protective effects against cisplatin-induced renal injury in rats. DZ (25, 50, or 100 mg/kg; intraperitoneally; 10 days) was administered along with Cisplatin, single dose, on the 7th day of the experiment. On the 11th day, the rats were euthanized, and different samples were collected for analysis. Biochemical, histopathological, and molecular parameters were assessed to evaluate the effect of daidzein. Cisplatin injection resulted in renal dysfunction, lipid peroxidation that led to consumption of antioxidants, exaggerated apoptosis, and inflammation. These changes were associated with increase in the signaling proteins. DZ attenuated the toxic effects of cisplatin on the kidney at 100 mg/kg dose. The study concludes with the finding that daidzein imparts protection against the nephrotoxic effect of Cisplatin and can be considered as a novel, potential therapy.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/dietoterapia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Isoflavonas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nefrite/dietoterapia , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Citocinas/sangue , Isoflavonas/administração & dosagem , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Ratos , Resultado do Tratamento
4.
Maturitas ; 132: 7-16, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31883666

RESUMO

AIM: The aim of this systematic review and meta-analysis was to clarify the effect of a specific standardised extract of red clover (Trifolium pratense) on the lipid profile of perimenopausal and postmenopausal women. METHODS: Medline (PubMed), EMBASE, and Cochrane Library electronic databases were searched for papers in English reporting randomized controlled trials published up to 2017. Reference lists from those papers were checked for further relevant publications. Studies were identified and reviewed for their eligibility for inclusion in this review. The changes from baseline in the levels of individual components of the lipid profiles were used to assess differences between the active treatment and placebo groups. Weighted mean differences and 95 % confidence intervals were calculated for continuous data using a random-effects model. RESULTS: Ten eligible studies (twelve comparisons) with 910 peri- and postmenopausal women were selected for systematic review. The meta-analysis showed changes in serum levels: total cholesterol, -0.29 (95 % CI: -0.53 to -0.06) mmol/L [-11.21 (95 % CI: -20.49 to -13.92) mg/dL], p = 0.0136; LDL-cholesterol, -0.13 (95 % CI: -0.35 to 0.09) mmol/L [-5.02 (95 % CI: -13.53 to 3.48) mg/dL], p = 0.2418; triglycerides, -0.15 (95 % CI: -0.32 to 0.01) mmol/L [-13.28 (95 % CI: -28.34 to 0.88) mg/dL], p = 0.0592; and HDL-cholesterol, 0.14 (95 % CI: -0.08 to 0.36) mmol/L [5.41 (95 % CI: -3.09-13.92) mg/dL], p = 0.2103. TheI2 statistic ranged from 87.95%-98.30 %, indicating significant heterogeneity. CONCLUSIONS: The results suggest that a red clover extract is efficacious in reducing the concentrations of total cholesterol; however, changes in HDL-C, LDL-C and triglycerides are not as pronounced. Potentially, this means that women takingTrifolium pratense for menopausal symptoms can derive additional benefits from the plant's specific effect that corrects abnormal cholesterol levels. Additional studies are needed to assess its effects on post-menopausal women.


Assuntos
Isoflavonas/farmacologia , Lipídeos/sangue , Extratos Vegetais/farmacologia , Trifolium , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Perimenopausa/sangue , Pós-Menopausa/sangue , Triglicerídeos/sangue
5.
Int J Nanomedicine ; 14: 8345-8360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695371

RESUMO

Background: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect. Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging. Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of -6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium. Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Isoflavonas/farmacologia , Micelas , Mitocôndrias/metabolismo , Miócitos Cardíacos/patologia , Fosfinas/química , Animais , Cátions , Linhagem Celular , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Isoproterenol , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos
6.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 355-358, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701722

