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Oil-Gan is the fruit of the genus Phyllanthus emblica L. The fruits have excellent effects on health care and development values. There are many methods for the management of diabetic nephropathy (DN). However, there is a lack of effective drugs for treating DN throughout the disease course. The primary aim of this study was to examine the protective effects (including analyses of urine and blood, and inflammatory cytokine levels) and mechanisms of the ethyl acetate extract of P. emblica (EPE) on db/db mice, an animal model of diabetic nephropathy; the secondary aim was to examine the expression levels of p- protein kinase Cα (PKCα)/t-PKCα in the kidney and its downregulation of vascular endothelial growth factor (VEGF) and fibrosis gene transforming growth factor-ß1 (TGF-ß1) by Western blot analyses. Eight db/m mice were used as the control group. Forty db/db mice were randomly divided into five groups. Treatments included a vehicle, EPE1, EPE2, EPE3 (at doses of 100, 200, or 400 mg/kg EPE), or the comparative drug aminoguanidine for 8 weeks. After 8 weeks of treatment, the administration of EPE to db/db mice effectively controlled hyperglycemia and hyperinsulinemia by markedly lowering blood glucose, insulin, and glycosylated HbA1c levels. The administration of EPE to db/db mice decreased the levels of BUN and creatinine both in blood and urine and reduced urinary albumin excretion and the albumin creatine ratio (UACR) in urine. Moreover, EPE treatment decreased the blood levels of inflammatory cytokines, including kidney injury molecule-1 (KIM-1), C-reactive protein (CRP), and NLR family pyrin domain containing 3 (NLRP3). Our findings showed that EPE not only had antihyperglycemic effects but also improved renal function in db/db mice. A histological examination of the kidney by immunohistochemistry indicated that EPE can improve kidney function by ameliorating glomerular morphological damage following glomerular injury; alleviating proteinuria by upregulating the expression of nephrin, a biomarker of early glomerular damage; and inhibiting glomerular expansion and tubular fibrosis. Moreover, the administration of EPE to db/db mice increased the expression levels of p- PKCα/t-PKCα but decreased the expression levels of VEGF and renal fibrosis biomarkers (TGF-ß1, collagen IV, p-Smad2, p-Smad3, and Smad4), as shown by Western blot analyses. These results implied that EPE as a supplement has a protective effect against renal dysfunction through the amelioration of insulin resistance as well as the suppression of nephritis and fibrosis in a DN model.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Modelos Animales de Enfermedad , Phyllanthus emblica , Extractos Vegetales , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratones , Phyllanthus emblica/química , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Acetatos/química , Factor A de Crecimiento Endotelial Vascular/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Proteína Quinasa C-alfa/metabolismo , Glucemia/metabolismo , Glucemia/efectos de los fármacosRESUMEN
Background: The fruits of Phyllanthus emblica L. are high in nutrients and have excellent health care function and developmental value. There are many management strategies available for diabetes and hyperlipidemia. Nevertheless, there is a lack of an effective and nontoxic drug. Objective: The present study was designed to first screen four extracts of P. emblica L. on insulin signaling target gene expression levels, including glucose transporter 4 (GLUT4) and p-Akt/t-Akt. The ethyl acetate extract of P. emblica L. (EPE) exhibited the most efficient activity among the four extracts and was thus chosen to explore the antidiabetic and antihyperlipidemic activities in streptozotocin (STZ)-induced type 1 diabetic mice. Design: All mice (in addition to one control (CON) group) were administered STZ injections (intraperitoneal) for 5 consecutive days, and then STZ-induced mice were administered EPE (at 100, 200, or 400 mg/kg body weight), fenofibrate (Feno) (at 250 mg/kg body weight), glibenclamide (Glib) (at 10 mg/kg body weight), or vehicle by oral gavage once daily for 4 weeks. Finally, histological examination, blood biochemical parameters, and target gene mRNA expression levels were measured, and liver tissue was analyzed for the levels of malondialdehyde (MDA), a maker of lipid peroxidation. Results: EPE treatment resulted in decreased levels of blood glucose, HbA1C, triglycerides (TGs), and total cholesterol and increased levels of insulin compared with the vehicle-treated STZ group. EPE treatment decreased blood levels of HbA1C and MDA but increased glutathione levels in liver tissue, implying that EPE exerts antioxidant activity and could prevent oxidative stress and diabetes. The EPE-treated STZ mice displayed an improvement in the sizes and numbers of insulin-expressing ß cells. EPE treatment increased the membrane expression levels of skeletal muscular GLUT4, and also reduced hepatic mRNA levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase thereby inhibiting hepatic gluconeogenesis. This resulted in a net glucose lowering effect in EPE-treated STZ mice. Furthermore, EPE increased the expression levels of p-AMPK/t-AMPK in both the skeletal muscle and liver tissue compared with vehicle-treated STZ mice. EPE-treated STZ mice showed enhanced expression levels of fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα), but reduced expression levels of lipogenic genes including fatty acid synthase, as well as decreased mRNA levels of sterol regulatory element binding protein 1c (SREBP1c), apolipoprotein-CIII (apo-CIII), and diacylglycerol acyltransferase-2 (DGAT2). This resulted in a reduction in plasma TG levels. EPE-treated STZ mice also showed reduced expression levels of PPAR γ. This resulted in decreased adipogenesis, fatty acid synthesis, and lipid accumulation within liver tissue, and consequently, lower TG levels in liver tissue and blood. Furthermore, EPE treatment not only displayed an increase in the Akt activation in liver tissue, but also in C2C12 myotube in the absence of insulin. These results implied that EPE acts as an activator of AMPK and /or as a regulator of the insulin (Akt) pathway. Conclusions: Taken together, EPE treatment exhibited amelioration of the diabetic and hyperlipidemic state in STZ-induced diabetic mice.
