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2010-01-01
This paper considers the role of putative adipokines that might be involved in the enhanced inflammatory response of human adipose tissue seen in obesity. Inflammatory adipokines [IL-6, IL-10, ACE,...Full Text Available
2010-01-01
Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance...Full Text Available
Functional Food Targeting the Regulation of Obesity-Induced Inflammatory Responses and Pathologies
2010-01-01
Obesity is associated with a low-grade systemic chronic inflammatory state, characterized by the abnormal production of pro- and anti-inflammatory adipocytokines. It has been found that immune cells...Full Text Available
Inflammation marker related to obesity is elevated in patients with pancreatic cancer
2010-02-03
The levels of an inflammatory chemokine were significantly elevated in patients with pancreatic cancer who were extremely obese, according to research conducted by scientists at the Jefferson Pancreatic, Biliary and ...
2010-01-01
Overweight and obesity are highly prevalent in developed countries and are also becoming more frequent in the developing world. Overweight and obese patients have elevated levels of several inflammatory...Full Text Available
The Role of Adipose Tissue and Adipokines in Obesity-Related Inflammatory Diseases
2010-01-01
Full Text Available.Obesity is an energy-rich condition associated with overnutrition, which impairs systemic metabolic homeostasis and elicits stress. It also activates an inflammatory process in metabolically active sites, such as white adipose tissue, liver, and immune cells. As consequence, increased circulating levels of proinflammatory cytokines, hormone-like molecules, and other inflammatory markers are induced. This determines a chronic active inflammatory condition, associated with the development of the obesity-related inflammatory diseases. This paper describes the role of adipose tissue and the biological effects of many adipokines in these diseases.
2010-01-01
Overweight and obesity are associated with low grade of inflammation and chronic inflammatory response characterized by abnormal production and activation of some pro-inflammatory signalling pathways. Taking into account that obesity is the direct result of an imbalance between energy intake and energy expenditure, the nutritional factors in the diet, with particular focus on zinc, may play a pivotal role in the development of obesity-associated comorbidities. Considering the potential interactions among zinc nutritional status, inflammation, overweight/obesity and insulin secretion, the aim of the present work was to clarify the influence of zinc dietary intake on some metabolic, inflammatory and zinc status parameters in adult overweight/obese subjects. We found a close interrelationship...
2010-06-01
Elevated plasma free fatty acid (FFA), inflammatory marker, and altered adipokine concentrations have been observed in obese type 2 diabetes patients. It remains unclear whether these altered plasma...Full Text Available
Role of Heme Oxygenase in Inflammation, Insulin-Signalling, Diabetes and Obesity
2010-01-01
Diabetes and obesity are chronic conditions associated with elevated oxidative/inflammatory activities with a continuum of tissue insults leading to more severe cardiometabolic and renal complications...Full Text Available
A strong relationship exists between increased inflammatory cytokines and muscle insulin resistance in obesity. This study focused on identifying a relationship between metabolic propensity and myostatin...Full Text Available
2010-05-01
A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of...Full Text Available
Mangosteen juice could protect health in the obese
2009-10-19
Mangosteen juice has anti-inflammatory properties which could prove to be valuable in preventing the development of heart disease and diabetes in obese patients. A study, published in BioMed Central's open access ...
Common allergy drug reduces obesity and diabetes in mice
2009-07-26
Two new studies connect the immune system with obesity and type 2 diabetes. In the first study, researchers used two common over-the-counter allergy medications known to stabilize a group of inflammatory immune cells to ...
Hypertension, Obesity, and Inflammation: The Complex Designs of a Deadly Trio
2010-01-01
Abstract Hypertension is a powerful risk factor for cardiovascular disease and frequently occurs in conjunction with obesity and the metabolic syndrome. Recent research into the underlying pathophysiologic processes common to these entities has uncovered the role of a heightened inflammatory state signified by a host of circulating biocytokines. Systemic and local hormonal effectors, such as angiotensin II and aldosterone, interact with inflammatory and oxidative stress to augment endothelial damage in a complex manner. The kidneys play a prominent role in the reninangiotensin cascade and the abnormal pressor response that ensues. Insulin resistance underlies the pathogenesis of obesity and the metabolic syndrome. The interplay of hypertension, insulin resistance, and obesity vastly enh...
Anti-Inflammatory Nutrition as a Pharmacological Approach to Treat Obesity
2011-01-01
Full Text Available.Obesity is a multifactorial condition resulting from improper balances of hormones and gene expression induced by the diet. Obesity also has a strong inflammatory component that can be driven by diet-induced increases in arachidonic acid. The purpose of this paper is to discuss the molecular targets that can be addressed by anti-inflammatory nutrition. These molecular targets range from reduction of proinflammatory eicosanoids to the modulation of features of the innate immune system, such as toll-like receptors and gene transcription factors. From knowledge of the impact of these dietary nutrients on these various molecular targets, it becomes possible to develop a general outline of an anti-inflammatory diet that can offer a unique synergism with more traditional pharmacological approaches in treating obesity and its associated comorbidities.
2009-12-01
BackgroundChronic low grade inflammation is closely linked to type II diabetes, obesity, and atherosclerosis. Macrophages play a key role in the regulation of pro- or anti-inflammatory...Full Text Available
2008-11-01
Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory...Full Text Available
2010-01-01
Summary Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.
Chronic Inflammation in Obesity and the Metabolic Syndrome
2010-01-01
Full Text Available.The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.
Glycine regulates inflammatory markers modifying the energetic balance through PPAR and UCP-2
2010-01-01
Obesity is widely recognized as cause of metabolic syndrome and cardiovascular disease. It is provoked by imbalance between the spending and consumption of energy associated with a chronic inflammatory condition due to excessive storage of fat tissue. Obese patients have an impaired inflammatory profile that contributes to the development of vascular complications, with fat tissue being partially responsible for controlling both processes: energy balance (through PPAR) and inflammatory condition (through inflammatory markers). White adipose tissue produces cytokines (IL-6, TNF-a, resistin, adiponectin, etc.) and participates in a broad spectrum of processes. Recently, glycine has been reported to have anti-inflammatory properties which reduce TNF-a and IL-6 levels and increase adiponectin ...
2009-10-02
Although our previous studies found Pre-B-cell colony-enhancing factor (PBEF) as a highly up-regulated gene in acute lung injury that could stimulate expressions of other inflammatory cytokines, the...Full Text Available
2010-01-01
Please cite this paper as: Gene expression demonstrates increased resilience toward harmful inflammatory stimuli in the proliferating epidermis of human skin wounds. Experimental Dermatology 2010; 19: e329-e332. Abstract: We examined the epidermal gene expression during the proliferative phase of wound healing. Matrix metalloproteases were the group of proteases most prominently up-regulated in skin wounds, whereas serine protease inhibitors were the most strongly up-regulated protease inhibitors. Furthermore, we found down-regulation of genes involved in the extrinsic pathway of apoptosis. This together with the up-regulation of inhibitors of leukocyte serine proteases likely represents a protective step to ensure survival of keratinocytes in the inflammatory wound environment. The down-r...
Should obesity be blamed for the high prevalence rates of hypertension in black South African women?
2008-01-01
Hypertension is highly prevalent in South Africa, resulting in high stroke mortality rates. Since obesity is very common among South African women, it is likely that obesity contributes to the hypertension prevalence. The aims were to determine whether black African women have higher blood pressures (BPs) than Caucasian women, and whether obesity is related to their cardiovascular risk. African (N=102) and Caucasian (N=115) women, matched for age and body mass index, were included. Correlations between obesity (total body fat, abdominal obesity and peripheral fat) and cardiovascular risk markers (haemodynamic parameters, lipids, inflammatory markers, prothrombotic factors, adipokines, HOMA-IR (homoeostasis model assessment insulin resistance)) were compared between the ethnic groups (adjus...
2010-01-01
Abstract Obesity and its associated complications, including diabetes, dyslipidemia, atherosclerosis, and some cancers, have been a global health problem with a rapid increase of the obese population. In this study, we selected 31 obesity candidate genes in the liver of high-fat-induced obese C57BL/6J mice through investigation of literature search and analyzed functional proteinprotein interaction of the genes using the STRING database. Most of the obesity candidate genes were closely connected through lipid metabolism, and in particular acyl-coenzyme A oxidase 1 appeared to be a core obesity gene. Overall, genes involved in fatty acid -oxidation, fatty acid synthesis, and gluconeogenesis were up-regulated, and genes involved in sterol biosynthesis, insulin signaling, and oxidative s...
2010-01-01
Obesity has been implicated in several inflammatory diseases and in different types of cancer. Chronic inflammation induced by exposure to ultraviolet (UV) radiation has been implicated in various skin diseases, including melanoma and nonmelanoma skin cancers. As the relationship between obesity and susceptibility to UV radiation-caused inflammation is not clearly understood, we assessed the role of obesity on UVB-induced inflammation, and mediators of this inflammatory response, using the genetically obese (leptin-deficient) mouse model. Leptin-deficient obese (ob/ob) mice and wild-type counterparts (C57/BL6 mice) were exposed to UVB radiation (120 mJ/cm2) on alternate days for 1 month. The mice were then euthanized and skin samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ...
Inflammatory Bio marker Levels in Obese Prepubertal Children
2009-01-01
Childhood obesity has grown at an alarming rate, and is associated with metabolic disturbances that determine a higher risk of type 2 diabetes (T2DM) and atherosclerotic cardiovascular disease (CVD) in adulthood. These disturbances may arise at a very early age in obese children. These metabolic disturbances may be associated with insulin resistance (IR), a systemic low-grade inflammatory state and endothelial dysfunction. Thus it was aimed to determine the concentration levels of C-reactive protein (CRP), interleukin 6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) in obese pre-pubertal children, and their possible relation with metabolic syndrome. For this reason weight (kg), height (m), body mass index (BMI, kg/m2), systolic and diastolic blood pressure (SBP and DBP, mm Hg), fasting plasma glucose (FPG), lipid profile [total ...
2010-01-01
Obesity is a growing problem that threatens the health and welfare of a large proportion of the human population. The n-3 polyunsaturated fatty acids (PUFA) are dietary factors that have potential to facilitate reduction in body fat deposition and improve obesity-induced metabolic syndromes. The n-3 PUFA up-regulate several inflammation molecules including serum amyloid A (SAA), tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) in hepatocytes and adipocytes. Actions of these inflammation mediators resemble those of n-3 PUFA in the modulation of many lipid metabolism-related genes. For instance, they both suppress expressions of perilipin, sterol regulatory element binding protein-1 (SREBP-1) and lipoprotein lipase (LPL) to induce lipolysis and reduce lipogenesis. This review will co...
The 2009 Stock Conference Report: Inflammation, Obesity and Metabolic Disease
2010-01-01
Summary Obesity is linked with many deleterious health consequences and is associated with increased risk of chronic disease including type 2 diabetes, atherosclerosis and certain forms of cancer. Recent work has highlighted the impact of obesity to activate inflammatory gene networks and suggests a causal function of inflammation in the pathogenesis of the metabolic syndrome. Since 2005, when Dr Gokhan Hotamisligil chaired the fourth Stock Conference in Istanbul, Turkey, entitled `Obesity and Inflammation', there has been an explosion of studies investigating the relationship between obesity, inflammation and substrate metabolism. The exuberance surrounding this field of research is exemplified by the body of work that has been published in these past 4 years, including over 1400 publicat...
Obesity as a Risk Factor for Nosocomial Infections in Trauma Patients
2010-01-01
Background Obesity, like multiple trauma, is associated with an inflammatory condition that leads to an immunodeficient state. Obese trauma patients are thus thought to be at higher risk of infection compared to patients of normal body mass. Despite this risk, studies to date have not defined obesity as an independent risk factor for infection in trauma patients. Study Design Retrospective data were collected on 1,024 patients admitted to a Level I trauma center during a 12-month period. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2. Outcomes analyzed included urinary tract infection, pneumonia, septicemia, and wound infection and Clostridium difficile infection. Multiple logistic regression was used to evaluate the contribution of each BMI category to infection while ad...
2010-01-01
Systemic glucocorticoid excess, as exemplified by the Cushing syndrome, leads to obesity and all further symptoms of the metabolic syndrome. The current obesity epidemic, however, is not characterized by increased plasma cortisol concentrations, but instead comes along with chronic low-grade inflammation in adipose tissue and concomitant increased levels of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1, gene HSD11B1), a parameter known to cause obesity in a mouse model. 11b-HSD1 represents an intracellular amplifier of active glucocorticoid, thus enhances the associated effects on the inflammatory response as well as on nutrient and energy metabolism, and may therefore cause and exacerbate obesity by local increase of glucocorticoid concentrations. Obtained by extensive literature and ...
2010-01-01
Objective:Chronic subclinical inflammation and regular physical activity have opposing relationships to obesity-related metabolic diseases. Yet, the association between chronic inflammation and physical activity has rarely been examined in obese subjects. We examined the association between physical activity energy expenditure (PAEE), total (TEE) and resting energy expenditure (REE) and cardiorespiratory fitness (VO2peak) with inflammatory markers in overweight/obese women.Design:Cross-sectional study.Methods:The study included 152 overweight/obese postmenopausal women who were sedentary and free of chronic/inflammatory diseases (mean age: 57.5 (95% confidence interval (CI) 56.7–58.3) years, body mass index (BMI): 32.5 (95% CI 31.8–33.2) kg m−2). The following param...
Researchers identify protein that modulates metabolic dysfunction in obesity
2010-06-17
Researchers from Boston University School of Medicine have discovered that Sfrp5, which refers to secreted frizzled-related protein 5, is an anti-inflammatory adipokine whose expression is disrupted in animal models of ...
2010-04-30
With the global increase in the epidemic of obesity and type 2 diabetes with a concomitant increase in atherosclerotic disease, an investigation into the effects of various macronutrients and food products...Full Text Available
2006-07-01
Airborne particulate matter (PM) may lead to increased cardiac risk through an inflammatory pathway. Therefore, we investigated associations between ambient PM and markers of systemic inflammation among...Full Text Available
Resveratrol, obesity and diabetes
2010-01-01
Resveratrol belongs to the large group of biologically active substances found in plants. This compound is classified as phytoestrogen because of its ability to interact with estrogen receptor. Numerous beneficial effects of resveratrol described in the literature involve cardioprotective, anti-cancer, anti-inflammatory and antioxidant action. Recently, this broad spectrum of effects is enlarged by new data demonstrating a great potency of this compound in relation to obesity and diabetes. It is well established that resveratrol exerts beneficial effects in rodents fed a high-calorie diet. In some studies, resveratrol was reported to reduce body weight and adiposity in obese animals. The action of this compound involves favourable changes in gene expressions and in enzyme activities. The a...
Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals
2008-10-01
Full Text Available.SUMMARYObese adipose tissue is characterized by infiltration of macrophages. We and others recently showed that a specific subset of macrophages is recruited to obese adipose and muscle tissue. This subset expresses CD11c and produces high levels of pro-inflammatory cytokines that are linked to the development of obesity-associated insulin resistance. We used a conditional cell ablation system, based on transgenic expression of the diphtheria toxin receptor under the control of the CD11c promoter, to study the effects of depletion of CD11c
2010-01-01
Summary Atrial fibrillation is the most common sustained cardiac arrhythmia. Obesity and metabolic syndrome are independent risk factors for atrial fibrillation, and epicardial adipose tissues are highly associated with the genesis of atrial fibrillation, compared to visceral fat. Adipocytes can produce inflammatory cytokines and adipocytokines, which may enhance inflammation and oxidative stress in patients with obesity or metabolic syndrome. Moreover, it is possible that local interactions between epicardial adipose tissue and the adjacent myocardium can directly produce electrical or structural remodelings in the atrium. Taken together, we hypothesized that epicardial adipocytes contain distinctive arrhythmogenicity through increases in inflammatory cytokines, adipocytokines, and adipoc...
2010-07-01
Background and ObjectivesAs shown in previous studies, pentraxin 3 (PTX3) can be a useful inflammatory marker for metabolic syndrome and central obesity. Serum PTX3 levels are also...Full Text Available
BackgroundInflammatory cytokines are linked to obesity-related insulin resistance and may predict type 2 diabetes independently of obesity. We previously reported that a majority...Full Text Available
Full Text Available. Caloric restriction (CR), in the absence of malnutrition, delays aging and prevents aging-related diseases through multiple mechanisms. A reduction in chronic inflammation is widely observed in experimental models of caloric restriction. The low inflammation status may contribute to the reduced incidence of osteoporosis, Alzheimer's disease, cardiovascular diseases and cancer in the aging subjects. The association of caloric restriction with low inflammation suggests a role of energy accumulation in the origin of the chronic inflammation. This point is enforced by recent advances in obesity research. Abundant literature on obesity suggests that chronic inflammation is a consequence of energy accumulation in the body. The emerging evidence strongly supports that the inflammatory response induces energy expenditure in a feedback manner to fight against energy surplus in obesity. If this feedback system is deficient (Inflammation Resistance), energy expenditure will be reduced and energy accumulation will lead to obesity. In this perspective, we propose that an increase in inflammation in obesity promotes energy expenditure with a goal to get rid of energy surplus. A decrease in inflammation under caloric restriction contributes to energy saving. Inflammation is a mechanism for energy balance in the body. Inflammation resistance will lead to obesity. We will review the recent literature in support of the viewpoints.
