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Sirtuin 2 (Sirt2) is known to negatively regulate anoxia-reoxygenation injury in myoblasts. Because protein levels of Sirt2 are increased in ischemia-reperfusion (I/R)-injured liver tissues, we examined whether Sirt2 is protective or detrimental against hepatic I/R injury. We overexpressed Sirt2 in the liver of C57BL/6 mice using a Sirt2 adenovirus. Wild-type and Sirt2 knockout mice were subjected to a partial (70%) hepatic ischemia for 45 minutes, followed by various periods of reperfusion. In another set of experiments, wild-type mice were pretreated intraperitoneally with AGK2, a Sirt2 inhibitor. Isolated hepatocytes and Kupffer cells from wild-type and Sirt2 knockout mice were subjected to hypoxia-reoxygenation injury to determine the in vitro effects of Sirt2. Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Prior injection with Sirt2 adenovirus aggravated liver injury, as demonstrated by increases in serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration relative to control virus-injected mice. Pretreatment with AGK2 resulted in significant improvements in serum aminotransferase levels and histopathologic findings. Similarly, experiments with Sirt2 knockout mice also revealed reduced hepatocellular injury. The molecular mechanism of Sirt2's involvement in this aggravation of hepatic I/R injury includes the deacetylation and inhibition of mitogen-activated protein kinase phosphatase-1 and consequent activation of mitogen-activated protein kinases. CONCLUSION: Sirt2 is an aggravating factor during hepatic I/R injury. (Hepatology 2017;65:225-236).
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Fosfatasa 1 de Especificidad Dual/metabolismo , Hepatopatías/enzimología , Hepatopatías/etiología , Hígado/irrigación sanguínea , Daño por Reperfusión/complicaciones , Sirtuina 2/fisiología , Acetilación , Animales , Progresión de la Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
We investigated the immune-stimulating and anti-diabetic effects of Allium hookeri leaves grown in a plant factory with artificial lights. The immunomodulatory effects of A. hookeri leaves' ethanol extracts were evaluated with immune-related hematological factors in blood, the proliferation of splenocytes, NK cell activity, IgG and cytokine levels, and their mechanisms in immunosuppressed obese mice. Anti-diabetic effects were determined by the inhibitory activity against α-amylase and α-glucosidase in vitro and fasting blood glucose levels and biochemical factors in the serum of immunosuppressed obese mice. A. hookeri leaf extracts increased WBC and LYM counts, the proliferation of splenocytes, and serum IgG and IL-1ß concentrations compared to those of the NC group, which was used as a negative control. A. hookeri leaf extracts also improved serum HDL levels while they decreased the activities of digestive enzymes, fasting blood glucose, and biochemical factors (ALT, AST, T-Chol, TG, LDL, and GLU). The expressions of IL-1ß, JNK, c-Jun, p65, and iNOS in the thymus of immunosuppressed mice were activated by the treatment of A. hookeri leaf extracts. The results suggest that A. hookeri leaves grown in a plant factory with artificial lights also have immune-stimulatory and anti-diabetic effects and can be used as novel functional supplements to control related diseases and to improve public health.
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Opuntia ficus-indica (OF) phytochemicals have received considerable attention because of their health benefits. However, the structure-activity relationship between saponin and flavonoid antioxidant compounds among secondary metabolites has rarely been reported. In a molecular docking study, selected compounds from both Opuntia ficus-indica callus (OFC) and OF ethanol extract were found to be involved in Toll-like receptor 4 and mitogen-activated protein kinase (MAPK) signaling pathways. High affinity was specific for MAPK, and it was proposed to inhibit the oxidative and inflammatory responses with poricoic acid H (-8.3 Kcal/mol) and rutin (-9.0 Kcal/mol). The pro-inflammatory cytokine factors at a concentration of 200 µg/mL were LPS-stimulated TNF-α (OFC 72.33 ng/mL, OF 66.78 ng/mL) and IL-1ß (OFC 49.10 pg/mL, OF 34.45 pg/mL), both of which significantly decreased OF (p < 0.01, p < 0.001). Taken together, increased NO, PGE2, and pro-inflammatory cytokines were significantly decreased in a dose-dependent manner in cells pretreated with OFC and the OF extract (p < 0.05). These findings suggest that OFC and OF have important potential as natural antioxidant, anti-inflammatory agents in health-promoting foods and medicine.