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Oil-Gan, also known as emblica, is the fruit of the genus Phyllanthus emblica L. The fruits are high in nutrients and display excellent health care functions and development values. The primary aim of this study was to investigate the activities of ethyl acetate extract from Phyllanthus emblica L. (EPE) on type 1 diabetes mellitus (T1D) and immunoregulatory activities in non-obese diabetes (NOD) mice with spontaneous and cyclophosphamide (Cyp)-accelerated diabetes. EPE was vehicle-administered to spontaneous NOD (S-NOD) mice or Cyp-accelerated NOD (Cyp-NOD) mice once daily at a dose of 400 mg/kg body weight for 15 or 4 weeks, respectively. At the end, blood samples were collected for biological analyses, organ tissues were dissected for analyses of histology and immunofluorescence (IF) staining (including expressions of Bcl and Bax), the expression levels of targeted genes by Western blotting and forkhead box P3 (Foxp3), and helper T lymphocyte 1 (Th1)/Th2/Th17/Treg regulatory T cell (Treg) cell distribution by flow cytometry. Our results showed that EPE-treated NOD mice or Cyp-accelerated NOD mice display a decrease in levels of blood glucose and HbA1c, but an increase in blood insulin levels. EPE treatment decreased blood levels of IFN-γ and tumor necrosis α (TNF-α) by Th1 cells, and reduced interleukin (IL)-1ß and IL-6 by Th17 cells, but increased IL-4, IL-10, and transforming growth factor-ß1 (TGF-ß1) by Th2 cells in both of the two mice models by enzyme-linked immunosorbent assay (ELISA) analysis. Flow cytometric data showed that EPE-treated Cyp-NOD mice had decreased the CD4+ subsets T cell distribution of CD4+IL-17 and CD4+ interferon gamma (IFN-γ), but increased the CD4+ subsets T cell distribution of CD4+IL-4 and CD4+Foxp3. Furthermore, EPE-treated Cyp-NOD mice had decreased the percentage per 10,000 cells of CD4+IL-17 and CD4+IFNγ, and increased CD4+IL-4 and CD4+Foxp3 compared with the Cyp-NOD Con group (p < 0.001, p < 0.05, p < 0.05, and p < 0.05, respectively). For target gene expression levels in the pancreas, EPE-treated mice had reduced expression levels of inflammatory cytokines, including IFN-γ and TNF-α by Th1 cells, but increased expression levels of IL-4, IL-10, and TGF-1ß by Th2 cells in both two mice models. Histological examination of the pancreas revealed that EPE-treated mice had not only increased pancreatic insulin-expressing ß cells (brown), and but also enhanced the percentage of Bcl-2 (green)/Bax (red) by IF staining analyses of islets compared with the S-NOD Con and the Cyp-NOD Con mice, implying that EPE displayed the protective effects of pancreas ß cells. EPE-treated mice showed an increase in the average immunoreactive system (IRS) score on insulin within the pancreas, and an enhancement in the numbers of the pancreatic islets. EPE displayed an improvement in the pancreas IRS scores and a decrease in proinflammatory cytokines. Moreover, EPE exerted blood-glucose-lowering effects by regulating IL-17 expressions. Collectively, these results implied that EPE inhibits the development of autoimmune diabetes by regulating cytokine expression. Our results demonstrated that EPE has a therapeutic potential in the preventive effects of T1D and immunoregulation as a supplementary.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Phyllanthus emblica , Ratones , Animales , Diabetes Mellitus Tipo 1/genética , Interleucina-10/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ratones Endogámicos NOD , Interleucina-17 , Phyllanthus emblica/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/uso terapéutico , Interleucina-4/metabolismo , Proteína X Asociada a bcl-2 , Citocinas/uso terapéutico , Interferón gamma/metabolismo , Insulina/uso terapéutico , Linfocitos T Reguladores , Ciclofosfamida/efectos adversos , Factores de Transcripción ForkheadRESUMEN
Many elderly individuals frequently experience cataracts that interfere with vision. After cataract surgery, the left lens epithelial cell (LEC) exhibited fibrosis and posterior capsule opacification (PCO). Sometimes, there is a need for a second surgery; nevertheless, people try other methods, such as a good pharmacological agent, to treat PCO to reduce transforming growth factor-ß2 (TGF-ß2) amounts to avoid secondary surgery. The aim of the present study was to explore the potential anti-PCO activity of five 2,4-dihydro-3H-pyrazol-3-one (DHPO) derivatives in a TGF-ß2-induced fibrogenesis SRA01/04 cell model. The 2-phenyl-5-propyl-DHPO (TSE; no. 2: TSE-2) compound showed the best activity of reduced expression levels of TGF-ß2 among five derivatives and therefore was chosen to evaluate the anti-PCO activity and molecular mechanisms on the Sma and mad protein (SMAD) signaling pathway (including TGF-ß2, SMADs, and the inhibition of nuclear translocation of SMADs), non-SMAD pathway proteins, including p-extracellular, regulated protein kinases (ERK) 1/2, or p-c-Jun N-terminal kinase (JUN) by Western blotting, PCR, or confocal immunofluorescence analyses. Following treatment with 10 µg/mL of the five compounds, the cells displayed great viability by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTT) assay. In this study, the result of lactate dehydrogenase (LDH) activity measurement did not affect the cytotoxicity of the five compounds. In TGF-ß2-induced fibrogenesis in SRA01/04 cells, treatment with the TSE compound decreased the TGF-ß2/SMAD signaling genes, including reduced mRNA or expression levels of TGF-ß2, SMAD3, and SMAD4, leading to inhibition of TGF-ß2-induced fibrogenesis. Our confocal immunofluorescence analyses demonstrated that TSE treatment displays a suppressive effect on SMAD2/3 or SMAD4 translocation to the nucleus. Furthermore, TSE treatment exhibits a reduction in the non-SMAD target gene expression levels of p- c-Jun N-terminal kinase (JUN), p- extracellular, regulated protein kinases (ERK)1/2, p- p38 mitogen-activated protein kinase (p38), p-phosphatidylinositol 3-kinase (PI3K), p-mammalian target of rapamycin complex (mTORC), p-Akt (Ser473), and p-Akt (Thr308). The overall effect of TSE is to reduce the expression levels of collagen I and fibrinogen (FN), thus contributing to antifibrotic effects in cell models mimicking PCO. Our findings reveal the benefits of TSE by regulating TGF-ß/SMAD signaling and non-SMAD signaling-related gene proteins to display antifibrotic activity in cells for the possibility of preventing PCO after cataract surgery.