2010-01-01
Please cite this paper as: Up-regulation of TNF-alpha secretion by cigarette smoke is mediated by Egr-1 in HaCaT human keratinocytes. Experimental Dermatology 2010; 19: e206-e212. Abstract: Many epidemiologic studies have pointed to a significant association between cigarette smoking and inflammatory skin disease such as psoriasis. Cigarette smoke induces expression of regulators of inflammation such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-a. It was recently demonstrated that early growth response-1 (Egr-1) transcription factor is significantly up-regulated in the skin lesions of patients with psoriasis. The mechanism by which cigarette smoke extract (CSE) regulates inflammatory cytokine expression in keratinocyte was still unknown. The aim of this study was to in...
2010-01-01
Abstract. Caesar R, Fak F, Backhed F (Department of Molecular and Clinical Medicine, Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden). Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism. (Review) J Intern Med 2010; 268: 320-328. Recent studies have revealed a close relationship between inflammatory and metabolic pathways, and inflammation is now recognized to have a major role in obesity and metabolic diseases such as insulin resistance and atherosclerosis. The human body is home to a large number of distinct microbial communities, with the densest population in the distal gut (the gut microbiota). Bacteria have long been known to activate inflammatory ...
2009-01-01
Background: Obstructive sleep apnea (OSA) is associated with several conditions that could facilitate the onset of cardiovascular and metabolic dysfunctions. Continuous positive airway pressure (CPAP) therapy has been shown to improve cardiovascular morbidity and mortality related to OSA, but the mechanisms underlying this association are not fully understood. Objective: The aim of the present study was to evaluate whether sleep apnea contributes to insulin resistance and inflammatory marker alterations and to evaluate the benefits of nasal CPAP therapy in severe obese patients with OSA. Methods: Plasma inflammatory cytokines and the homeostasis model assessment of insulin resistance index (HOMA-IR, Insulin Sensitivity Index [ISI]) were measured in severe obese male with OSA (n = 16) and c...
2009-08-25
Full Text Available.Neutrophil migration into injured tissues is invariably accompanied by pain. Bv8/prokineticin 2 (PK2), a chemokine characterized by a unique structural motif comprising five disulfide bonds, is highly expressed in inflamed tissues associated to infiltrating cells. Here, we demonstrate the fundamental role of granulocyte-derived PK2 (GrPK2) in initiating inflammatory pain and driving peripheral sensitization. In animal models of complete Freund's adjuvant-induced paw inflammation the development and duration of pain temporally correlated with the expression levels of PK2 in the inflamed sites. Such an increase in PK2 mRNA depends mainly on a marked up-regulation of PK2 gene transcription in granulocytes. A substantially lower up-regulation was also detected in macrophages. From a pool of peritoneal granulocytes, elicited in rats by oyster glycogen, we purified the GrPK2 protein, which displayed high affinity for the prokineticin receptors (PKRs) and, when injected into the rat paw, induced hypersensitivity to noxious stimuli as the amphibian prokineticin Bv8 did. Mice lacking PKR1 or PKR2 developed significantly less inflammation-induced hyperalgesia in comparison with WT mice, confirming the involvement of both PKRs in inflammatory pain. The inflammation-induced up-regulation of PK2 was significantly less in pkr1 null mice than in WT and pkr2 null mice, demonstrating a role of PKR1 in setting PK2 levels during inflammation. Pretreatment with a nonpeptide PKR antagonist, which preferentially binds PKR1, dose-dependently reduced and eventually abolished both prokineticin-induced hypernociception and inflammatory hyperalgesia. Inhibiting PK2 formation or antagonizing PKRs may represent another therapeutic approach for controlling inflammatory pain.
Fishing Out a Sensor for Anti-inflammatory Oils
2010-01-01
The -3 fatty acids have anti-inflammatory and antidiabetic effects in humans. Now, Oh et al. (2010) demonstrate that the G protein-coupled receptor GPR120 is a receptor for -3 fatty acids on macrophages and fat cells. Activation of GPR120 by -3 fatty acids inhibits multiple inflammation cascades in macrophages and reverses insulin resistance in obese mice.
The role of osteopontin in D-galactosamine-induced liver injury in genetically obese mice
2010-01-01
Various epidemiological studies have shown that obesity increases the risk of liver disease, but the precise mechanisms through which this occurs are poorly understood. In the present study, we hypothesized that osteopontin (OPN), an extracellular matrix and proinflammatory cytokine, has an important role in making obese mice more susceptible to inflammatory liver injury. After exposure of genetically obese ob/ob and db/db mice to a single dose of D-galactosamine (GalN), the plasma liver enzyme levels, histology and expression levels of cytokines and OPN were evaluated. The ob/ob and db/db mice, which were more sensitive to GalN-induced inflammatory liver injury compared with wild-type mice, had significantly higher plasma and hepatic OPN expression levels. Increased OPN expression was mainly found in hepatocytes and inflammatory cells and was correlated with ...
2010-01-01
The benefits of exercise on glucose metabolism, inflammation, and serum tartrate-resistant acid phosphatase 5a (TRACP 5a) protein levels in Chinese male adolescents have not been extensively analyzed. Therefore, we examined the effects of a 12-week exercise program on weight, adiposity, insulin sensitivity (IS), and inflammatory marker expression, including the novel macrophage marker TRACP 5a, in obese Chinese male adolescents. A total of 106 male adolescents were recruited from the Army Academy in Taiwan and classified as lean (body mass index [BMI], 20.9 +/- 0.2 kg/m^2) or obese (BMI, 27.7 +/- 0.2 kg/m^2). Body composition, IS, and inflammatory markers were measured in both groups at baseline and in the obese group after completion of a 12-week exercise program. Body weight, BMI, waist ...
2008-07-01
Full Text Available.Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. We tested the hypothesis that the plant polyphenolic compound curcumin, which is known to exert potent antiinflammatory and antioxidant effects, would ameliorate diabetes and inflammation in murine models of insulin-resistant obesity. We found that dietary curcumin admixture ameliorated diabetes in high-fat diet-induced obese and leptin-deficient ob/ob male C57BL/6J mice as determined by glucose and insulin tolerance testing and hemoglobin A1c percentages. Curcumin treatment also significantly reduced macrophage infiltration of white adipose tissue, increased adipose tissue adiponectin production, and decreased hepatic nuclear factor-κB activity, hepatomegaly, and markers of hepatic inflammation. We therefore conclude that orally ingested curcumin reverses many of the inflammatory and metabolic derangements associated with obesity and improves glycemic control in mouse models of type 2 diabetes. This or related compounds warrant further investigation as novel adjunctive therapies for type 2 diabetes in man.
2010-01-01
The adipocyte-derived catabolic protein leptin alters cell-mediated immunity and cytokine crosstalk. This may provide new insights into the altered immune response, seen in obese individuals. Therefore, we determined the tissue distribution of immune cells in diet-induced obese (dio) and normal weight F344 rats challenged with MADB106 tumor cells or leptin. Immune cell distribution in blood (by FACS analysis) and tissues (NK cells in spleen and liver, immunohistologically) as well as pro-inflammatory cytokines (IL-6, TNF-; by flow cytometry) were investigated in 28 normal weight and 28 dio rats (n=46/group). Pro-inflammatory cytokines were increased 3-fold for IL-6 and 7-fold for TNF- in obese animals. Higher numbers of blood monocytes and NK cells were found in obese as compare...
Increased oxidative stress and altered substrate metabolism in obese children
2010-01-01
Abstract Objective. Pediatric obesity, a major risk factor for cardiovascular diseases and diabetes, has steadily increased in the last decades. Although excessive inflammation and oxidation are possible biochemical links between obesity and cardiovascular events in adults, little information is available in children. Furthermore, effects of gender and fitness on the interaction between dyslipidemia and oxidative/inflammatory stress in children are mostly unknown. Methods. Therefore, we measured systemic markers of oxidation (F2-isoprostanes [F2-IsoP] and antioxidants) and inflammation (interleukin-6 [IL-6] and leukocyte counts) and metabolic variables in 113 peripubertal children (55 obese [Ob] age and gender-adjusted BMI%≥95th, 25 Females [F]; 15 overweight [OW] BMI% 85th-95th, 8 F; 4...
HDL-paraoxonase and Membrane Lipid Peroxidation: A Comparison Between Healthy and Obese Subjects
2010-01-01
High-density lipoproteins (HDLs) play a key role in the protection against oxidative damage. The enzyme paraoxonase-1 (PON1) associated at the surface of HDL modulates the antioxidant and anti-inflammatory role of HDL. Previous studies have demonstrated a decrease of serum PON in obese patients. The aim of this study was to investigate whether modifications of PON1 activity reflect in a different ability to protect and/or repair biological membranes against oxidative damage. Thirty obese patients at different grades of obesity (BMI ranging from 30.4 to 64.0 kg/m2) and 62 age-matched control subjects (BMI
Disease preventionshould we target obesity or sedentary lifestyle?
2010-01-01
Obesity is a major health challenge facing the modern world. Some evidence points to obesity itself as the main driver of premature mortality. We propose that this view is oversimplified. For example, high levels of physical activity and cardiorespiratory fitness are associated with lower mortality, even in those who are overweight or obese. To address this issue, we combine epidemiological and physiological evidence in a new paradigm that integrates excess calorie intake, sedentary behavior, and a maladaptive response to stress. Human physiology is optimized to allow large distances to be covered on foot every day in order to find enough food to sustain brain metabolism. Furthermore, when the body is immobilized by an injury, it triggers efficient life-saving metabolic and inflammatory re...
2009-01-01
Summary Asian Indians are highly prone to insulin resistance syndrome, obesity, diabetes, and coronary disease. At any given BMI, they tend to have more body fat and more central fat than other groups - yet their insulin resistance is disproportionately high relative to their body composition. They are also tend to have very poor vitamin D status, even in UV-drenched India, primarily owing to highly pigmented skin and a cultural tendency to avoid direct sun exposure. The resulting up-regulation of parathyroid hormone (PTH) arguably may play a role in their high risk for insulin resistance and associated pathologies. There is suggestive evidence that moderate elevations of PTH may promote insulin resistance, weight gain, hypertension, left ventricular hypertrophy, and the acute phase respon...
2008-01-01
Obesity is associated with impaired fatty acid (FA) oxidation and increased de novo hepatic lipogenesis that may contribute to the development of hypertriglyceridemia, an important risk factor for the development of cardiovascular disease. Strategies to improve hepatocyte FA metabolism, including dietary interventions, are therefore important for the prevention of obesity-associated co-morbidities. Farnesol is consumed in the diet as a component of plant products. In the present study, we administered farnesol orally to rats for seven days and found significantly reduced serum triglyceride concentrations compared with controls. Potential mechanisms underlying the hypotriglyceridemic effect of farnesol were investigated using clone-9 cultured rat hepatocytes. Farnesol significantly upregula...
2010-01-01
Background: Postprandial dyslipidaemia occurs in obesity and insulin resistance (IR), and is associated with an increased risk of developing cardiovascular disease. We have recently established that the JCR:LA-cp rodent model develops postprandial dyslipidaemia concomitant with complications of the metabolic syndrome. Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) are proposed to modulate plasma lipids, serum hormone levels, lipoprotein metabolism and the inflammatory state; however, results remain inconsistent during conditions of IR. Aim: To assess the acute metabolic and inflammatory effects of dietary fish oil supplementation on existing postprandial dyslipidaemia in the JCR:LA-cp model. Methods: JCR:LA-cp rats (14 weeks of age) were fed either a control, isocaloric, lipid balance...
2010-01-01
Summary Mammals are metagenomic, in that they are composed not only of their own genome but also those of all of their associated microbes (microbiome). Individual variations in the microbiome influence host health and may be implicated in disease aetiology. Therefore, it is not surprising that decreased microbial diversity is associated with both obesity and inflammatory bowel disease. Studies in germ-free mice have demonstrated that the gut microbiota is required for development of diet-induced obesity as well as inflammatory diseases. However, the underlying molecular mechanism(s) for how the gut microbiota causes metabolic diseases is only beginning to be clarified. Furthermore, emerging data suggest that the gut microbiota may predispose or protect against other important diseases suc...
Increased expression of protease-activated receptor-2 in mucosal mast cells in Crohn's ileitis
2009-01-01
Background and aims Activation of protease-activated receptor-2 (PAR-2) may stimulate various events of importance in inflammatory processes, including release of inflammatory mast cell mediators. PAR-2 is frequently up-regulated during inflammatory conditions, but it is not known if the expression is altered in Crohn's disease. The aim of the present study was to investigate the ileal mucosal PAR-2 expression in Crohn's ileitis, with particular emphasis on the expression in ileal mucosal mast cells. Methods Surgical specimens from the distal ileum were collected from patients with Crohn's ileitis and patients with colonic cancer as controls. The overall expression of PAR-2 was investigated by Western blot, and the presence of PAR-2 expressing mucosal mast cells by immunohistochemistry and...
2010-01-01
IkB kinase (IKK)-mediated intracellular signaling mechanisms may be involved in airway hyperresponsiveness through up-regulation of bradykinin receptors. This study was designed to examine if organ culture of rat bronchial segments induces airway hyperresponsiveness to bradykinin and if inhibition of IKK can abrogate the airway hyperresponsiveness to bradykinin via suppressing the expression of bradykinin B1 and B2 receptors. Rat bronchi were isolated and cut into ring segments. The segments were then organ cultured in the presence or absence of IKK inhibitors, BMS-345541 or TPCA-1. des-Arg^9-bradykinin (B1 receptor agonist) - and bradykinin (B2 receptor agonist) - induced contractions of the segments were monitored by a sensitive organ bath system. The expression of bradykinin B1 and B2 r...
Up-regulation of MHC class I and class II in the skeletal muscles of myasthenia gravis
2010-01-01
The up-regulation of MHC in muscles is thought to be associated with inflammatory myopathies. The expression of MHC class I and class II was examined in muscles of myasthenia gravis (MG). MG muscle specimens from all 5 patients with thymoma and 2 of 5 without thymoma showed MHC class I up-regulation and 3 of 5 with thymoma showed MHC class II. The up-regulation of MHC in MG muscles is thus considered to be a common phenomenon. MG muscles expressed not only MHC class I but also class II, and these muscles could thus act as immunoregulating cells in MG.
Homocysteine-induced toxicity increases TG2 expression in Neuro2a cells
2009-01-01
High levels of homocysteine promote cell damage mainly through induction of oxidative stress, endoplasmic reticulum (ER) stress, and activation of pro-inflammatory factors. The effects of homocysteine were here examined in the continuously dividing neuroblastoma cell line Neuro2a. Cell treatment with homocysteine (100500M) for 4h increased ROS production while reducing cell viability in a dose-dependent manner. Cell exposure to 250M homocysteine was able to induce transglutaminase 2 up-regulation and increased in situ transglutaminase activity. These effects were prevented by the incubation with the transglutaminase activity inhibitor cystamine. Homocysteine also induced NF-B activation that seemed associated with transglutaminase 2 up-regulation since the specific NF-B in...
Full Text Available.BackgroundCalorie restriction (CR) and endurance exercise are known to attenuate obesity and improve the metabolic syndrome. The aim of this study was to directly compare the effects of CR and endurance exercise in a mouse model of diet-induced obesity and insulin resistance.MethodsAdult male C57BL/6N mice were randomly assigned and subjected to one of the six interventions for 8 weeks: low-fat diet (LC, 10% fat), low-fat diet with 30% calorie restriction (LR), high-fat diet (HC, 60% fat), high-fat diet with 30% calorie restriction (HR), high-fat diet with voluntary running exercise (HE), and high-fat diet with a combination of 30% calorie restriction and exercise (HRE). The impacts of the interventions were assessed by comprehensive metabolic analyses and pro-inflammatory cytokine gene expression.ResultsEndurance exercise significantly attenuated high-fat diet-induced obesity. CR dramatically prevented high-fat diet-induced metabolic abnormalities. A combination of CR and endurance exercise further reduced obesity and insulin resistance under the condition of high-fat diet. CR and endurance exercise each potently suppressed the expression of inflammatory cytokines in white adipose tissues with additive effects when combined, but the effects of diet and exercise interventions in the liver were moderate to minimal.ConclusionsCR and endurance exercise share a potent anti-inflammatory function in adipose tissues in ameliorating diet-induced obesity and insulin resistance.