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Allium cepa L. (onion) has been reported to have various pharmacological effects, such as preventing heart disease, and improving antimicrobial activity and immunological effects. The Republic of Korea produced 1,195,563 tons of onions (2022). The flesh of onion is used as food while the onion skin (OS) is thrown away as an agro-food by-product and is considered to induce environmental pollution. Thus, we hypothesize that increasing usage of OS as functional food material could help protect from the environment pollution. The antioxidant effects and immune-enhancing effects of OS were evaluated as functional activities of OS. In this study, OS showed high 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities and xanthine oxidase (XO) inhibitory activity. The antioxidant activities increased in a dose-dependent manner. The IC50 values of DPPH, ABTS radical scavenging activity, and XO inhibitory activity were 954.9 µg/mL, 28.0 µg/mL, and 10.7 µg/mL, respectively. Superoxide dismutase and catalase activities of OS in RAW 264.7 cells were higher than those of the media control. There was no cytotoxicity of OS found in RAW 264.7 cells. Nitric oxide and cytokines (IL-1ß, IL-6, IFN-γ, and TNF-α) concentrations in RAW 264.7 cells significantly increased in a dose dependent manner. Immune-stimulating effects of OS were evaluated in immunosuppressed mice induced by cyclophosphamide. White blood cell count and the B cell proliferation of splenocytes were higher in OS100 (OS extract 100 mg/kg body weight) and OS200 (OS extract 200 mg/kg body weight) groups than in the negative control (NC) group. Serum IgG and cytokine (IL-1ß and IFN-γ) levels were also higher in OS100 and OS200 groups than in the NC group. OS treatment increased NK cell activity compared with the NC group. The results suggested that OS can improve antioxidant and immune stimulating effects. The use of OS as functional supplement can reduce the agro-food by-product and it may contribute to carbon neutrality.
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Although multiple studies have shown that Angelica keiskei of the Umbelliferae family has potent anti-inflammatory and antioxidative activities and that it reduces the serum bile acids in humans, whether A. keiskei has protective effects against cholestasis-induced liver injury remains unexplored until now. This study tests the hypothesis that Angelica keiskei root extract (AKE) alleviates liver injury, inflammation, and fibrosis in mouse models of acute cholestasis induced by bile duct ligation (BDL). Oral administration of AKE (200 or 500 mg/kg) attenuated hepatocellular necrosis and significantly reduced serum levels of bile acids and bilirubin in BDL mice. The critical enzyme of bile acid synthesis, CYP7A1, was repressed by AKE, suggesting that reduced bile acid production may contribute to liver protection. Moreover, we determined through gene expression and cytokine analysis and histological examination that AKE treatment decreased liver inflammation, oxidative stress, and fibrosis. AKE also suppressed the NF-κB pathway, suggesting this as a possible mediator of its anti-inflammatory effect. Our findings substantiate that AKE may be promising for treating cholestatic liver diseases in the future.
