RESUMEN
It is well known that GLP-1 activates GLP-1R to reduce body weight by inhibiting eating. GLP-1 is cleaved by the neutral endopeptidase (NEP) 24.11 into a pentapeptide GLP-1 (32-36) amide, which increases basal energy expenditure and inhibits weight gain in obese mice. It is well known that GLP-1 analogs can reduce weight by suppressing eating. However, there are few reports of reducing weight through the dual effects of inhibiting eating and increasing basic energy. Here, we report the peptide EGLP-1, a GLP-1 analogue, which can reduce food intake and increase basal energy expenditure. In C2C12 myotubes, EGLP-1 can increase both phosphorylation of acetyl CoA carboxylase (ACC) and the ratio between phosphorylation of ACC and the total expression of ACC (pACC/ACC). In diet-induced obese mice, EGLP-1 is more effective than exendin-4 in reducing body weight, reducing fat mass and improving hepatic steatosis. At the same time, EGLP-1 can improve hyperglycemia, reduce food intake, and improve insulin resistance, just like exendin-4. In addition, EGLP-1, not exendin-4, can improve physiological parameters associated with lipid metabolism and increase oxygen consumption by increasing uncoupling proteins 3 (UCP3) expression and pACC/ACC ratio in skeletal muscle. Taken together, this data showed that EGLP-1 is able to reduce body weight by reducing food intake and increasing basal energy expenditure, suggesting it may be more effective in treating diabetic and non-diabetic overweight or obese people than pure GLP-1R agonist exendin-4.
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Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Péptido 1 Similar al Glucagón/farmacología , Obesidad/metabolismo , Animales , Fármacos Antiobesidad/farmacología , Células Cultivadas , Dieta Alta en Grasa , Ingestión de Alimentos/fisiología , Exenatida/farmacología , Exenatida/uso terapéutico , Péptido 1 Similar al Glucagón/química , Péptido 1 Similar al Glucagón/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/etiología , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéuticoRESUMEN
Tracking of drugs in cancer cells is important for basic biology research and therapeutic applications. Therefore, we designed and synthesised a Zn(II)-thiosemicarbazone complex with photoluminescent property for organelle-specific imaging and anti-cancer proliferation. The Zn(AP44eT)(NO3)2 coordination ratio of metal to ligand was 1:1, which was remarkably superior to 2-((3-aminopyridin-2-yl) methylene)-N, N-diethylhydrazinecarbothioamide (AP44eT·HCl) in many aspects, such as fluorescence and anti-tumour activity. Confocal fluorescence imaging showed that the Zn(AP44eT)(NO3)2 was aggregated in mitochondria. Moreover, Zn(AP44eT)(NO3)2 was more effective than the metal-free AP44eT·HCl in shortening the G2 phase in the MCF-7 cell cycle and promoting apoptosis of cancer cells. Supposedly, the effects of these complexes might be located mainly in the mitochondria and activated caspase-3 and 9 proteins.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Mitocondrias/efectos de los fármacos , Tiosemicarbazonas/farmacología , Zinc/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Mitocondrias/química , Mitocondrias/metabolismo , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tiosemicarbazonas/química , Zinc/químicaRESUMEN
P277 is a 24 amino-acids peptide, residues 437-460 of human heat shock protein 60 (HSP60). P277 or sequence repeated 6â¯×â¯P277 was previously found showing potency preventive and therapeutic anti-diabetes functions in NOD mice, but aroused atherosclerosis due to the induction of anti-HSP65 autoantibodies as reported. To determine the intrinsic B epitope sequence, we screened P277 with pepscan method and then proved by detection of sera IgG from peptide fragments vaccinated mouse and rabbits. Results indicated HSP60 443-448 (ALLRCI) is potential intrinsic B epitope sequence of P277. We modified P277 by deleting the former three amino acids of ALLRCI (VP) or replacing these six with alanine (AP). The detection of serum lipid parameter in NOD mice and aorta endothelial damage levels in high-cholesterol diets fed rabbits demonstrated that VP induced higher anti-diabetes efficacy and caused less arteriosclerosis-liked diseases separately. With less TLR2/4 activation of dendritic cells and macrophages, VP treatment reduced Th1 related P277 specific pro-inflammatory cytokines production and increased regulatory immune responses both in vivo and in vitro. These results indicated that optimized VP peptide might serve as a promising candidate for mouse type 1 diabetes therapy.
