RESUMEN
Hypertension affects a large number of individuals globally and is a common cause of nephropathy, stroke, ischaemic heart disease and other vascular diseases. While many anti-hypertensive medications are used safely and effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, a xanthone molecule extracted from the pericarp of Garcinia mangostana L., has shown various beneficial effects such as anti-tumor, anti-hyperuricemia, and anti-inflammatory properties. However, the effects of α-Mangostin on hypertension remain unknown. In this study, we observed that α-Mangostin significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR), possibly through the down-regulation of angiotensin II (Ang II). We also identified early markers of hypertensive nephropathy, including urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG), which were reduced by α-Mangostin treatment. Mechanistic studies suggested that α-Mangostin may inhibit renal tubular epithelial-to-mesenchymal transformation (EMT) by down-regulating the TGF-ß signaling pathway, thus potentially offering a new therapeutic approach for hypertension and hypertensive nephropathy.
Asunto(s)
Angiotensina II , Presión Sanguínea , Transición Epitelial-Mesenquimal , Hipertensión , Xantonas , Animales , Humanos , Masculino , Ratas , Angiotensina II/metabolismo , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Línea Celular , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis/tratamiento farmacológico , Garcinia mangostana/química , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/patología , Nefritis , Ratas Endogámicas SHR , Transducción de Señal/efectos de los fármacos , Xantonas/farmacología , Xantonas/uso terapéuticoRESUMEN
Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.
Asunto(s)
Neoplasias Pulmonares , Ratones , Animales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores ErbB/genética , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia a Antineoplásicos/genética , Mutación , Serina-Treonina Quinasas TOR/genética , FosfatidilinositolesRESUMEN
AIMS: Alzheimer's disease (AD) and type 2 diabetes (T2D) are two of the most common diseases in elderly population and they have a high rate of comorbidity. Study has revealed that T2D is a major risk factor of AD, and thus exploring therapeutic approaches that can target both diseases has drawn much interest in recent years. In this study, we tried to explore drugs that could be potentially used to prevent or treat both AD and T2D via a drug repositioning approach. METHODS: We first searched the known drugs that may be effective to T2D treatment based on the network distance between the T2D-associated genes and drugs deposited in the DrugBank database. Then, via molecular docking, we further screened these drugs by examining their interaction with islet amyloid polypeptide (IAPP) and Aß42 peptide, the key components involved in the pathogenesis of T2D or AD. Finally, the binding between the selected drug candidates and the target proteins was verified by molecular dynamics (MD) simulation; and the potential function of the drug candidates and the corresponding targets were analyzed. RESULTS: From multiple resources, 734 T2D-associated genes were collected, and a list of 1109 drug candidates for T2D was obtained. We found that hypericin had the lowest binding energy and the most stable interaction with either IAPP or Aß42 peptide. In addition, we also found that the target genes regulated by hypericin were differentially expressed in the tissues related to the two diseases. CONCLUSION: Our results show that hypericin may be able to bind with IAPP and Aß42 stably and prevent their accumulation, and thus could be a promising drug candidate for treating the comorbidity of AD and T2D.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Anciano , Humanos , Enfermedad de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Simulación del Acoplamiento Molecular , Reposicionamiento de Medicamentos , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Péptidos beta-Amiloides/metabolismoRESUMEN
The pollutants degradation rate of iron ore tailings-based heterogeneous catalysts is the main factor limiting its application. Herein, an iron ore tailings-based Fenton-like catalyst (I/W(3:1)-900-60) with a relatively fast catalysis rate was constructed by co-pyrolysis (900°C, 60 min holding time) of iron ore tailings and wheat straw with a mass ratio of 3:1. With wheat straw blending, the generated I/W(3:1)-900-60 presented a larger surface area (24.53 m2/g), smaller pore size (3.76 nm), reduced iron species (Fe2+ from magnetic), and a higher catalytic activity (0.0229 min-1) than I-900-60 (1.32 m2/g, 12.87 nm, 0.012 min-1) pyrolyzed using single iron ore tailing under the same pyrolysis conditions. In addition, biochar and iron ore tailings in I/W(3:1)-900-60 were tightly combined through chemical bonding. The optimal catalyst remains active after three cycles, indicating its catalytic stability and recyclability. The good Fenton-like methylene blue degradation efficiency of I/W(3:1)-900-60 was ascribed to the sacrificial role of biochar, as well as the electron transfer between biochar and iron active sites or the redox cycles of ≡Fe3+/Fe2+. This finding provides a facile construction strategy for highly active iron ore tailings-based Fenton-like catalyst and thereby had a great potential application in wastewater treatment.