2010-01-01
Objective: Septic shock related morbidity is increased further in obese patients. Obese mice have exaggerated inflammatory response compared to lean mice when exposed to cecal ligation and puncture (CLP). The current study employs use of erythropoietin (EPO), an anti-inflammatory agent in obese and lean mice with CLP to study inflammation. Method: Intravital videomicroscopy was used to quantify CLP-induced platelet (PA) and leukocyte (LA) adhesion in cerebral microcirculation of WT (C57Bl/6) and ob/ob (B6.V-Lepob/J) mice with or without EPO (500units/kg) treatment. P-selectin expression (P-sel) in various tissues, blood-brain barrier (BBB) and behavioral function and serum tumor necrosis factor (TNF) levels were quantified in these animals. LA, PA, BBB function and P-sel were measured in T...
2009-07-23
Full Text Available.SummaryMacrophages clear pathogens and damaged or aged cells from the blood stream via phagocytosis. Cell-surface CD47 interacts with its receptor on macrophages, SIRPα, to inhibit phagocytosis of normal, healthy cells. We find that mobilizing cytokines and inflammatory stimuli cause CD47 to be transiently up-regulated on mouse hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo. CD47 is also constitutively up-regulated on mouse and human myeloid leukemias and over-expression of CD47 on a myeloid leukemia line increases its pathogenicity by allowing it to evade phagocytosis. We conclude that CD47 up-regulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing.
SummaryMacrophages clear pathogens and damaged or aged cells from the blood stream via phagocytosis. Cell-surface CD47 interacts with its receptor on macrophages, SIRPα, to inhibit phagocytosis of normal, healthy cells. We find that mobilizing cytokines and inflammatory stimuli cause CD47 to be transiently up-regulated on mouse hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo. CD47 is also constitutively up-regulated on mouse and human myeloid leukemias and over-expression of CD47 on a myeloid leukemia line increases its pathogenicity by allowing it to evade phagocytosis. We conclude that CD47 up-regulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing.
2010-01-01
Full Text Available.The kinetics of metabolic and inflammatory parameters associated with obesity were evaluated in a murine diet-induced obesity (DIO) model using a diet high in fat and cholesterol. Cellular infiltration and mediator production were assessed and shown to be therapeutically modulated by the PPARgamma agonist rosiglitazone. C57BL/6 mice were maintained on a 45% fat/ 0.12% cholesterol (HF/CH) or Chow diet for 3, 6, 16, or 27 weeks. Flow cytometry was employed to monitor peripheral blood monocytes and adipose tissue macrophages (ATM). Gene expression and protein analysis methods were used to evaluate mediator production from total epididymal fat (EF), stromal vascular fraction (SVF), and sorted SVF cells. To investigate therapeutic intervention, mice were fed a HF/CH diet for 12 weeks and then a diet formulated with rosiglitazone (5 mg/kg) for an additional 6 weeks. A HF/CH diet correlated with obesity and a dramatic proinflammatory state. Therapeutic intervention with rosiglitazone attenuated the HF/CH induced inflammation. In addition, a novel population was found that expressed the highest levels of the pro-inflammatory mediators CCL2 and IL-6.
Glutamate and several neuropeptides are synthesized and released by subpopulations of primary afferent neurons. These sensory neurons play a role in regulating the inflammatory and immune responses in peripheral tissues. Using quantitative receptor autoradiography we have explored what changes occur in the location and concentration of receptor binding sites for sensory neurotransmitters in the colon in two human inflammatory diseases, ulcerative colitis and Crohn's disease. The sensory neurotransmitter receptors examined included bombesin, calcitonin gene related peptide-alpha, cholecystokinin, galanin, glutamate, somatostatin, neurokinin A (substance K), substance P, and vasoactive intestinal polypeptide. Of the nine receptor binding sites examined only substance P binding sites associated with arterioles, venules and lymph nodules were dramatically up-regulated in the inflamed tissue. These data suggest that substance P is involved in regulating the inflammatory and immune responses in human inflammatory diseases and indicate a specificity of efferent action for each sensory neurotransmitter in peripheral tissues.
1989-05-01
Glutamate and several neuropeptides are synthesized and released by subpopulations of primary afferent neurons. These sensory neurons play a role in regulating the inflammatory and immune responses in peripheral tissues. Using quantitative receptor autoradiography we have explored what changes occur in the location and concentration of receptor binding sites for sensory neurotransmitters in the colon in two human inflammatory diseases, ulcerative colitis and Crohn's disease. The sensory neurotransmitter receptors examined included bombesin, calcitonin gene related peptide-alpha, cholecystokinin, galanin, glutamate, somatostatin, neurokinin A (substance K), substance P, and vasoactive intestinal polypeptide. Of the nine receptor binding sites examined only substance P binding sites associated with arterioles, venules and lymph nodules were dramatically up-regulated in the inflamed tissue. These data suggest that substance P is involved in regulating the inflammatory and immune responses in human inflammatory diseases and indicate a specificity of efferent action for each sensory neurotransmitter in peripheral tissues.
2010-01-01
Background Obesity is associated with increased tumerogenesis. Previously, we demonstrated that inflammation in obesity caused cancer fighting cells to display greater surface receptor levels, predisposing them to early cell death. We measured the inflammatory tumor growth factor levels to determine whether inflammation in obesity increases expression of these factors, potentially predisposing these patients to greater rates of neoplasia. Methods A total of 24 patients undergoing weight loss surgery had samples collected preoperatively and at 6 and 12 months after surgery. The growth factors analyzed included tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, vascular endothe...
2010-01-01
Aims Obesity is associated with both an increased risk of postmenopausal breast cancer and increased mortality rates. The mechanism is unclear, and central (visceral) obesity, insulin resistance, altered sex steroids and altered adipokines are mooted as possible factors. These features may cluster in the so-called metabolic syndrome. The relevance of metabolic syndrome to the biology of breast cancer is unknown, and this was the focus of the present study. Materials and methods All postmenopausal women with newly diagnosed breast cancer (n=105) were recruited. A detailed clinical history was carried out, as well as a body composition analysis, metabolic screen and measurement of adipokines and inflammatory markers. Results The median age was 68 years (40-94 years) and the mean body mass in...
Magnesium, inflammation, and obesity in chronic disease
2010-01-01
About 60% of adults in the United States do not consume the estimated average requirement for magnesium, but widespread pathological conditions attributed to magnesium deficiency have not been reported. Nevertheless, low magnesium status has been associated with numerous pathological conditions characterized as having a chronic inflammatory stress component. In humans, deficient magnesium intakes are mostly marginal to moderate (approximately 50% to 100% of the recommended dietary allowance). Animal experiments indicate that signs of marginal-to-moderate magnesium deficiency can be compensated or exacerbated by other factors influencing inflammatory and oxidative stress; recent studies suggest a similar happening in humans. This suggestion may have significance in obesity, which is charact...
2010-01-01
Interleukin-10 (IL-10) is a centrally operating anti-inflammatory cytokine that plays a crucial role in the regulation of the innate immune system. It has strong inactivating properties on the inflammatory host response and has been related with viral persistence. We aimed to evaluate the association among circulating IL-10, obesity phenotypes, IL-10 and IL-10R1 gene polymorphisms, and the environmental exposure to viral infection. IL-10 -819C/T gene promoter and IL-10 receptor-1 -243A/G gene polymorphisms were studied in 760 subjects, whereas the former was also investigated in a replication study of 676 subjects. The association of circulating IL-10 levels (enzyme-linked immunosorbent assay) with the serum IgG against adenoviruses and enteroviruses was evaluated in a subset of 189 subjec...
Effects of body weight and alcohol consumption on insulin sensitivity
Full Text Available.BackgroundObesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways.MethodAdipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes.ResultsObesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1α; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9).ConclusionWe show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity.
Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease
2010-03-19
Full Text Available.The endoplasmic reticulum (ER) is the major site in the cell for protein folding and trafficking and is central to many cellular functions. Failure of the ER's adaptive capacity results in activation of the unfolded protein response (UPR), which intersects with many different inflammatory and stress signaling pathways. These pathways are also critical in chronic metabolic diseases such as obesity, insulin resistance, and type 2 diabetes. The ER and related signaling networks are emerging as a potential site for the intersection of inflammation and metabolic disease.
2010-04-01
Full Text Available.Obesity is considered a mild inflammatory state, and the secretion of inflammation-related cytokines rises as adipose tissue expands. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interlukin 6 (IL-6) and monocyte-chemoattractant protein 1 (MCP-1), are modulated by adipose tissue and known to play an important role in insulin resistance which is the common characteristics of obesity related disorders. In this study we analyzed the effects of Sasa borealis leaves extract on inflammatory cytokines and insulin resistance in diet induced obese C57/BL6J mice. The obese state was induced by a high fat diet for 20 weeks and then the mice were divided into two groups; obese control group (OBC, n = 7) and experimental group (OB-SBE, n = 7). The OBC group was fed a high fat diet and the OB-SBE group was fed a high fat diet containing 5% Sasa borealis leaves extract (SBE) for 12 weeks. We also used mice fed a standard diet as a normal control (NC, n = 7). The body weight and adipose tissue weight in the OB group were significantly higher than those in the NC group. The effects of the high fat diet were reduced by SBE treatments, and the body weight and adipose tissue deposition in the OB-SBE group were significantly decreased compared to the OBC group. The OBC group showed higher serum glucose and insulin levels which resulted in a significant increase of incremental area under the curve (IAUC) and HOMA-IR than the NC group. Also, serum leptin, TNF-α, and IL-6 levels were significantly higher in the OBC group than in the NC group. In contrast, the OB-SBE group showed a reversal in the metabolic defects, including a decrease in glucose, insulin, IAUC, HOMA-IR, TNF-α, IL-6 and leptin levels. These results suggest that BSE can suppress increased weight gain and/or fat deposition induced by a high fat diet and theses effects are accompanied by modulation of the inflammatory cytokines, TNF-α and IL-6 secretion resulting in improved insulin resistance.
Up-Regulation of Interleukin 33 and Soluble ST2 Serum Levels in Liver Failure
2010-01-01
Background IL-33, a member of the IL-1 family, induces the production of pro-inflammatory and Th2-associated cytokines and may also serve as an `alarmin' similar to HMGB1. Soluble ST2 has been implicated as a decoy receptor, to attenuate Th2 inflammatory responses. The relevance of both molecules in hepatic failure is unknown. Materials and Methods The trial was a prospective preliminary study in a university hospital surgical ICU; 11 patients with acute liver failure (ALF) and 12 patients with acute-on-chronic liver failure (ACLF), who were admitted to the ICU; 14 patients with chronic hepatic failure (CHF) awaiting liver transplantation; 13 healthy individuals served as controls. IL-33 and soluble ST2 concentrations were determined by enzyme linked immunosorbent assay (ELISA). Results Th...
Inflammatory, Apoptotic, and Survival Gene Signaling in Alzheimers Disease
2010-01-01
Aging is associated with an enhanced susceptibility to brain dysfunction, loss of memory, and cognitive decline and significantly influences the quality of life for the affected individual. Recent moleculargenetic approaches have provided powerful insights into common age-related diseases that are both progressive and multifactorial, such as Alzheimers disease (AD), and in vitro in AD models. These investigations have uncovered consistent deficits in brain gene signaling mechanisms and neurotrophic substances known to contribute to normal brain function. Inflammatory signaling pathways involving up-regulation of cytosolic phospholipase A2 and the arachidonic acid cycle, the depletion of the brain-essential fatty acid docosahexaenoic acid (DHA) and DHA-derived neuroprotectin D1, and c...
Gene transcript changes in individual rainbow trout livers following an inflammatory stimulus
2007-01-01
Inflammatory stimuli elicit liver synthesis and subsequent release into the plasma of several proteins (positive acute phase proteins, APP) with functions in innate immunity, tissue repair and restoration of homeostasis. To expand the basis for evaluating the degree of conservation of the APR in vertebrates and to assess the extent to which genes encoding both cellular and plasma proteins are affected, we profiled transcriptional changes in livers of individual rainbow trout (Oncorhynchus mykiss) after intraperitoneal injection of Listonella (Vibrio) anguillarum bacterin in Freund's Incomplete Adjuvant. Twenty genes were down-regulated, some unexpectedly such as complement component 3 and a2-macroglobulin. Sixteen up-regulated genes included three encoding proteins involved in iron metabol...
Deletion of aquaporin-4 renders retinal glial cells more susceptible to osmotic stress
2010-01-01
The glial water channel aquaporin-4 (AQP4) is implicated in the control of ion and osmohomeostasis in the sensory retina. Using retinal slices from AQP4-deficient and wild-type mice, we investigated whether AQP4 is involved in the regulation of glial cell volume under altered osmotic conditions. Superfusion of retinal slices with a hypoosmolar solution induced a rapid swelling of glial somata in tissues from AQP4 null mice but not from wild-type mice. The swelling was mediated by oxidative stress, inflammatory lipid mediators, and sodium influx into the cells and was prevented by activation of glutamatergic and purinergic receptors. Distinct inflammatory proteins, including interleukin-1b, interleukin-6, and inducible nitric oxide synthase, were up-regulated in the retina of AQP4 null mice...
Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro
2009-01-01
Bromelain (Br), an extract from pineapple stem with cysteine protease activity, exerts anti-inflammatory effects in a number of inflammatory models. We have previously shown that Br treatment decreased activated CD4+ T cells and has a therapeutic role in an ovalbumin-induced murine model of allergic airway disease. The current study was designed to determine the effect of Br on CD4+ T cell activation, specifically the expression of CD25 in vitro. CD25 is up regulated upon T cell activation, found as a soluble fraction (sCD25) and is a therapeutic target in inflammation, autoimmunity and allergy. Br treatment of anti-CD3 stimulated CD4+ T cells reduced CD25 expression in a dose and time dependent manner. This reduction of CD25 was dependent on the proteolytic action of Br as the addition of...
2010-01-01
Cilostazol, a phosphodiesterase 3 inhibitor, is a platelet aggregation inhibitor and vasodilator that is useful for treating intermittent claudication. Experimental studies have shown that cilostazol has potent anti-inflammatory effects. In the present study, we examined the effect of cilostazol on lipopolysaccharide (LPS)-induced inflammatory cytokines in macrophages and endotoxin shock in mice. Our results indicate that cilostazol inhibits LPS-stimulated up-regulation of pro-inflammatory cytokines in a concentration-dependent manner without appreciable cytotoxicity in RAW 264.7 cells. Cilostazol did not enhance intracellular cyclic AMP (cAMP) levels. To further elucidate the mechanism responsible for the inhibition of production of pro-inflammatory mediators by cilostazol, we examined th...
BackgroundHp2 alleles of the haptoglobin α–chain polymorphism reduce the anti-oxidant properties and increase the pro-inflammatory actions of this acute-phase protein in a gene-dosage fashion. We hypothesized that the haptoglobin polymorphism might contribute to the increased oxidative stress and low-grade chronic inflammation frequently associated with polycystic ovary syndrome, obesity, and abnormalities of glucose tolerance.Methodology/Principal FindingsSerum haptoglobin and the haptoglobin α–chain polymorphism were determined in 141 patients with polycystic ovary syndrome and 102 non-hyperandrogenic women. Of the whole group of 243 premenopausal women, 117 were obese and 51 showed abnormal glucose tolerance. Although serum haptoglobin concentrations were similar in PCOS patients and controls, the former presented with an increased frequency of Hp2 alleles (62% vs. 52%, P = 0.023). Circulating haptoglobin levels increased with obesity (P<0.001), yet no association was found between obesity and haptoglobin genotypes. No differences were observed in haptoglobin levels or genotype frequencies depending on glucose tolerance. Fifty percent of the variation in serum haptoglobin concentrations was explained by the variability in serum C-reactive protein concentrations, BMI, insulin sensitivity and haptoglobin genotypes.Conclusions/SignificanceSerum haptoglobin concentrations in premenopausal women are largely dependent on the haptoglobin polymorphism and on the presence of obesity, with insulin resistance and chronic inflammation possibly modulating this relationship. The association of polycystic ovary syndrome with Hp2 alleles suggests that the anti-oxidant and anti-inflammatory properties of haptoglobin may be reduced in these patients.
2010-01-01
The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging...Full Text Available
Four studies were designed to assess the interactions between lipopolysaccaride (LPS), leptin, and inflammatory cytokines, tumor necrosis factor-a (TNF) and interleukin-1b (IL-1). For experiments 1 and 2, ewes were assigned, based on ultrasonic assessments of last-rib subcutaneous fat measurements i...
2010-01-01
Aims: The purpose of the present work was to investigate the effect of cyclooxygenase-2 (COX-2) inhibition on the cardiovascular and inflammatory aspects promoted by monosodium glutamate (MSG)-induced obesity in rats. Main methods: Neonatal Wistar male rats were injected with MSG (4mg/g body weight ID) or equimolar saline (control). Treatment with celecoxib (50mg/kg ip) or saline (0.9% NaCl ip) began at 60days of age. At 90days, all rats were anesthetized for catheterization of the femoral artery, and the mean arterial pressure (MAP) and heart rate (HR) were recorded once consciousness was regained. Key findings: MSG obese rats were hypertensive (MAP=138+/-4mm Hg) compared with controls (MAP=118+/-2mm Hg). After treatment with celecoxib, the hypertension was attenuated (MAP=126+/-2mm Hg) i...