Asunto(s)
Sustitución de Aminoácidos , Aterosclerosis/prevención & control , Chaperonina 60/inmunología , Diabetes Mellitus Tipo 1/terapia , Mutación , Fragmentos de Péptidos/inmunología , Secuencia de Aminoácidos , Animales , Aorta/efectos de los fármacos , Aorta/inmunología , Aorta/patología , Aterosclerosis/inducido químicamente , Aterosclerosis/inmunología , Aterosclerosis/patología , Chaperonina 60/administración & dosificación , Chaperonina 60/síntesis química , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Epítopos de Linfocito B/química , Epítopos de Linfocito B/inmunología , Hemocianinas/administración & dosificación , Hemocianinas/inmunología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/síntesis química , Hipoglucemiantes/inmunología , Inmunización , Inmunoconjugados/administración & dosificación , Inmunoconjugados/inmunología , Inmunoglobulina G/sangre , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/síntesis química , Conejos , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunologíaRESUMEN
BACKGROUND/AIMS: Abnormal glucose metabolism and lipid metabolism are two key issues in Type 1 diabetes mellitus (T1DM). Insulin can control carbohydrate metabolism adequately, but cannot regulate lipid metabolism well in patients with T1DM. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have cured type 2 diabetes mellitus in clinical trials and have improved T1DM glycemic control in preclinical studies. However, previous studies have not reported whether GLP-1 can lower the serum concentration of non-esterified fatty acids (NEFAs). In this study, we examine whether GLP-1 can affect serum NEFA levels. METHODS: The bioactivity of EGLP-1 (a novel GLP-1 analog) in vitro was analyzed in CG-HEK293 cells and with high-performance liquid chromatography. An intraperitoneal glucose tolerance test (IPGTT) was used to analyze the acute and sustained hypoglycemic effects of EGLP-1 in normal C57BL/6J mice. Streptozotocin-induced hyperglycemic mice were used to study the effects of EGLP-1 on blood glucose and NEFAs as well as its mechanism. RESULTS: EGLP-1 activated GLP-1R and resisted dipeptidyl peptidase-IV digestion in vitro. Additionally, EGLP-1 had an insulinotropic action in vivo that lasted for approximately 6 h. In Streptozotocin-induced hyperglycemic mice, EGLP-1 improved hyperglycemia, inhibited food intake, and increased ß-cell area. Serum physiological indexes showed that insulin and C-peptide levels were increased, while NEFA and triacylglycerol concentrations were decreased. Western blot analysis revealed that EGLP-1 significantly reduced phosphorylated-hormone sensitive lipase (pHSL) levels in white adipose tissue. CONCLUSIONS: EGLP-1 can improve hyperglycemia by increasing islet ß-cell area and improving ß-cell function, possibly due to reduced NEFA content in serum by lowering pHSL levels.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/uso terapéutico , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Células 3T3-L1 , Secuencia de Aminoácidos , Animales , Glucemia/análisis , Glucemia/metabolismo , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Péptido 1 Similar al Glucagón/farmacología , Células HEK293 , Humanos , Hipoglucemiantes/farmacología , Insulina/sangre , Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
It is well known that glucagon-like peptide 1 (GLP-1) has antidiabetic action. It has 2 distinct functions, an insulinotropic effect dependent on GLP-1 receptor (GLP-1R) and an insulinomimetic effect independent of GLP-1R. However, use of GLP-1 in vivo is limited by its short half-life. Therefore, our lab designed PGLP-1, a novel 2-function candidate peptide as a potential substitute. Using a streptozotocin-induced hyperglycemic mouse model, we demonstrated in vitro and in vivo that PGLP-1 had insulinotropic actions dependent on GLP-1R and insulinomimetic functions independent of GLP-1R. PGLP-1 treatment increased islet ß-cell mass, plasma insulin, and C-peptide levels and Ki-67-immunoreactive ß-cell numbers, verifying that PGLP-1 can work as a short GLP-1R agonist, similar to commercially available exendin-4. Additionally, PGLP-1 improved insulin sensitivity, inhibited gluconeogenesis by increasing expression of AMPK and receptor subfamily 0, group B, member 2 (SHP), and inhibited body weight loss by inhibiting ß-oxidation, suggesting that PGLP-1 had insulinomimetic action. Taken together, these data indicated that PGLP-1, as a dual-function peptide, improved glycemic control and inhibited body weight loss, suggesting it could be useful for type 1 diabetes mellitus patients as an adjunctive therapy to insulin.