RESUMEN
Mulberry leaf has been recognized as a traditional Chinese medicinal plant, which was distributed throughout the Asia. The aqueous extract of mulberry leaf extract (MLE) has various biologically active components such as polyphenols and flavonoids. However, the inhibitory effect of MLE in hepatocarcinogenesis is poorly understood. In this study, we determined the role of MLE supplementation in preventing hepatocarcinogenesis in a carcinogen-initiated high-fat diet (HFD)-promoted Sprague-Dawley (SD) rat model. The rats were fed an HFD to induce obesity and spontaneous hepatomas by administering 0.01% diethylnitrosamine (DEN) in their drinking water for 12 weeks (HD group), and also to fed MLE through oral ingestion at daily doses of 0.5%, 1%, or 2%. At the end of the 12-week experimental period, the liver tumors were analyzed to identify markers of oxidative stress and antioxidant enzyme activities, and their serum was analyzed to determine their nutritional status and liver function. Histopathological analysis revealed that MLE supplementation significantly suppressed the severity and incidence of hepatic tumors. Furthermore, compared with the HFD + DEN groups, the expression of protein kinase C (PKC)-α and Rac family small GTPase 1 (Rac1) was lower in the MLE groups. These findings suggest that MLE prevents obesity-enhanced, carcinogen-induced hepatocellular carcinoma development, potentially through the protein kinase C (PKC)α/Rac1 signaling pathway. MLE might be an effective chemoprevention modality for nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH)-related hepatocarcinogenesis.
RESUMEN
Non-alcoholic fatty liver disease (NAFLD) is mainly characterized by excessive fat accumulation in the liver. It spans a spectrum of diseases from hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Brassica juncea is rich in glucosinolates and has been proven to possess many potential pharmacological properties, including hypoglycemic, anti-oxidation, anti-inflammatory, and anti-carcinogenic activities. This study aims to investigate whether whole-plant Brassica juncea (WBJ) and its glucosinolates extracts (BGE) have hepatoprotective effects against a high-fat diet (HFD)-induced NAFLD and further explore the mechanism underlying this process in vivo and in vitro. WBJ treatment significantly reduced body fat, dyslipidemia, hepatic steatosis, liver injury, and inflammation; WBJ treatment also reversed the antioxidant enzyme activity to attenuate oxidative stress in HFD-fed rat liver. Moreover, WBJ and BGE enhanced the activation of AMPK to reduce SREBPs, fatty acid synthase, and HMG-CoA reductase but increased the expression of CPT-I and PPARα to improve hepatic steatosis. In addition, WBJ and BGE could ameliorate NAFLD by inhibiting TNF-α and NF-κB. Based on the above results, this study demonstrates that WBJ and BGE ameliorate HFD-induced hepatic steatosis and liver injury. Therefore, these treatments could represent an unprecedented hope toward improved strategies for NAFLD.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratas , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Glucosinolatos/farmacología , Planta de la Mostaza , Dieta Alta en Grasa/efectos adversos , Antioxidantes/farmacología , Extractos Vegetales/farmacologíaRESUMEN
Ageing is one of the major risk factors of human diseases, including cancer, diabetes, and cardiovascular disease. Mulberry exhibits a wide range of functions, such as anti-oxidant, anti-inflammation, and anti-diabetes. In this study, we investigated the role of mulberry polyphenol extract (MPE) in K-Ras-induced senescence of smooth muscle cells. Forced expression of K-Ras enhanced senescence of smooth muscle A7r5 cells as shown by the elevation of ß-galactosidase activity. Treatment with MPE significantly repressed the Ras, phosphorylated ERK, and ß-galactosidase level. MPE triggered the association of cyclins with their corresponding cyclin-dependent protein kinases and hyperphosphorylated retinoblastoma (RB). MPE also down-regulated the levels of K-Ras-induced CDK inhibitors. MPE enhanced the phosphorylated AMP-dependent protein kinase (AMPK) and inducible nitric oxide synthase (iNOS) level in the presence of K-Ras. Pretreatment with either L-NAME or AMPK inhibitor reversed the effects of MPE. In addition, L-NAME and AMPK inhibitor repressed the MPE-induced total and phosphorylated 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co A) level. MPE repressed K-Ras-induced G0/G1 arrest, whereas L-NAME and AMPK inhibitor blocked the effects of MPE. Our results indicated that MPE recovered the K-Ras-induced senescence of vascular smooth muscle cells through iNOS and AMPK-dependent pathway. Our findings suggested that MPE may prevent ageing-induced atherosclerosis.