Multiple Markers of Inflammation and Weight Status: Cross-sectional Analyses Throughout Childhood
2010-04-01
Full Text Available.OBJECTIVEInflammatory markers such as C-reactive protein (CRP) are related to obesity in adults, but the association is less clear in children. Our objective was to examine relationships between multiple markers of inflammation and children’s weight status; we hypothesized that the prevalence of inflammatory markers would increase as weight status increased.METHODSWe conducted a cross-sectional analysis of children in the United States aged 1 to 17 years in the National Health and Nutrition Examination Survey, 1999–2006. Children were categorized using weight-for-length when age < 2 years and BMI for ≥2 years, as very obese (≥99th percentile), obese (< 99th and ≥95th percentile), overweight (< 95th and ≥85th percentile), and healthy weight (> 5th to ≤85 thpercentile)according to expert consensus. Our main outcome measures were high-sensitivity CRP and absolute neutrophil count, in addition to a novel third measure: ferritin controlled for iron status using a ferritin/transferrin ratio. We used Cox proportional hazards models to examine risk of abnormal values of inflammatory markers according to weight.RESULTSIncreased risk of a CRP level of > 1.0 mg/L was evident among very obese children from ages 3 to 5 years (hazard ratio [HR]: 2.29; P < .01) through 15 to 17 years (HR: 4.73; P < .01). Increased risk of abnormal neutrophil count among very obese children began at 6 to 8 years (HR: 2.00; P = .049), and increased prevalence of abnormal ferritin/transferrin ratio began at 9 to 11 years (HR: 7.06; P < .001).CONCLUSIONSMultiple inflammatory markers are strongly and positively associated with increasing weight status in children, and this relationship starts as young as age 3. Elevated inflammatory markers in very young obese children are particularly concerning, because inflammation may cause long-term, cumulative vascular damage. This deserves additional research via longitudinal design.
The medical complications of childhood obesity
2007-01-01
[Truncated abstract] Introduction: Childhood obesity is currently a serious worldwide public health issue associated with many medical and psychosocial complications. The increasing disease burden with the potential for the development of medical co-morbidities has implications for future health care provision. This thesis adds to the understanding of the medical complications of overweight and obesity in childhood. Design and Aims: Two different, but related, research studies are reported. The first study is a cross-sectional study, designed to quantify the medical complications of childhood obesity in primary school-aged children in Western Australia. This study aims to identify the medical complications of primary school children with overweight/obesity. The study also aims to compare the medical complications of obesity in a community sample who have never sought treatment with a clinical sample who are actively seeking treatment for overweight/obesity. Finally, this study also aims to examine the relationship between the medical complications of childhood obesity and a continuum of children's Body Mass Index z-scores, including those in the normal range. The second study is an exercise intervention study to investigate the effect of exercise on one specific medical complication of obesity, namely insulin resistance. This study aims to determine if a structured eight-week exercise program significantly changes insulin resistance in obese children, and to determine if this decrease in insulin resistance is associated with changes in body composition and inflammatory markers. ... Conclusion: The prevalence of the medical complications of overweight and obesity in primary school children indicates that all children should have body mass index regularly checked from a young age. Children who are overweight/obese should be screened for the presence of co-morbidities despite a young age. Parents and health professionals needs to be educated that childhood obesity is associated with medical co-morbidities and is not simply a social or cosmetic concern. The continuous nature of the BMI z-score/co-morbidities relationship suggests that public health and health education strategies should include adopting a populationbased approach to weight management. This continuous relationship means that even in the normal BMI spectrum, the risk of developing co-morbidities rises with increasing BMI. Such an approach would encourage maintenance of normal weight for all children, rather than targeting overweight/obese children only. Increased activity and decreased sedentary behaviours should be recommended for all children in line with the population-based public health approach suggested above. However, exercise has a specific role in weight management strategies for overweight/obese children, and in management strategies for adiposityrelated co-morbidities. Significant metabolic benefits of exercise occur in the absence of changes in body shape and weight. After an exercise program, simple blood investigations (such as lipid profiles, fasting insulin and OGTTs) are likely to miss important metabolic improvements and anthropometry (BMI calculation, waist circumference) may be more indicative of potential metabolic improvement and decreased co-morbidity risk. Language: |||
The medical complications of childhood obesity
2008-01-01
[Truncated abstract] Introduction: Childhood obesity is currently a serious worldwide public health issue associated with many medical and psychosocial complications. The increasing disease burden with the potential for the development of medical co-morbidities has implications for future health care provision. This thesis adds to the understanding of the medical complications of overweight and obesity in childhood. Design and Aims: Two different, but related, research studies are reported. The first study is a cross-sectional study, designed to quantify the medical complications of childhood obesity in primary school-aged children in Western Australia. This study aims to identify the medical complications of primary school children with overweight/obesity. The study also aims to compare the medical complications of obesity in a community sample who have never sought treatment with a clinical sample who are actively seeking treatment for overweight/obesity. Finally, this study also aims to examine the relationship between the medical complications of childhood obesity and a continuum of children's Body Mass Index z-scores, including those in the normal range. The second study is an exercise intervention study to investigate the effect of exercise on one specific medical complication of obesity, namely insulin resistance. This study aims to determine if a structured eight-week exercise program significantly changes insulin resistance in obese children, and to determine if this decrease in insulin resistance is associated with changes in body composition and inflammatory markers. ... Conclusion: The prevalence of the medical complications of overweight and obesity in primary school children indicates that all children should have body mass index regularly checked from a young age. Children who are overweight/obese should be screened for the presence of co-morbidities despite a young age. Parents and health professionals needs to be educated that childhood obesity is associated with medical co-morbidities and is not simply a social or cosmetic concern. The continuous nature of the BMI z-score/co-morbidities relationship suggests that public health and health education strategies should include adopting a populationbased approach to weight management. This continuous relationship means that even in the normal BMI spectrum, the risk of developing co-morbidities rises with increasing BMI. Such an approach would encourage maintenance of normal weight for all children, rather than targeting overweight/obese children only. Increased activity and decreased sedentary behaviours should be recommended for all children in line with the population-based public health approach suggested above. However, exercise has a specific role in weight management strategies for overweight/obese children, and in management strategies for adiposityrelated co-morbidities. Significant metabolic benefits of exercise occur in the absence of changes in body shape and weight. After an exercise program, simple blood investigations (such as lipid profiles, fasting insulin and OGTTs) are likely to miss important metabolic improvements and anthropometry (BMI calculation, waist circumference) may be more indicative of potential metabolic improvement and decreased co-morbidity risk. Publisher: University of Western Australia. School of Population Health Language: eng Rights: Copyright Lana Michelle Bell; http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html
2010-01-01
BACKGROUND AND PURPOSE Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT1) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear. EXPERIMENTAL APPROACH Male obese Koletsky (fak/fak) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mgkg-1day-1) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting. KEY RESULTS In Koletsky (fak/fak) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased pl...
The emerging role of the endocannabinoid system in cardiovascular disease
Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB1 and CB2. Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB1 receptors. Furthermore, tonic activation of CB1 receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB2 receptors in immune cells exerts various immunomodulatory effects, and the CB2 receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders.
2010-01-01
Summary Omega-3 fatty acids (-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an -3 FA receptor/sensor. Stimulation of GPR120 with -3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without -3 FA supplementation. The -3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice....
LRP1 Receptor Controls Adipogenesis and Is Up-Regulated In Human and Mouse Obese Adipose Tissue
Full Text Available.The cell surface low-density lipoprotein receptor-related protein 1, LRP1, plays a major role in lipid metabolism. The question that remains open concerns the function of LRP1 in adipogenesis. Here, we show that LRP1 is highly expressed in murine preadipocytes as well as in primary culture of human adipocytes. Moreover, LRP1 remains abundantly synthesised during mouse and human adipocyte differentiation. We demonstrate that LRP1 silencing in 3T3F442A murine preadipocytes significantly inhibits the expression of PPARγ, HSL and aP2 adipocyte differentiation markers after adipogenesis induction, and leads to lipid-depleted cells. We further show that the absence of lipids in LRP1-silenced preadipocytes is not caused by lipolysis induction. In addition, we provide the first evidences that LRP1 is significantly up-regulated in obese C57BI6/J mouse adipocytes and obese human adipose tissues. Interestingly, silencing of LRP1 in fully-differentiated adipocytes also reduces cellular lipid level and is associated with an increase of basal lipolysis. However, the ability of mature adipocytes to induce lipolysis is independent of LRP1 expression. Altogether, our findings highlight the dual role of LRP1 in the control of adipogenesis and lipid homeostasis, and suggest that LRP1 may be an important therapeutic target in obesity.
2010-01-01
The role of tumor cells in synthesizing pro-inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF-7 human mammary adenocarcinoma cell line induced activation of hypoxia-inducible factor 1a (HIF-1a) and nuclear factor-kappa B (NF-kB). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up-regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute-phase protein pentraxin-3 (PTX3). Hypoxia also stimulated chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal-derived factor-1a (SDF-1a) increased invasion and migration of hypox...
The role of cytokines in UbD promoter regulation and Mallory-Denk body-like aggresomes
2010-01-01
Mallory-Denk bodies (MDBs) are found in chronic liver diseases. Previous studies showed that diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) induced formation of MDBs and the up regulation of UbD expression in mouse liver. UbD is a protein over expressed in hepatocellular carcinomas. It is a potential preneoplastic marker in the mouse. It is hypothesized that inflammatory cytokines play a critical role in UbD up regulation and MDB formation. TNFa and IFNg treatment of HCC cell line Hepa 1-6, induced the expression of UbD and the expression of genes coding for the immunoproteasome (LMP2, LMP7, and MECL-1 subunits). TNFa and IFNg induced the activity of the UbD promoter, using a luciferase assay. The cotreatment with TNFa and IFNg induced the activity of the UbD promoter ...
2010-01-01
Extracellular and intracellular mediators of inflammation, such as tumor necrosis factor alpha (TNFa) and NF-kappaB (NF-kB), play major roles in breast cancer pathogenesis, progression and relapse. SLUG, a mediator of the epithelial-mesenchymal transition process, is over-expressed in CD44+/CD24- tumor initiating breast cancer cells and in basal-like carcinoma, a subtype of aggressive breast cancer endowed with a stem cell-like gene expression profile. Cancer stem cells also over-express members of the pro-inflammatory NF-kB network, but their functional relationship with SLUG expression in breast cancer cells remains unclear. Here, we show that TNFa treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-kB/HIF1a signaling, which is strongly enhanced by ...
2005-01-01
Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-kappaB in the lungs of the exposed mice. In the ...
Glucocorticoid up-regulation of high-affinity interleukin 6 receptors on human epithelial cells
1990-01-01
Interleukin 6 (IL-6) is a potent pleiotropic cytokine, known, among others, to stimulate immunoglobulin production by B cells and to trigger acute-phase protein synthesis by hepatocytes. Similar to IL-1, it is produced by monocytes and macrophages following an inflammatory challenge. Analysis of IL-6 receptor (IL-6R) expression on different human cell lines indicates that dexamethasone could up-regulate the number of IL-6R on one epithelial cell line (UAC) and on two hepatoma cell lines (HepG2 and Hep3B). This effect was confirmed by Scatchard analysis of binding experiments, using [35S]methionine and [35S]cysteine metabolically labeled IL-6. It was confirmed at the level of mRNA expression by Northern blot analysis. These results provide evidence for a link between IL-6 and glucocorticoids. They could represent an example of a system in ...
2008-01-01
Dipyrithione (PTS2) possesses anti-bacterial and anti-fungal activity. In the present study, we found that PTS2 dose-dependently inhibited the LPS-induced up-regulation of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein level in RAW264.7 cells. RT-PCR experiments showed that PTS2 suppressed LPS-induced iNOS but not COX-2 expression at the mRNA level. As expected, PTS2 prevented NO secretion in RAW264.7 cells. Furthermore, PTS2 administration significantly decreased LPS-induced mortality in mice. Mechanistically, PTS2 decreased expression and phosphorylation of STAT1, but did not interfere with the MAPK and NF-kB pathways. In conclusion, PTS2 protects mice against endotoxic shock and inhibits LPS-induced production of pro-inflammatory mediators, suggesting that PTS2 could ...
2008-01-01
Cardiovascular disease secondary to atherosclerosis is the most common cause of human morbidity and mortality. An early and fundamental event in the development of atherosclerosis is abnormal vascular endothelial and smooth muscle function. This can be measured by flow mediated dilatation and glyceryl trinitrate mediated dilatation in children at risk of atherosclerosis. Folic acid improves endothelial function (flow mediated dilatation) in adults with coronary artery disease. No studies have previously investigated the effects of folic acid on vascular function in at risk children with diabetes or obesity. In a cross sectional study an evaluation of vascular endothelial and smooth muscle function and their determinants was performed in 159 children with type 1 diabetes, 58 children with obesity, and 53 healthy children. Children with type 1 diabetes and children with mild to moderate obesity had comparable and severe vascular dysfunction but different determinants. Vascular function in healthy and obese children related to both body mass index and weight (adjusted for age and sex), and blood glucose. Children with obesity had lower folate levels and higher homocysteine levels than children with type 1 diabetes, an abnormal lipid profile and raised inflammatory markers. A randomised double blind placebo controlled cross over trial of 8 weeks of folic acid supplementation was performed in 38 children with type 1 diabetes. In these children, folic acid improved endothelial function with a sustained increase in folate levels but independent of homocysteine levels. Folic acid did not improve smooth muscle function. A randomised double blind placebo controlled parallel trial of 8 weeks folic acid supplementation was performed including 53 obese children. Folic acid did not improve vascular function in obese children in spite of sustained increase in folate levels, and a decrease in homocysteine levels. It was concluded that children with type 1 diabetes and obesity have comparable and severe endothelial and smooth muscle function. Determinants of vascular function in children, including weight and glucose, represent a continuum effect. Folic acid supplementation improved endothelial function in children with type 1 diabetes but not in children with obesity, whose metabolic changes causing endothelial dysfunction differ from children with diabetes.http://proxy.library.adelaide.edu.au/login?url=http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1317003Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2008
2010-01-01
Background Because of the strong association between abdominal obesity (AO) and other cardiovascular risk factors, it has been difficult to determine which changes in vascular function are directly related to this condition. Our objective was to evaluate the changes in ex-vivo vascular reactivity, circulating levels of adipokines and inflammatory markers associated with the presence of AO in subjects who underwent coronary artery bypass graft (CABG) controlling by the presence of other cardiovascular risk factors. Methods Subjects scheduled for a CABG with (n=17) and without (n=17) AO (defined as a waist circumference 90cm for male or 80cm for female) whom were matched by several cardiovascular risk factors, were included in the study. Lipid profile and plasma levels of glucose, ...
Reduced serum resistin levels in diabetic patients: Study from western India
2009-01-01
Objective Resistin is an adipocyte-derived peptide that might play a role in obesity and insulin resistance (IR); however, its role in humans is largely unknown. The aim of the study was to elucidate the role of serum resistin and explore its relationship with inflammatory marker C-reactive protein (CRP) and adipocytokine (leptin, adiponectin) in Indian diabetic patients. Design and methods A total of 171 subjects including 41 controls, 41 obese and 89 Type 2 diabetes mellitus (T2DM) patients were recruited in this cross-sectional study. Fasting serum resistin, leptin, adiponectin, insulin and CRP were measured by enzyme immunoassay. The relation between these variables was studied by univariate and multiple regression analysis. Results Serum resistin levels were significantly reduced in n...
2010-01-01
Excess visceral adiposity may predispose to chronic diseases like hypertension and type 2 diabetes with a high risk for coronary artery disease. Adipose tissue secreted cytokines and oxidative stress play an important role in chronic disease progression. To combat adiposity, plant-derived triterpenes are currently receiving much attention as they possess antioxidant and anti-inflammatory properties and the ability to regulate glucose and lipid metabolism. In the search for potential antiobese compounds from natural sources, this study evaluated the effects of oleanolic acid (OA), a pentacyclic triterpene commonly present in fruits and vegetables, in glucose tolerance test and on high-fat diet (HFD)-induced obesity in mice. Adult male Swiss mice treated or not with OA (10mg/kg) were fed a H...
2010-01-01
The neuroendocrine theory of aging identified a cluster of conditions (hypertension, obesity, dyslipidemia, diabetes type 2, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer, e.g., breast and prostate) as age-associated neuroendocrine disorders (AAND). Obesity, dyslipidemia, hypertension, and type 2 diabetes were later described as metabolic syndromes (MetS). Chronic inflammation is currently considered as a common feature of MetS/AAND. One of the mechanisms by which chronic inflammation might trigger and/or maintain the development of MetS/AAND is transcriptional induction of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of tryptophan (TRY)-kynurenine (KYN) pathway, by pro-inflammatory cytokines (PIC). Activa...