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This study used a wireless EEG system to investigate neural dynamics in preschoolers with ADHD who exhibited varying cognitive proficiency pertaining to working memory and processing speed abilities. Preschoolers with ADHD exhibiting high cognitive proficiency (ADHD-H, n = 24), those with ADHD exhibiting low cognitive proficiency (ADHD-L, n = 18), and preschoolers with typical development (TD, n = 31) underwent the Conners' Kiddie Continuous Performance Test and wireless EEG recording under different conditions (rest, slow-rate, and fast-rate task). In the slow-rate task condition, compared with the TD group, the ADHD-H group manifested higher delta and lower beta power in the central region, while the ADHD-L group manifested higher parietal delta power. In the fast-rate task condition, in the parietal region, ADHD-L manifested higher delta power than those in the other two groups (ADHD-H and TD); additionally, ADHD-L manifested higher theta as well as lower alpha and beta power than those with ADHD-H. Unlike those in the TD group, the delta power of both ADHD groups was enhanced in shifting from rest to task conditions. These findings suggest that task-rate-related neural dynamics contain specific neural biomarkers to assist clinical planning for ADHD in preschoolers with heterogeneous cognitive proficiency. The novel wireless EEG system used was convenient and highly suitable for clinical application.
RESUMEN
OBJECTIVES: This study investigated the discriminative validity of various single or combined measurements of electroencephalogram (EEG) data, Conners' Kiddie Continuous Performance Test (K-CPT), and Disruptive Behavior Disorder Rating Scale (DBDRS) to differentiate preschool children with ADHD from those with typical development (TD). METHOD: We recruited 70 preschoolers, of whom 38 were diagnosed with ADHD and 32 exhibited TD; all participants underwent the K-CPT and wireless EEG recording in different conditions (rest, slow-rate, and fast-rate task). RESULTS: Slow-rate task-related central parietal delta (1-4 Hz) and central alpha (8-13 Hz) and beta (13-30 Hz) powers between groups with ADHD and TD were significantly distinct (p < .05). A combination of DBDRS, K-CPT, and specific EEG data provided the best probability scores (area under curve = 0.926, p < .001) and discriminative validity to identify preschool children with ADHD (overall correct classification rate = 85.71%). CONCLUSIONS: Multi-method and multi-informant evaluations should be emphasized in clinical diagnosis of preschool ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Déficit de la Atención y Trastornos de Conducta Disruptiva , Preescolar , Electroencefalografía , Humanos , Instituciones AcadémicasRESUMEN
The present study aimed to characterize children at risk of attention-deficit/hyperactivity disorder (ADHD) during preschool age and provide early intervention. The continuous performance test (CPT) and electroencephalography (EEG) can contribute additional valuable information to facilitate diagnosis. This study measured brain dynamics at slow and fast task rates in the CPT using a wireless wearable EEG and identified correlations between the EEG and CPT data in preschool children with ADHD. Forty-nine preschool children participated in this study, of which 29 were diagnosed with ADHD and 20 exhibited typical development (TD). The Conners Kiddie Continuous Performance Test (K-CPT) and wireless wearable EEG recordings were employed simultaneously. Significant differences were observed between the groups with ADHD and TD in task-related EEG spectral powers (central as well as parietal delta, P < 0.01), which were distinct only in the slow-rate task condition. A shift from resting to the CPT task condition induced overall alpha powers decrease in the ADHD group. In the task condition, the delta powers were positively correlated with the CPT perseveration scores, whereas the alpha powers were negatively correlated with specific CPT scores mainly on perseveration and detectability (P < 0.05). These results, which complement the findings of other sparse studies that have investigated within-task-related brain dynamics, particularly in preschool children, can assist specialists working in early intervention to plan training and educational programs for preschoolers with ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Encéfalo , Preescolar , Electroencefalografía , Humanos , Pruebas NeuropsicológicasRESUMEN
Age-related cataract (ARC) is one of the leading causes of visual impairment and blindness worldwide among the elderly. Here, we used sodium selenite-induced cataract mouse model, which shares with similarities with human senile cataract to investigate whether the extracts of Phellinus linteus (PLE) could have the potential protective effects of ARC or not. The mice pups were randomly divided into 4 treatment groups (n = 7): (1) normal saline on postpartum day 26; (2) Na selenite injected s.c on day 26; (3) Na selenite s.c on day 26+ gavaged PLE (40 mg/kg) on days 26-47; and (4) Na selenite s.c on day 26 + resveratrol on days 26-47. On day 47, encapsulated lenses and plasma were analyzed for the levels of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), a marker of lipid peroxidation. Lens epithelial cells (LECs) were also analyzed for the mRNA and protein expressions of glutathione S-transferase Mu (GSTM3). We demonstrated that PLE could prevent selenite-induced oxidative stress and cataract formation in mice by higher GSH and SOD and lower MDA in LECs, plasma, and liver tissues and the increases in the mRNA and protein expressions of GSTM3 in LECs. Our data show the increasing oxidative stress in selenite-induced cataract mice. Our data reveal the benefits of PLE for preventive activity in selenite-induced cataract in mice and there is a good possibility that PLE could ameliorate human senile cataract.