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Angelica , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Colestasis , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/farmacología , Ácidos y Sales Biliares/uso terapéutico , Conductos Biliares/metabolismo , Conductos Biliares/cirugía , Colestasis/tratamiento farmacológico , Colestasis/metabolismo , Colestasis/patología , Fibrosis , Inflamación/metabolismo , Hígado/metabolismo , Ratones , Extractos Vegetales/uso terapéuticoRESUMEN
Oenanthe javanica, commonly known as water dropwort, has long been used to treat acute and chronic hepatitis, abdominal pain, alcohol hangovers, and inflammation in various traditional medicine systems in Asia. However, whether O. javanica has beneficial effects on colitis-induced intestinal damage remains elusive. This study tested the hypothesis that O. javanica has anti-inflammatory and antioxidant activities in mice with dextran sulfate sodium (DSS)-induced colitis. First, treatment of O. javanica ethanol extract (OJE) inhibited the production of inflammatory cytokines in lipopolysaccharide-affected macrophages. Second, in mice with DSS-induced colitis, OJE administration reduced pathological damage to the colon while alleviating weight gain and decreasing colon length, including inflammation and mucosal necrosis. In addition, OJE significantly (p < 0.01) restricted the activation of nuclear factor-κB (NF-κB) and the secretion of pro-inflammatory mediators and increased the expression of Nrf2-phase 2 antioxidant enzymes. The results of 16S rRNA gene sequencing workflows for taxonomic assignment analysis confirmed that the diversity (richness and evenness) of fecal microbiota was markedly elevated in the OJE group. OJE administration reduced the abundance of Proteobacteria including Escherichia and increased the abundance of the genus Muribaculum. These results suggested that OJE exerts beneficial effects on inflammation and gut microbial composition in a mouse model of colitis.
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Cholestatic liver disease, or cholestasis, is a condition characterized by liver inflammation and fibrosis following a bile duct obstruction and an intrahepatic accumulation of bile acids. Inhibiting inflammation is a promising therapeutic strategy for cholestatic liver diseases. Acer tegmentosum Maxim extract (ATE) is best known for its anti-inflammatory and antioxidative properties. In this study, we investigated the effects of ATE on liver injury and fibrosis in mice with bile duct ligation (BDL)-induced cholestasis through analysis of gene expression, cytokines, and histological examination. Oral administration of ATE (20 or 50 mg/kg) for 14 days significantly attenuated hepatocellular necrosis compared to vehicle-treated BDL mice, which was accompanied by the reduced level of serum bile acids and bilirubin. We determined that ATE treatment reduced liver inflammation, oxidative stress, and fibrosis. These beneficial effects of ATE were concurrent with the decreased expression of genes involved in the NF-κB pathway, suggesting that the anti-inflammatory effect of ATE could be a possible mechanism against cholestasis-associated liver injury. Our findings substantiate ATE's role as an alternative therapeutic agent for cholestasis-induced liver injury and fibrosis.
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Acer , Colestasis , Hepatitis , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/farmacología , Ácidos y Sales Biliares/uso terapéutico , Conductos Biliares/metabolismo , Conductos Biliares/cirugía , Colestasis/tratamiento farmacológico , Colestasis/metabolismo , Colestasis/patología , Fibrosis , Hepatitis/complicaciones , Hepatitis/tratamiento farmacológico , Hepatitis/patología , Inflamación/tratamiento farmacológico , Hígado/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Ratones , Extractos Vegetales/farmacologíaRESUMEN
The generation of nitric oxide (NO) via inducible NO synthase (iNOS) and reactive oxygen species plays a key role in cytokine-mediated pancreatic ß-cell damage. Oxidative stress due to reactive oxygen species activates the nuclear factor-κB (NF-κB) transcription factor, which regulates iNOS expression. In this regard, suppression of the NF-κB pathway is a novel strategy for protecting ß-cells from damage. This study was performed to explore the effects of kazinol U, a prenylated flavan from Broussonetia kazinoki, on the NF-κB activation pathway in interleukin-1ß (IL-1ß)- and interferon-γ (IFN-γ)-treated ß-cells. The cytotoxic effects of cytokines were completely abolished when RINm5F cells or islets were pretreated with kazinol U. Kazinol U inhibited the nuclear translocation and DNA binding of NF-κB subunits, which correlated with the inhibitory effects on IκB kinase (IKK) phosphorylation and IκBα degradation. In addition, kazinol U suppressed NO and hydrogen peroxide production and apoptotic cell death by cytokines in RINm5F cells. The protective effects of kazinol U were further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Taken together, these results suggest that using kazinol U to block the NF-κB pathway in pancreatic ß-cells reduces cell damage. Therefore, kazinol U may have therapeutic value in delaying pancreatic ß-cell destruction in type 1 diabetes.