Metabolic Factors and Non-Alcoholic Fatty Liver Disease as Co-Factors in Other Liver Diseases
2010-01-01
Abstract Over the last few years, the paradigm in hepatology has changed from focusing on a single liver disease to considering concurrent diseases, in particular obesity and related metabolic factors. Obesity has reached epidemic proportions globally and is associated with insulin resistance, steatosis and a low-grade systemic inflammatory state. These metabolic factors have a synergistic role in the natural history and treatment outcomes related to chronic liver disease. This is characterized best in chronic hepatitis C where steatosis and insulin resistance are caused by viral and metabolic effects. Non-alcoholic fatty liver disease and related metabolic abnormalities also exacerbate other diseases, such as alcoholic liver disease and haemochromatosis. In addition, there is growing evid...
2006-01-01
The integrated relationship between inflammation, obesity and cardiovascular disease is currently a subject of much research interest. These specific relationships, however, have not been studied in-depth in South African population groups in order to determine the role of ethnicity. It is known that Africans, compared to Caucasians, suffer from a high prevalence of hypertension. It was therefore hypothesized that the levels of inflammatory markers (high-sensitivity C-reactive protein (hsCRP), fibrinogen and leptin) are higher in Africans compared to Caucasians and are notably associated with cardiovascular dysfunction in Africans. Apparently healthy African (N=102) and Caucasian (N=115) women, matched for age and body mass index (BMI), were recruited. Leptin, hsCRP, fibrinogen and lipid l...
2010-01-01
Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor a (TNFa), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observatio...
Diet-induced Obese Mice Are Leptin Insufficient After Weight Reduction
2009-01-01
Behavioral therapies aimed at reducing excess body fat result in limited fat loss after dieting. To understand the causes for maintenance of adiposity, high-fat (HF) diet–induced obese (DIO) mice were switched to a low-fat chow diet, and the effects of chow on histological and molecular alterations of adipose tissue and metabolic parameters were examined. DIO mice reduced and stabilized their body weights after being switched to chow (HF-chow), but retained a greater amount of adiposity than chow-fed mice. Reduction in adipocyte volume, not number, caused a decrease in fat mass. HF-chow mice showed normalized circulating insulin and leptin levels, improved glucose tolerance, and reduced inflammatory status in white adipose tissue (WAT). Circulating leptin levels corrected for fat mas...
2010-01-01
The adipose tissue derived protein adiponectin exerts anti-diabetic, anti-inflammatory and anti-atherosclerotic effects. Adiponectin serum concentrations are in the microgram per milliliter range in healthy humans and inversely correlate with obesity and metabolic disorders. Accordingly, raising circulating adiponectin levels by direct administration may be an intriguing strategy in the treatment of obesity-related metabolic disorders. However production of large amounts of recombinant adiponectin protein is a primary obstacle so far. Here, we report a novel method for large amount production of globular adiponectin from E. coli inclusion bodies utilizing an alkaline-shock solubilization method without chaotropic agents followed by precipitation of the readily renaturing protein. Precipita...
Full Text Available.BackgroundMacrophage infiltration in adipose tissue together with the aberrant production of pro-inflammatory cytokines has been identified as the key link between obesity and its related metabolic disorders. This study aims to isolate bioactive ingredients from the traditional Chinese herb Radix Astragali (Huangqi) that alleviate obesity-induced metabolic damage through inhibiting inflammation.MethodsActive fraction (Rx) that inhibits pro-inflammatory cytokine production was identified from Radix Astragali by repeated bioactivity-guided high-throughput screening. Major constituents in Rx were identified by column chromatography followed by high-performance liquid chromatography (HPLC) and mass-spectrometry. Anti-diabetic activity of Rx was evaluated in db/db mice.ResultsTreatment with Rx, which included calycosin-7-β-D-glucoside (0.9%), ononin (1.2%), calycosin (4.53%) and formononetin (1.1%), significantly reduced the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and MCP-1) in human THP-1 macrophages and lipopolysaccharide (LPS)-induced activation of NF-κB in mouse RAW-Blue macrophages in a dose-dependent manner. Chronic administration of Rx in db/db obese mice markedly decreased the levels of both fed and fasting glucose, reduced serum triglyceride, and also alleviated insulin resistance and glucose intolerance when compared to vehicle-treated controls. The mRNA expression levels of inflammatory cell markers CD68 and F4/80, and cytokines MCP-1, TNF-α and IL-6 were significantly reduced in epididymal adipose tissue while the alternatively activated macrophage marker arginase I was markedly increased in the Rx-treated mice.ConclusionThese findings suggest that suppression of the inflammation pathways in macrophages represents a valid strategy for high-throughput screening of lead compounds with anti-diabetic and insulin sensitizing properties, and further support the etiological role of inflammation in the pathogenesis of obesity-related metabolic disorders.
This study was conducted to determine the time course of gene expression associated with specific signaling pathways in normal human bronchial epithelial (NHBE) cells after exposure to 2 concentrations of 2R4F tobacco mainstream smoke (MSS). Expression of 84 genes representing 18 signal transduction pathways was quantitated in MSS- and air-exposed cultures using real-time polymerase chain reaction (PCR) arrays at 1, 4, and 24 hours following exposure. A confidence score, calculated based on statistical analysis of the degree and reproducibility of expression changes, was used to identify potential biologically significant changes in gene expression. Stimulation of NIAP, an apoptosis inhibitor, suppression of NFKB1 and MYC, representing pro-apoptotic activity, and down-regulation of TCF7 and up-regulation of KLK2, representing anti-/pro-inflammatory responses, were altered 1 hour after exposure to the high concentration of MSS. At the 4-hour time point, the pattern had changed such that 10 different genes were now up-regulated and an additional gene was now down-regulated. Significant changes included genes involved in inflammatory response (LTA, SELPLG, and IL8), repair and wound-healing activity (MMP10), and growth activity (GREB1, EGR1), suggesting repair in this period. By 24 hours, the only up-regulated genes in common with the 4-hour profile were SELPLG and IL8, suggesting continued inflammatory signaling. These results suggest that identification of specific gene expression-based biomarkers of MSS toxicity is promising for investigating specific mechanisms of cellular damage. As expected, the expressed signals were dependent on the concentration of MSS and the postexposure times.
2009-06-01
Full Text Available.Obesity-associated cardiovascular disease exerts profound human and monetary costs, creating a mounting need for cost-effective and relevant in vivo models of the complex metabolic and vascular interrelationships of obesity. Obesity is associated with endothelial dysfunction and inflammation. Free fatty acids (FFA), generated partly through β-adrenergic receptor-mediated lipolysis, may impair endothelium-dependent vasodilation (EDV) by proinflammatory mechanisms. β-Adrenergic antagonists protect against cardiovascular events by mechanisms not fully defined. We hypothesized that β antagonists may exert beneficial effects, in part, by inhibiting lipolysis and reducing FFA. Further, we sought to evaluate the fat-fed rat as an in vivo model of obesity-induced inflammation and EDV. Control and fat-fed rats were given vehicle or β antagonist for 28 d. Serum FFA were measured to determine the association to serum IL6, TNFα, and C-reactive protein and to femoral artery EDV. Compared with controls, fat-fed rats weighed more and had higher FFA, triglyceride, leptin, and insulin levels. Unexpectedly, in control and fat-fed rats, β antagonism increased FFA, yet inflammatory cytokines were reduced and EDV was preserved. Therefore, reduction of FFA is unlikely to be the mechanism by which β antagonists protect the endothelium. These results reflect the need for validation of ex vivo models of obesity-induced inflammation and endothelial dysfunction, concurrent with careful control of dietary fat composition and treatment duration.
Full Text Available.BackgroundAn increase in the intestinal permeability is considered to be associated with the inflammatory tone and development in the obesity and diabetes, however, the pathogenesis of the increase in the intestinal permeability is poorly understood. The present study was performed to determine the influence of obesity itself as well as dietary fat on the increase in intestinal permeability.MethodsAn obese rat strain, Otsuka Long Evans Tokushima Fatty (OLETF), and the lean counter strain, Long Evans Tokushima Otsuka (LETO), were fed standard or high fat diets for 16 weeks. Glucose tolerance, intestinal permeability, intestinal tight junction (TJ) proteins expression, plasma bile acids concentration were evaluated. In addition, the effects of rat bile juice and dietary fat, possible mediators of the increase in the intestinal permeability in the obesity, on TJ permeability were explored in human intestinal Caco-2 cells.ResultsThe OLETF rats showed higher glucose intolerance than did the LETO rats, which became more marked with the prolonged feeding of the high fat diet. Intestinal permeability in the OLETF rats evaluated by the urinary excretion of intestinal permeability markers (Cr-EDTA and phenolsulfonphthalein) was comparable to that in the LETO rats. Feeding the high fat diet increased intestinal permeability in both the OLETF and LETO rats, and the increases correlated with decreases in TJ proteins (claudin-1, claudin-3, occludin and junctional adhesion molecule-1) expression in the small, but not in the large intestine (cecum or colon). The plasma bile acids concentration was higher in rats fed the high fat diet. Exposure to bile juice and the fat emulsion increased TJ permeability with concomitant reductions in TJ protein expression (claudin-1, claudin-3, and junctional adhesion molecule-1) in the Caco-2 cell monolayers.ConclusionExcessive dietary fat and/or increased levels of luminal bile juice, but not genetic obesity, are responsible for the increase in small intestinal permeability resulting from the suppression of TJ protein expression.
Full Text Available.BackgroundChronic systemic low-grade inflammation in obese subjects is associated with health complications including cardiovascular diseases, insulin resistance and diabetes. Reducing inflammatory responses may reduce these risks. However, available markers of inflammatory status inadequately describe the complexity of metabolic responses to mild anti-inflammatory therapy.MethodsTo address this limitation, we used an integrative omics approach to characterize modulation of inflammation in overweight men during an intervention with the non-steroidal anti-inflammatory drug diclofenac. Measured parameters included 80 plasma proteins, >300 plasma metabolites (lipids, free fatty acids, oxylipids and polar compounds) and an array of peripheral blood mononuclear cells (PBMC) gene expression products. These measures were submitted to multivariate and correlation analysis and were used for construction of biological response networks.ResultsA panel of genes, proteins and metabolites, including PGE
2005-01-01
Resistin, a recently discovered 92 amino acid protein involved in the development of insulin resistance, has been associated with obesity and type 2 diabetes. The elevated serum resistin in human diabetes is often associated with a pro-inflammatory milieu. However, the role of resistin in the development of inflammation is not well understood. Addition of recombinant human resistin protein (hResistin) to macrophages (both murine and human) resulted in enhanced secretion of pro-inflammatory cytokines, TNF-alpha and IL-12, similar to that obtained using 5 mug/ml lipopolysaccharide. Both oligomeric and dimeric forms of hResistin were able to activate these cytokines suggesting that the inflammatory action of resistin is independent of its conformation. Heat denatured hResistin abrogated cytokine induction while treatment of recombinant ...
c/EBP^2 Is a Major Regulatory Element Driving Transcriptional Activation of the CXCL12 Promoter
2010-01-01
CXCL12 is considered a constitutively expressed chemokine with homeostatic functions. However, induction of CXCL12 expression and its potential role in several pathologic conditions have been reported, suggesting that CXCL12 gene expression can be induced by different stimuli. To elucidate the molecular mechanisms involved in the regulation of CXCL12 gene expression, we aim to define the molecular factors that operate at the transcriptional level. Basal, constitutive expression of CXCL12 was dependent on basic helix-loop-helix factors. Transcriptional up-regulation of the CXCL12 gene was induced by cellular confluence or inflammatory stimuli such as interleukin-1 and interleukin-6, in a CCAAT/enhancer binding protein b (c/EBPb)-dependent manner. Chromatin immunoprecipitation assays confirm...
2010-01-01
Objective The signal transducers and activators of transcription (STAT) family of proteins are intracellular signal transduction molecules involved in the expression of numerous proinflammatory genes in inflammatory cells. This study was executed to determine the association between the expression pattern of STAT-3 in the colonic mucosa of patients with ulcerative colitis (UC) and the progression of this disease. Methods We carried out the real-time reverse transcription-polymerase chain reaction (RT-PCR), Western-blot analysis and immunohistochemical staining to examine the expression of STAT-3 at both mRNA and protein levels in 25 patients with UC and 10 normal controls. The association between STAT-3 expression pattern and the severity of the disease was also analyzed. Results The expre...
2010-01-01
Harpagifer antarcticus (the Antarctic plunderfish), a shallow-water benthic fish distributed around the Antarctic Peninsula, is a member of the notothenioid family, one of whose adaptations to the cold waters of Antarctica has been the loss of the classic heat shock response. In order to gain a more comprehensive understanding of the effects of temperature stress on H. antarcticus, we constructed a liver cDNA library and a 10,371 feature microarray. This was hybridized with material from a time course series of animals held at 6^oC for 48h. The resulting expression profiles show that this fish displays the classical vertebrate acute inflammatory response. There was also a pronounced signal for increased energy requirements via up-regulation of genes involved in the b oxidation of fatty aci...
Tissue transglutaminase and the stress response
2007-01-01
Summary. The expression of the protein crosslinking enzyme tissue transglutaminase (TG2, tTG), the ubiquitous member of transglutaminase family, can be regulated by multiple factors. Although it has been suggested that TG2 can be involved in apoptotic cell death, high levels of enzyme have also been associated with cell survival in response to different stimuli. Furthermore, evidence indicates that increases in TG2 production cause enzyme translocation to cell membrane. Cell stress can also lead to TG2 accumulation on the cell surface and in the extracellular matrix resulting in changes in cell-matrix interactions. Here, we discuss the underlying mechanisms of TG2 up-regulation induced by various stimuli including glutamate exposure, calcium influx, oxidative stress, UV, and inflammatory c...
2010-01-01
We examined if and how mammary epithelial cells (MECs) calibrate and confine the intensity of an inflammatory response elicited by different concentrations of mastitis pathogens. Therefore we quantified in primary bovine MEC the effect of different E. coli pathogen concentrations upon the abundance of mRNA molecules encoding factors of immune defence. Induced synthesis of the mRNAs encoding tumor necrosis factor alpha and interleukin 8 both clearly correlated with the E. coli dose 1h after stimulation. Also the decay rate of those mRNAs reflected the pathogen load. The higher the concentration of E. coli, the faster and stronger was the up regulation and also the subsequent degradation of those particular mRNA species. Modulation of the mRNA concentration of tristetraprolin, a factor cruci...
2010-01-01
Bacterial flagellins are potent inducers of innate immune responses in the mouse lung because they bind to TLR5 expressed on the apical surfaces of airway epithelial cells. TLR engagement leads to the initiation of a signaling cascade that results in a pro-inflammatory response with subsequent up-regulation of several cytokines and leads to adaptive immune responses. We examined the ability of two soluble flagellins, a monomeric flagellin expressed in Escherichia coli and a highly purified polymeric flagellin directly isolated from Salmonella, to enhance the efficacy of influenza vaccines in mice. Here we demonstrate that both flagellins co-administered intranasally with inactivated A/PR/8/34 (PR8) virus induced robust increases of systemic influenza-specific IgA and IgG titers and resulte...
2010-01-01
Infection with H. pylori is a primary factor in the etiology of gastric disease, and the excessive NO generation and a massive rise in apoptosis are well recognized features that characterize the mucosal inflammatory responses to the bacterium and its lipopolysaccharide (LPS). Here, we report that H. pylori LPS-induced enhancement in gastric mucosal cell apoptosis and NO generation was associated with the suppression in constitutive nitric oxide synthase (cNOS) activity and a marked up-regulation in the activity of inducible nitric oxide synthase (iNOS). Further, we demonstrate that the detrimental effect of the LPS on cNOS was manifested in the enzyme protein S-nitrosylation, that was susceptible to suppression by iNOS inhibitor, 1400W. Moreover, we show that the countering effect of pept...
Leukocyte Activation and Circulating Leukocyte-Derived Microparticles in Preeclampsia
2009-01-01
Problem Preeclampsia shows characteristics of an inflammatory disease including leukocyte activation. Analyses of leukocyte-derived microparticles (MP) and mRNA expression of inflammation-related genes in leukocytes may establish which subgroups of leukocytes contribute to the development of preeclampsia. Method of Study Blood samples were obtained from preeclamptic patients, normotensive pregnant and non-pregnant controls. sL-selectin and elastase were measured by ELISA. mRNA was isolated from leukocytes and gene expression was determined by multiplex ligation-dependent probe amplification (MLPA). MP were characterized by flow cytometry. Results Altered concentrations of sL-selectin and elastase confirmed leukocyte activation in preeclampsia. These leukocytes showed up-regulation of Nucle...