Asunto(s)
Senescencia Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Morus/química , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Acilcoenzima A/metabolismo , Células Cultivadas , Expresión Génica , Humanos , Miocitos del Músculo Liso/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación , Proteolisis , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , beta-Galactosidasa/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is one of the most common malignancies in Taiwan. Many risks factors induce liver chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mulberry fruits containing polyphenols to remove free radicals and mitigate inflammation has been reported to not only against gastric cancer, melanoma and leukemia but also prevent liver injury induced by alcohol or CCl4 in previous researches. The aim of this study is to examine whether Mulberry could inhibit hepatocarcinogenesis. In animal experiment, diethylnitrosamine (DEN) was used to induce hepatic tumorgenesis. After injecting DEN, the rats treated with mulberry water extracts (MWE) had less and smaller tumor than others without MWE. Moreover, MWE reduced the serum ALT and AST, HCC marker, cleavage caspases, Ser-15-p53 and Ser46-p53 induced by DEN. Further, we observed that mulberry polyphenol extracts (MPE) inhibited the cell growth of HepG2 cell and Hep3B cell. By using flow cytometry and western blotting methods, MPE induced HepG2 cell apoptosis by increase subG1 cells and the elevated expression of caspase-3/8/9. Instead of apoptosis, MPE caused Hep3B cells autophagy by inhibiting Akt and mTOR phosphorylation. Comprehensively, mulberry extracts has a potential to be a health supplement to prevent hepatocarcinogenesis in the future.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Morus/química , Extractos Vegetales/uso terapéutico , Animales , Frutas/química , RatasRESUMEN
P-cresol (PC) shows toxic effects on a variety of cells such as renal proximal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts, monocytes, osteoblasts and osteoclasts. The molecular mechanism and role of PC in the progression of urothelial carcinoma have not been documented. To understand the impact of PC on bladder cancer progression, human bladder cancer TSGH8301 cells were treated PC with various concentration (25-100⯵M). MTT assay revealed the toxicity of PC on TSGH8301 cells dose-dependently. MMP-2 and MMP-9 expressions of the PC-treated cells were enhanced by using gelatin zymography. The wound healing assay and transwell migration analysis were performed to assay the migratory and invasive effects of PC on TSGH8301 cell and the migrated cell numbers were markedly increased by PC treatment. Moreover, we further detected the expression of Ras, PI3K and Akt proteins that involved in the invasion/migration of the cancer. Inhibiting the Ras and mTOR signaling pathways by Y27632 or/and everolimus improved cancer cell progression induced by PC. This study may clarify the impact of PC on migration and invasion of carcinoma cells.