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The present study was designed to evaluate the protective effect of sulphurenic acid (SA), a pure compound from Antrodia camphorata, on diabetes and hyperlipidemia in an animal model study and to clarify the underlying molecular mechanism. Diabetes was induced by daily 55 mg/kg intraperitoneal injections of streptozotocin (STZ) solution over five days. Diabetic mice were randomly divided into six groups and orally gavaged with SA (at three dosages) or glibenclamide (Glib), fenofibrate (Feno) or vehicle for 3 weeks. Our findings showed that STZ-induced diabetic mice had significantly increased fasting blood glucose, glycated hemoglobin (HbA1C), plasma triglyceride (TG), and total cholesterol (TC) levels (p < 0.001, p < 0.001, p < 0.001, and p < 0.05, respectively) but decreased blood insulin, adiponectin, and leptin levels compared to those of the control group (p < 0.001, p < 0.001, and p < 0.001, respectively). Administration of SA to STZ-induced diabetic mice may lower blood glucose but it increased the insulin levels with restoration of the size of the islets of Langerhans cells, implying that SA protected against STZ-induced diabetic states within the pancreas. At the molecular level, SA treatment exerts an increase in skeletal muscle expression levels of membrane glucose transporter 4 (GLUT4) and phospho-Akt to increase the membrane glucose uptake, but the mRNA levels of PEPCK and G6Pase are decreased to inhibit hepatic glucose production, thus leading to its hypoglycemic effect. Moreover, SA may cause hypolipidemic effects not only by enhancing hepatic expression levels of peroxisome proliferator-activated receptor α (PPARα) with increased fatty acid oxidation but also by reducing lipogenic fatty acid synthase (FAS) as well as reducing mRNA levels of sterol regulatory element binding protein (SREBP)1C and SREBP2 to lower blood TG and TC levels. Our findings demonstrated that SA displayed a protective effect against type 1 diabetes and a hyperlipidemic state in STZ-induced diabetic mice.
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Antrodia/química , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Triterpenos/farmacología , Animales , Biomarcadores , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hipoglucemiantes/química , Hipolipemiantes/química , Hígado/metabolismo , Hígado/patología , Ratones , Estructura Molecular , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Triterpenos/químicaRESUMEN
The study is designed to examine the potential effects and underlying mechanisms of eburicoic acid (TRR), a compound from Antrodia camphorata, in streptozotocin (STZ)-induced diabetic mice. Diabetic mice were randomly divided into six groups and given TRR orally by gavage (at three dosage rates) or fenofibrate (Feno) (250 mg kg-1 body weight) or metformin (Metf) (300 mg kg-1 body weight) or vehicle for 2 weeks. STZ-induced diabetic mice were found to have increased blood glucose, HbA1C, plasma triglyceride (TG) and total cholesterol (TC) levels, but reduced blood insulin, adiponectin, and leptin levels as compared with the CON group. TRR was found to lower blood glucose and HbA1C, but increase insulin levels. Plasma TG and TC levels were significantly lowered in TRR, Feno, or Metf-treated STZ-induced diabetic mice as compared with the vehicle-treated STZ group, indicating that TRR, Feno, and Metf ameliorated hyperlipidemia. The islet cells of STZ-induced diabetic mice exhibited a marked reduction from their classic round-shape as compared to the CON mice. The TRR-treated STZ mice revealed restoration of the size of Langerhans islet cells with ß-cell repair as compared with the vehicle-treated STZ mice, implying that TRR ameliorated STZ-induced diabetic states within the pancreas. STZ-induction was found to decrease the expressions of membrane glucose transporter 4 (GLUT4), and phosphorylation of Akt in skeletal muscles, and administration of TRR reversed all the decreases. Moreover, administration of TRR increased blood insulin levels and enhanced hepatic expression levels of phospho-Akt and phospho-FoxO1 but decreased the mRNA levels of glucose-6-phosphatase (G6 Pase) and phosphoenolpyruvate carboxykinase (PEPCK) to suppress hepatic glucose production, thus leading to TRR's antidiabetic activity. Additionally, TRR caused an increase in the expression levels of fatty acid oxidation gene peroxisome proliferator-activated receptor α (PPARα), but a decrease in lipogenic fatty acid synthase (FAS) and PPARγ expressions in the liver. TRR treatment suppressed hepatic mRNA levels of sterol regulatory element binding protein (SREBP) 1c and SREBP2, leading to decreased plasma triglyceride and total cholesterol levels. These findings indicate that TRR may effectively enhance therapeutic potential in the treatment of type 1 diabetes mellitus and/or hyperlipidemia.