Asunto(s)
Compuestos de Hierro , Pirólisis , Catálisis , Peróxido de Hidrógeno/química , Hierro/química , Residuos Sólidos , TriticumRESUMEN
The effects of the combination of bis (α-furancarboxylato) oxovanadium (IV) (BFOV) and metformin (Met) on hepatic steatosis were investigated in high-fat diet-induced obese C57BL/6J mice (HFC57 mice) for 6 weeks. Oral glucose tolerance test was performed to evaluate glucose metabolism. Moreover, blood and hepatic biochemical and histological indices were detected. Besides, Affymetrix-GeneChip analysis and Western blot of the liver were performed. Comparing to the monotherapy group, BFOV + Met showed more effective improvement in glucose metabolism, which decreased the fasting blood glucose, insulin levels and improved insulin sensitivity in HFC57 mice. BFOV + Met significantly decreased serum ALT and AST activities and reduced hepatic triglyceride content and iNOS activities, accompanied by ameliorating intrahepatic fat accumulation and hepatocellular vacuolation. Enhanced hepatic insulin signalling transduction and attenuated inflammation pathway were identified as the major pathways in the BFOV + Met group. BFOV + Met significantly down-regulated the protein expression levels of MMPs, NF-κB, iNOS and up-regulated phosphorylation of AKT and AMPK levels. We concluded that a combination of BFOV and metformin ameliorates hepatic steatosis in HFC57 mice via alleviating hepatic inflammation and enhancing insulin signalling pathway, suggesting that the combination of BFOV and metformin is a potential treatment for hepatic steatosis.
Asunto(s)
Hígado Graso/tratamiento farmacológico , Inflamación/metabolismo , Metformina/farmacología , Compuestos Organometálicos/farmacología , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Dieta Alta en Grasa , Combinación de Medicamentos , Expresión Génica , Insulina/sangre , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/inducido químicamente , Proteína Oncogénica v-akt/metabolismo , Proteínas Quinasas/metabolismoRESUMEN
Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5-4.0â¯mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hiperuricemia/tratamiento farmacológico , Ácido Úrico/sangre , Ácido Úrico/orina , Xantenos/farmacología , Xantina Oxidasa/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/uso terapéutico , Células HEK293 , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/metabolismo , Xantenos/uso terapéuticoRESUMEN
A manganese Schiff base complex with N,N'-1,2-phenylenediamine-bis(salicyladimine) was synthesized and characterized by X-ray crystallography. This complex was administered intragastrically to alloxan-diabetic mice 3â¯weeks. In vivo tests showed that the complex significantly lowered serum glucose levels in alloxan-diabetic mice at doses of 77â¯mgâ¯Vâ¯kg-1. Meanwhile, this complex was investigated as dipeptidyl peptidase IV (DPP-IV) inhibitor for the treatment of type 2 diabetes. The compound exhibit moderate inhibition against DPP-IV and possessed an IC50 value of 30⯵M. Lineweaver-Burk transformation of the inhibition kinetics data demonstrated that it was a noncompetitive inhibitor of DPP-IV and Ki value was 136.3⯵M. Moreover, molecular modeling studies suggested that the complex could fit well within the active-site cleft of DPP-IV. An acute toxicity study showed that animals treated intragastically with complex 1 at a dose of 5.0â¯g/kg did not show any significantly abnormal signs. These preliminary results suggest that the manganese Schiff base complex can induce a hypoglycemic effect in alloxan-diabetic mice.