Asunto(s)
Cresoles/toxicidad , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Proteínas ras/metabolismo , Amidas/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Everolimus/farmacología , Humanos , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Uremia , Neoplasias de la Vejiga Urinaria/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Proteínas ras/antagonistas & inhibidoresRESUMEN
Atherosclerosis is characterized by the buildup of plaque inside arteries. Our recent studies demonstrated that polyphenolic natural products can reduce oxidative stress, inflammation, angiogenesis, hyperlipidemia, and hyperglycemia. A previous study also showed that mulberry water extract (MWE) can inhibit atherosclerosis and contains considerable amounts of polyphenols. Therefore, in the present study, we investigated whether mulberry polyphenol extract (MPE) containing high levels of polyphenolic compounds could affect vascular smooth muscle cell (VSMC; A7r5 cell) motility. We found that MPE inhibited expression of FAK, Src, PI3K, Akt, c-Raf, and suppressed FAK/Src/PI3K interaction. Further investigations showed that MPE reduced expression of small GTPases (RhoA, Cdc42, and Rac1) to affect F-actin cytoskeleton rearrangement, down-regulated expression of MMP2 and vascular endothelial growth factor (VEGF) mRNA through NFκB signaling, and thereby inhibited A7r5 cell migration. Taken together, these findings highlight MPE inhibited migration in VSMC through FAK/Src/PI3K signaling pathway.
Asunto(s)
Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Morus/química , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/farmacología , Polifenoles/farmacología , Familia-src Quinasas/metabolismo , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/citología , Fosfatidilinositol 3-Quinasas/genética , Extractos Vegetales/aislamiento & purificación , Polifenoles/aislamiento & purificación , Ratas , Transducción de Señal/efectos de los fármacos , Familia-src Quinasas/genéticaRESUMEN
Bladder cancer is known as the world's ninth most prevalent cancer in 2012. New cytotoxic drugs have created considerable progress in the treatment. Gallic acid (GA) has been shown to inhibit carcinogenesis in animal models and various cancer cell lines. The aim of the present study was to evaluate the effect of GA on proliferation and migration inhibition of a bladder cancer cell line. The results showed that GA inhibited fatty acid synthase (FAS) activity and increased ER alpha level of TSGH-8301 bladder cancer cell. GA regulated the cell proliferation via the PI3K/AKT and MAPK/ERK pathway. Immunoprecipitation assay demonstrated that GA decreased Skp2 protein level and attenuated Skp2-p27 association. It was suggested that GA acted upstream of the proteasome to control p27 levels and ultimately inhibited G2/M phase transition. Further, transwell chambers assay showed that GA suppressed bladder cancer cell invasion and migration through p-AKT/MMP-2 signaling pathway. The finding indicated that GA inhibited TSGH-8301 bladder cancer cell growth, invasion and migration through inhibition of fatty acid synthase.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ácido Graso Sintasas/antagonistas & inhibidores , Ácido Gálico/farmacología , Neoplasias de la Vejiga Urinaria/fisiopatología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Humanos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
Cell cycle regulation is an important issue in cancer therapy. Delphinidin and cyanidin are two major anthocyanins of the roselle plant (Hibiscus sabdariffa). In the present study, we investigated the effect of Hibiscus anthocyanins (HAs) on cell cycle arrest in human leukemia cell line HL-60 and the analyzed the underlying molecular mechanisms. HAs extracted from roselle calyces (purity 90%) markedly induced G2/M arrest evaluated with flow cytometry analysis. Western blot analyses revealed that HAs (0.1-0.7 mg mL-1 ) induced G2/M arrest via increasing Tyr15 phosphorylation of Cdc2, and inducing Cdk inhibitors p27 and p21. HAs also induced phosphorylation of upstream signals related to G2/M arrest such as phosphorylation of Cdc25C tyrosine phosphatase at Ser216, increasing the binding of pCdc25C with 14-3-3 protein. HAs-induced phosphorylation of Cdc25C could be activated by ATM checkpoint kinases, Chk1, and Chk2. We first time confirmed that ATM-Chk1/2-Cdc25C pathway as a critical mechanism for G2/M arrest in HAs-induced leukemia cell cycle arrest, indicating that this compound could be a promising anticancer candidate or chemopreventive agents for further investigation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1290-1304, 2017.