2010-01-01
Background: Dysfunctions in memory T cells contribute to various inflammatory autoimmune diseases and neoplasms. We hypothesize that investigating the differences of genetic profiles between resting and activated naive and memory T cells may provide insight into the characterization of abnormal memory T cells in diseases, such as Sezary syndrome (SS), a neoplasm composed of CD4^+ CD45RO^+ cells. Objective: We determined genes distinctively expressed between resting and activated naive and memory cells. Levels of up-regulated genes in resting and activated memory cells were measured in SS PBMCs, which were largely comprised of CD4^+ CD45RO^+ cells, to quantitatively assess how different Sezary cells were from memory cells. Methods: We compared gene expression profiles using high-density oli...
2010-01-01
The aim of the present work was to identify proteins of Dirofilaria immitis recognized by the immune system of naturally and experimentally infected cats, using two-dimensional electrophoresis and mass spectrometry. Thirty-five immunoreactive proteins of D. immitis were identified. These proteins are involved in metabolism, plasminogen binding, anti-oxidant and detoxificant activity, up-regulation of the Th2 anti-inflammatory response and other processes. The timing evolution of this recognition pattern indicated that at 2 months post-infection a wide recognition of many parasite proteins belonging to many functional groups is still observed, increasing progressively during the course of the infection. The real effect on the vital capacity of D. immitis worms and on the development of path...
2010-01-01
Objective Chemokines coordinate leukocyte trafficking in homeostasis and during immune responses. Prior studies of their role in arthritis have used animal models with both an initial adaptive immune response and an inflammatory effector phase. We undertook analysis of chemokines and their receptors in the effector phase of arthritis using the K/BxN mouse serum-transfer model. Methods A time-course microarray analysis of serum-transferred arthritis was performed, examining ankle tissue, synovial fluid, and peripheral blood leukocytes. Up-regulation of chemokines was confirmed by quantitative reverse transcriptase-polymerase chain reaction. The functional relevance of chemokine induction was assessed by transferring serum into mice deficient in CCR1-7, CCR9, CXCR2, CXCR3, CXCR5, CX3CR1, CCL...
2008-01-01
Congenital hydronephrosis is a serious disease occurring among infants and children. Besides the intrinsic genetic factors, in utero exposure to a xenobiotic, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been suggested to induce hydronephrosis in rodents owing to anatomical obstruction in the ureter. Here, we report that hydronephrosis induced in mouse pups exposed lactationally to TCDD is not associated with anatomical obstruction, but with abnormal alterations in the subepithelial mesenchyma of the ureter. In the kidneys of these pups, the expressions of a battery of inflammatory cytokines including monocyte chemoattractant protein (MCP)-1, tumor necrosis factor alpha (TNFalpha) and interleukin (IL) -1beta were up-regulated as early as postnatal day (PND) 7. The amounts of cyclooxygenase (COX) -2 mRNA and protein as ...
Cloning, sequencing and expression analysis of the equine hepcidin gene by real-time PCR
2010-01-01
Equine serum or plasma iron concentration drops quickly during inflammation. Accumulation of iron inside macrophages and reduction of the intestinal absorption of this element cause hypoferremia during systemic inflammatory processes. These mechanisms are mediated by hepcidin, a 25 amino acids peptide synthesized mainly in the liver in response to iron stores and inflammation. Hepcidin is an important peptide for systemic iron homeostasis and also has antibacterial and antifungal activities. Hepcidin up-regulation is particularly useful during acute inflammation, especially before adaptive immunity occurs, restricting iron availability necessary for pathogenic microorganism growth. Hepcidin gene products have been previously characterized in man, non-human primates, rat, mouse, dog swine, ...
Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice
2007-01-01
Objective To determine the consequences of pharmacologic up-regulation of heme oxygenase 1 (HO-1), and inhibition of HO-1 by injection of an anti-HO-1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis. Methods In the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO-1 was up-regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E2 (PGE2) production, and matrix metalloproteinase 9 (MMP-9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes. Results Intraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP-induced expression of HO-1 in the joints and liver was associated with marked decreases in IL-1, IL-6, and TNF levels, PGE2 secretion, and MMP-9 activity in serum, and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO-1 induction. Specific inhibition of HO-1 by in vivo delivery of anti-HO-1 siRNA repressed the protective effects. Conclusion Our data provide the first evidence that pharmacologically induced up-regulation of HO-1 triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO-1 may have potential as therapy in the acute phase of inflammatory arthritis in humans. Publisher: John Wiley & Sons Coverage: 2007-01-01T00:00:00Z
Ultrasonography and computed tomography of inflammatory abdominal wall lesions
1982-09-01
Twenty-four patients with inflammatory lesions of the abdominal wall were examined by ultrasonography. Nine of these patients underwent computed tomographic (CT) scanning as well. Both ultrasonography and CT clearly delineated the exact location and extent of abdominal wall abscesses. Abscesses were easily differentiated from cellulitis or phlegmon with ultrasound. The peritoneal line was more clearly delineated on ultrasonograms than on CT scans; abscesses were also more distinct on the ultrasonograms because of their low echogenicity compared with the surrounding structures. Gas bubbles, fat density with specific low attenuation values, and underlying inflamed bowel loops in obese patients with Crohn's disease were better delineated by CT.
The role of resistin as a regulator of inflammation: Implications for various human pathologies
2009-01-01
Resistin was originally described as an adipocyte-secreted peptide that induced insulin resistance in rodents. Increasing evidence indicates its important regulatory roles in various biological processes, including several inflammatory diseases. Further studies have shown that resistin in humans, in contrast to its production by adipocytes in mice, is synthesized predominantly by mononuclear cells both within and outside adipose tissue. Possible roles for resistin in obesity-related subclinical inflammation, atherosclerosis and cardiovascular disease, non-alcoholic fatty liver disease, rheumatic diseases, malignant tumors, asthma, inflammatory bowel disease, and chronic kidney disease have already been demonstrated. In addition, resistin can modulate several molecular pathways involved in ...
Inflammation and brain injury: Acute cerebral ischaemia, peripheral and central inflammation
2010-01-01
Inflammation is a classical host defence response to infection and injury that has many beneficial effects. However, inappropriate (in time, place and magnitude) inflammation is increasingly implicated in diverse disease states, now including cancer, diabetes, obesity, atherosclerosis, heart disease and, most relevant here, CNS disease. A growing literature shows strong correlations between inflammatory status and the risk of cerebral ischaemia (CI, most commonly stroke), as well as with outcome from an ischaemic event. Intervention studies to demonstrate a causal link between inflammation and CI (or its consequences) are limited but are beginning to emerge, while experimental studies of CI have provided direct evidence that key inflammatory mediators (cytokines, chemokines and inflammator...
2010-01-01
We compared the gene expression of inflammatory and other proteins by real-time quantitative polymerase chain reaction in epicardial, substernal (mediastinal) and subcutaneous sternal, upper abdominal, and leg fat from coronary bypass patients and omental (visceral) fat from extremely obese women undergoing bariatric surgery. We hypothesized that (1) epicardial fat would exhibit higher expression of inflammatory messenger RNAs (mRNAs) than substernal and subcutaneous fat and (2) epicardial mRNAs would be similar to those in omental fat. Epicardial fat was clearly different from substernal fat because there was a far higher expression of haptoglobin, prostaglandin D2 synthase, nerve growth factor b, the soluble vascular endothelial growth factor receptor (FLT1), and a1 glycoprotein but not ...
Fat tissue, aging, and cellular senescence
2010-01-01
Summary Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro-inflammatory, tissue-remodeling, senescent-like state. Other mesenchymal progenitors also can acquire a pro-inflammatory, adipocyte-like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization...
2010-01-01
Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding...
2009-01-01
Background: Diabetes and obesity are metabolic disorders induced by an excessive dietary intake of fat, usually related to inflammation and oxidative stress. Aims: The aim of the study is to investigate the effect of the antioxidant coenzyme Q10 (CoQ10) on hepatic metabolic and inflammatory disorders associated with diet-induced obesity and glucose intolerance. Methods: C57bl6/j mice were fed for 8 weeks, either a control diet (CT) or a high-fat diet plus 21% fructose in the drinking water (HFF). CoQ10 supplementation was performed in this later condition (HFFQ). Results: HFF mice exhibit increased energy consumption, fat mass development, fasting glycaemia and insulinemia and impaired glucose tolerance. HFF treatment promoted the expression of genes involved in reactive oxygen species pro...
2009-01-01
Abstract Aims Obesity is associated with inflammation. Anti-inflammatory interventions such as aspirin and statins (anti-IFRx) might be a novel approach to the treatment of obesity and Type 2 diabetes mellitus (T2DM). The present study was designed to determine whether exposure to anti-IFRx is associated with weight loss in T2DM patients. Methods Exposure to anti-IFRx was compared between T2DM patients with a history of weight loss (n = 100) and those with no weight loss or with weight gain (n = 102) during a 1-year follow-up period. Logistic regression was used to develop odds ratios for weight loss status. Results Subjects who lost weight were more frequently exposed to anti-IFRx (85.0 vs. 71.5%, P = 0.018) than subjects who maintained or gained weight during follow-up. The 158 subjects ...
Comparison of orlistat treatment and placebo in obese type 2 diabetic patients
2010-01-01
Aim: To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients. Materials and methods: Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-a, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR). Results: Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-a, and a faster decrease of ...
Comparison of orlistat treatment and placebo in obese type 2 diabetic patients
2010-01-01
Aim: To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients. Materials and methods: Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-a, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR). Results: Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-a, and a faster decrease of ...
Posterior Tibial Tendon Dysfunction
2006-01-01
Posterior tibialis tendon dysfunction is the most common cause of acquired flatfoot deformity in adults. It is most commonly caused by chronic tendinopathy with subsequent functional impairment from elongation or rupture and it is most often seen in patients with obesity, diabetes mellitus, hypertension, and systemic inflammatory diseases. Degenerative tears occur most often distal and posterior to the medial malleolus in the critical zone of hypovascularity. There is a characteristic deformity consisting of hindfoot valgus, forefoot abduction, loss of the longitudinal arch, and, with increasing hindfoot valgus, a compensatory forefoot supination. The diagnosis is usually clinical. There is medial pain and swelling, pain or inability to perform a single heel rise, loss of the medial longit...
Nutritional support in patients with oesophageal cancer
2010-01-01
Background Obesity and overweight are risk factors for developing an oesophageal cancer, especially the adenocarcinoma in the distal oesophagus or at the gastroesophageal junction, and many patients still are overweight at the clinical presentation even if they are losing weight. Main mechanisms involved in weight loss are a decreased nutrients intake and an alteration in metabolism due to a cytokine-driven inflammatory status. Malnutrition is a risk factor for a poor compliance to chemotherapy and radiation therapy and finally for the oncologic outcome. There is scientific evidence that frequently both conditions exist but in the advanced stages of disease metabolic alterations play a major role and are responsible for the poor response to nutritional support. Methods The literature ab...
MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4
2009-12-21
Full Text Available.Adipose tissue macrophages (ATMs) play a critical role in obesity-induced inflammation and insulin resistance. Distinct subtypes of ATMs have been identified that differentially express macrophage galactose-type C-type lectin 1 (MGL1/CD301), a marker of alternatively activated macrophages. To evaluate if MGL1 is required for the anti-inflammatory function of resident (type 2) MGL1
Endocannabinoids in the retina: From marijuana to neuroprotection
2008-01-01
The active component of the marijuana plant Cannabis sativa, D9-tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids. The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems. There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, t...
BackgroundLung cancer often develops in association with chronic pulmonary inflammatory diseases with an influx of neutrophils. More detailed information on inflammatory pathways and the role of neutrophils herein is a prerequisite for understanding the mechanism of inflammation associated cancer.MethodsIn the present study, we used microarrays in order to obtain a global view of the transcriptional responses of the lung to LPS in mice, which mimics an acute lung inflammation. To investigate the influence of neutrophils in this process, we depleted mice from circulating neutrophils by treatment with anti-PMN antibodies prior to LPS exposure.ResultsA total of 514 genes was greater than 1.5-fold differentially expressed in the LPS induced lung inflammation model. 394 of the 514 were up regulated genes mostly involved in cell cycle and immune/inflammation related processes, such as cytokine/chemokine activity and signalling. Down regulated genes represented nonimmune processes, such as development, metabolism and transport. Notably, the number of genes and pathways that were differentially expressed, was reduced when animals were depleted from circulating neutrophils, confirming the central role of neutrophils in the inflammatory response. Furthermore, there was a significant correlation between the differentially expressed gene list and the promutagenic DNA lesion M1dG, suggesting that it is the extent of the immune response which drives genetic instability in the inflamed lung. Several genes that were specifically regulated by the presence of activated neutrophils could be identified and these were mostly involved in interferon signalling, oxidative stress response and cell cycle progression. The latter possibly refers to a higher rate of cell turnover in the inflamed lung with neutrophils, suggesting that the neutrophil influx is associated with a higher risk for the accumulation and fixation of mutations.ConclusionGene expression profiling identified specific genes and pathways that are related to neutrophilic inflammation and could be associated to cancer development and indicate an active role of neutrophils in mediating the LPS induced inflammatory response in the mouse lung.
2009-01-01
Abstract The neuropeptide vasoactive intestinal peptide (VIP) is anti-inflammatory and protective in the immune and nervous systems, respectively. This study demonstrated in corneal endothelial (CE) cells injured by severe oxidative stress (1.4 mM H2O2) in bovine corneal organ cultures that VIP pre-treatment (0, 10-10, 10-8, and 10-6 M; 15 min), in a VIP concentration-dependent manner, switched the inflammation-causing necrosis to inflammation-neutral apoptosis (showing annexin V-binding, chromatin condensation, and DNA fragmentation) and upheld ATP levels in a VIP antagonist (SN)VIPhyb-sensitive manner, while up-regulated mRNA levels of the anti-apoptotic Bcl-2 and the differentiation marker N-cadherin in a kinase A inhibitor-sensitive manner. As a result, VIP, in a concentration-dependen...
2010-01-01
Advanced glycation end products (AGE) are involved in tissue damage and remodeling. This study investigated whether AGE could elicit inflammatory and fibrogenic reactions in fibroblast cell line MRC-5 cells via autocrine production of aldosterone and if nifedipine could block the AGE actions through mineralocorticoid receptor (MR) antagonistic activity. AGE significantly up-regulated monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-b (TGF-b), type III collagen and receptor for AGE (RAGE) mRNA levels in MRC-5 cells, all of which were completely blocked by nifedipine or an MR antagonist spironolactone. Aldosterone also dose-dependently increased MCP-1, TGF-b and type III collagen mRNA levels in MRC-5 cells, which were suppressed by nifedipine, but not amlodipine, a cont...
2010-01-01
Failed medical therapy is a common problem in inflammatory bowel disease. P-glycoprotein (P-gp), an efflux pump encoded by MDR1 (ABCB1) gene can actively pump drugs out of cells conferring the phenotype of multidrug resistance. Various studies evoked that cyclooxygenase (COX) system may be involved in the regulation of P-gp activity. Since COX-2 isoform is overexpressed in colic inflammatory states, we examined the inhibitory effect of COX-2-inhibitors on P-gp expression and function under COX-2 stimulated conditions mediated by trinitrobenzene sulfonic acid (TNBS) in vitro, in Caco-2 cells, and in TNBS-induced colitis in mice. COX-2 and P-gp expressions were evaluated by real-time PCR and western blot. The activity of P-gp was measured by intracellular accumulation of rhodamine123 (Rho123...
Activation of an IL-6:STAT3-dependent Transcriptome in Pediatric-onset Inflammatory Bowel Disease
2008-04-01
Full Text Available.Background:While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation.Methods:Patients with pediatric-onset IBD were enrolled at diagnosis and during therapy. Serum cytokine analysis was performed using Bioplex. STAT3 phosphorylation (pSTAT3) in peripheral blood leukocytes (PBLs) was assessed by flow cytometry. Immunohistochemistry of colonic mucosa was used to localize pSTAT3 and STAT3 target genes. Microarray analysis was used to determine RNA expression profiles from colon biopsies.Results:Circulating IL-6 was upregulated in active IBD patients at diagnosis and during therapy. STAT3 activation was increased in PB granulocytes, IL-6-stimulated CD3
2010-01-01
Full Text Available. Background. Obstructive Sleep Apnea Syndrome (OSAS) is associated with inflammation, but obesity may be a confounding factor. Thus, the aim of this study was to explore differences in serum levels of inflammation markers between obese individuals with or without OSAS. Methods. Healthy individuals (n = 61) from an outpatient obesity clinic were examined by polysomnography and blood analysis, for measurement of TNF-α, IL-6, CRP, and fibrinogen levels. According to Apnea-Hypopnea Index (AHI), participants were divided into two BMI-matched groups: controls (AHI < 15/h, n = 23) and OSAS patients (AHI ≥ 15/h, n = 38). Results. OSAS patients had significantly higher TNF-α levels (P < .001) while no other difference in the examined inflammation markers was recorded between groups. Overall, TNF-α levels were correlated with neck circumference (P < .001), AHI (P = .002), and Oxygen Desaturation Index (P = .002). Conclusions. Obese OSAS patients have elevated TNF-α levels compared to BMI-matched controls, suggesting a role of OSAS in promoting inflammation, possibly mediated by TNF-a.
