Investigation on key molecular targets responsible for antidiabetic properties of Symplocos cochinchinensis (Lour.) S. Moore

Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycemia with disturbances in carbohydrate, protein and lipid metabolism resulting from defects in insulin secretion, insulin action or both. Currently there are 387 million people with diabetes worldwide and is expected to affect 592 million people by 2035. Insulin resistance in peripheral tissues and pancreatic beta cell dysfunction are the major challenges in the pathophysiology of diabetes. Diabetic secondary complications (like liver cirrhosis, retinopathy, microvascular and macrovascular complications) arise from persistent hyperglycemia and dyslipidemia can be disabling or even life threatening. Current medications are effective for control and management of hyperglycemia but undesirable effects, inefficiency against secondary complications and high cost are still serious issues in the present prognosis of this disorder. Hence the search for more effective and safer therapeutic agents of natural origin has been found to be highly demanding and attract attention in the present drug discovery research. The data available from Ayurveda on various medicinal plants for treatment of diabetes can efficiently yield potential new lead as antidiabetic agents. For wider acceptability and popularity of herbal remedies available in Ayurveda scientific validation by the elucidation of mechanism of action is very much essential. Modern biological techniques are available now to elucidate the biochemical basis of the effectiveness of these medicinal plants. Keeping this idea the research programme under this thesis has been planned to evaluate the molecular mechanism responsible for the antidiabetic property of Symplocos cochinchinensis, the main ingredient of Nishakathakadi Kashayam, a wellknown Ayurvedic antidiabetic preparation. A general introduction of diabetes, its pathophysiology, secondary complications and current treatment options, innovative solutions based on phytomedicine etc has been described in Chapter 1. The effect of Symplocos cochinchinensis (SC), on various in vitro biochemical targets relevant to diabetes is depicted in Chapter 2 including the preparation of plant extract. Since diabetes is a multifactorial disease, ethanolic extract of the bark of SC (SCE) and its fractions (hexane, dichloromethane, ethyl acetate and 90 % ethanol) were evaluated by in vitro methods against multiple targets such as control of postprandial hyperglycemia, insulin resistance, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B) and dipeptidyl peptidase-IV (DPPxxi IV). Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition, insulin dependent glucose uptake (3 fold increase) in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F and reduced triglyceride accumulation in 3T3-L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence of bioactives (beta-sitosterol, phloretin 2’glucoside, oleanolic acid) in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test (OGTT) to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. Chapter 3 highlights the beneficial effects of hydroethanol extract of Symplocos cochinchinensis (SCE) against hyperglycemia associated secondary complications in streptozotocin (60 mg/kg body weight) induced diabetic rat model. Proper sanction had been obtained for all the animal experiments from CSIR-CDRI institutional animal ethics committee. The experimental groups consist of normal control (NC), N + SCE 500 mg/kg bwd, diabetic control (DC), D + metformin 100 mg/kg bwd, D + SCE 250 and D + SCE 500. SCEs and metformin were administered daily for 21 days and sacrificed on day 22. Oral glucose tolerance test, plasma insulin, % HbA1c, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein etc. were analysed. Aldose reductase (AR) activity in the eye lens was also checked. On day 21, DC rats showed significantly abnormal glucose response, HOMA-IR, % HbA1c, decreased activity of antioxidant enzymes and GSH, elevated AR activity, hepatic and renal oxidative stress markers compared to NC. DC rats also exhibited increased level of plasma urea and creatinine. Treatment with SCE protected from the deleterious alterations of biochemical parameters in a dose dependent manner including histopathological alterations in pancreas. SCE 500 exhibited significant glucose lowering effect and decreased HOMA-IR, % HbA1c, lens AR activity, and hepatic, renal oxidative stress and function markers compared to DC group. Considerable amount of liver and muscle glycogen was replenished by SCE treatment in diabetic animals. Although metformin showed better effect, the activity of SCE was very much comparable with this drug. xxii The possible molecular mechanism behind the protective property of S. cochinchinensis against the insulin resistance in peripheral tissue as well as dyslipidemia in in vivo high fructose saturated fat diet model is described in Chapter 4. Initially animal were fed a high fructose saturated fat (HFS) diet for a period of 8 weeks to develop insulin resistance and dyslipidemia. The normal diet control (ND), ND + SCE 500 mg/kg bwd, high fructose saturated fat diet control (HFS), HFS + metformin 100 mg/kg bwd, HFS + SCE 250 and HFS + SCE 500 were the experimental groups. SCEs and metformin were administered daily for the next 3 weeks and sacrificed at the end of 11th week. At the end of week 11, HFS rats showed significantly abnormal glucose and insulin tolerance, HOMA-IR, % HbA1c, adiponectin, lipid profile, liver glycolytic and gluconeogenic enzyme activities, liver and muscle triglyceride accumulation compared to ND. HFS rats also exhibited increased level of plasma inflammatory cytokines, upregulated mRNA level of gluconeogenic and lipogenic genes in liver. HFS exhibited the increased expression of GLUT-2 in liver and decreased expression of GLUT-4 in muscle and adipose. SCE treatment also preserved the architecture of pancreas, liver, and kidney tissues. Treatment with SCE reversed the alterations of biochemical parameters, improved insulin sensitivity by modifying gene expression in liver, muscle and adipose tissues. Overall results suggest that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with antiglycation and antioxidant activities.