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Apoptosis/efectos de los fármacos , Broussonetia/química , Citocinas/antagonistas & inhibidores , Flavonoides/farmacología , Islotes Pancreáticos/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Animales , Línea Celular , Citocinas/fisiología , Flavonoides/aislamiento & purificación , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Prenilación , RatasRESUMEN
BACKGROUND: Allium hookeri is widely consumed as a vegetable and herbal medicine in Asia. A. hookeri has been reported anti-inflammatory, anti-obesity, osteoblastic, anti-oxidant, and anti-diabetic effects in animal studies. We investigated the anti-diabetic effects of A. hookeri aqueous extract (AHE) in the Korean subjects. METHODS: Prediabetic subjects (100 ≤ fasting plasma glucose (FPG) < 126 mg/dL) who met the inclusion criteria were recruited for this study. The enrolled subjects (n = 30) were randomly divided into either an AHE (n = 15, 486 mg/day) or placebo (n = 15) group. Outcomes were measurements of FPG, glycemic response to an oral glucose tolerance test (OGTT), insulin, C-peptide, hemoglobin A1c (HbA1c), total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol. The t-test was used to assess differences between the groups. A p-value < 0.05 was considered statistically significant. RESULTS: Eight weeks after AHE supplementation, HbA1c level was significantly decreased in the AHE group compared with the placebo group. No clinically significant changes in any safety parameter were observed. CONCLUSION: The findings suggest that AHE can be effective in reducing HbA1c, indicating it as an adjunctive tool for improving glycemic control. TRIAL REGISTRATION: The study protocol was retrospectively registered at www.clinicaltrials.gov ( NCT03330366 , October 30, 2017).
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Allium , Glucemia/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Extractos Vegetales/uso terapéutico , Estado Prediabético/tratamiento farmacológico , Adulto , Anciano , Biomarcadores/sangre , Péptido C/sangre , Estudios Cruzados , Método Doble Ciego , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , República de CoreaRESUMEN
BACKGROUND: Augmenting glucose utilization in skeletal muscle via the phosphatidylinositol-3 kinase (PI3 kinase)/protein kinase B (Akt) pathway or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway is necessary to regulate hyperglycemia in patients with type 2 diabetes mellitus. OBJECTIVE: We investigated the effect of mulberry leaf extract (MLE) on glucose uptake in skeletal muscle cells and explored its in vivo antidiabetic potential. DESIGN: Male db/db mice were treated with either MLE (50 mg/kg, 100 mg/kg, and 250 mg/kg) or metformin (100 mg/kg) for 8 weeks. RESULTS: MLE treatment stimulated glucose uptake, driven by enhanced translocation of glucose transporter 4 to cell membranes in L6 myotubes. These effects of MLE were synergistic with those of insulin and were abolished in the presence of PI3K inhibitor or AMPK inhibitor. In db/db mice, supplementation with MLE decreased fasting blood glucose and insulin levels and enhanced insulin sensitivity, with increases of p-Akt and p-AMPK in skeletal muscle. Moreover, MLE improved blood lipid parameters and attenuated hepatic steatosis in diabetic db/db mice. DISCUSSION: These findings suggest that MLE exerts antidiabetic activity through stimulating glucose disposal in skeletal muscle cells via the PI3K/Akt and AMPK pathways. CONCLUSIONS: MLE can potentially improve hyperglycemia and hepatic steatosis in patients with type 2 diabetes.