RESUMO

OBJECTIVE: To investigate the therapeutic effects of puerarin on rats with type 2 diabetes mellitus (T2DM). METHODS: T2DM models were established by high fat and high glucose feeding combined with a one-time intraperitoneal injection of streptozotocin (STZ, 60 mg/kg). Then the rats were randomly divided into normal group, model group, metformin group (MET, 40 mg/kg), puerarin low-dose group, medium-dose group and high-dose group (40, 80, 160 mg/kg), n=10. After the model was successfully established, rats were treated with corresponding drug intervention by intragastrical administration for 4 weeks. The body weight and fasting blood glucose (FBG) were measured per week, and blood samples were collected 24 h after the last administration, and serum levels of blood glucose, serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholestrol (HDL-C), serum enzyme activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), serum creatinine (SCr), and blood uric acid (UA) were measured. RESULTS: As compared with normal group, the body weight was decreased after 4 weeks-intervention in the model group, and the levels of FBG, TC, TG, LDL-C, ALT, AST, BUN, SCr and UA were all increased,while HDL-C level was decreased (P<0.05). As compared with model group,the body weight was increased after 4 weeks-intervention in metformin group and puerarin groups, and the levels of FBG, TC, TG, LDL-C, ALT, AST, BUN, SCr and UA were decreased (P<0.01); meanwhile, HDL-C level was increased significantly (P<0.05). CONCLUSION: Puerarin can reduce the weight loss of T2DM rats, decrease the blood lipid and blood glucose levels of T2DM rats, which can be used to control T2DM.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Isoflavonas/farmacologia , Animais , Glicemia , Lipídeos/sangue , Distribuição Aleatória , Ratos , Estreptozocina , Perda de Peso
7.
Life Sci ; 239: 117073, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751581

RESUMO

AIMS: Recently, strategies of cancer treatment using combination of agents with distinct molecular mechanism(s) of action are considered more promising due to its high efficacy and reduced systemic toxicity. The study is aimed to improve the efficacy of selective estrogen receptor modulator, Centchroman (CC) by combination with the phytoestrogen Genistein (GN). METHODS: Cytotoxicity was evaluated by Sulforhodamine B assay. Cell cycle analysis was done through flow cytometry. Further, Apoptosis was analyzed using Annexin V/PI staining, tunel assay and electron microscopic examination and verified using western blot analysis. In order to validate the in vitro results, in vivo analysis was performed using 4T1-syngeneic mouse model. KEY FINDINGS: In this study, we report that the dietary isoflavone genistein (GN) synergistically improved antineoplasticity of CC in breast cancer by arresting cells at G2/M phase culminating in ROS dependent apoptosis. The combination of CC plus GN caused dysregulation of Bax and Bcl-2 ratio inducing mitochondrial dysfunction, activation of Caspase-3/7, -9 and PARP cleavage. Further, combination significantly suppresses phosphorylation of PI3K/Akt/NF-κB, enhancing apoptosis. Additionally, combination markedly reduced tumor growth compared to CC and GN alone in mouse 4T1 breast tumor model. SIGNIFICANCE: Together, these studies suggest that GN represents a potential adjunct molecule whose role in CC induced apoptosis deserves attention.


Assuntos
Neoplasias da Mama/metabolismo , Centocromano/farmacologia , Genisteína/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Centocromano/metabolismo , Sinergismo Farmacológico , Feminino , Genisteína/metabolismo , Humanos , Isoflavonas/farmacologia , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Fitoestrógenos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
BMC Complement Altern Med ; 19(1): 269, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615565