Asunto(s)
Antocianinas/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Hibiscus/química , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Proteínas 14-3-3/metabolismo , Antocianinas/química , Antocianinas/aislamiento & purificación , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteína Quinasa CDC2/metabolismo , Supervivencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quinasa de Punto de Control 2/metabolismo , Células HL-60 , Hibiscus/metabolismo , Humanos , Leucemia/metabolismo , Leucemia/patología , Fosforilación/efectos de los fármacos , Extractos Vegetales/química , Proteína p53 Supresora de Tumor/deficiencia , Fosfatasas cdc25/metabolismoRESUMEN
BACKGROUND: Previous studies have shown that mulberry polyphenolic compounds have an anti-atherosclerotic effect in rabbits. Apoptosis of vascular smooth muscle cells (VSMCs) is the key determinant of the number of VSMCs in remodeling. To examine the effect of mulberry polyphenol extracts (MPEs) on the apoptosis of VSMCs and thus the prevention of atherosclerosis, this study investigated the ability of MPEs to induce apoptosis in vitro and the underlying mechanism. RESULTS: It was found that MPEs initially activated JNK/p38 and p53, which in turn activated both Fas-ligand and mitochondrial pathways, thereby causing mitochondrial translocation of Bax and a reduction in Bcl-2. This then triggered the cleavage of procaspases, finally resulting in apoptosis of VSMCs. CONCLUSION: This study shows that MPEs may suppress atherosclerosis through stimulating apoptosis of VSMCs via activating JNK/p38 and p53 signaling.
Asunto(s)
Apoptosis/efectos de los fármacos , Morus/química , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Animales , Caspasas/genética , Caspasas/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Proteína Ligando Fas/genética , Proteína Ligando Fas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , MAP Quinasa Quinasa 4/antagonistas & inhibidores , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Extractos Vegetales/química , Polifenoles/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Diabetic nephropathy (DN) is a major cause of end-stage renal disease and its mortality is continuously increasing worldwide. Previous studies indicate that reactive oxygen species play an important role in high glucose-induced renal injury. Myrciaria cauliflora has been reported as a functional food rich in anthocyanins possessing anti-oxidative and anti-inflammatory properties. This study examined whether M. cauliflora extracts (MCE) can attenuate diabetic nephropathy progression in type 2 diabetes mellitus mice. First, the composition of the anthocyanins and polyphenols of MCE were determined by high-performance liquid chromatography and spectrophotometry. One hundred mg/kg of streptozotocin and 240 mg/kg nicotinamide were administered to C57BL/6J mice fed a high fat diet and varied concentrations of MCE. The plasma glucose concentration, body weight, oral glucose tolerance, blood pressure, renal ultrasound ultrasonic wave were monitored every 2 weeks. Following euthanasia, the kidneys of the mice were analyzed using hematoxylin-eosin, periodic acid Schiff, Masson's trichrome, and immunohistochemistry staining. The results showed that MCE stabilized the plasma glucose and indirectly improved insulin sensitivity in diabetic mice. In addition, diabetes-caused glomerular atrophy, accumulation of saccharide, and formation of collagen IV were recovered or reduced under treatment with MCE in diabetic mice. Our results indicate that MCE has beneficial effects in DN and the mechanism has been confirmed to inhibit Ras/PI3K/Akt and kidney fibrosis related proteins. This work illustrates the potential of MCE rich in anthocyanins and polyphenols as a natural food to inhibit DN.