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This study was designed to investigate the antidiabetic and antihyperlipidemic effects and mechanisms of eburicoic acid (TRR); one component of Antrodia camphorata in vitro and in an animal model for 14 weeks. Expression levels of membrane glucose transporter type 4 (GLUT4); phospho-5'-adenosine monophosphate-activated protein kinase (AMPK)/total AMPK; and phospho-Akt/total-Akt in insulin-resistant C2C12 myotube cells were significantly decreased by palmitate; and such decrease was prevented and restored by TRR at different concentrations. A group of control (CON) was on low-fat diet over a period of 14 weeks. Diabetic mice; after high-fat-diet (HFD) induction for 10 weeks; were randomly divided into six groups and were given once a day oral gavage doses of either TRR (at three dosage levels); fenofibrate (Feno) (at 0.25 g/kg body weight); metformin (Metf) (at 0.3 g/kg body weight); or vehicle (distilled water) (HF group) over a period of 4 weeks and still on HFD. Levels of glucose; triglyceride; free fatty acid (FFA); insulin; and leptin in blood were increased in 14-week HFD-fed mice as compared to the CON group; and the increases were prevented by TRR, Feno, or Metf as compared to the HF group. Moreover, HFD-induction displayed a decrease in circulating adiponectin levels, and the decrease was prevented by TRR, Feno, or Metf treatment. The overall effect of TRR is to decrease glucose and triglyceride levels and improved peripheral insulin sensitivity. Eburicoic acid, Feno, and Metf displayed both enhanced expression levels of phospho-AMPK and membrane expression levels of GLUT4 in the skeletal muscle of HFD-fed mice to facilitate glucose uptake with consequent enhanced hepatic expression levels of phospho-AMPK in the liver and phosphorylation of the transcription factor forkhead box protein O1 (FOXO1) but decreased messenger RNA (mRNA) of phosphenolpyruvate carboxykinase (PEPCK) to inhibit hepatic glucose production; resulting in lowered blood glucose levels. Moreover; TRR treatment increased hepatic expression levels of the peroxisome proliferator-activated receptor α (PPARα) to enhance fatty acid oxidation; but displayed a reduction in expressions of hepatic fatty acid synthase (FAS) but an increase in fatty acid oxidation PPARα coincident with a decrease in hepatic mRNA levels of sterol response element binding protein-1c (SREBP-1c); resulting in a decrease in blood triglycerides and amelioration of hepatic ballooning degeneration. Eburicoic acid-treated mice reduced adipose expression levels of lipogenic FAS and peroxisome proliferator-activated receptor γ (PPARγ) and led to decreased adipose lipid accumulation. The present findings demonstrated that TRR exhibits a beneficial therapeutic potential in the treatment of type 2 diabetes and hyperlipidemia.
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Antrodia/química , Dieta Alta en Grasa/efectos adversos , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Lanosterol/análogos & derivados , Fibras Musculares Esqueléticas/efectos de los fármacos , Animales , Glucemia/análisis , Glucemia/metabolismo , Línea Celular , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Ácidos Grasos/sangre , Ácidos Grasos/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Hiperlipidemias/sangre , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/química , Hipolipemiantes/uso terapéutico , Insulina/sangre , Insulina/metabolismo , Lanosterol/química , Lanosterol/farmacología , Lanosterol/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Palmitatos/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
The objective of this study was to evaluate the effects and molecular mechanism of (-)-epicatechin-3-O-ß-D-allopyranoside from Davallia formosana (BB) (also known as Gu-Sui-Bu) on type 1 diabetes mellitus and dyslipidemia in streptozotocin (STZ)-induced diabetic mice. This plant was demonstrated to display antioxidant activities and possess polyphenol contents. Diabetic mice were randomly divided into six groups and were given daily oral gavage doses of either BB (at three dosage levels), metformin (Metf) (at 0.3 g/kg body weight), fenofibrate (Feno) (at 0.25 g/kg body weight) or vehicle (distilled water) and a group of control (CON) mice were gavaged with vehicle over a period of 4 weeks. Treatment with BB led to reduced levels of blood glucose, HbA1C, triglycerides and leptin and to increased levels of insulin and adiponectin compared with the vehicle-treated STZ group. The diabetic islets showed retraction from their classic round-shaped as compared with the control islets. The BB-treated groups (at middle and high dosages) showed improvement in islets size and number of Langerhans islet cells. The membrane levels of skeletal muscular glucose transporter 4 (GLUT4) were significantly higher in BB-treated mice. This resulted in a net glucose lowering effect among BB-treated mice. Moreover, BB enhanced the expression of skeletal muscle phospho-AMPK in treated mice. BB-treated mice increased expression of fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα) and mRNA levels of carnitine palmitoyl transferase Ia (CPT1a). These mice also expressed lower levels of lipogenic genes such as fatty acid synthase (FAS), as well as lower mRNA levels of sterol regulatory element binding protein 1c (SREBP1c) and liver adipocyte fatty acid binding protein 2 (aP2). This resulted in a reduction in plasma triglyceride levels. BB-treated mice also expressed lower levels of PPARγ and FAS protein. This led to reduced adipogenesis, fatty acid synthesis and lipid accumulation within adipose tissue, and consequently, to lower triglyceride levels in liver, blood, and adipose tissue. Moreover, BB treatment not only displayed the activation Akt in liver tissue and skeletal muscle, but also in C2C12 myotube to cause an increase in phosphorylation of Akt in the absence of insulin. These results demonstrated that BB act as an activator of AMPK and /or regulation of insulin pathway (Akt), and the antioxidant activity within the pancreas. Therefore, BB treatment ameliorated the diabetic and dyslipidemic state in STZ-induced diabetic mice.