-Gao, H., Zhao, Q., Song, Z., Yang, Z., Wu, Y., Tang, S., Alahdal, M., Zhang, Y., Jin, L. PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Fragmentos de Péptidos/uso terapéutico , Secuencia de Aminoácidos , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Péptido 1 Similar al Glucagón/uso terapéutico , Gluconeogénesis/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , ARN Mensajero/metabolismo , Pérdida de Peso/efectos de los fármacosRESUMEN
Glucagon-like peptide 1 (GLP-1) has recently received significant attention as an efficacious way to treat diabetes mellitus. However, the short half-life of the peptide limits its clinical application in diabetes. In our previous study, a novel GLP-1 analog (PGLP-1) with a longer half-life was synthesized and evaluated. Herein, we prepared the PGLP-1-loaded poly(d,l-lactide- co-glycolide) microspheres to achieve long-term effects on blood glucose control. The incorporation of zinc ion into the formulation can effectively decrease the initial burst release, and a uniform drug distribution was obtained, in contrast to native PGLP-1 encapsulated microspheres. We demonstrated that the solubility of the drug encapsulated in microspheres played an important role in in vitro release behavior and drug distribution inside the microspheres. The Zn-PGLP-1 microspheres had a prominent acute glucose reduction effect in the healthy mice. A hypoglycemic effect was observed in the streptozotocin (STZ) induced diabetic mice through a 6-week treatment of Zn-PGLP-1-loaded microspheres. Meanwhile, the administration of Zn-PGLP-1 microspheres led to the ß-cell protection and stimulation of insulin secretion. The novel GLP-1 analog-loaded sustained microspheres may greatly improve patient compliance along with a desirable safety feature.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Portadores de Fármacos/química , Péptido 1 Similar al Glucagón/administración & dosificación , Hipoglucemiantes/administración & dosificación , Animales , Preparaciones de Acción Retardada/administración & dosificación , Diabetes Mellitus Experimental/inducido químicamente , Composición de Medicamentos/métodos , Liberación de Fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Hipoglucemiantes/farmacocinética , Islotes Pancreáticos/efectos de los fármacos , Masculino , Cumplimiento de la Medicación , Ratones , Ratones Endogámicos C57BL , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Estreptozocina/toxicidad , Acetato de Zinc/químicaRESUMEN
pH could play vital role in the wound healing process due to the bacterial metabolites, which is one essential aspect of desirable wound dressings lies in being pH-responsive. This work has prepared a degradable hyaluronic acid hydrogel dressing with wound pH response-ability. The aldehyde-modified hyaluronic acid (AHA) was obtained, followed by complex mixture formation of eugenol and oregano antibacterial essential oil in the AHA-CMCS hydrogel through the Schiff base reaction with carboxymethyl chitosan (CMCS). This hydrogel composite presents pH-responsiveness, its disintegration mass in acidic environment (pH = 5.5) is 4 times that of neutral (pH = 7.2), in which the eugenol release rate increases from 37.6 % to 82.1 %. In vitro antibacterial and in vivo wound healing investigations verified that hydrogels loaded with essential oils have additional 5 times biofilm removal efficiency, and significantly accelerate wound healing. Given its excellent anti-biofilm and target-release properties, the broad application of this hydrogel in bacteria-associated wound management is anticipated.