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Nonalcoholic steatohepatitis (NASH) arises from nonalcoholic fatty liver disease (NAFLD) as a consequence of oxidative stress. Gynostemma pentaphyllum extract (GPE) is proven to be beneficial for patients suffering from NAFLD. However, the precise mechanism by which GPE confers these benefits remains largely unknown. The purpose of this study was to investigate the underlying mechanism and to determine whether supplementation with the newly discovered GPE gypenoside UL4 mitigates NASH progression. Male c57BL/6 mice were fed a normal chow diet, a methionine choline-deficient (MCD) diet, or an MCD diet supplemented with various doses of UL4-rich GPE for eight weeks. GPE supplementation suppressed oxidative stress induced by the MCD diet by increasing levels of sirtuin 6 and phase 2 anti-oxidant enzymes in mouse liver and HepG2 cells. Additionally, GPE supplementation prevented diet-induced hepatic fat accumulation, hepatocellular injury, inflammation, and fibrosis in mice fed the MCD diet. These results indicate the possible therapeutic potential of dietary supplementation of UL4-rich GPE in preventing the development of fatty liver and its progression to NASH.
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Gynostemma/química , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Fitoterapia , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Animales , Deficiencia de Colina/complicaciones , Suplementos Dietéticos , Células Hep G2 , Humanos , Hígado/metabolismo , Masculino , Metionina/deficiencia , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Estrés Oxidativo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Sirtuinas/metabolismoRESUMEN
The prevalence of metabolic diseases has risen globally in parallel with the obesity epidemic over the past few decades. Green tea has been reported to have metabolically beneficial effects on obesity; however, the mechanism by which green tea regulates lipid metabolism is not clearly understood. Male c57BL/6 mice were fed a normal chow diet, a high-fat diet (HFD), or an HFD supplemented with various doses of epigallocatechin gallate-rich green tea extract (GTE) for 12 weeks. GTE supplementation reduced body weight gain, prevented hepatic fat accumulation, decreased hypertriglyceridemia, and improved hyperglycemia and insulin resistance in HFD-fed mice. The underlying mechanisms of these beneficial effects of GTE might involve the upregulation of sirtuin 1 and AMP activated protein kinase (AMPK) and the downregulation of enzymes related to de novo lipogenesis. Consistent with the in vivo findings, GTE increased the expression and activity of sirtuin 1, enhanced the binding of sirtuin 1 to liver kinase B1 (LKB1) and subsequent deacetylation of LKB1, and reduced triglyceride accumulation in HepG2 cells. These results suggest the possible therapeutic potential of dietary epigallocatechin gallate-rich GTE supplementation for preventing the development and progression of hepatic steatosis and obesity.
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Catequina/análogos & derivados , Dieta Alta en Grasa/efectos adversos , Hígado Graso/prevención & control , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Obesidad/prevención & control , Fitoterapia , Extractos Vegetales/farmacología , Sirtuina 1/metabolismo , Té/química , Aumento de Peso/efectos de los fármacos , Animales , Catequina/administración & dosificación , Catequina/farmacología , Supervivencia Celular/efectos de los fármacos , Hígado Graso/etiología , Células Hep G2 , Humanos , Hiperglucemia/prevención & control , Hipertrigliceridemia/prevención & control , Resistencia a la Insulina , Masculino , Ratones Endogámicos C57BL , Obesidad/etiología , Extractos Vegetales/administración & dosificaciónRESUMEN
The prevention and management of type 2 diabetes mellitus has become a major global public health challenge. Decursin, an active compound of Angelica gigas Nakai roots, was recently reported to have a glucose-lowering activity. However, the antidiabetic effect of Angelica gigas Nakai extract (AGNE) has not yet been investigated. We evaluated the effects of AGNE on glucose homeostasis in type 2 diabetic mice and investigated the underlying mechanism by which AGNE acts. Male C57BL/KsJ-db/db mice were treated with either AGNE (10 mg/kg, 20 mg/kg, and 40 mg/kg) or metformin (100 mg/kg) for 8 weeks. AGNE supplementation (20 and 40 mg/kg) significantly decreased fasting glucose and insulin levels, decreased the areas under the curve of glucose in oral glucose tolerance and insulin tolerance tests, and improved homeostatic model assessment-insulin resistant (HOMA-IR) scores. AGNE also ameliorated hepatic steatosis, hyperlipidemia, and hypercholesterolemia. Mechanistic studies suggested that the glucose-lowering effect of AGNE was mediated by the activation of AMP activated protein kinase, Akt, and glycogen synthase kinase-3[Formula: see text]. AGNE can potentially improve hyperglycemia and hepatic steatosis in patients with type 2 diabetes.