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Lecture notes

Lessons from nothing : activities for language teaching with limited and resources.

Recurso con alrededor de setenta actividades de enseñanza de idiomas para profesores que buscan actividades fáciles de utilizar, que fomenten la interacción y la cooperación en el aula y que no requieran gran cantidad de recursos, instalaciones o preparación.

99 ideas and activities for teaching English learners with the SIOP model.

El modelo SIOP (Shelthered Instruction Observation Protocol) consiste en treinta indicadores agrupados en ocho categorías, que ayudan a diseñar y planificar la práctica educativa para ser utilizada en contextos en los que haya alumnos que tienen que aprender en una lengua que no es su lengua materna. Este modelo tiene en cuenta las necesidades lingüístico-académicas de los alumnos y propone diferentes estrategias y técnicas para enseñarlos de una manera más comprensible, a la vez que se potencia su desarrollo lingüístico. Dentro de la preparación de la unidad didáctica, el SIOP señala la importancia de definir claramente tanto los objetivos de contenido como los objetivos de lenguaje y compartirlos con los alumnos. Asimismo destaca la necesidad de adaptar los contenidos a las necesidades académico-lingüísticas de los alumnos mediante el uso de materiales complementarios.

Fun with messy play : ideas and activities for children with special needs.

Colores vivos, sonidos suaves, texturas extrañas, sabores y olores, forman parte de cómo los niños desarrollan la conciencia sensorial. Las actividades propuestas en este manual aumentan la percepción sensorial de los niños con necesidades especiales, mediante el uso imaginativo de la vida cotidiana, que les ayuda a mejorar su coordinación, habilidades comunicativas y cognitivas, así como su autoestima y habilidades sociales. Al permitir a los niños explorar sus sentidos mientras se divierten, proporciona una terapia relajante que fomenta la capacidad de respuesta sensorial sin crearles estrés.

101 games and activities for children with aurism, Asperger's and sensory processing disorders.

Una de las mejores maneras para que los niños con autismo, Asperger, trastornos sensoriales aprendan es a través del juego, sin embargo, los mayores desafíos a los que padres y maestros se enfrentan con estos niños es la manera de hacerlos participar con éxito en el juego. En este manual, se ofrece más de un centenar de juegos que ayudan al niño: hacer contacto visual, mantenerse concentrado, y fortalecer sus habilidades motoras; asociar las palabras con los objetos y mejorar las habilidades lingüísticas y numéricas; aprender a interactuar con otras personas, como tomar turnos, y otras habilidades sociales necesarias para asistir a la escuela preescolar.

Teaching students with behavior disorders : techniques and activities for classroom instruction.

Manual que describe lo que los maestros pueden hacer para promover el aprendizaje de jóvenes con problemas. Comienza con una visión general sobre estos estudiantes. Continúa con la planificación inicial y la organización del ambiente de la clase, de acuerdo con las diversas fases del programa académico, seguido por el diagnóstico de las fortalezas y debilidades de los estudiantes. Se proporcionan ejemplos de aula para ilustrar cómo se pueden aplicar las técnicas sugeridas tanto en especial como en las aulas ordinarias para captar la atención del alumno y estimular el pensamiento creativo.

Social skills activities for secondary students with special needs.