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Catequina/análogos & derivados , Diabetes Mellitus Experimental/prevención & control , Dislipidemias/prevención & control , Helechos/química , Glicósidos/farmacología , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Animales , Catequina/aislamiento & purificación , Catequina/farmacología , Glicósidos/aislamiento & purificación , Hipoglucemiantes/aislamiento & purificación , Hipolipemiantes/aislamiento & purificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Rizoma/químicaRESUMEN
The purpose of this study was to screen firstly the potential effects of antcin K (AnK), the main constituent of the fruiting body of Antrodia camphorata, in vitro and further evaluate the activities and mechanisms in high-fat-diet- (HFD-) induced mice. Following 8-week HFD-induction, mice were treated with AnK, fenofibrate (Feno), metformin (Metf), or vehicle for 4 weeks afterward. In C2C12 myotube cells, the membrane GLUT4 and phospho-Akt expressions were higher in insulin and AnK-treated groups than in the control group. It was observed that AnK-treated mice significantly lowered blood glucose, triglyceride, total cholesterol, and leptin levels in AnK-treated groups. Of interest, AnK at 40 mg/kg/day dosage displayed both antihyperglycemic effect comparable to Metf (300 mg/kg/day) and antihypertriglyceridemic effect comparable to Feno (250 mg/kg/day). The combination of significantly increased skeletal muscular membrane expression levels of glucose transporter 4 (GLUT4) but decreased hepatic glucose-6-phosphatase (G6 Pase) mRNA levels by AnK thus contributed to a decrease in blood glucose levels. Furthermore, AnK enhanced phosphorylation of AMP-activated protein kinase (phospho-AMPK) expressions in the muscle and liver. Moreover, AnK treatment exhibited inhibition of hepatic fatty acid synthase (FAS) but enhancement of fatty acid oxidation peroxisome proliferator-activated receptor α (PPARα) expression coincident with reduced sterol response element binding protein-1c (SREBP-1c) mRNA levels in the liver may contribute to decreased plasma triglycerides, hepatic steatosis, and total cholesterol levels. The present findings indicate that AnK displays an advantageous therapeutic potential for the management of type 2 diabetes and hyperlipidemia.
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This study investigated the potential effects of dehydroeburicoic acid (TT), a triterpenoid compound from Antrodia camphorata, in vitro and examined the effects and mechanisms of TT on glucose and lipid homeostasis in high-fat-diet (HFD)-fed mice. The in vitro study examined the effects of a MeOH crude extract (CruE) of A. camphorata and Antcin K (AnK; the main constituent of fruiting body of this mushroom) on membrane glucose transporter 4 (GLUT4) and phospho-Akt in C2C12 myoblasts cells. The in vitro study demonstrated that treatment with CruE, AnK and TT increased the membrane levels of glucose transporter 4 (GLUT4) and phospho-Akt at different concentrations. The animal experiments were performed for 12 weeks. Diabetic mice were randomly divided into six groups after 8 weeks of HFD-induction and treated with daily oral gavage doses of TT (at three dose levels), fenofibrate (Feno) (at 0.25 g/kg body weight), metformin (Metf) (at 0.3 g/kg body weight) or vehicle for another 4 weeks while on an HFD diet. HFD-fed mice exhibited increased blood glucose levels. TT treatment dramatically lowered blood glucose levels by 34.2%~43.4%, which was comparable to the antidiabetic agent-Metf (36.5%). TT-treated mice reduced the HFD-induced hyperglycemia, hypertriglyceridemia, hyperinsulinemia, hyperleptinemia, and hypercholesterolemia. Membrane levels of GLUT4 were significantly higher in CruE-treated groups in vitro. Skeletal muscle membrane levels of GLUT4 were significantly higher in TT-treated mice. These groups of mice also displayed lower mRNA levels of glucose-6-phosphatase (G6 Pase), an inhibitor of hepatic glucose production. The combination of these agents produced a net hypoglycemic effect in TT-treated mice. TT treatment enhanced the expressions of hepatic and skeletal muscle AMP-activated protein kinase (AMPK) phosphorylation in mice. TT-treated mice exhibited enhanced expression of hepatic fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα) and increased mRNA levels of carnitine palmitoyl transferase Ia (CPT-1a). These mice also exhibited decreased expression levels of lipogenic fatty acid synthase (FAS) in liver and adipose tissue and reduced mRNA levels of hepatic adipocyte fatty acid binding protein 2 (aP2) and glycerol-3-phosphate acyltransferase (GPAT). These alterations resulted in a reduction in fat stores within the liver and lower triglyceride levels in blood. Our results demonstrate that TT is an excellent therapeutic approach for the treatment of type 2 diabetes and hypertriglyceridemia.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antrodia/química , Diabetes Mellitus Experimental/metabolismo , Dislipidemias/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Lanosterol/análogos & derivados , PPAR alfa/metabolismo , Animales , Biomarcadores , Diabetes Mellitus Experimental/tratamiento farmacológico , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Dislipidemias/tratamiento farmacológico , Metabolismo Energético , Expresión Génica , Perfilación de la Expresión Génica , Transportador de Glucosa de Tipo 4/genética , Hipoglucemiantes/farmacología , Lanosterol/farmacología , Hígado/metabolismo , Ratones , Especificidad de Órganos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
The purpose of this experiment was to determine the antidiabetic and lipid-lowering effects of (-)-epicatechin-3-O-ß-D-allopyranoside (BB) from the roots and stems of Davallia formosana in mice. Animal treatment was induced by high-fat diet (HFD) or low-fat diet (control diet, CD). After eight weeks of HFD or CD exposure, the HFD mice were treating with BB or rosiglitazone (Rosi) or fenofibrate (Feno) or water through gavage for another four weeks. However, at 12 weeks, the HFD-fed group had enhanced blood levels of glucose, triglyceride (TG), and insulin. BB treatment significantly decreased blood glucose, TG, and insulin levels. Moreover, visceral fat weights were enhanced in HFD-fed mice, accompanied by increased blood leptin concentrations and decreased adiponectin levels, which were reversed by treatment with BB. Muscular membrane protein levels of glucose transporter 4 (GLUT4) were reduced in HFD-fed mice and significantly enhanced upon administration of BB, Rosi, and Feno. Moreover, BB treatment markedly increased hepatic and skeletal muscular expression levels of phosphorylation of AMP-activated (adenosine monophosphate) protein kinase (phospho-AMPK). BB also decreased hepatic mRNA levels of phosphenolpyruvate carboxykinase (PEPCK), which are associated with a decrease in hepatic glucose production. BB-exerted hypotriglyceridemic activity may be partly associated with increased mRNA levels of peroxisome proliferator activated receptor α (PPARα), and with reduced hepatic glycerol-3-phosphate acyltransferase (GPAT) mRNA levels in the liver, which decreased triacylglycerol synthesis. Nevertheless, we demonstrated BB was a useful approach for the management of type 2 diabetes and dyslipidemia in this animal model.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/prevención & control , Hiperlipidemias/prevención & control , Hipoglucemiantes/uso terapéutico , Plantas Medicinales/química , Proteínas Quinasas Activadas por AMP/genética , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Fenofibrato/uso terapéutico , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación , Rosiglitazona , Tiazolidinedionas/uso terapéuticoRESUMEN
