The therapeutic effects of a pentacyclic triterpene derivative, bardoxolone methyl, in preventing high-fat diet-induced obesity and associated neural, hepatic, cardiovascular, and renal complications

The prevalence of obesity is a growing problem since it significantly increases the risk of developing type 2 diabetes and associated complications of the brain, liver, heart, and kidneys. Therefore, there is an urgency to find novel therapies which can prevent obesity and the development of associated complications. This PhD project investigated whether selected pentacyclic triterpenes (oleanolic acid (OA), its isomer, ursolic acid (UA), and derivative, bardoxolone methyl (BM)) administered at 10 mg/kg daily in drinking water could prevent obesity in mice fed a chronic HF diet for 21 weeks. These compounds were chosen based on recent studies demonstrating that they have a number of anti-obese and anti-diabetes properties. In preliminary studies, BM prevented HF diet-induced body weight gain, while UA and OA had no effect. Following this, the molecular mechanisms underlying the ability of BM to prevent HF diet-induced obesity and associated complications were then examined. BM administration for 21 weeks prevented HF diet-induced increases in body weight, energy intake, plasma leptin, and peripheral fat (Chapter 2). Furthermore, in the mediobasal and paraventricular nuclei regions of the hypothalamus, BM treatment prevented HF diet-induced impairments of downstream leptin JAK2-Akt-FOXO1 signalling and increases in the inflammatory molecules, pJNK, TNFα and IL-6. These findings identify a potential novel neuropharmacological application for BM to prevent HF diet-induced obesity, hypothalamic inflammation and leptin resistance. BM administration also prevented HF diet-induced impairments in recognition memory (Chapter 3). Furthermore, in the hippocampus and prefrontal cortex (PFC), BM treatment prevented HF diet-induced decreases in downstream BDNF signalling molecules and increases in the inflammatory molecule, PTP1B. In summary, the findings from this chapter suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, and reducing inflammation in the PFC and hippocampus. BM treatment prevented HF diet-induced insulin resistance and hepatic steatosis in mice fed a HF diet (Chapter 4). Furthermore, in the livers of mice, BM prevented HF diet-induced impairments to hepatic IR-IRS-FOXO1 insulin signalling, ACOX-induced lipid metabolism, macrophage infiltration, and inflammation. These findings suggest that BM prevents HF dietinduced insulin resistance and the development of hepatic steatosis through modulation of molecules involved in insulin signalling, lipid metabolism, and inflammation in the liver. BM administration prevented HF diet-induced structural changes in the heart and kidneys (Chapter 5). Furthermore, in these tissues, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and TNFα gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Collectively, this thesis is novel in demonstrating that BM treatment prevents HF diet-induced obesity and associated leptin resistance, insulin resistance, cognitive deficits, and liver, kidney, and heart pathophysiologies in mice fed a HF diet for 21 weeks. These results suggest that these therapeutic effects were through anti-inflammatory mechanisms. Overall, these findings highlight BM as a potential novel therapeutic for preventing HF diet-induced obesity and a variety of associated complications

Medical education: meeting the challenge of implementing primary health care in sub-saharan Africa

The ideas expressed in this discourse have been derived from the experience of planning for undergraduate medical education at the Aga Khan University (AKU) Medical College, Nairobi, which is a private university for the East African region; broad-based general education and the principles of liberal arts are incorporated in the curriculum. Medical education in sub-Saharan Africa (SSA) must be defined by its health needs and the health care services required. This article begins by describing the sociodemographic milieu that determines the disease pattern. Then it considers the compelling case for primary health care (PHC) in the context of community participation and multisector development as the driver of a medical education plan. An attempt is made to define the attributes of a doctor required to be effective in the region and to anticipate the inevitable challenges that lie ahead, including authorization and implementation of the plan as well as productive retention of graduates in the region, their professional development, and their contributions to the efficiency of health care.The potential roles of the AKU and the wider Aga Khan Development Network (AKDN) in East Africa are discussed in this regard