RESUMEN
Myrciaria cauliflora is a functional food rich in anthocyanins, possessing antioxidative and anti-inflammatory properties. Our previous results demonstrated M. cauliflora extract (MCE) had beneficial effects in diabetic nephropathy (DN) and via the inhibition of Ras/PI3K/Akt and kidney fibrosis-related proteins. The purpose of this study was to assess the benefit of MCE in diabetes associated with kidney inflammation and glycemic regulation in streptozotocin-nicotinamide (STZ/NA)-induced diabetic mice. Compared with the untreated diabetic group, MCE significantly improved blood glucose and serum biochemical characteristic levels. Exposure to MCE increased antioxidative enzyme activity and diminished reactive oxygen synthesis. Mice receiving MCE supplementation had reduced intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), colony stimulating factor 1 (CSF-1), interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor α (TNF-α) levels compared to the untreated diabetic mice. Inflammatory and fibrotic related proteins such as collagen IV, fibronectin, Janus kinase (JAK), phosphorylated signal transducer and activator of transcription 3 (STAT3), protein kinase C beta (PKC-ß), and nuclear factor kappa B (NF-κB) were also inhibited by MCE treatment in STZ/NA mice. These results suggest that MCE may be used as a hypoglycemic agent and antioxidant in Type 2 diabetic mice.
Asunto(s)
Myrtaceae , Animales , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Inflamación , Ratones , Niacinamida , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas , Extractos Vegetales , EstreptozocinaRESUMEN
Endothelial dysfunction is an early indicator of cardiovascular diseases. Increased stimulation of tumor necrosis factor-α (TNF-α) triggers the inflammatory mediator secretion of endothelial cells, leading to atherosclerotic risk. In this study, we investigated whether sulforaphane (SFN) affected the expression of intracellular adhesion molecule-1 (ICAM-1) in TNF-α-induced ECV 304 endothelial cells. Our data showed that SFN attenuated TNF-α-induced expression of ICAM-1 in ECV 304 cells. Pretreatment of ECV 304 cells with SFN inhibited dose-dependently the secretion of proinflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and IL-8. SFN inhibited TNF-α-induced nuclear factor-κB (NF-κB) DNA binding activity. Furthermore, SFN decreased TNF-α-mediated phosphorylation of IκB kinase (IKK) and IκBα, Rho A, ROCK, ERK1/2, and plasminogen activator inhibitor-1 (PAI-1) levels. Collectively, SFN inhibited the NF-κB DNA binding activity and downregulated the TNF-α-mediated induction of ICAM-1 in endothelial cells by inhibiting the Rho A/ROCK/NF-κB signaling pathway, suggesting the beneficial effects of SFN on suppression of inflammation within the atherosclerotic lesion.
Asunto(s)
Molécula 1 de Adhesión Intercelular/genética , Isotiocianatos/farmacología , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Línea Celular , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Células Endoteliales/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , FN-kappa B/genética , Sulfóxidos , Factor de Necrosis Tumoral alfa/genética , Quinasas Asociadas a rho/genética , Proteína de Unión al GTP rhoA/genéticaRESUMEN
Previous studies have shown that mulberry water extracts (MWEs), which contain polyphenolic compounds, have an antiatherosclerotic effect in vivo and in vitro through stimulating apoptosis of vascular smooth muscle cells (VSMCs). Histological analysis was performed on atherosclerotic lesions from high-cholesterol diet (HCD)-fed rabbits after treatment with 0.5-1% MWEs for 10 weeks. Immunohistochemistry showed that the expressions of SMA, Ras, and matrix metalloproteinase-2 in the VSMCs were dose-dependently inhibited after MWE treatment. The antimigratory effects of MWEs on A7r5 VSMCs were assessed by western blot analysis of migration-related proteins, visualization of F-actin cytoskeleton, and reverse transcription polymerase chain reaction. The results showed that MWEs inhibited VSMC migration through reducing interactions of the integrin-ß3/focal adhesion kinase complex, alterations of the cytoskeleton, and downregulation of glycogen synthase kinase 3ß/nuclear factor κB signaling. Taken together, MWEs inhibited HCD-induced rabbit atherogenesis through blocking VSMC migration via reducing interactions of integrin-ß3 and focal adhesion kinase and downregulating migration-related proteins.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Integrina beta3/metabolismo , Morus/química , FN-kappa B/metabolismo , Extractos Vegetales/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Aterosclerosis/metabolismo , Aterosclerosis/fisiopatología , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Humanos , Masculino , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Extractos Vegetales/metabolismo , Conejos , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