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Proteínas Quinasas Activadas por AMP/metabolismo , Angelica/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hígado Graso/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Transducción de Señal/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Humanos , Hiperlipidemias/tratamiento farmacológico , Insulina/metabolismo , Resistencia a la Insulina , Masculino , Ratones Endogámicos C57BL , Extractos Vegetales/aislamiento & purificaciónRESUMEN
Insulin-like growth factor-1 (IGF-1) is known to inhibit reperfusion-induced apoptosis. IGF-binding protein-3 (IGFBP-3) is the major circulating carrier protein for IGF-1 and induces apoptosis. In this study, we determined if IGFBP-3 was important in the hepatic response to I/R. To deliver IGFBP-3, we used an adenovirus containing IGFBP-3 cDNA (AdIGFBP-3) or an IGFBP-3 mutant devoid of IGF binding affinity but retaining IGFBP-3 receptor binding ability (AdIGFBP-3(GGG)). Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Protein levels of IGFBP-3 were increased after reperfusion and showed a positive correlation with the extent of liver injury. Prior injection with AdIGFBP-3 aggravated liver injury: serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration were markedly increased compared to control mice. A decrease in antioxidant potential and an upregulation of NADPH oxidase might have caused these aggravating effects of IGFBP-3. Experiments using HepG2 cells and N-acetylcysteine-pretreated mice showed a discernible effect of IGFBP-3 on reactive oxygen species generation. Lastly, AdIGFBP-3 abolished the beneficial effects of ischemic preconditioning and hypothermia. Mice treated with AdIGFBP-3(GGG) exhibited effects similar to those of AdIGFBP-3, suggesting a ligand-independent effect of IGFBP-3. Our results suggest IGFBP-3 as an aggravating factor during hepatic I/R injury.
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Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Hígado/metabolismo , Necrosis/metabolismo , Daño por Reperfusión/genética , Acetilcisteína/farmacología , Adenoviridae/genética , Alanina Transaminasa/sangre , Animales , Apoptosis/genética , Aspartato Aminotransferasas/sangre , Depuradores de Radicales Libres/farmacología , Regulación de la Expresión Génica , Vectores Genéticos , Células Hep G2 , Humanos , Hipotermia Inducida , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Precondicionamiento Isquémico , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Necrosis/genética , Necrosis/patología , Necrosis/prevención & control , Infiltración Neutrófila/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & control , Transducción de Señal , TransgenesRESUMEN
Previously, powdered persimmon leaves have been reported to have glucose- and lipid-lowering effects in diabetic (db/db) mice. As persimmon leaf is commonly consumed as tea, an aqueous extract of persimmon leaves (PLE) was prepared and its anti-diabetic efficacy was investigated. In the present study, PLE was tested for its inhibitory activity on α-glucosidase in vitro. An oral maltose tolerance test was performed in diabetic mice. Next, the acute effect of PLE was examined in streptozotocin-induced diabetic mice. Last, the long-term effect of PLE supplementation was assessed in db/db after eight weeks. An oral glucose tolerance test, biochemical parameters, as well as histological analyses of liver and pancreas were evaluated at the end of the study. PLE inhibited α-glucosidase activity and increased antioxidant capacity. Streptozotocin-induced diabetic mice pre-treated with PLE displayed hypoglycemic activity. Daily oral supplementation with PLE for eight weeks reduced body weight gain without affecting food intake, enhanced the glucose tolerance during the oral glucose tolerance test (OGTT), improved blood lipid parameters, suppressed fat accumulation in the liver and maintained islet structure in db/db mice. Further mechanistic study showed that PLE protected pancreatic islets from glucotoxicity. In conclusion, the results of the present study indicated that PLE exhibits considerable anti-diabetic effects through α-glucosidase inhibition and through the maintenance of functional ß-cells. These results provided a rationale for the use of persimmon leaf tea for the maintenance of normal blood glucose levels in diabetic patients.