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Antibacterianos , Biopelículas , Ácido Hialurónico , Hidrogeles , Aceites Volátiles , Cicatrización de Heridas , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Biopelículas/efectos de los fármacos , Aceites Volátiles/farmacología , Aceites Volátiles/química , Concentración de Iones de Hidrógeno , Animales , Antibacterianos/farmacología , Antibacterianos/química , Quitosano/química , Quitosano/análogos & derivados , Quitosano/farmacología , Staphylococcus aureus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , VendajesRESUMEN
BACKGROUND: In recent years, miRNAs have emerged as potentially valuable tumor markers, and their sensitive and accurate detection is crucial for early screening and diagnosis of tumors. However, the analysis of miRNAs faces significant challenges due to their short sequence, susceptibility to degradation, high similarity, low expression level in cells, and stringent requirements for in vitro research environments. Therefore, the development of sensitive and efficient new methods for the detection of tumor markers is crucial for the early intervention of related tumors. RESULTS: An ultrasensitive electrochemical/colorimetric dual-mode self-powered biosensor platform is established to detect microRNA-21 (miR-21) via a multi-signal amplification strategy. Gold nanoparticles (AuNPs) and VS4 nanosheets self-assembled 3D nanorods (VS4-Ns-Nrs) are prepared for constructing a superior performance enzyme biofuel cell (EBFC). The double-signal amplification strategy of Y-shaped DNA nanostructure and catalytic hairpin assembly (CHA) is adopted to further improve enhance the strength and specificity of the output signal. In addition, a capacitor is matched with EBFC to generate an instantaneous current that is amplified several times, and the output detection signal is improved once more. At the same time, electrochemical and colorimetric methods are used for dual-mode strategy to achieve the accuracy of detection. The linear range of detection is from 0.001 pg/mL to 1000 pg/mL, with a relatively low limit of detection (LOD) of 0.16 fg/mL (S/N = 3). SIGNIFICANCE: The established method enables accurate and sensitive detection of markers in patients with lung cancer, providing technical support and data reference for precise identification. It is anticipated to offer a sensitive and practical new technology and approach for early diagnosis, clinical treatment, and drug screening of cancer and other related major diseases.
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Biomarcadores de Tumor , Técnicas Biosensibles , Colorimetría , Técnicas Electroquímicas , Oro , Neoplasias Pulmonares , Nanopartículas del Metal , MicroARNs , Humanos , Técnicas Biosensibles/métodos , Neoplasias Pulmonares/diagnóstico , Técnicas Electroquímicas/métodos , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Oro/química , MicroARNs/análisis , Nanopartículas del Metal/química , Límite de DetecciónRESUMEN
Pathogenic bacteria residing inside cells could cause disruption of cellular metabolic balance. Therefore, basing on high oxidative stress response of the intracellular bacteria infected micro-environment, a novel amphipathic micelle (HATAD-TCS) was developed consisting of hyaluronic acid-derivative and reactive oxygen species (ROS) - responsive group and antibacterial agent triclosan (TCS). ROS-generating cinnamaldehyde (CA) was incorporated into ROS-cleavable linkages which are future linked to the 1-decylamine to form hydrophobicity. The cinnamaldehyde released did not just killed bacteria however, also maintained intracellular ROS levels. In this study, the HATAD-TCS micelles have been characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS). The HATAD-TCS micelles could release drug gradually upon exposure to endogenous ROS being caused by infected intracellular bacteria. Furthermore, the more promising therapeutic effect of the HATAD-TCS micelles was observed in a mouse pneumonia model. These results might highlight a ROS-responsive hyaluronic acid-based nanoparticle, which could effectively treat intracellular bacterial infections.
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Infecciones Bacterianas , Micelas , Animales , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ácido HialurónicoRESUMEN
Fibroblast growth factor 21 (FGF21) is a member of FGF family. It has been demonstrated that FGF21 is an independent, safe and effective regulator of blood glucose levels in vivo. In order to improve the activity of FGF21, we exchanged the beta10-beta12 domain of the human FGF21 with that of the mouse FGF21 to construct a novel FGF21 gene (named hmFGF21), and then subcloned hmFGF21 gene into the SUMO expression vector to create pSUMO-hmFGF21 and transformed it into E. coli Rosetta for expression of the fusion protein SUMO-hmFGF21. Both in vitro and in vivo glucose regulation activity of hmFGF21 was evaluated. The SDS-PAGE result showed that compared with wild-type hFGF21, the soluble expression of hmFGF21 increased about 2-fold. HmFGF21 was more potent in stimulation of glucose uptake in HepG2 cells in vitro. The results of anti-diabetic effect on db/db mice demonstrated that hmFGF21 had better efficacy on controlling the blood glucose of the db/db diabetic animals than wild-type hFGF21. These results suggest that the biological properties of FGF21 are significantly improved by optimization.