Asunto(s)
Complejos de Coordinación/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Etilenodiaminas/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Animales , Glucemia/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Etilenodiaminas/síntesis química , Etilenodiaminas/química , Prueba de Tolerancia a la Glucosa , Humanos , Ratones , Ratones Endogámicos NOD , Simulación del Acoplamiento Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Bases de Schiff/químicaRESUMEN
Two oxidovanadium(IV) complexes carrying Schiff base ligands obtained from the condensation of 4,5-dichlorobenzene-1,2-diamine and salicylaldehyde derivatives were synthesised and characterised, including their X-ray crystallographic structures. They were evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. These compounds were moderate inhibitors of DPP-IV, with IC50 values of ca. 40µM. In vivo tests showed that complexes 1 and 2 could lower significantly the level of glucose in the blood of alloxan-diabetic mice at doses of 22.5mgV·kg-1 and 29.6mgV·kg-1, respectively. Moreover, molecular modeling studies suggested that the oxidovanadium complexes 1 and 2 could fit well into the active-site cleft of the kinase domain of DPP-IV. To the best of our knowledge, this is the first report of vanadium complexes capable of inhibiting DPP-IV.
Asunto(s)
Complejos de Coordinación , Diabetes Mellitus Experimental , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV , Simulación del Acoplamiento Molecular , Vanadio , Animales , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/enzimología , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Dominios Proteicos , Vanadio/química , Vanadio/farmacologíaRESUMEN
Coke plant wastewater (CPW) is an intractable chemical wastewater, and it contains many toxic pollutants. This article presents the results of research on a semi-industrial adsorption method of coking wastewater treatment. As a sorbent, the coking coal (CC) was a dozen times less expensive than active carbon. The treatment was conducted within two scenarios, as follows: (1) adsorption after biological treatment of CPW with CC at 40 g L(-1); the chemical oxygen demand (COD) removal was 75.66%, and the concentration was reduced from 178.99 to 43.56 mg L(-1); (2) given an adsorption by CC of 250 g L(-1) prior to the biological treatment of CPW, the eliminations of COD and phenol were 58.08% and 67.12%, respectively. The CC that adsorbed organic pollution and was returned to the coking system might have no effect on both coke oven gas and coke.
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Carbón Mineral/análisis , Residuos Industriales/análisis , Compuestos Orgánicos/química , Eliminación de Residuos Líquidos/métodos , Aguas Residuales/química , Adsorción , Análisis de la Demanda Biológica de Oxígeno , Coque/análisis , Fenol/química , Eliminación de Residuos Líquidos/instrumentaciónRESUMEN
UNLABELLED: The Lyme disease spirochete Borrelia burgdorferi migrates to distant sites in the tick vectors and mammalian hosts through robust motility and chemotaxis activities. FliH and FliI are two cytoplasmic proteins that play important roles in the type III secretion system (T3SS)-mediated export and assembly of flagellar structural proteins. However, detailed analyses of the roles of FliH and FliI in B. burgdorferi have not been reported. In this study, fliH and fliI transposon mutants were utilized to dissect the mechanism of the Borrelia type III secretion system. The fliH and fliI mutants exhibited rod-shaped or string-like morphology, greatly reduced motility, division defects (resulting in elongated organisms with incomplete division points), and noninfectivity in mice by needle inoculation. Mutants in fliH and fliI were incapable of translational motion in 1% methylcellulose or soft agar. Inactivation of either fliH or fliI resulted in the loss of the FliH-FliI complex from otherwise intact flagellar motors, as determined by cryo-electron tomography (cryo-ET). Flagellar assemblies were still present in the mutant cells, albeit in lower numbers than in wild-type cells and with truncated flagella. Genetic complementation of fliH and fliI mutants in trans restored their wild-type morphology, motility, and flagellar motor structure; however, full-length flagella and infectivity were not recovered in these complemented mutants. Based on these results, disruption of either fliH or fliI in B. burgdorferi results in a severe defect in flagellar structure and function and cell division but does not completely block the export and assembly of flagellar hook and filament proteins. IMPORTANCE: Many bacteria are able to rapidly transport themselves through their surroundings using specialized organelles called flagella. In spiral-shaped organisms called spirochetes, flagella act like inboard motors and give the bacteria the ability to bore their way through dense materials (such as human tissue) in a corkscrew manner. In this article, we studied how two proteins, called FliH and FliI, are important for the production of full-length flagella in the Lyme disease spirochete Borrelia burgdorferi. Mutants with defective production of FliH and FliI have reduced flagellar length and motility; this deficiency in turn affects many aspects of B. burgdorferi's biology, including the ability to undergo cell division and cause disease in mammals. Using a microscopic computed tomography (CT) scan approach called cryo-electron tomography, the structure that contains FliH and FliI was defined in the context of the flagellar motor, providing clues regarding how this amazing nanomachine is assembled and functions.