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Antioxidantes/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diospyros/química , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , Fitoterapia/métodos , Animales , Antioxidantes/aislamiento & purificación , Compuestos de Bifenilo/antagonistas & inhibidores , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Ingestión de Alimentos , Prueba de Tolerancia a la Glucosa , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Humanos , Hipoglucemiantes/aislamiento & purificación , Insulina/agonistas , Insulina/biosíntesis , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Picratos/antagonistas & inhibidores , Extractos Vegetales/química , Hojas de la Planta/química , Estreptozocina , alfa-Glucosidasas/metabolismoRESUMEN
Protein kinase 2 (CK2) activation was reported to enhance reactive oxygen species production and activate the nuclear factor κB (NF-κB) pathway. Because oxidative stress and inflammation are critical events for tissue destruction during ischemia reperfusion (I/R), we sought to determine whether CK2 was important in the renal response to I/R. Mice underwent 25 min of renal ischemia and were then reperfused. We confirmed an increased expression of CK2α during the reperfusion period, while expression of CK2ß remained consistent. We administered tetrabromobenzotriazole (TBBt), a selective CK2α inhibitor before inducing I/R injury. Mice subjected to I/R injury showed typical patterns of acute kidney injury; blood urea nitrogen and serum creatinine levels, tubular necrosis and apoptosis, inflammatory cell infiltration and proinflammatory cytokine production, and oxidative stress were markedly increased when compared to sham mice. However, pretreatment with TBBt abolished these changes and improved renal function and architecture. Similar renoprotective effects of CK2α inhibition were observed for emodin. Renoprotective effects of CK2α inhibition were associated with suppression of NF-κB and mitogen activated protein kinase (MAPK) pathways. Taken together, these results suggest that CK2α mediates proapoptotic and proinflammatory signaling, thus the CK2α inhibitor may be used to prevent renal I/R injuries observed in clinical settings.
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Quinasa de la Caseína II/antagonistas & inhibidores , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Inhibidores de Proteínas Quinasas/farmacología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica , Mediadores de Inflamación/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/genética , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/genética , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
SCOPE: In this study, we focus on the effects of n-3 polyunsaturated fatty acids (PUFAs) on tunicamycin-, streptozotocin-, or high fat diet (HFD)-induced ß-cell damage and dysfunction. MATERIALS AND METHODS: Pretreatment with n-3 PUFAs protected RINm5F cells and mouse islets against tunicamycin-induced ß-cell damage through suppression of ER stress and apoptosis induction. This protective effect of n-3 PUFAs on ß-cells was further demonstrated by the normalization of insulin secretion in response to glucose in tunicamycin-treated islets. In multiple low-dose streptozotocin-induced diabetes models, fat-1 mice, which endogenously synthesize n-3 PUFAs from n-6 PUFAs, were fully resistant to the development of diabetes, with normal islet morphology, high insulin immunoreactivity, and decreased apoptotic cells. In HFD-induced diabetes models, fat-1 mice also exhibited improved glucose tolerance and functional ß-cell mass. In both diabetes models, we observed an attenuation of ER stress in fat-1 mice. Interestingly, n-3 PUFAs attenuated the nuclear translocation of lipogenic transcription factors sterol regulatory element-binding protein-1 (SREBP-1) and C/EBPß, induced by tunicamycin or HFD, suggesting that n-3 PUFAs suppress ER stress via modulation of SREBP-1 and C/EBPß. CONCLUSION: Together, these results suggest that n-3 PUFAs block ER stress, thus protecting ß cells against diabetogenic insult; therefore, dietary supplementation of n-3 PUFAs has therapeutic potential for the preservation of functional ß-cell mass.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Dieta Alta en Grasa/efectos adversos , Relación Dosis-Respuesta a Droga , Insulina/sangre , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Estreptozocina , TunicamicinaRESUMEN