The aim of this study was to examine the effects of dehydroeburicoic acid (TT) on type 1 diabetes mellitus and dyslipidemia in streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice were randomly divided into six groups and given orally by gavage TT (at three dosages), metformin (Metf), fenfibrate (Feno), or vehicle for 4 weeks. STZ-induced diabetic mice showed elevations in blood glucose levels (P < 0.001). TT treatment markedly decreased blood glucose levels by 42.6-46.5%. Moreover, STZ-induced diabetic mice displayed an increase in circulating triglyceride (TG) and total cholesterol (TC) levels (P < 0.001 and P < 0.01, respectively) but a decrease in blood insulin and adiponectin levels (P < 0.01 and P < 0.05, respectively). These substances are also reversed by TT treatment, indicating TT ameliorated diabetes and dyslipidemia. Membrane skeletal muscular expression levels of glucose transporter 4 (GLUT4) and expression levels of AMPK phosphorylation (phospho-AMPK) in both liver and skeletal muscle were reduced in STZ-induced diabetic mice, which normalized upon TT treatment and correction of hyperglycemia accompanied with a decrease in mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6 Pase), which was related to the inhibition of hepatic glucose production and attenuating diabetic state. In addition, TT also showed hypolipidemic effect by increasing hepatic expression levels of peroxisome proliferator-activated receptor α (PPARα) and mRNA levels of carnitine palmitoyl transferase Ia (CPT-1a) but decreasing expression levels of fatty acid synthase (FAS), which further contributed to a decrease in circulating TG levels. TT-treated mice displayed decreased SREBP2 mRNA levels and reduced blood TC levels. These findings strongly support that TT prevents diabetic and dyslipidemic states in STZ-induced diabetic mice evidenced by regulation of GLUT4, PPARα, FAS, and phosphorylation of AMPK.
Asunto(s)
Antrodia/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes , Hipolipemiantes , Lanosterol/análogos & derivados , Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/sangre , Tejido Adiposo/patología , Animales , Glucemia/análisis , Colesterol/sangre , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Ácido Graso Sintasas/genética , Expresión Génica , Transportador de Glucosa de Tipo 4/análisis , Transportador de Glucosa de Tipo 4/genética , Insulina/sangre , Lanosterol/uso terapéutico , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR gamma/genética , Fosforilación , Fitoterapia , Triglicéridos/sangreRESUMEN
This study was designed to explore the effects and mechanism of ergostatrien-3ß-ol (EK100) from the submerged whole broth of Antrodia camphorata on diabetes and dyslipidemia in high fat diet (HFD)-fed mice for 12 weeks. The C57BL/6J mouse fed with a high fat diet (HFD) could induce insulin resistance and hyperlipidemia. After 8 week of induction, mice were receiving EK100 (at three dosages) or fenofibrate (Feno) or rosiglitazone (Rosi) or vehicle by oral gavage 4 weeks afterward. HFD-fed mice display increased blood glucose, glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), insulin, and leptin levels. These blood markers were significantly lower in EK100-treated mice, and finally ameliorated insulin resistance. EK100 treatment exhibited reduced hepatic ballooning degeneration and size of visceral adipocytes. Glucose transporter 4 (GLUT4) proteins and phosphorylation of Akt in skeletal muscle were significantly increased in EK100- and Rosi-treated mice. EK100, Feno, and Rosi treatment led to significant increases in phosphorylation of AMP-activated protein kinase (phospho-AMPK) protein in both skeletal muscle and liver. Moreover, EK100 caused a decrease in hepatic expressions of phosphenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6 Pase), and decreased glucose production. EK100 lowered blood TG level by inhibition of hepatic fatty acid synthesis by dampening sterol response element binding protein-1c (SREBP-1c) but increasing expression of peroxisome proliferator activated receptor α (PPARα). Moreover, EK100-treated mice reduced blood TC levels by decreased hepatic expressions of SREBP2, which plays a major role in the regulation of cholesterol synthesis. EK100 increased high-density lipoprotein cholesterol (HDL-C) concentrations by increasing expressions of apolipoprotein A-I (apo A-I) in liver tissue. Our findings manifest that EK100 may have therapeutic potential in treating type 2 diabetes associated with hyperlipidemia in HFD-fed mice by regulation of GLUT4, PEPCK, G6 Pase, SREBP1c, SREBP2, apo A-I, and AMPK phosphorylation.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antrodia/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Ergosterol/análogos & derivados , Transportador de Glucosa de Tipo 4/metabolismo , Hiperlipidemias/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/genética , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Ergosterol/administración & dosificación , Transportador de Glucosa de Tipo 4/genética , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Triglicéridos/metabolismoRESUMEN
Peroxyauraptenol (PXT) is a peroxide-containing coumarin compound isolated from the seeds of Cnidium monnieri. PXT exerts anti-inflammatory activities, as it reduces the levels of inducible nitric oxide synthase, nitric oxide, IL-6, and NLRP3 inflammasome-derived IL-1ß in lipopolysaccharide-activated macrophages. PXT also exerts anti-inflammatory activity by reducing reactive oxygen species generation (including mitochondrial), mitogen-activated protein kinase, protein kinase C-α/δ phosphorylation, and the release of mitochondrial DNA into the cytosol. In addition, PXT suppresses the phagocytic activity of macrophages and IL-1ß secretion by Klebsiella pneumoniae-infected macrophages. The unique peroxide group is important for the anti-inflammatory activity of PXT, as this activity is reduced when the peroxide group is replaced by a hydroxyl group. These findings suggest that PXT may be a candidate for the development of anti-inflammatory agents or a healthy supplement for preventing and ameliorating inflammation-related diseases.