La devolución en la formación de profesores de teatro

El objetivo principal de este escrito es desplegar algunas reflexiones acerca de los procesos devolutivos en los profesorados de teatro. La devolución es una herramienta utilizada cotidianamente, muchas veces de manera acrítica y desconociendo su impacto subjetivo y formativo en les estudiantes. Realizaré un breve recorrido por el enfoque didáctico-pedagógico que he denominado “sin cuerpo”, ya que desconoce la corporeidad y el componente performático en la devolución, al mismo tiempo que la subsume a la evaluación. Luego, propondré una devolución situada, encarnada y descentrada, arraigada en la lectura del existente escénico y la resonancia y circulación fantasmática en la  trama grupal-institucional. Propongo dos vertientes de la devolución como posibles instrumentos a tener en cuenta en nuestra caja de herramientas: la devolución enunciada/verbal y la devolución enunciada/performática, reconociendo la importancia de ambas y su concomitancia en los procesos de enseñanza-aprendizaje-creación en teatro

Bardoxolone methyl prevents mesenteric fat deposition and inflammation in high-fat diet mice

Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue. © 2015 Chi H. L. Dinh et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet

Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies

Survey and alignment of the synchrotron SIS18

Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue

Bardoxolone methyl: a potential therapeutic for the prevention of anti-psychotic drug-induced obesity?

Abstract of a presentation

Bardoxolone methyl prevents fat deposition and inflammation in brown adipose tissue and enhances sympathetic activity in mice fed a high-fat diet

Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks. BARD was administered daily in drinking water. Interscapular BAT, and ventrolateral medulla (VLM) and dorsal vagal complex (DVC) in the brainstem, were collected for analysis by histology, immunohistochemistry and Western blot. BARD prevented fat deposition in BAT, demonstrated by the decreased accumulation of lipid droplets. When administered BARD, HFD mice had lower numbers of F4/80 and CD11c macrophages in the BAT with an increased proportion of CD206 macrophages, suggesting an anti-inflammatory effect. BARD increased phosphorylation of tyrosine hydroxylase in BAT and VLM. In the VLM, BARD increased energy expenditure proteins, including beta 3-adrenergic receptor (β3-AR) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Overall, oral BARD prevented fat deposition and inflammation in BAT, and stimulated sympathetic nerve activity. © 2015 by the authors; licensee MDPI, Basel, SwitzerlandThis article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). Copy acquired from MDPI: http://www.mdpi.com/2072-6643/7/6/4705

Occurrence of Steroid Sex Hormone Progesterone in influent and effluent of Oxidation Pond and the river outlet of waste water treatment case study

Background and Objective: This studied about the occurrence of Endocrine Disrupting Compound (EDC) in interest of steroid sex hormone progesterone excretion in the environment, that focusing on water resource in terms of effluent and influent of the waste water treatment into the outlet river and environment. Materials and Methods: A method called dispersive liquid-liquid micro extraction with solidification of floating organic drop followed by High Performance Liquid Chromatography (HPLC) was used for determination of progesterone. The water sample was obtained through grab sample from the influent and effluent of waste water treatment-oxidation pond and the outlet river (Kalansanan river) where the effluent was discharged. Results: Based on the result obtained it is found that there were few detections and occurrences of steroid sex hormone progesterone in the study with detection range from lowest concentration of 4.278±7.411 ng mL–1 and the highest concentration recorded at 16.687±6.233 ng mL–1 and the average concentration of progesterone is at 6.356±3.112 ng mL–1. The highest detection of the progesterone was recorded in the effluent site sampling that indicates that the conventional treatment plant was not able to remove steroid sex hormone progesterone effectively and efficiently. Conclusion: From that point of the study, monitoring on the progesterone presence and status should be done due to the presence of progesterone even in nanogram per milliliter in environment bring and posed a life threat towards the living organism in the environment