RESUMO

BACKGROUND: Puerarin exerts therapeutic effect on osteoporosis due to its inhibitory effect on the formation of osteoclasts. Puerarin is also widely established as an autophagy inhibitor. The study aimed to investigate the significance of autophagy in Puerarin-treated osteoclast formation. METHODS: Osteoclast precursors (OCPs) derived from bone marrow-derived macrophages (BMMs) were treated with Puerarin along with RANKL or without RANKL, and then the autophagic parameters of OCPs (including autophagic proteins, LC3 transformation, autophagosome or LC3-puncta) were observed through Western Blotting, Transmission Electron Microscopy and Immunofluorescence assays. Next, after using overexpression vectors of autophagic genes (Atg7, Atg5 and BECN1) to alter autophagy activity, OCP proliferation was measured by Ethynyl deoxyuridine (EdU) assays and Cell Counting Kit-8 (CCK-8) kit, and osteoclast differentiation was assessed by Tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: The results showed that Puerarin could directly inhibit the autophagy and proliferation of OCPs. Importantly, overexpression of autophagic genes Atg5, Atg7 and BECN1 reversed Puerarin-inhibited OCP autophagy and proliferation. What's more, RANKL could promote the autography of OCPs, which was recovered by Puerarin treatment. Interestingly, different from single-Puerarin treatment, we found that in the presence of RANKL, only BECN1 overexpression significantly reversed Puerarin-inhibited osteoclast differentiation and OCP autophagy. CONCLUSION: In conclusion, Puerarin could inhibit the OCP autophagy in the presence or absence of RANKL, which blocked the OCP proliferation and osteoclast differentiation respectively. Moreover, BECN1 plays an essential role in Puerarin-inhibited osteoclastogenesis. Our study provides potential clue to further complete the intrinsic mechanism of Puerarin in treating osteoporosis.


Assuntos
Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Isoflavonas/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Animais , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Células Cultivadas , Feminino , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteoclastos/metabolismo , Pueraria/química , Transdução de Sinais/efeitos dos fármacos
9.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3786-3791, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602954

RESUMO

It is reported that energy metabolism is the core feature of tumor cells. This study is aimed to investigate the regulatory effect of two flavonoids( glabridin and quercetin) on energy supply and glycolysis of breast cancer cells,and provide reference for developing some anticancer herbal drugs with the function of regulating tumor energy metabolism. Based on the characteristics of each pathway during energy metabolism,in the present study,the triple negative breast cancer tumor cells( MDA-MB-231) were selected to investigate the effects of glabridin and quercetin on the energy metabolism of breast cancer cells and discuss the possible mechanisms from the following five potential targets: glucose uptake,protein expression of glucose transporter 1( GLUT1),adenosine triphosphate( ATP) level,lactate dehydrogenase( LDH) activity,and lactic acid( LD) concentration. The results showed that both quercetin and glabridin could decrease the glucose uptake capacity of breast cancer cells by down-regulating the protein expression of GLUT1. Quercetin had no significant effect on LDH activity and LD concentration; it did not affect the glycolysis process,but increased the intracellular ATP level. Glabridin decreased the activity of LDH and reduced LD concentration,thereby inhibiting the glycolysis metabolism of breast cancer cells. Therefore,both quercetin and glabridin can regulate the energy metabolism of breast cancer cells and can be used as potential anticancer agents or anti-cancer adjuvants.


Assuntos
Neoplasias da Mama/metabolismo , Metabolismo Energético , Isoflavonas/farmacologia , Fenóis/farmacologia , Quercetina/farmacologia , Linhagem Celular Tumoral , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos
10.
Comput Biol Chem ; 83: 107137, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639647

RESUMO

Xanthine oxidase (XO) is a form of xanthine oxidoreductase, a type of enzyme that plays a key role in the induction of hyperuricemia and raising superoxide radical level in blood. The present study was performed to evaluate the inhibitory activity of isoflavonoids (1-3) isolated from the ethyl acetate fraction of Apios americana, on the catalytic reaction mediated by XO. The isoflavonoids exhibited potential inhibitory activity within microgram/mL along with quenching effect towards XO. A reduction in the respective IC50 values was observed in the presence of high concentration of substrate. Molecular docking study revealed Ser876 and Arg880 as the key amino acids involved in the interaction of the enzyme with inhibitor. Apparently, the results demonstrated isoflavonoids as one of the natural products with a potential inhibitory effect on XO.