N-Acetylcysteine (Nac) is an antioxidant administered in both oral and injectable forms. In this study, we used Nac topically to treat burn wounds in vitro and in vivo to investigate mechanisms of action. In vitro, we monitored glutathione levels, cell proliferation, migration, scratch-wound healing activities and the epithelialization-related proteins, matrixmetalloproteinase-1 (MMP-1) and proteins involved in regulating the expression of MMP-1 in CCD-966SK cells treated with Nac. Various Nac concentrations (0.1, 0.5, and 1.0 mM) increased glutathione levels, cell viability, scratch-wound healing activities and migration abilities of CCD-966SK cells in a dose-dependent manner. The MMP-1 expression of CCD-966SK cells treated with 1.0 mM Nac for 24 h was significantly increased. Levels of phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), janus kinase 1 (Jak1), signal transducer and activator of transcription 3 (Stat3), c-Fos and Jun, but not extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), were also significantly increased in a dose-dependent manner compared to the controls. In addition, Nac induced collagenous expression of MMP-1 via the PKC/Stat3 signaling pathway. In vivo, a burn wound healing rat model was applied to assess the stimulation activity and histopathological effects of Nac, with 3.0% Nac-treated wounds being found to show better characteristics on re-epithelialization. Our results demonstrated that Nac can potentially promote wound healing activity, and may be a promising drug to accelerate burn wound healing.
Asunto(s)
Acetilcisteína/uso terapéutico , Antioxidantes/uso terapéutico , Quemaduras/tratamiento farmacológico , Proteína Quinasa C/metabolismo , Factor de Transcripción STAT3/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Acetilcisteína/administración & dosificación , Administración Tópica , Animales , Antioxidantes/administración & dosificación , Quemaduras/metabolismo , Quemaduras/patología , Línea Celular , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patologíaRESUMEN
A previous study reported that anthocyanins from roselle (Hibiscus sabdariffa L.) showed significant anticancer activity in human promyelocytic leukemia cells. To explore the antitumor effect of anthocyanin, a roselle bioactive polyphenol in a rat model of chemical-induced leukemia was assayed. Anthocyanin extract of roselle (Hibiscus anthocyanins, HAs) was supplemented in the diet (0.1 and 0.2%). This study was carried out to evaluate the protective effect of HAs on N-nitrosomethylurea (NMU)-induced leukemia of rats. The study employed male Sprague-Dawley rats (n = 48), and leukemia was induced by intravenous injection of 35 mg kg(-1) body weight of NMU dissolved in physiologic saline solution. The rats were divided into four groups (n = 12): control, NMU only, and HAs groups that received different doses of HAs (0.1 and 0.2%) daily, orally, after NMU injection. After 220 days, the animals were killed, and the following parameters were assessed: morphological observation, hematology examination, histopathological assessment, and biochemical assay. When compared with the NMU-only group, HAs significantly prevented loss of organ weight and ameliorated the impairment of morphology, hematology, and histopathology. Treatment with HAs caused reduction in the levels of AST, ALT, uric acid, and MPO. Also, the results showed that oral administration of HAs (0.2%) remarkably inhibited progression of NMU-induced leukemia by approximately 33.3% in rats. This is the first report to demonstrate that the sequential administration of HAs followed by NMU resulted in an antileukemic activity in vivo.