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Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Endopeptidasas/genética , Factores de Crecimiento de Fibroblastos , Hipoglucemiantes , Secuencia de Aminoácidos , Animales , Cisteína Endopeptidasas , Escherichia coli , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/farmacología , Vectores Genéticos , Glucosa/metabolismo , Células Hep G2/metabolismo , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Masculino , Ratones , Mutación , Plásmidos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Transformación GenéticaRESUMEN
OBJECTIVE: This study aimed to explore the correlation between glycemic control, microvascular complications and serum glycogen antigen (CA199) in patients with type 2 diabetes mellitus (T2DM). METHODS: 519 patients with T2DM admitted to our hospital were included. All patients had CA199 levels measured. Patients were divided into low glycation (LH) group (HbA1C <7.5%), Hyperglycemia (HH) group (HbA1C ≥7.5%), fasting glucose compliance (SF) group (FBG <7.0 mmol/L), high fasting glucose (HF) group (FBG ≥7.0 mmol/L), postprandial glucose compliance (SP) group (PBG <10.0 mmol/L) and high postprandial glucose (HP) group (PBG ≥10.0 mmol/L) and with microvascular complications group, and no microvascular complications group. Division was according to levels of glycated hemoglobin (HbA1C), fasting blood glucose (FBG), 2-hour postprandial blood glucose (2hPBG), and diabetic microvascular complications. RESULTS: CA199 levels were significantly higher in the HH and HF groups than in the LH and SF groups (P<0.05); HbA1C and FBG were positively correlated with CA199; CA199 levels were not significantly different between SP and HP groups (P>0.05), and PBG was not significantly correlated with CA199 levels. CA199 levels were significantly higher in the group with microvascular complications than in the group without microvascular complications (P<0.05); HbA1C was an independent risk factor for elevated CA199. CONCLUSION: Patients with T2DM and higher CA199 levels need to be evaluated for glycemic status and the presence of microvascular complications. HbA1C is a major risk factor for elevated CA199 levels.
RESUMEN
OBJEVTIVE: To investigate the effects of Cyclocarya paliurus (C. paliurus) polysaccharides on the spleen injury of diabetic rats. METHODS: Animals were divided into 6 groups, including normal group, model group, control group, low-dose group of C. paliurus polysaccharides treatment, middle-dose group of C. paliurus polysaccharides treatment and high-dose group of C. paliurus polysaccharides treatment. Histological analysis of spleen was analyzed using hematoxilin and eosin. Levels of biological parameters and anti-oxidative enzymes were determined by spectrophotometry. Interleukin-7 (IL-7) and IL-10 were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with that of model group, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase level increased 78.63% (P < 0.05), 51.76% (P < 0.05), 2.95 times (P < 0.01) and 41.11% (P < 0.05) in the high-dose group of C. paliurus polysaccharides treatment, respectively. IL-7 and IL-10 increase 1.66 (P < 0.01) and 1.21 times (P < 0.01) in the high-dose group of C. paliurus polysaccharides treatment, respectively. CONCLUSION: It is suggested that C. paliurus polysaccharides may play a protecting role for spleen injury of diabetic rats by enhancing the antioxidative ability and evaluating the immunity.