Assuntos
Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fabaceae/química , Isoflavonas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Isoflavonas/química , Isoflavonas/isolamento & purificação , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
11.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502574

RESUMO

The antitumor effect of calycosin has been widely studied, but the targets of calycosin against glioblastomas are still unclear. In this study we focused on revealing c-Met as a potential target of calycosin suppressing glioblastomas. In this study, suppressed-cell proliferation and cell invasion together with induced-cell apoptosis appeared in calycosin-treated U251 and U87 cells. Under treatment of calycosin, the mRNA expression levels of Dtk, c-Met, Lyn and PYK2 were observed in U87 cells. Meanwhile a western blot assay showed that c-Met together with matrix metalloproteinases-9 (MMP9) and phosphorylation of the serine/threonine kinase AKT (p-AKT) was significantly down-regulated by calycosin. Furthermore, overexpressed c-Met in U87 enhanced the expression level of MMP9 and p-AKT and also improved cell invasion. Additionally, the expression levels of c-Met, MMP9 and p-AKT were inhibited by calycosin in c-Met overexpressed cells. However, an AKT inhibitor (LY294002) only effected on MMP9 and p-AKT, not on c-Met. These data collectively indicated that calycosin possibility targeting on c-Met and exert an anti-tumor role via MMP9 and AKT.


Assuntos
Glioblastoma/tratamento farmacológico , Isoflavonas/farmacologia , Metaloproteinase 9 da Matriz/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
12.
Molecules ; 24(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533249

RESUMO

Bellevalia saviczii is a medicinal plant used as anti-rheumatic and anti-inflammatory herbal remedy in Iraqi-Kurdistan. The aim of this study was to evaluate the anti-inflammatory activity of its extract and the isolated homoisoflavonoid (Dracol) by studying the Ca2+-dependent NF-kB pathway. Nuclear translocation of p65 NF-kB subunit, as parameter of NF-kB activation, was visualized in human leukemic monocytes by immunofluorescence and Western blot analyses, after cell treatment with B. saviczii root extract or Dracol followed by Lipopolysaccharide stimulation. In parallel, Ca2+ signals responsible for NF-kB activation and levels of inflammatory cytokines were investigated. LPS-induced p65 translocation was evident in monocytes and both treatments, in particular that with Dracol, were able to counteract this activation. Intracellular Ca2+ oscillations were halted and the cytokine release reduced. These results confirm the traditional anti-inflammatory efficacy of B. saviczii and identify one of the molecules in the extract which appears to be responsible of this action.


Assuntos
Anti-Inflamatórios/farmacologia , Asparagales/química , Sinalização do Cálcio/efeitos dos fármacos , Isoflavonas/farmacologia , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico , Citocinas/metabolismo , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plantas Medicinais
13.
Int J Mycobacteriol ; 8(3): 229-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31512598

RESUMO

Background: Leprosy is a neglected tropical disease affecting millions of people. The current treatment against leprosy includes various antibacterial drugs of which dapsone is known to bind to dihydropteroate synthase of Mycobacterium leprae. Dapsone is an expensive antibacterial drug with many side effects. A natural alternative for dapsone having less to no side effects and cheaper in production is needed. The three-dimensional protein structure of dihydropteroate synthase of M. leprae is not available. Methods: Protein homology modeling of target protein was carried out, and protein structure validation and energy minimization were performed. Phytochemicals mentioned in literature having anti-leprosy properties were studied for absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and that which passed ADMET filters were further carried for comparative in silico docking analysis along with dapsone. Preliminary docking analysis was carried using AutoDock Vina, and results obtained were validated using AutoDock 4.2.6 and SwissDock. Results: Neobavaisoflavone was predicted to be ten times safer for administration than dapsone. On performing in silico docking, it was found that neobavaisoflavone has better binding affinity than dapsone and forms a stable protein-ligand complex. Residues GLY.50, THR.88, and VAL.107 play an important role as binding site residues. Conclusion: Further, in vitro and in vivo experimental studies are required to confirm anti-leprosy properties of neobavaisoflavone over drug dapsone.