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Proteínas Bacterianas/metabolismo , Borrelia burgdorferi/fisiología , Flagelos/fisiología , Biogénesis de Organelos , ATPasas de Translocación de Protón/metabolismo , Sistemas de Secreción Tipo III , Animales , Proteínas Bacterianas/genética , Técnicas Bacteriológicas , Borrelia burgdorferi/citología , Borrelia burgdorferi/genética , Borrelia burgdorferi/metabolismo , División Celular , Elementos Transponibles de ADN , Modelos Animales de Enfermedad , Eliminación de Gen , Prueba de Complementación Genética , Locomoción , Enfermedad de Lyme/microbiología , Enfermedad de Lyme/patología , Ratones , Microscopía , Mutagénesis Insercional , ATPasas de Translocación de Protón/genética , VirulenciaRESUMEN
BACKGROUND: 3-Hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Currently, statins are used as first-line therapy in the treatment of diabetic dyslipidemia. However, effects of statins on ß cell function remains unclear. This study aims to examine effects of atorvastatin treatment on pancreatic ß cell function in obese C57BL/6 J mice and the possible mechanisms. METHODS: Diet-induced obesity (DIO) C57BL/6 J mice were treated with atorvastatin (30 mg/kg/day) for 58 days. ß cell function was assessed by hyperglycemic clamp and the area of insulin-positive ß cells was examined by immunofluorescence. Gene expression was assessed by RT-PCR, and endoplasmic reticulum (ER) stress related proteins were examined by Western blot. Additionally, cell viability and apoptosis of the cholesterol-loaded NIT-1 cells were investigated after atorvastatin treatment. RESULTS: Hyperglycemic clamp study revealed that glucose infusion rate (GIR) and insulin stimulation ratio in atorvastatin-treated DIO mice were markedly higher than control mice (P < 0.05, P < 0.01 vs. con), indicating preserved ß-cell sensitivity to glucose. Lipid profiles of plasma triglyceride (TG), pancreas TG and plasma cholesterol (CHO) were improved. Pancreas weight and weight index were improved significantly after atorvastatin treatment (P < 0.05 vs. con). Immunofluorescence results showed that atorvastatin-treated mice had significantly larger insulin-positive ß cell area (P < 0.05 vs. con). Furthermore, RT-PCR and western blot showed that the mRNA and protein expression of pancreatic and duodenal homeobox 1 (Pdx1) in the pancreas were upregulated (P < 0.001, P < 0.01 vs. con). Moreover, the expression level of ER stress markers of activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2α (eIF2α) were downregulated in the pancreas of atorvastatin-treated mice (P < 0.001, P < 0.01, P < 0.01 vs. con). Besides, atorvastatin protected the pancreatic ß cell line of NIT-1 from cholesterol-induced apoptosis. Western blot showed increased expression of anti-apoptotic protein of B-cell lymphoma 2 (Bcl-2). CONCLUSION: Pancreatic ß cell function of obese C57BL/6 J mice was preserved after atorvastatin treatment, and this improvement may be attributed to enhanced pancreas proliferation and amelioration of pancreatic ER stress.