Influence of parental obesity on school children
2010-01-01
Objective To find out the association between parental obesity and Childhood obesity. Methods Children in middle schools were screened for obesity. For each obese child two controls were studied. Results Parental history of obesity was present for 32.7% of obese children. Children with parental history of obesity showed 25.2 times more chances of developing obesity than controls. 33.8% of the obese girls and 31.6% of the obese boys had history of parental obesity. If the father was obese, boys had 6.5 times more chance and girls had 40.1 times more chance of developing obesity. Mothers obesity had an influence on 23.7 % of the boys and only 16 % of the girls. Conclusion The childhood obesity has been influenced by genetic factors in the present study and it also shows that maternal obes...
2009-04-01
Full Text Available.Because of inherent differences between deceased donor (DD) and living donor (LD) liver grafts, we hypothesize that the molecular signatures will be unique, correlating with specific biologic pathways and clinical patterns.Microarray profiles of 63 biopsies in 13 DD and 8 LD liver grafts done at serial time points (procurement, backbench, and post-reperfusion) were compared between groups using class comparisons, network and biological function analyses. Specific genes were validated by quantitative PCR and immunopathology. Clinical findings were also compared.Following reperfusion, 579 genes in DD grafts and 1324 genes in LDs were differentially expressed (p<0.005). Many up-regulated LD genes were related to regeneration, biosynthesis and cell cycle, and a large number of down-regulated genes were linked to hepatic metabolism and energy pathways correlating with post-transplant clinical laboratory findings. There was significant up-regulation of inflammatory/immune genes in both DD and LD, each with a distinct pattern. Gene expression patterns of select genes associated with inflammation and regeneration in LD and DD grafts correlated with protein expression.Unique patterns of early gene expression are seen in LD and DD liver grafts, correlating with protein expression and clinical results, demonstrating distinct inflammatory profiles and significant down-regulation of metabolic pathways in LD grafts.
Cattle demonstrate divergent and heritable phenotypes of resistance and susceptibility to infestation with the cattle tick Rhipicephalus (Boophilus) microplus. Bos indicus cattle are generally more resistant to tick infestation than Bos taurus breeds although large variations in resistance can occur within subspecies and within breed. Increased tick resistance has been previously associated with an intense hypersensitivity response in B. taurus breeds; however, the mechanism by which highly resistant B. indicus cattle acquire and sustain high levels of tick resistance remains to be elucidated. Using the commercially available Affymetrix microarray gene expression platform, together with histological examination of the larval attachment site, this study aimed to describe those processes responsible for high levels of tick resistance in Brahman (B. indicus) cattle that differ from those in low-resistance Holstein-Friesian (B. taurus) cattle. We found that genes involved in inflammatory processes and immune responsiveness to infestation by ticks, although up-regulated in tick-infested Holstein-Friesian cattle, were not up-regulated in Brahman cattle. In contrast, genes encoding constituents of the extracellular matrix were up-regulated in Brahmans. Furthermore, the susceptible Holstein-Friesian animals displayed a much greater cellular inflammatory response at the site of larval R. microplus attachment compared with the tick-resistant Brahman cattle.
Full Text Available.Schistosomiasis continues to be an important cause of parasitic morbidity and mortality world-wide. Determining the molecular mechanisms regulating the development of granulomas and fibrosis will be essential for understanding how schistosome antigens interact with the host environment. We report here the first whole genome microarray analysis of the murine liver during the progression of Schistosoma japonicum egg-induced granuloma formation and hepatic fibrosis. Our results reveal a distinct temporal relationship between the expression of chemokine subsets and the recruitment of cells to the infected liver. Genes up-regulated earlier in the response included T- and B-cell chemoattractants, reflecting the early recruitment of these cells illustrated by flow cytometry. The later phases of the response corresponded with peak recruitment of eosinophils, neutrophils, macrophages and myofibroblasts/hepatic stellate cells (HSCs) and the expression of chemokines with activity for these cells including CCL11 (eotaxin 1), members of the Monocyte-chemoattractant protein family (CCL7, CCL8, CCL12) and the Hepatic Stellate Cell/Fibrocyte chemoattractant CXCL1. Peak expression of macrophage chemoattractants (CCL6, CXCL14) and markers of alternatively activated macrophages (e.g. Retnla) during this later phase provides further evidence of a role for these cells in schistosome-induced pathology. Additionally, we demonstrate that CCL7 immunolocalises to the fibrotic zone of granulomas. Furthermore, striking up-regulation of neutrophil markers and the localisation of neutrophils and the neutrophil chemokine S100A8 to fibrotic areas suggest the involvement of neutrophils in S. japonicum-induced hepatic fibrosis. These results further our understanding of the immunopathogenic and, especially, chemokine signalling pathways that regulate the development of S. japonicum-induced granulomas and fibrosis and may provide correlative insight into the pathogenesis of other chronic inflammatory diseases of the liver where fibrosis is a common feature.
Congenital hydronephrosis is a serious disease occurring among infants and children. Besides the intrinsic genetic factors, in utero exposure to a xenobiotic, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been suggested to induce hydronephrosis in rodents owing to anatomical obstruction in the ureter. Here, we report that hydronephrosis induced in mouse pups exposed lactationally to TCDD is not associated with anatomical obstruction, but with abnormal alterations in the subepithelial mesenchyma of the ureter. In the kidneys of these pups, the expressions of a battery of inflammatory cytokines including monocyte chemoattractant protein (MCP)-1, tumor necrosis factor {alpha} (TNF{alpha}) and interleukin (IL) -1{beta} were up-regulated as early as postnatal day (PND) 7. The amounts of cyclooxygenase (COX) -2 mRNA and protein as well as prostaglandin E2 (PGE{sub 2}) were conspicuously up-regulated in an arylhydrocarbon-receptor-dependent manner in the TCDD-induced hydronephrotic kidney, with a subsequent down-regulation of the gene expressions of Na{sup +} and K{sup +} transporters, NKCC2 and ROMK. Daily administration of a COX-2 selective inhibitor to newborns until PND 7 completely abrogated the TCDD-induced PGE{sub 2} synthesis and gene expressions of inflammatory cytokines and electrolyte transporters, and eventually prevented the onset of hydronephrosis. These findings suggest an essential role of COX-2 in mediating the TCDD action of inducing hydronephrosis through the functional impairment rather than the anatomical blockade of the ureter.
Resistin induces rat insulinoma cell RINm5F apoptosis
2009-01-01
Beta-cell apoptosis induced by adipokines may result in beta-cell dysfunction in type 2 diabetes. Resistin, an adipokine-linked obesity with type 2 diabetes, impairs glucose-stimulated insulin secretion (GSIS) in beta-cells. Presently, the effects of resistin on rat insulinoma cells RINm5F were examined. Treatment of RINm5F with resistin induced cell damage. Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) protected resistin-mediated cytotoxicity in RINm5F. Incubation with resistin up-regulated caspase-3 activity and induced the formation of a DNA ladder. TIMP-1 attenuated these effects. The molecular mechanism of TIMP-1 inhibition of resistin-mediated cytotoxicity appeared to involve Akt phosphorylation and activation of IkB- phosphorylation. Resistin treatment suppressed Akt phosphoryl...
Full Text Available.BackgroundChronic inflammation is a key player in pathogenesis. The inflammatory cytokine, tumor necrosis factor-alpha is a well known inflammatory protein, and has been a therapeutic target for the treatment of diseases such as Rheumatoid Arthritis and Crohn's Disease. Obesity is a well known risk factor for developing non-insulin dependent diabetes melitus. Adipose tissue has been shown to produce tumor necrosis factor-alpha, which has the ability to reduce insulin secretion and induce insulin resistance. Based on these observations, we sought to investigate the impact of unsaturated fatty acids such as oleic acid in the presence of TNF-α in terms of insulin production, the molecular mechanisms involved and the in vivo effect of a diet high in oleic acid on a mouse model of type II diabetes, KKA
Resistin, a recently discovered 92 amino acid protein involved in the development of insulin resistance, has been associated with obesity and type 2 diabetes. The elevated serum resistin in human diabetes is often associated with a pro-inflammatory milieu. However, the role of resistin in the development of inflammation is not well understood. Addition of recombinant human resistin protein (hResistin) to macrophages (both murine and human) resulted in enhanced secretion of pro-inflammatory cytokines, TNF-{alpha} and IL-12, similar to that obtained using 5 {mu}g/ml lipopolysaccharide. Both oligomeric and dimeric forms of hResistin were able to activate these cytokines suggesting that the inflammatory action of resistin is independent of its conformation. Heat denatured hResistin abrogated cytokine induction while treatment of recombinant resistin with polymyxin B agarose beads had no effect thereby ruling out the role of endotoxin in the recombinant hResistin mediated cytokine induction. The pro-inflammatory nature of hResistin was further evident from the ability of this protein to induce the nuclear translocation of NF-{kappa}B transcription factor as seen from electrophoretic mobility shift assays. Induction of TNF-{alpha} in U937 cells by hResistin was markedly reduced in the presence of either dominant negative I{kappa}B{alpha} plasmid or PDTC, a pharmacological inhibitor of NF-{kappa}B. A protein involved in conferring insulin resistance is also a pro-inflammatory molecule that has important implications.
S100A8: Emerging functions and regulation
1999-01-01
The functional importance of members of the S100 Ca2+-binding protein family is becoming apparent. Murine (m)S100A8 (initially named CP-10) is a potent chemoattractant (10(-13) to 10(-11) M) for myeloid cells and the chemotactic activity of other S100s has since been reported, suggesting a new class of chemoattractants. Murine S100A8 has been associated with a number of acute and chronic inflammatory conditions including bacterial infection, atherogenesis, and cystic fibrosis, It is expressed constitutively with S100A9 in neutrophils and is regulated by inflammatory stimulants in macrophages and microvascular endothelial cells. The lack of co-expression of S100A9 with S100A8 in activated macrophages suggests distinct functions for the proteins expressed by different cell types. Glucocorticoids up-regulate induction of mS100A8 by inflammatory mediators, and its exquisite sensitivity to oxidation suggests that it may protect against oxidative tissue damage, Inactivation of the mS100A8 gene is embryonic lethal, providing the first evidence for non-redundant function of a member of the S100 gene family, S100A8 may have au immunoregulatory role by contributing to the regulation of fetal-maternal interactions. It may play a protective role and its absence may allow infiltration by maternal cells, a process eventually manifesting as resorption, This review focuses on the variety of emerging functions attributed to murine S100A8, a protein implicated in embryogenesis, growth, differentiation, and immune and inflammatory processes. Publisher: Federation of American Society of Experimental Biology Coverage: 1999-10-01T00:00:00Z
Pro-inflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes
2009-05-01
Full Text Available.HIV encephalitis (HIVE), the pathologic correlate of HIV-associated dementia (HAD) is characterized by astrogliosis, cytokine/chemokine dysregulation and neuronal degeneration. Increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD. In fact, the severity of HAD/HIVE correlates more closely with the presence of activated glial cells than with the presence and amount of HIV-infected cells in the brain. Astrocytes, the most numerous cell type within the brain, provide an important reservoir for the generation of inflammatory mediators, including interferon-γ inducible peptide-10 (CXCL10), a neurotoxin and a chemoattractant, implicated in the pathophysiology of HAD. Additionally, the pro-inflammatory cytokines, IFN-γ and TNF-α, are also markedly increased in CNS tissues during HIV-1 infection. In the present study we hypothesized that the interplay of host cytokines and HIV-1 could lead to enhanced expression of the toxic chemokine, CXCL10. Our findings demonstrate a synergistic induction of CXCL10 mRNA and protein in human astrocytes exposed to HIV-1 and the pro-inflammatory cytokines. Signaling molecules, including JAK, STATs, MAPK (via activation of Erk1/2, AKT, and p38), and NF-κB were identified as instrumental in the synergistic induction of CXCL10. Understanding the mechanisms involved in HIV-1 and cytokine mediated up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.
Gene Expression Profile in Interleukin-4–Stimulated Human Vascular Endothelial Cells
2004-01-01
Full Text Available.Interleukin-4 (IL-4)–mediated pro-oxidative and pro-inflammatory vascular environments have been implicated in the pathogenesis of atherosclerosis. The cellular and molecular regulatory mechanisms underlying this process, however, are not fully understood. In the present study, we employed GeneChip microarray analysis to investigate global gene expression patterns in human vascular endothelial cells after treatment with IL-4. Our results showed that mRNA levels of a total of 106 genes were significantly up-regulated and 41 genes significantly down-regulated with more than a 2-fold change. The majority of these genes are critically involved in the regulation of inflammatory responses, apoptosis, signal transduction, transcription factors, and metabolism; functions of the remaining genes are unknown. The changes in gene expression of selected genes related to inflammatory reactions, such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6), were verified by quantitative real-time reverse transcriptase–polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. IL-4 treatment also significantly increased the adherence of inflammatory cells to endothelial cell monolayers in a dose-dependent manner. These results may help determine the molecular mechanisms of action of IL-4 in human vascular endothelium. In addition, a better understanding of IL-4–induced vascular injury at the level of gene expression could lead to the identification of new therapeutic strategies for atherosclerosis.
2009-01-01
Abstract Transient receptor potential vanilloid (TRPV) 1 channels function as sensors for a variety of noxious and inflammatory signals, including capsaicin, heat and protons, and are up-regulated under inflammatory conditions. As end-stage kidney disease (ESKD) is associated with chronic inflammation, impaired immunity and depressed lymphocyte numbers, we sought to determine whether altered TRPV1 (and related TRPV2) expression in immune cells might be a contributing factor. TRPV1 and TRPV2 mRNA expression in peripheral blood mononuclear cells (PBMC) was similar in controls and ESKD patients by quantitative real-time RT-PCR. However, using immunocytochemistry, TRPV1-immunoreactivity was significantly higher and TRPV2-immunoreactivity was significantly lower in PBMC from ESKD patients compared to controls. The plant-derived TRPV1 agonists, capsaicin and resiniferatoxin (RTX) and the putative endovanilloid/endocannabinoids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA), induced concentration-dependent death of PBMC from healthy donors with a rank order of potency of RTX > NADA > OLDA >> capsaicin. TRPV1 (5′-iodoresiniferatoxin) and cannabinoid (CB2; AM630) receptor antagonists blocked the cytotoxic effect of NADA. In subsequent experiments, PBMC from ESKD patients exhibited significantly increased susceptibility to NADA-induced death compared to PBMC from controls. The apparent up-regulation of TRPV1 may be a response to the inflammatory milieu in which PBMC exist in ESKD and may be responsible for the increased susceptibility of these cells to NADA-induced death, providing a possible explanation as to why ESKD patients have reduced lymphocyte counts and impaired immune function. Thus, TRPV1 (and possibly CB2) antagonists may have potential for the treatment of immune dysfunction in ESKD. Publisher: Elsevier BV Contributor: B A Oostra; P E Fraser Coverage: 2009-10-01T00:00:00Z
Full Text Available.Proteinase-activated receptor 2 (PAR-2), activated by trypsin and other serine proteinases, is a key initiator of inflammatory responses in the intestine of mammals. Atlantic salmon fed diets with standard qualities of soybean meal (SBM) show enteritis of the distal intestine as well as increased activity of trypsin in both luminal contents and wall tissue. Luminal trypsin activity may possibly be involved in immune related disorders of the intestine also in Atlantic salmon via activation of PAR 2. In the present study our aim was to investigate if PAR-2 play a role in SBM induced enteritis. We performed multiple alignments based on nucleic acid sequences of PAR-2 from various animals available from public databases, and designed primers for use in cloning of the Atlantic salmon PAR-2 transcript. We further cloned and characterized the full length sequence of Atlantic salmon PAR-2 and investigated the expression in both early and chronic stages of SBM induced enteropathy. Two full length versions of PAR-2 cDNA were identified and termed PAR-2a and PAR-2b. Expression of the two PAR-2 transcripts was detected in all 18 tissues examined, but most extensively in the intestine and gills. A significant up-regulation in the distal intestine was observed for the PAR-2a transcript after 1 day feeding diets containing SBM. After 3 weeks of feeding, PAR-2a was down-regulated compared to the fish fed control diets. These findings may indicate that PAR-2a participates in inflammatory responses in both the early and later stages of the SBM enteropathy. In the chronic stages of the enteropathy, down-regulation of PAR-2a may indicate a possible desensitization of the PAR-2a receptor. Expression of PAR-2b was not altered in the first 7 days of SBM feeding, but a significant up regulation was observed after 3 weeks, suggesting a putative role in chronic stages of SBM induced enteritis. The expression differences of the two PAR-2 transcripts in the feed trials may indicate that they have different roles in the SBM induced enteritis.
BackgroundLeptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss.Methodology/Principal FindingsWe utilized microarray technology to compare hepatic gene expression changes after two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented.Conclusions/SignificanceIn this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.