Assuntos
Dapsona/farmacologia , Di-Hidropteroato Sintase/antagonistas & inibidores , Isoflavonas/farmacologia , Hansenostáticos/farmacologia , Simulação de Acoplamento Molecular , Mycobacterium leprae/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Mycobacterium leprae/enzimologia , Compostos Fitoquímicos/farmacologia , Ligação Proteica
14.
Mol Med Rep ; 20(3): 2893-2901, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524234

RESUMO

High glucose­induced endothelial Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is associated with the development and progression of the vascular complications of diabetes. The present study aimed to investigate whether formononetin, a biologically active compound isolated from Astragalus membranaceus (Fisch.) Bge, was able to regulate the JAK/STAT signaling pathway, improving endothelial function. In the present study, formononetin was identified to act as a JAK2 inhibitor, similarly to tyrphostin AG 490 (AG490), by significantly inhibiting the phosphorylation and the mRNA expression levels of JAK2 and STAT in HUVECs exposed to high glucose levels. In addition, formononetin and AG490 improved the viability of HUVECs and inhibited the protein expression levels of caspase­3. Furthermore, formononetin and AG490 attenuated the inflammatory response in HUVECs by downregulating the protein and mRNA expression levels of interleukin (IL)­1ß and intercellular adhesion molecule 1 (ICAM­1). Formononetin and AG490 also restored nitric oxide (NO) synthesis in HUVECs. Notably, formononetin was able to reverse the abnormal levels of phosphorylated (p)­JAK2, p­STAT3, IL­1ß, ICAM­1 and NO induced by cotreatment with high glucose and IL­6, an agonist of the JAK/STAT signaling pathway. Additionally, the present results suggested that formononetin restored phenylephrine­mediated contraction and acetylcholine­induced relaxation in aortic tissues of rats fed a high­glucose diet, in a dose­dependent manner. Collectively, formononetin could improve endothelial function under glucose stress in vivo and in vitro, suggesting that formononetin may represent a novel potential therapeutic compound to treat diabetic vascular complications.


Assuntos
Endotélio/metabolismo , Glucose/metabolismo , Isoflavonas/farmacologia , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Sobrevivência Celular , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Ratos
15.
Phytomedicine ; 64: 153075, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31476558

RESUMO

BACKGROUND: Obesity is one of the major health problems worldwide. The induction of brown adipocyte formation and activity represents a promising therapeutic option by increasing energy expenditure. Asian herbs have the potential to treat obesity, however, pharmacological effects should be well documented at the molecular level first. HYPOTHESIS: A novel hypothesis-driven screening approach identified the root of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep (PLR) to have potential effects on obesity by stimulating brown adipocytes. STUDY DESIGN: This study explored the metabolic effects of PLR water extract (PLRE) in a high-fat diet-induced obesity mouse model and characterized its secondary metabolite composition. METHODS: Animals were orally treated daily for two weeks and the bioactivity of PLRE evaluated by measuring various parameters including body weight, circulating metabolites, energy expenditure and insulin sensitivity. The chemical composition of the mains components was obtained by HPLC-MS-ELSD-PDA. Based on the dereplication results and semi-quantitative estimation, pure molecules were selected for tests on adipocytes in vitro. RESULTS: PLRE induces brown adipocyte activity and triggers the formation of brown-like cells in inguinal fat tissue, weight loss, and improved glucose metabolism. These effects are primarily caused by cell-autonomous activation of brown adipocytes and not by autonomic nervous system regulation. Even though the analysis of PLRE revealed puerarin as the most abundant secondary metabolite, it showed no effect on brown adipocyte formation and function. Brown adipocyte activity was induced dose-dependently by two other isoflavones, daidzein, and genistein. Daidzein is present in a very small amount in PLRE, but various glycosidic isoflavones, including puerarin, may release daidzein after metabolism. CONCLUSION: This approach demonstrated the positive effects of PLRE on a diet-induced obesity mouse model and provided clues on the mode of action of PLRE at the molecular level.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Pueraria/química , Adipócitos/efeitos dos fármacos , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Animais , Fármacos Antiobesidade/química , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Genisteína/farmacologia , Resistência à Insulina , Isoflavonas/farmacologia , Camundongos , Obesidade/etiologia , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Pueraria/metabolismo
16.
Phytother Res ; 33(11): 2948-2959, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478281