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Diabetes Mellitus Experimental , Juglandaceae , Animales , Antioxidantes/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Hojas de la Planta , Polisacáridos/uso terapéutico , Ratas , BazoRESUMEN
Multiple animal and human studies have shown that administration of GLP-1RA can enhance ß-cell recovery, reduce insulin dosage, reduce HbA1c content in the blood, reduce the risk of hypoglycemia and reduce inflammation. In the NOD mouse model, peptide VP treatment can prevent and treat type 1 diabetes through immunomodulation. Therefore, we designed a new dual-functional PGLP-1-VP, which is expected to combine the anti-inflammatory effect of PGLP-1 and the immunomodulatory effect of VP peptide. In streptozotocin-induced hyperglycemic mice model, we demonstrated that PGLP-1-VP can act as a GLP-1R agonist to improve hyperglycemia and increase insulin sensitivity. In the NOD mouse model, PGLP-1-VP treatment reduced morbidity, mortality, and pancreatic inflammation, and showed superior effect to PGLP-1 or VP treatment alone, confirming that PGLP-1-VP may act as a dual-function peptide. PGLP-1-VP provided immunomodulatory effect through increasing Th2 cell percentage and balancing the ratio of Th2/Th1 in spleen and PLN, similar to P277 and VP. Additionally, PGLP-1-VP and PGLP-1 act the anti-inflammation by increasing Treg cells and TGF-ß1 content like DPP-IV inhibitor. Taken together, our data shows that the dual-functional PGLP-1-VP reduces morbidity and mortality in the NOD model, suggesting a potential role in preventing and treating type 1 diabetes.
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Diabetes Mellitus Experimental/genética , Péptido 1 Similar al Glucagón/análogos & derivados , Receptor del Péptido 1 Similar al Glucagón/genética , Inflamación/genética , Fragmentos de Péptidos/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Antiinflamatorios/metabolismo , Linfocitos B/inmunología , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/mortalidad , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Péptido 1 Similar al Glucagón/genética , Péptido 1 Similar al Glucagón/inmunología , Humanos , Inmunomodulación , Inflamación/inmunología , Inflamación/mortalidad , Ratones , Fragmentos de Péptidos/inmunologíaRESUMEN
Anoectochilus roxburghii is a traditional herb in China that can be potentially used to treat diabetes. A novel polysaccharide ARLP-W was isolated from Anoectochilus roxburghii by chromatography on DEAE-52 cellulose. Chemical analysis indicated that ARLP-W (8.1 × 104 Da) was mainly composed of mannose and glucose. The main linkages of glycosidic bonds of ARLP-W were ß-1, 4-Manp and α-1, 4-Glcp. The terminal Glcp was connected to Manp-via O-3. RT-qPCR and western blotting analysis showed that ARLP-W caused a significant reduction in the levels of the key gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) in the liver. The results of the insulin resistance tests indicated that ARLP-W increased glucose absorption. These results indicate that ARLP-W has a good therapeutic effect on type 2 diabetes and can assist with further development and application treatment of diabetes.
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Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/dietoterapia , Carbohidratos de la Dieta/uso terapéutico , Orchidaceae/química , Polisacáridos , Animales , Glucosa/química , Masculino , Manosa/química , Ratones , Ratones Endogámicos C57BL , Polisacáridos/química , Polisacáridos/farmacologíaRESUMEN
Therapeutic efficacy of P277 against type 1 diabetes was extensively investigated and clinically evidenced. Clinical trials Phases I and II concluded promising results, while the data of P277 immunogenicity in Phase III trials represented weak responses that led to abolish medical use. But, a therapeutic performance of P277 cannot be forgotten. So, in order to exploit its therapeutic benefits and improve its immunogenicity, we developed a new analogue VP to optimize therapeutic efficacy and enhancing immunosuppressive modulations. However, new analogue was purified, and then used to immunize diabetic NOD mice to investigate antidiabetic effects through modulation of immunological status. So, DCs immune responses, relative TLRs, MyD88, and NF-Kß1 mRNA expression on DCs and splenocytes under VP effect were tested. Circulating and intracellular cytokines were also evaluated at treated and non-treated mice. Splenic T lymphocytes proliferation (Th1 and Treg cells) were also determined. Results revealed that VP significantly down regulates DCs maturation through TLR2, TLR4, and MyD88 pathways. It also shifts DCs to a tolerogenic polarization through NF-Kß1 pathway that mediates Th1 immunosuppression and enhances iTreg expanding in type1diabetes mice. Meanwhile, we noticed that VP significantly enhances iTreg CD25 + FoxP3+ proliferation. In conclusion, VP showed promising immune potential to modulate immune regulatory responses and shifts DCs to suppress autoreactive Th1 cells which ameliorated immunosuppressive potency in the type1 diabetic mice.