RESUMEN
The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a reactive oxygen species-sensitive multiprotein complex that regulates IL-1ß maturation via caspase-1. It also plays an important role in the pathogenesis of inflammation-related disease. Cyclooxygenase-2 (COX-2) is induced by inflammatory stimuli and contributes to the pathogenesis of inflammation-related diseases. However, there is currently little known about the relationship between COX-2 and the NLRP3 inflammasome. Here, we describe a novel role for COX-2 in regulating the activation of the NLRP3 inflammasome. NLRP3 inflammasome-derived IL-1ß secretion and pyroptosis in macrophages were reduced by pharmaceutical inhibition or genetic knockdown of COX-2. COX-2 catalyzes the synthesis of prostaglandin E2 and increases IL-1ß secretion. Conversely, pharmaceutical inhibition or genetic knockdown of prostaglandin E2 receptor 3 reduced IL-1ß secretion. The underlying mechanisms for the COX-2-mediated increase in NLRP3 inflammasome activation were determined to be the following: (1) enhancement of lipopolysaccharide-induced proIL-1ß and NLRP3 expression by increasing NF-κB activation and (2) enhancement of the caspase-1 activation by increasing damaged mitochondria, mitochondrial reactive oxygen species production and release of mitochondrial DNA into cytosol. Furthermore, inhibition of COX-2 in mice in vivo with celecoxib reduced serum levels of IL-1ß and caspase-1 activity in the spleen and liver in response to lipopolysaccharide (LPS) challenge. These findings provide new insights into how COX-2 regulates the activation of the NLRP3 inflammasome and suggest that it may be a new potential therapeutic target in NLRP3 inflammasome-related diseases.
Asunto(s)
Proteínas Portadoras/metabolismo , Ciclooxigenasa 2/metabolismo , Inflamasomas/metabolismo , Inflamación/metabolismo , Interleucina-1beta/biosíntesis , Animales , Caspasa 1/metabolismo , Regulación de la Expresión Génica/fisiología , Lipopolisacáridos/toxicidad , Macrófagos/metabolismo , Ratones , Mitocondrias/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiologíaRESUMEN
This study was undertaken to examine the effect and mechanism of Bofu-tsusho-san formula (BO) on hyperglycemia and hyperlipidemia and in mice fed with a high-fat (HF) diet. The C57BL/6J mice were received control/HF diet for 12 weeks, and oral administration of BO (at three doses) or rosiglitazone (Rosi) or vehicle for the last 4 weeks. Blood, skeletal muscle and tissues were examined by means of measuring glycaemia and dyslipidaemia-associated events. BO treatment effectively prevented HF diet-induced increases in the levels of triglyceride (TG), free fatty acid (FFA) and leptin (p<0.01, p<0.01, p<0.01, respectively). BO treatment exhibited reduced both visceral fat mass and hepatic triacylglycerol content; moreover, BO treatment displayed significantly decreased both the average area of the cut of adipocytes and ballooning of hepatocytes. BO treatment exerted increased the protein contents of glucose transporter 4 (GLUT4) in skeletal muscle, and caused lowered blood glucose levels. BO treatment displayed increased levels of phosphorylated AMP-activated protein kinase (AMPK) in both skeletal muscle and liver tissue. Furthermore, BO reduced the hepatic expression of glucose-6-phosphatase (G6Pase) and phosphenolpyruvate carboxykinase (PEPCK) and glucose production. Therefore, it is possible that the activation of AMPK by BO leads to diminished gluconeogenesis in liver tissue. BO increased hepatic expressions of peroxisome proliferator-activated receptor α (PPARα), whereas down-regulating decreasing expressions of fatty acid synthesis, including sterol regulatory element binding protein 1c (SREBP1c) and fatty acid synthase (FAS), resulting in a decrease in circulating triglycerides. This study originally provides the evidence that amelioration of dyslipidemic and diabetic state by BO in HF-fed mice occurred by regulation of GLUT4, SREBP1c, FAS, PPARα, adiponectin and AMPK phosphorylation.