Asunto(s)
Antocianinas/administración & dosificación , Hibiscus/química , Leucemia/prevención & control , Extractos Vegetales/administración & dosificación , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Humanos , Leucemia/tratamiento farmacológico , Masculino , Metilnitrosourea/efectos adversos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Caffeic acid (CA) can inhibit toxin-induced liver injury. In this study, CA is assessed for its lipid lowering potential when oleic acid is used to induce non-alcoholic fatty liver disease in human HepG2 cells. RESULTS: The results showed that both the triglyceride and cholesterol content are decreased in the HepG2 cells by using the enzymatic colorimetric method. CA enhances the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase. CA down-regulates the lipogenesis gene expression of sterol regulatory element-binding protein-1 and its target genes, fatty acid synthase in the presence of oleic acid. In addition, CA significantly decreases cholesterol and triglyceride production via inhibition the expression of both 3-hydroxy-3-methyglutary coenzyme A reductase and glycerol-3-phosphate acyltransferase. These effects are eliminated by pretreatment with compound C, an AMPK inhibitor. CONCLUSIONS: These results demonstrate that CA inhibits oleic acid induced hepatic lipogenesis and the promotion of lipolysis via up-regulation of AMP-activated kinase.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Ácidos Cafeicos/farmacología , Hígado Graso/metabolismo , Lipogénesis/efectos de los fármacos , Lipólisis/efectos de los fármacos , Ácido Oléico/metabolismo , Extractos Vegetales/farmacología , Proteínas Quinasas Activadas por AMP/genética , Acetil-CoA Carboxilasa/metabolismo , Ácidos Cafeicos/uso terapéutico , Colesterol/metabolismo , Dieta , Grasas de la Dieta/metabolismo , Inhibidores de la Síntesis de Ácidos Grasos/farmacología , Inhibidores de la Síntesis de Ácidos Grasos/uso terapéutico , Hígado Graso/prevención & control , Expresión Génica , Células Hep G2 , Humanos , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Lipogénesis/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico , Fosforilación , Extractos Vegetales/uso terapéutico , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/metabolismo , Regulación hacia ArribaRESUMEN
Many plant extracts and their bioactive substances are well recognized for their potential to exert as chemoprotective agents against common alcoholic liver injury. In this study, the effects of Mulberry water extracts (MWE) treatment in the prevention of alcohol-induced liver injury were investigated in mice. MWE contain many nutrients and bioactive substances, including fifteen types of polyphenols and anthocyanin compounds. The parameters of histopathology, immunohistochemistry, antioxidant defense and proinflammatory mediator demonstrated the inhibitory effect of MWE on alcohol-induced liver injury. Plasma and hepatic content analysis showed that MWE inhibited the levels of liver injury biomarkers (AST, ALT and ALP), triglyceride (TG) and cholesterol (TC). Furthermore, treatment with MWE lessened the expression of lipid synthesis-related proteins, increased the p-AMPK/AMPK ratio and PPAR-α. Fatty acid oxidation and export via microsomal triglyceride transfer protein (MTP) were both activated as well as carnitine palmitoyltransferase-1 (CPT1). These results suggested that MWE prevents alcohol-induced liver injury through the activation of the AMPK and PPAR-α signal. This may be mediated by multiple pathways, including reduced lipid accumulation and lipid synthesis, increased fatty acid transport and fatty acid oxidation responses, decreased oxidative stress and facilitated anti-inflammation.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Etanol/toxicidad , Lipogénesis/efectos de los fármacos , Morus/química , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antioxidantes/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inflamación/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR alfa/metabolismo , Fosforilación/efectos de los fármacos , Extractos Vegetales/análisis , Extractos Vegetales/química , Triglicéridos/metabolismoRESUMEN
Mulberry (Morus alba L.) has been considered to possess different benefits such as protecting liver; improving fever, urine excretion disorder, hypertension, and diabetic syndrome; and preventing cardiovascular diseases. Recently, mounting evidence has shown that mulberry anthocyanin extract (MAE) is beneficial to hyperlipidemia; however, the mechanisms remain unclear. The present study was aimed to investigate the protective effects of MAE on hepatocyte cultured with high fatty acid and the underlying mechanisms. By using human hepatoma cell HepG2 as cell model, the results showed that MAE suppressed fatty acid synthesis and enhanced fatty acid oxidation, contributing to amelioration of lipid accumulation induced by oleic acid (OA). Moreover, MAE also inhibited acetyl coenzyme A carboxylase (ACC) activities by stimulating adenosine monophosphate-activated protein kinase (AMPK). MAE attenuated the expression of sterol regulatory element-binding protein-1 (SREBP-1) and its target molecules, such as fatty acid synthase (FAS). Similar results were also found in the expressions of enzymes involved in triglyceride and cholesterol biosyntheses including glycerol-3-phosphate acyltransferase (GPAT), 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCoR), adipocyte-specific fatty acid binding protein (A-FABP), and SREBP-2. In contrast, the lipolytic enzyme expressions of peroxisome proliferator activated receptor α (PPARα) and carnitinepalmitol- transferase-1 (CPT1) were increased. This study suggests the hypolipidemic effects of MAE occur via phosphorylation of AMPK and inhibition of lipid biosynthesis and stimulation of lipolysis. Therefore, the mulberry anthocyanins may actively prevent nonalcoholic fatty liver disease.