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Autoinmunidad/efectos de los fármacos , Chaperonina 60/farmacología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Tolerancia Inmunológica/efectos de los fármacos , Inmunosupresores/farmacología , Fragmentos de Péptidos/farmacología , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Comunicación Celular/inmunología , Chaperonina 60/genética , Chaperonina 60/inmunología , Chaperonina 60/uso terapéutico , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Diabetes Mellitus Tipo 1/inmunología , Modelos Animales de Enfermedad , Epítopos de Linfocito B/genética , Femenino , Humanos , Inmunosupresores/uso terapéutico , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Mutagénesis , Subunidad p50 de NF-kappa B/inmunología , Subunidad p50 de NF-kappa B/metabolismo , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/uso terapéutico , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/inmunología , Células TH1/metabolismoRESUMEN
The main challenge of anticancer drugs is poor tumor targeting. Now cellular carriers are widely investigated to deliver anticancer agents. As an ideal cellular candidate, human umbilical cord derived mesenchymal stem cells (hUC-MSCs) possess inherent tropism potential to tumor. Here, we constructed hUC-MSCs carrying transferrin-inspired-nanoparticles that contain doxorubicin(hUC-MSCs-Tf-inspired-NPs) to achieve enhanced anti-tumor efficacy and made an evaluation. Results represented that hUC-MSCs-Tf-inspired-NPs not only exhibit the controlled-release property of Tf-inspired-NPs, but also integrate tumor tropism and penetrative abilities of MSCs. The tumor volume of nude mice bearing breast cancer MCF-7 treated with hUC-MSCs-Tf-inspired-NPs, was remarkably reduced compared to those treated with free drug or Tf-inspired-NPs. Thus, Tf-inspired-NPs loaded hUC-MSCs have a potential to deliver anticancer drugs.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Portadores de Fármacos/química , Células Madre Mesenquimatosas/química , Nanoestructuras/química , Cordón Umbilical/citología , Animales , Neoplasias de la Mama/patología , Doxorrubicina/uso terapéutico , Portadores de Fármacos/metabolismo , Liberación de Fármacos , Femenino , Humanos , Células MCF-7 , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Desnudos , Terapia Molecular DirigidaRESUMEN
To elucidate the genetic characteristics of the bovine Inhibin α subunit (INHA) gene, the polymorphisms in exon 1 of INHA and its bilateral sequences were assayed using PCR with direct sequencing in buffalo, gayal and yak. A comparative analysis was conducted by pooled the results in this study with the published data of INHA on some mammals including some bovine species together. A synonymous substitution c.73C>A was identified in exon 1 of INHA for buffalo, which results in identical encoding product in river and swamp buffalo. In gayal, two non-synonymous but same property substitutions in exon 1 of INHA, viz. c.62 C>T and c.187 G>A, were detected, which lead to p. P21L, p. V63M changes in INHA, respectively. In yak, nucleotide substitution c.62C> T, c.129A>G were found in exon 1 of INHA, the former still causes p. P21L substitution and the latter is synonymous. For the sequence of the 5'-flanking region of INHA examined, no SNPs were found within the species, but a substitution, c. -6T>G, was found. The nucleotide in this site in gayal, yak and cattle was c. -6G, whereas in buffalo it was c. -6T. Meanwhile, a 6-bp deletion, namely c. 262+31_262+36delTCTGAC, was found in the intron of buffalo INHA gene. For this deletion, wild types (+/+) account for main part in river buffalo while mutant types (-/-) are predominant in swamp buffalo. This deletion was not found in gayal, yak and cattle, though these all have another deletion in the intron of INHA, c. 262+78_262+79delTG. The results of sequence alignment showed that the substitutions c. 43A and c. 67G in exon 1 of INHA are specific to buffalo, whereas the substitutions c. 173A and c. 255G are exclusive to gayal, yak and cattle, and c. 24C, c. 47G, c. 174T and c. 206T are specific to goat. Furthermore, there are few differences among gayal, yak and cattle, but there relatively great differences between buffalo, goat and other bovine species regarding the sequences of INHA exon 1.