RESUMO

The balance between the osteoblasts and the osteoclasts is important for the maintenance of the skeleton of the human body. The osteoclasts absorb bone after differentiated into polymorphonuclear cells by the fusion of monocytes/macrophages. We have found that 6,7,4'-Trihydroxyflavone (THF), a compound from the heartwood of Dalbergia Odorifera inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, actin ring formation, and bone resorption in RAW 264.7 cells and bone marrow macrophage. THF significantly inhibited the c-Jun-N-terminal kinase signaling pathway without affecting extracellular signal-regulated kinase, p38, and AKT signaling. Moreover, THF inhibited the expression of c-Fos, nuclear factor-activated T cells cytoplasm 1, cathepsin K, and c-src by RANKL. We used a lipopolysaccharide (LPS)-induced bone loss model in mice. Consequently, bone volume per tissue volume, trabecular number's reduction was recovered in THF-treated mice, and trabecular separation's augmentation was also attenuated by THF administration. In summary, THF inhibits RANKL-induced osteoclast differentiation by MAPK signaling pathway and inhibits bone resorption by destroying the actin ring in mature osteoclasts. THF also prevented LPS-induced bone loss in a mice model. Thus, THF may be useful in the treatment of bone diseases associated with excessive osteoclast differentiation and bone resorption.


Assuntos
Reabsorção Óssea/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoclastos/efeitos dos fármacos , Animais , Células Cultivadas , Dalbergia/química , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
17.
Nutrients ; 11(9)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470503

RESUMO

Chronic obstructive pulmonary disease (COPD), a lung disease caused by chronic exposure to cigarette smoke, increases the number of inflammatory cells such as macrophages and neutrophils and emphysema. Isoflavone is a polyphenolic compound that exists in soybeans. Daidzein and genistein, two types of isoflavones, have been reported to have anti-inflammatory effects in various organs. We hypothesized that the daidzein-rich soy isoflavone aglycones (DRIAs) attenuate cigarette smoke-induced emphysema in mice. Mice were divided into four groups: the (i) control group, (ii) isoflavone group, (iii) smoking group, and (iv) isoflavone + smoking group. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and the airspace enlargement using the mean linear intercept (MLI) were determined 12 weeks after smoking exposure. Expressions of neutrophilic inflammatory cytokines and chemokines were also examined. In the isoflavone + smoking group, the number of neutrophils in BALF and MLI was significantly less than that in the smoking group. Furthermore, the gene-expressions of TNF-α and CXCL2 (MIP-2) in the isoflavone + smoking group were significantly less than those in the smoking group. Supplementation of the COPD murine model with DRIAs significantly attenuates pathological changes of COPD via suppression of neutrophilic inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Isoflavonas/farmacologia , Pulmão/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Fumaça , Produtos do Tabaco , beta-Glucanas/farmacologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais
18.
Med Sci Monit ; 25: 6523-6531, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31471534