Asunto(s)
Antocianinas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Morus/química , Ácido Oléico/metabolismo , Extractos Vegetales/farmacología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Hígado/enzimología , Hígado/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
Mulberry ( sang shèn zÇ), a traditional Chinese medicine (TCM) in Taiwan, has many bioactive substances, including polyphenol and anthocyanins compounds. Over the past decade, many scientific and medical studies have examined mulberry fruit for its antioxidation and antiinflammation effects both in vitro and in vivo. This review thus focuses on the recent advances of mulberry extracts (MEs) and their applications in the prevention and treatment of human cancer, liver disease, obesity, diabetes, and cardiovascular disease. The ME modulates several apoptotic pathways and matrix metalloproteinases (MMPs) to block cancer progression. Mulberry can increase detoxicated and antioxidant enzyme activities and regulate the lipid metabolism to treat hepatic disease resulting from alcohol consumption, high fat diet, lipopolysaccharides (LPS) and CCl4 exposure. Of the various compounds in ME, cyanidin 3-glucoside (C3G) is the most abundant, and the active compound studied in mulberry research. Herein, the antioxidant and antiinflammatory actions of C3G to improve diabetes and cardiovascular disease are also discussed. These studies provide strong evidence ME may possess the bioactivity to affect the pathogenesis of several chronic diseases.
RESUMEN
BACKGROUND: Aristolochic acid I (AAI) has been implicated in urothelial cell carcinoma (UCC) in humans. However, whether AAI promotes invasion/migration of UCC has not been established. METHODS: A study of human UCC TSGH cells cultured with AAI was conducted. Cell viability, the effects of AAI on the activity of matrix metalloproteinase (MMP)-9, the abilities of invasion/migration and the migration-related proteins (Ras, RhoA, ROCK1, PI-3K, pAkt and nuclear factor-kappaB) of the TSGH cells were assessed. The TSGH cells were subcategorized to 1-day or 30-day AAI exposure. An in vivo study using a nude mice xenograft model was employed to test the antitumor effects of Rho kinase inhibitor or Y27632. RESULTS: A time- and dose-dependent increase in both activity and messenger RNA (mRNA) level of MMP-9 were demonstrated. The mRNA level of urokinase-type plasminogen activator was increased and tissue inhibitor of metalloproteinase-1 was decreased in the cells with 30-day but not 1-day AAI exposure. A dose-dependent enhancement in wound-healing rate and cell migration was demonstrated, especially in the 30-day AAI-exposed cells. Expressions of Ras/RhoA and other migration-related proteins were increased after AAI treatment, which could be inhibited by Y27632. The in vivo results demonstrated that Y27632 was able to attenuate the speed of growth of the inoculated tumors in nude mice. CONCLUSION: Clinically, the patients with prolonged AAI exposure are highly associated UCC, our results provided in vitro and in vivo evidence that prolonged AAI exposure enhances invasion and migration of human TSGH cells.