Asunto(s)
Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácidos Heptanoicos/uso terapéutico , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Pirroles/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Atorvastatina , Western Blotting , Supervivencia Celular/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Refined-JQ (JQ-R) is a mixture of refined extracts from three major herbal components of JinQi-JiangTang tablet: Coptis chinensis (Ranunculaceae), Astragalus membranaceus (Leguminosae), and Lonicera japonica (Caprifoliaceae). Our previous studies have indicated that JQ-R could decrease fasting blood glucose levels in diabetic mice and insulin resistance mice. Investigating the hypoglycemic effect of JQ-R on prediabetes has practical application value for preventing or delaying insulin resistance, impaired glucose tolerance and possibly the development of clinical diabetes. MATERIALS AND METHODS: The anti-diabetic potential of JQ-R was investigated using a high fat-diet (HFD)-induced obesity mouse model. C57BL/6J mice (HFD-C57 mice) were fed with high-fat diet for 4 months. HFD-C57 mice were treated with either JQ-R (administered intragastrically once daily for 4 weeks) or metformin (as positive control), and the effects of JQ-R on body weight, blood lipids, glucose metabolism, insulin sensitivity, and beta cell function were monitored. RESULTS: The body weight, serum cholesterol, and the Homeostasis Model Assessment ratio (insulin resistance index) were significantly reduced in JQ-R or metformin-treated mice, and the glucose tolerance was enhanced and insulin response was improved simultaneously. Moreover, both JQ-R and metformin could activate liver glycogen syntheses even under a relatively high glucose loading. Although glyconeogenesis was inhibited in the metformin treated mice, it was not observed in JQ-R treated mice. Similar to metformin, JQ-R could also improve the glucose infusion rate (GIR) in hyperglycemic clamp test. JQ-R was also shown to increase the levels of phosphorylated AMPKα and phosphorylated acetyl CoA carboxylase (ACC), similar to metformin. CONCLUSION: JQ-R could reduce HFD-induced insulin resistance by regulating glucose and lipid metabolism, increasing insulin sensitivity through activating the AMPK signaling pathway, and subsequently improving ß cell function. Therefore, JQ-R may offer an alternative in treating disorders associated with insulin resistance, such as prediabetes and T2DM.
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Medicamentos Herbarios Chinos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Células Secretoras de Insulina/efectos de los fármacos , Estado Prediabético/prevención & control , Animales , Glucemia , Grasas de la Dieta , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Hipoglucemiantes/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Soporte de PesoRESUMEN
CONTEXT: Mangiferin, a natural bioactive xanthone C-glycoside, is widely present in medicinal plants like the leaf of Mangifera indica L. (Anacardiaceae). It has been reported that mangiferin possesses a variety of biological activities, including antidiabetic, hepatoprotective, anti-inflammatory, antioxidant, and anticarcinogenic. OBJECTIVE: The hypouricemic effect and xanthine oxidoreductase (XOR) inhibitory activity of mangiferin were investigated here for the first time. MATERIALS AND METHODS: The hypouricemic effect of mangiferin was investigated in normal and hyperuricemic mice induced by potassium oxonate. Mangiferin at a dose of 0.75-100.0 mg/kg was given intragastrically to mice. The serum urate levels were determined using the phosphotungstic acid method. The hepatic activities of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) in hyperuricemic mice were assayed using commercially available kits. RESULTS: The results showed that mangiferin at a dose of 1.5, 3.0, and 6.0 mg/kg significantly reduced the serum urate levels (148.7 ± 37.8, 142.2 ± 44.5, 121.7 ± 21.7 µmmol/L) in hyperuricemic mice, compared with untreated hyperuricemic mice (201.8 ± 71.2 µmmol/L). However, mangiferin did not decrease the serum urate levels in normal mice until mangiferin was up to 100 mg/kg. In addition, the hepatic activities of XDH in hyperuricemic mice were significantly decreased by mangiferin, while no changes of XOD were observed. Acute toxicity study in mice showed that mangiferin was very safe at a dose of up to 25 g/kg. DISCUSSION AND CONCLUSION: These findings demonstrate that mangiferin has the potential to be developed as a new therapeutic agent for the treatment of hyperuricemia and gout.