The axis of nuclear factor κB (NF-κB)-inducible NO synthase (iNOS)-nitric oxide plays a key role in cytokine- and streptozotocin-mediated pancreatic ß-cell damage. In this study, we investigated the effects of kazinol C and isokazinol D isolated from Broussonetia kazinoki on the ß-cell viability and function. RINm5F cells and primary islets were used for in vitro and ex vivo cytokine toxicity experiments, respectively. For type 1 diabetes induction, mice were injected with multiple low-dose streptozotocin (MLDS). Cytokine-induced toxicity was completely abolished in both RINm5F cells and islets that were pretreated with either kazinol C or isokazinol D. Both kazinols inhibited the NF-κB signaling pathway, thereby inhibiting cytokine-mediated iNOS induction, nitric oxide production, apoptotic cell death and defects in insulin secretion. Moreover, the occurrence of diabetes in MLDS-treated mice was efficiently attenuated in kazinol-pretreated mice. Immunohistochemical analysis revealed that the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells and nuclear p65-positive cells were significantly decreased in kazinol-pretreated mice. Our results suggest that kazinol C and isokazinol D block the NF-κB pathway, thus reducing the extent of ß-cell damage. Therefore, kazinol C and isokazinol D may have therapeutic value in delaying pancreatic ß-cell damage in type 1 diabetes.
Asunto(s)
Broussonetia/química , Citocinas/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Hemiterpenos/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/patología , Resorcinoles/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Células Cultivadas , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Hemiterpenos/química , Hemiterpenos/aislamiento & purificación , Células Secretoras de Insulina/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/inmunología , Óxido Nítrico/inmunología , Ratas , Resorcinoles/química , Resorcinoles/aislamiento & purificación , Transducción de Señal/efectos de los fármacosRESUMEN
Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic ß cells and requires lifelong exogenous insulin therapy. Recently, islet transplantation has been developed, and although there have been significant advances, this approach is not widely used clinically due to the poor survival rate of the engrafted islets. We hypothesized that improving survival of engrafted islets through ex vivo genetic engineering could be a novel strategy for successful islet transplantation. We transduced islets with adenoviruses expressing betacellulin, an epidermal growth factor receptor ligand, which promotes ß-cell growth and differentiation, and transplanted these islets under the renal capsule of streptozotocin-induced diabetic mice. Transplantation with betacellulin-transduced islets resulted in prolonged normoglycemia and improved glucose tolerance compared with those of control virus-transduced islets. In addition, increased microvascular density was evident in the implanted islets, concomitant with increased endothelial von Willebrand factor immunoreactivity. Finally, cultured islets transduced with betacellulin displayed increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion in the presence of cytokines. These experiments suggest that transplantation with betacellulin-transduced islets extends islet survival and preserves functional islet mass, leading to a therapeutic benefit in type 1 diabetes.
Asunto(s)
Diabetes Mellitus Experimental/cirugía , Intolerancia a la Glucosa/cirugía , Células Secretoras de Insulina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Trasplante de Islotes Pancreáticos , Animales , Apoptosis , Betacelulina , Proliferación Celular , Humanos , Células Secretoras de Insulina/fisiología , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Endogámicos C57BL , RatasRESUMEN
Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 45 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-κB (NF-κB), which revealed that SPA0355 suppressed the nuclear translocation and DNA binding of NF-κB subunits. Concomitantly, the expression of NF-κB target genes such as IL-1ß, IL-6, TNF-α and iNOS was significantly downregulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.