RESUMO

BACKGROUND Acute respiratory distress syndrome (ARDS) in infants is acute and progressive hypoxic respiratory failure caused by various extrapulmonary pathogenic factors besides cardiogenic factors. Diffuse alveolar injury and progression to pulmonary fibrosis are pathological features of ARDS. The present study sought to determine how puerarin influences the inflammatory response caused by pulmonary fibrosis in ARDS in infants. MATERIAL AND METHODS The human lung fibroblasts cell line HLF1 was treated with different concentrations of puerarin in different groups for various times. TGF-ß1 was overexpressed by TGF-ß1 (2 ng/mL) in routine experiments, and the treated cells and culture supernatant were collected for analysis in each step. Cell apoptosis was measured by flow cytometry, TUNEL assay, and detection of caspase 3 and Bcl-2. Cell proliferation was assessed by CCK-8 assay. Real-time PCR and Western blot assay were used to assess mRNA and protein levels of TGF-ß1 and Smad3, respectively. The related cytokines were assessed by ELISA. RESULTS Results showed that puerarin promoted the apoptosis and inhibited the proliferation of HLF1 cells. Caspase 3 was upregulated, whereas Bcl-2, TGF-ß1, and Smad3 were downregulated by puerarin. IL-1, IL-2, and IL-4, secreted by HLF1 cells, were reduced, but IL-10 showed the opposite trend. When TGF-ß1 was overexpressed, Smad3 was promoted, and IL-1, IL-2, and IL-4 was increased in HLF1 cells. Finally, overexpression of TGF-ß1 reversed the effect of puerarin in HLF1 cells. CONCLUSIONS Puerarin regulated the proliferation and apoptosis of pulmonary fibrosis cells, and affected the secretion of inflammatory cytokines. Thus, puerarin alleviated the inflammatory response resulting from pulmonary fibrosis by regulating the TGF-ß1/Smad3 pathway in infants with ARDS.


Assuntos
Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Inflamação/patologia , Interleucinas/metabolismo , Isoflavonas/farmacologia , Pulmão/embriologia , Pulmão/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Síndrome do Desconforto Respiratório do Adulto/complicações , Síndrome do Desconforto Respiratório do Adulto/patologia
19.
Mol Med Rep ; 20(4): 3691-3700, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485606

RESUMO

Methylophiopogonanone B (MO­B), which belongs to a group of homoisoflavonoids, present in Ophiopogon japonicus, has been identified as an active component with antioxidative and anti­tumor properties. The present study investigated whether MO­B may exert protective effects on human umbilical vein endothelial cells (HUVECs) against H2O2­induced injury in vitro, and whether the MO­B effects may be modulated by the NADPH pathway. HUVECs were treated with MO­B in the presence or absence of H2O2. Malondialdehyde (MDA), reactive oxygen species (ROS) levels, and superoxide dismutase (SOD) activity were analyzed to evaluate cell injury and the antioxidative potential of MO­B. The results revealed that MO­B inhibited the production of MDA and ROS, but enhanced SOD activity. Furthermore, MO­B could alleviate H2O2­induced apoptosis in HUVECs, which is consistent with the expression of apoptosis­associated genes and proteins in cells, including Bax/Bcl­2 and caspase­3. To explore the potential mechanism, the present study investigated the effects of MO­B on NADPH­related signaling via the analysis of neutrophil cytochrome b light chain (p22phox) expression, which is the membrane­associated subunit of NADPH oxidase. MO­B could improve the survival of endothelial cells and therefore may be a potential drug in the treatment of cardiovascular diseases.


Assuntos
Antioxidantes/farmacologia , Células Endoteliais/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Isoflavonas/farmacologia , NADPH Oxidases/metabolismo , Apoptose/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Molecules ; 24(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487934

RESUMO

The rattans of Spatholobus suberectus Dunn are a traditional Chinese medicine activating blood circulation and removing stasis. They have often been used for the traditional Chinese medicinal treatment of breast cancer in modern China. In this study, four novel isoflavanes (1-3 and 5) and four known analogues (4 and 6-8) were isolated from an ethanolic extract of the rattans of S. suberectus. Their structures were elucidated by extensive spectroscopic analyses and electronic circular dichroism studies. MCF-7 and MDA-MB-231 human breast cancer cell lines were used to evaluate the cytotoxic effects of the isolates. Interestingly, compounds 1 and 2 only inhibited the proliferation of MCF-7 cells, while compound 6 showed a selective cytotoxicity against MDA-MB-231 cells. However, compound 4 had significant cytotoxicity against both MCF-7 and MDA-MB-231 cell lines.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Fabaceae/química , Isoflavonas/farmacologia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade
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