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Inhibidores Enzimáticos/uso terapéutico , Supresores de la Gota/uso terapéutico , Hiperuricemia/tratamiento farmacológico , Hígado/efectos de los fármacos , Ácido Úrico/sangre , Xantina Deshidrogenasa/antagonistas & inhibidores , Xantonas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Gota/tratamiento farmacológico , Supresores de la Gota/administración & dosificación , Supresores de la Gota/efectos adversos , Hiperuricemia/sangre , Hiperuricemia/enzimología , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos , Ácido Oxónico , Factores de Tiempo , Pruebas de Toxicidad Aguda , Xantina Deshidrogenasa/metabolismo , Xantina Oxidasa/metabolismo , Xantonas/administración & dosificación , Xantonas/efectos adversosRESUMEN
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that decreases postprandial glycemic excursions by enhancing insulin secretion but with short half-life due to rapid inactivation by enzymatic N-terminal truncation. Therefore, efforts are being made to improve the stability of GLP-1 via modifying its structure or inhibiting dipeptidyl-peptidase IV (DPP IV), which is responsible for its degradation. Here we report a novel GLP-1 analog BPI3006 with -NHCO- of Ala(8) replaced by -CH(CF(3))NH- and features of its metabolic stability, GLP-1 receptor trans-activation and in vivo biological activity. BPI3006 is highly resistant to DPP IV-mediated degradation with 91.1% of parental peptide left after 24h exposure to the enzyme. BPI3006 also effectively activates its target gene promoter through GLP-1 receptor activation by measuring the transiently transfected reporter gene green fluorescence protein (GFP) expression in NIT-1 cells. Furthermore, BPI3006 could well restrain the glycemia variation in fasted normal ICR mice after a single administration followed by an oral glucose loading. In spontaneous type 2 diabetic KKA(y) mice, BPI3006 injected twice daily could significantly improve the oral glucose tolerance and hyperinsulinemia, as well as ameliorate the food and water consumption. In conclusion, BPI3006 has enhanced resistance to DPP IV leading to improved stability, and shows excellent in vivo biological activity. Thus it may be a new candidate for T2DM treatment and its novel modification may provide valuable guidance for the future development of long-acting GLP-1 analogs.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/metabolismo , Péptidos/metabolismo , Receptores de Glucagón/agonistas , Secuencia de Aminoácidos , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Datos de Secuencia Molecular , Péptidos/química , Péptidos/farmacologíaRESUMEN
BACKGROUND: The necrosis of a large number of myocardial cells after acute myocardial infarction (AMI) results in a decrease of cardiac function and ventricle remodeling. Stem cell transplantation could improve cardiac function after AMI, but the involving mechanisms have not been completely understood. The present study aimed to investigate the effects of transplantation of autologous bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells (MSCs) via the coronary artery on the ventricle remodeling after AMI as well as the mechanisms of the effects of transplantation of different stem cells on ventricle remodeling. METHODS: A total of 36 male pigs were enrolled in this study, which were divided into 4 groups: control group, simple infarct model group, BM-MNC transplantation group, and MSCs transplantation group. At 90 minutes when a miniature porcine model with AMI was established, transplantation of autologous BM-MNC ((4.7 +/- 1.7) x 10(7)) and MSCs ((6.2 +/- 1.6) x 10(5)) was performed in the coronary artery via a catheter. Ultrasound, electron microscope, immunohistochemical examination and real time reverse transcriptase-polymerase chain reaction were used respectively to observe cardiac functions, counts of blood vessels of cardiac muscle, cardiac muscle nuclear factor (NF)-kappaB, myocardial cell apoptosis, and the expression of the mRNA of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cardiac muscles. Multivariate Logistic regression was used to analyze the correlation factors of left ventricular end-diastolic diameter (EDD). RESULTS: The number of blood vessels in the infarct zone and around its border in the BM-MNC transplantation group was more than those in the infarct model group and MSCs group (P = 0.0001) and there was less myocardial cell apoptosis in the stem cell transplantation group than that in the infarct model group (all P < 0.01). The positive rate of NF-kappaB in the stem cell transplantation group was lower than that in the infarct model group (P = 0.001). The gene expression of VEGF in the infarct border zone of the BM-MNC group was higher than that in the MSCs group (P = 0.0001). The gene expression of bFGF in the infarct border zone in the MSCs transplantation group was higher than that in the infarct model group and the BM-MNC group (P = 0.0001). Left ventricular ejection fraction was inversely proportional to the apoptotic rate of myocardial cells and cardiac muscle NF-kappaB but positively correlated with the number of blood vessels and the expression of VEGF and bFGF in the infarct zone and infarct border zone. The Multivariate Logistic regression analysis on the factors influencing the left ventricular end-diastolic diameter after stem cell transplantation showed that the expression of VEGF mRNA in the cardiac muscles in the infarct zone, the number of apoptotic myocardial cells and the expression of NF-kappaB in the infarct border zone were independent factors for predicting the inhibitory effect on the dilation of left ventricular EDD after stem cell transplantation. CONCLUSIONS: Transplantation of autologous BM-MNC and MSCs in pigs can improve the condition of left ventricular remodeling and recover the cardiac functions after AMI. The improvement of cardiac functions is related to the increase of blood vessels, the increased expression of VEGF and bFGF, the reduction of myocardial cell apoptosis, and the decrease of NF-kappaB level in cardiac muscle tissues after stem cell transplantation.