Recurso práctico diseñado como un programa autónomo para los profesionales y familiares que trabajan con estudiantes con necesidades especiales en los grados 6-12. Ofrece a los maestros y padres más de doscientas hojas de trabajo para ayudar a estos adolescentes a construir las habilidades que necesitan para lograr la independencia y tener éxito en la vida cotidiana. Las veintisiete unidades están centradas en las competencias básicas de la vida real tales como el manejo de dinero, éxito en la escuela, uso seguro de Internet, conseguir y mantener un trabajo.

Social skills activities for secondary students with special needs.

Recurso práctico diseñado como un programa autónomo para los maestros que trabajan con estudiantes con necesidades especiales en los grados 6-12. Ofrece una colección de doscientas hojas de trabajo para ayudar a los adolescentes a construir las habilidades sociales necesarias para interactuar eficazmente con los demás y aprender a aplicar estas habilidades a diferentes situaciones para la vida real en cinco escenarios diferentes: hogar, escuela, trabajo, entre colegas, y en la comunidad. También les ayudará a aprender a controlar las situaciones mediante la participación activa y contribuir a mejorar los resultados sociales.

Listen here! : intermediate listening activities with key.

Libro dirigido a estudiantes de inglés como lengua extranjera de nivel intermedio-bajo o intermedio, que quieran mejorar sus habilidades de compresión auditiva. Adecuado para su uso en clase como complemento de cualquier libro de texto, por cuenta propia o para preparar el examen Cambridge PET (Preliminary English Test). Está estructurado en 28 lecciones con temas y situaciones variadas, con diferentes pronunciaciones y acentos (inglés normativo y regional, americano y australiano), y ejercicios adicionales de pronunciación y expresión oral. Contiene las soluciones al final del libro.

Accumulated metal speciation in earthworm populations with multi-generational exposure to metalliferous soils: cell fractionation and high energy synchrotron analyses

Predicting metal bioaccumulation and toxicity in soil organisms is complicated by site-specific biotic and abiotic parameters. In this study we exploited tissue fractionation and digestion techniques, combined with X-ray absorption spectroscopy (XAS), to investigate the whole-body and subcellular distributions, ligand affinities, and coordination chemistry of accumulated Pb and Zn in field populations of the epigeic earthworm Lumbricus rubellus inhabiting three contrasting metalliferous and two unpolluted soils. Our main findings were (i) earthworms were resident in soils with concentrations of Pb and Zn ranging from 1200 to 27 000 mg kg(-1) and 200 to 34 000 mg kg(-1), respectively; (ii) Pb and Zn primarily accumulated in the posterior alimentary canal in nonsoluble subcellular fractions of earthworms; (iii) site-specific differences in the tissue and subcellular partitioning profiles of populations were observed, with earthworms from a calcareous site partitioning proportionally more Pb to their anterior body segments and Zn to the chloragosome-rich subcellular fraction than their acidic-soil inhabiting counterparts; (iv) XAS indicated that the interpopulation differences in metal partitioning between organs were not accompanied by qualitative differences in ligand-binding speciation, because crystalline phosphate-containing pyromorphite was a predominant chemical species in the whole-worm tissues of all mine soil residents. Differences in metal (Pb, Zn) partitioning at both organ and cellular levels displayed by field populations with protracted histories of metal exposures may reflect their innate ecophysiological responses to essential edaphic variables, such as Ca2+ status. These observations are highly significant in the challenging exercise of interpreting holistic biomarker data delivered by "omic" technologies.

Remediation of soils contaminated with petrol and diesel with lime

Lime treatment of hydrocarbon-contaminated soils offers the potential to stabilize and solidify these materials, with a consequent reduction in the risks associated with the leachate emanating from them. This can aid the disposal of contaminated soils or enable their on-site treatment. In this study, the addition of hydrated lime and quicklime significantly reduced the leaching of total petroleum hydrocarbons (TPH) from soils polluted with a 50:50 petrol/diesel mixture. Treatment with quicklime was slightly more effective, but hydrated lime may be better in the field because of its ease of handling. It is proposed that this occurs as a consequence of pozzolanic reactions retaining the hydrocarbons within the soil matrix. There was some evidence that this may be a temporary effect, as leaching increased between seven and 21 days after treatment, but the TPH concentrations in the leachate of treated soils were still one order of magnitude below those of the control soil, offering significant protection to groundwater. The reduction in leaching following treatment was observed in both aliphatic and aromatic fractions, but the latter were more affected because of their higher solubilty. The results are discussed in the context of risk assessment, and recommendations for future research are made.