2010-01-01
Full Text Available.IntroductionObesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet.MethodsFemale C57BL/6J mice were fed either a 10% kcal fat or a 45% kcal fat diet from 9 to 54 weeks of age. Longitudinal changes in musculoskeletal function and inflammation were compared with endpoint neurobehavioral and osteoarthritic disease states. Bivariate and multivariate analyses were conducted to determine independent associations with diet, percentage body fat, and knee osteoarthritis severity. We also examined healthy porcine cartilage explants treated with physiologic doses of leptin, alone or in combination with IL-1α and palmitic and oleic fatty acids, to determine the effects of leptin on cartilage extracellular matrix homeostasis.ResultsHigh susceptibility to dietary obesity was associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of osteoarthritis, including hyperalgesia and anxiety-like behaviors. Controlling for the effects of diet and percentage body fat with a multivariate model revealed a significant association between knee osteoarthritis severity and serum levels of leptin, adiponectin, and IL-1α. Physiologic doses of leptin, in the presence or absence of IL-1α and fatty acids, did not substantially alter extracellular matrix homeostasis in healthy cartilage explants.ConclusionsThese results indicate that diet-induced obesity increases the risk of symptomatic features of osteoarthritis through changes in musculoskeletal function and pain-related behaviors. Furthermore, the independent association of systemic adipokine levels with knee osteoarthritis severity supports a role for adipose-associated inflammation in the molecular pathogenesis of obesity-induced osteoarthritis. Physiologic levels of leptin do not alter extracellular matrix homeostasis in healthy cartilage, suggesting that leptin may be a secondary mediator of osteoarthritis pathogenesis.
Myeloid Differentiation Factor 88 (MyD88)-Deficiency Increases Risk of Diabetes in Mice
Full Text Available.BackgroundMultiple lines of evidence suggest innate immune response pathways to be involved in the development of obesity-associated diabetes although the molecular mechanism underling the disease is unknown. Recent observations suggest that saturated fatty acids can act as a ligand for toll-like receptor (TLR) 4, which is thought to mediate obesity-associated insulin resistance. Myeloid differentiation factor 88 (MyD88) is an adapter protein for TLR/IL-1 receptor signaling, which is involved in the activation of inflammatory pathways. To evaluate molecular mechanisms linking obesity-associated diabetes down-stream of TLR4, we investigated physiological role of MyD88 in high-fat diet (HFD)-induced obesity.Methodology/Principal FindingsIn the present study, we found MyD88-deficient mice fed a HFD had increased circulating levels of insulin, leptin and cholesterol, as well as liver dysfunction (increased induction of ALT levels, increased activation of JNK and cleavage of PARP), which were linked to the onset of severe diabetes. On the other hand, TNF-α would not be involved in HFD-induced diabetes in MyD88-deficient mice, because TNF-α level was attenuated in MyD88-deficient mice fed with HFD.Conclusions/SignificanceThe present finding of an unexpected role for MyD88 in preventing diabetes may provide a potential novel target/strategy for treating metabolic syndrome.
Full Text Available.A link has been established between prenatal nutrition and the development of metabolic and cardiovascular diseases later in life, a process referred to as developmental programming. It has been suggested that the trajectory of development is shifted by alterations in the maternal nutritional state leading to changes in developmental plasticity, in part underpinned by epigenetic changes in gene regulation. However, to date, only candidate gene approaches have been used to assess expression and molecular changes in the offspring of maternally undernourished animals. Furthermore, most work has focused on animals at an age where the programmed phenotype is already manifest and little is known about changes in gene expression in the offspring prior to development of obesity and related metabolic disorders. Gene expression profiles of liver, retroperitoneal white adipose fat, and biceps femoris skeletal muscle tissue from young adult male rats (55 days old) in which nutritional status had been manipulated in utero by maternal undernutrition (UN) were compared to the profiles of offspring of ad libitum fed mothers serving as the control group (AD) (8 offspring/group). The expression profiles were determined using the Illumina RatRef-12 BeadChip. No significant changes in expression were identified for skeletal muscle or white adipose tissue. However, studies of liver tissue showed 249 differentially expressed genes (143 up regulated, 106 down regulated). Although the animals at day 55 have yet to develop obesity they already show biochemical abnormalities and by day 110 express a phenotype characterized by increased adiposity and altered insulin sensitivity. An analysis of pathways affected suggests that intrauterine programming of UN animals to favor fat as an energy source results in mitochondrial dysfunction which initially affects the postnatal hepatic function and subsequently, via the resultant metabolic changes in other organs leads to the evolution of a phenotype similar to that of the metabolic syndrome.
2009-01-01
Abstract Objective: To determine how genetic factors might influence the progression of nonalcoholic fatty liver disease (NAFLD). Design/Intervention: Beginning in adolescence, male C57BL6 (BL6) and 129/SVJ mice were fed control (n=15/group) or high-fat (HF) diets (n=30/group) for 6 months. Main Outcome Measures: Assessed were body weight, insulin resistance, hepatic production of free radicals, expression of cytokines and fibrosis-related genes and severity of hepatic steatosis, injury and fibrosis. Results: High-fat diets induced comparable obesity, hepatic steatosis and insulin resistance in the two strains. Compared with BL6 mice, 129/SVJ mice had impaired induction of antioxidant genes, generated three- to four-fold more free radicals and exhibited two-fold greater induction of profib...
2009-01-01
Objective To investigate the effect of exercise training on markers of the lipoprotein-lipid profile and inflammatory markers in post-menopausal overweight/obese women with a moderately elevated systolic blood pressure. Methods A total of 267 women [mean body mass index (BMI)=32.0+-5.7kg/m2 and mean age=57.3+-6.6 years] underwent a 6-month exercise intervention program. Exercise training was performed 3-4 times per week at a targeted heart rate corresponding to 50% of the maximal oxygen consumption. Results Compared to baseline values, mean change in relative VO2 max (the primary endpoint) was of 1.18+-2.25mL/minkg (p
Decreased adiposity and improved insulin sensitivity in CD14ko mice.
2007-01-01
Low-grade, chronic, systemic inflammation supposedly contributes to the development of obesity and its co-morbidities, such as insulin resistance and type 2 diabetes. CD14 is a protein that facilitates binding of gram(+) and gram(-) bacterial pathogens to immune cells that initiate the inflammatory response. As CD14 may also bind circulating fatty acids, and as the absorption of bacterial pathogens may be increased with obesifying diets, CD14ko mice might develop less systemic inflammation than WT mice and might thus be protected against diet-induced obesity and its metabolic consequences. Nine-week-old CD14ko and WT mice (C57/Bl6) were fed chow (CH), HF (60% of the energy from lipid) or HS (CH+8% sucrose solution) diets. Food intake and body weight (BW) were measured periodically; intrape...
Tobacco Upregulates P. gingivalis Fimbrial Proteins Which Induce TLR2 Hyposensitivity
Full Text Available.BackgroundTobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. The underlying mechanisms are unknown. We have previously shown that cigarette smoke extract (CSE) represents an environmental stress to which P. gingivalis adapts by altering the expression of several virulence factors – including major and minor fimbrial antigens (FimA and Mfa1, respectively) and capsule – concomitant with a reduced pro-inflammatory potential of intact P. gingivalis.Methodology/Principal FindingsWe hypothesized that CSE-regulation of capsule and fimbrial genes is reflected at the ultrastructural and functional levels, alters the nature of host-pathogen interactions, and contributes to the reduced pro- inflammatory potential of smoke exposed P. gingivalis. CSE induced ultrastructural alterations were determined by electron microscopy, confirmed by Western blot and physiological consequences studied in open-flow biofilms. Inflammatory profiling of specific CSE-dysregulated proteins, rFimA and rMfa1, was determined by quantifying cytokine induction in primary human innate and OBA-9 cells. CSE up-regulates P. gingivalis FimA at the protein level, suppresses the production of capsular polysaccharides at the ultrastructural level, and creates conditions that promote biofilm formation. We further show that while FimA is recognized by TLR2/6, it has only minimal inflammatory activity in several cell types. Furthermore, FimA stimulation chronically abrogates the pro-inflammatory response to subsequent TLR2 stimulation by other TLR-2-specific agonists (Pam3CSK4, FSL, Mfa1) in an IκBα- and IRAK-1-dependent manner.Conclusions/SignificanceThese studies provide some of the first information to explain, mechanistically, how tobacco smoke changes the P. gingivalis phenotype in a manner likely to promote P. gingivalis colonization and infection while simultaneously reducing the host response to this major mucosal pathogen.
Microglia Are Mediators of Borrelia burgdorferi–Induced Apoptosis in SH-SY5Y Neuronal Cells
2009-11-01
Full Text Available.Inflammation has long been implicated as a contributor to pathogenesis in many CNS illnesses, including Lyme neuroborreliosis. Borrelia burgdorferi is the spirochete that causes Lyme disease and it is known to potently induce the production of inflammatory mediators in a variety of cells. In experiments where B. burgdorferi was co-cultured in vitro with primary microglia, we observed robust expression and release of IL-6 and IL-8, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES), but we detected no induction of microglial apoptosis. In contrast, SH-SY5Y (SY) neuroblastoma cells co-cultured with B. burgdorferi expressed negligible amounts of inflammatory mediators and also remained resistant to apoptosis. When SY cells were co-cultured with microglia and B. burgdorferi, significant neuronal apoptosis consistently occurred. Confocal microscopy imaging of these cell cultures stained for apoptosis and with cell type-specific markers confirmed that it was predominantly the SY cells that were dying. Microarray analysis demonstrated an intense microglia-mediated inflammatory response to B. burgdorferi including up-regulation in gene transcripts for TLR-2 and NFκβ. Surprisingly, a pathway that exhibited profound changes in regard to inflammatory signaling was triggering receptor expressed on myeloid cells-1 (TREM1). Significant transcript alterations in essential p53 pathway genes also occurred in SY cells cultured in the presence of microglia and B. burgdorferi, which indicated a shift from cell survival to preparation for apoptosis when compared to SY cells cultured in the presence of B. burgdorferi alone. Taken together, these findings indicate that B. burgdorferi is not directly toxic to SY cells; rather, these cells become distressed and die in the inflammatory surroundings generated by microglia through a bystander effect. If, as we hypothesized, neuronal apoptosis is the key pathogenic event in Lyme neuroborreliosis, then targeting microglial responses may be a significant therapeutic approach for the treatment of this form of Lyme disease.
The anti-inflammatory effects of an ethanol extract of Angelica gigas (EAG) were investigated in vitro and in vivo using croton oil-induced inflammation models. Croton oil (20 microg/mL) up-regulated mRNA expression of cyclooxygenase (COX)-I and COX-II in the macrophage cell line, RAW 264.7, resulting in the release of high concentrations of prostaglandin E(2) (PGE(2)). EAG (1 approximately 10 microg/mL) markedly suppressed croton oil-induced COX-II mRNA expression and PGE(2) production. Application of croton oil (5% in acetone) to mouse ears caused severe local erythema, edema and vascular leakage, which were significantly attenuated by oral pre-treatment with EAG (50 approximately 500 mg/kg). Croton oil dramatically increased blood levels of interleukin (IL)-6 and PGE(2) without affecting tumor-necrosis factor (TNF)-alpha and nitric oxide (NO) levels. EAG pre-treatment remarkably lowered IL-6 and PGE(2), but did not alter TNF-alpha or NO concentrations. These results indicate that EAG attenuates inflammatory responses in part by blocking the COX - PGE(2) pathway. Therefore, EAG could be a promising candidate for the treatment of inflammatory diseases.
Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-{kappa}B in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.
2009-02-28
Full Text Available.The infiltration of monocytes into the CNS represents one of the early steps to inflammatory events in AIDS-related encephalitis and dementia. Increased activity of selected matrix metalloproteinases (MMPs) such as MMP-9 impairs the integrity of blood-brain barrier leading to enhanced monocyte infiltration into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of MMP-9 in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein levels of MMP-9, as measured by Western blot analysis, zymography and an ELISA. Treatment of CRT-MG cells with HIV-1 Tat protein markedly increased mRNA levels of MMP-9, as analyzed by RT-PCR. Pretreatment of CRT-MG cells with NF-κB inhibitors led to decrease in Tat-induced protein and mRNA expression of MMP-9. Pretreatment of CRT-MG cells with MAPK inhibitors suppressed Tat-induced MMP-9 expression. Furthermore, HIV-1 Tat-induced expression of MMP-9 was significantly inhibited by neutralization of TNF-α, but not IL-1β and IL-6. Taken together, our results indicate that HIV-1 Tat can up-regulate expression of MMP-9 via MAPK-NF-κB-dependent mechanisms as well as Tat-induced TNF-α production in astrocytes.
VTE prophylaxis for the medical patient: where do we stand? - A focus on cancer patients
2010-01-01
Acutely ill medical patients are at moderate to high risk of venous thromboembolism (VTE): approximately 10-30% of general medical patients may develop deep-vein thrombosis or pulmonary embolism, and the latter is a leading contributor to deaths in hospital. Medical conditions associated with a high risk of VTE include cardiac disease, cancer, respiratory disease, inflammatory bowel disease, rheumatological and infectious diseases. Pre-disposing risk factors in medical patients include a history of VTE, history of malignancy, complicating infections, increasing age, thrombophilia, prolonged immobility and obesity. Hence active cancer and a history of cancer are both strongly related to VTE in medical (non-surgical) patients. Heparins, both unfractionated (UFH) and low molecular weight (LMW...
Therapeutic applications of pomegranate (Punica granatum L.): a review.
The pomegranate, Punica granatum L., is an ancient, mystical, unique fruit borne on a small, long-living tree cultivated throughout the Mediterranean region, as far north as the Himalayas, in Southeast Asia, and in California and Arizona in the United States. In addition to its ancient historical uses, pomegranate is used in several systems of medicine for a variety of ailments. The synergistic action of the pomegranate constituents appears to be superior to that of single constituents. In the past decade, numerous studies on the antioxidant, anticarcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer's disease, arthritis, and obesity.
The role of testosterone in the metabolic syndrome: A review
2009-01-01
Over the last three decades it has become apparent that testosterone plays a significant role in the maintenance of bone and muscle mass, in erythropoiesis, and in mental functions. But testosterone is also a key player in glucose homeostasis and lipid metabolism. The metabolic syndrome is a clustering of risk factors predisposing to late onset diabetes mellitus, atherosclerosis and cardiovascular morbidity and mortality. The main components of the syndrome are visceral obesity, glucose intolerance, raised blood pressure and dyslipidaemia (elevated triglycerides, low levels of high-density lipoprotein cholesterol), and a pro-inflammatory and thrombogenic state. Cross-sectional epidemiological studies have reported a direct correlation between plasma testosterone and insulin sensitivity, an...
Testosterone deficiency: a risk factor for cardiovascular disease?
2010-01-01
Male gender is a major risk factor for premature cardiovascular death, a relationship not yet explained. Low testosterone in men is a risk factor for the metabolic syndrome and type 2 diabetes and is associated independently with individual components of the metabolic syndrome - visceral obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia. Epidemiological studies report increased mortality in men with low testosterone. Testosterone replacement in the short-term reduces waist circumference, cholesterol and circulating pro-inflammatory cytokines and improves insulin sensitivity and glycemic control in diabetics. Testosterone also has beneficial effects on cardiac ischemia, angina and chronic heart failure. This manuscript reviews the current evidence supporting a link b...
2009-01-01
Serotonin (5-hydroxytryptamine, 5-HT) participates in several functions of the gastrointestinal tract. Receptors in seven families (5-HT1-5-HT7) were identified, many of which are present on enterocytes, intrinsic and extrinsic neurons, interstitial cells, and gut myocytes. Most 5-HT is released from enterochromaffin cells in response to physiologic and pathologic stimuli. Roles of 5-HT in health include control of normal gut motor activity, secretion, and sensation, and regulation of food intake and cell growth. Abnormalities of serotonergic function contribute to symptom genesis in functional bowel disorders, inflammatory and infectious diseases of the gut, emetic responses to varied stimuli, obesity, and dysregulation of cell growth. Therapies acting as agonists or antagonists of 5-HT r...
Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats
2009-01-01
In view of the central role of preadipocyte factor-1, adiponectin and leptin in white adipose tissue function, the aim of the present study was to analyze the mRNA expression of these proteins and of the inflammatory markers interleukin-6 and tumor necrosis factor-a in visceral and subcutaneous fat pads of rats with different metabolic disorders. We demonstrated highly divergent expression of preadipocyte factor-1, upregulated expression of adiponectin, interleukin-6 and TNF-a mRNA in adipose tissues of the diabetic Goto Kakizaki rat compared to the obese Zucker rat. This was correlated to an increased number of large adipocytes and serum levels of adiponectin. Furthermore, in all four strains studied (as above plus Wistar Furth and Zucker Lean), significant heterogeneity was evident in ad...
2008-01-01
Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome. Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic s...
2010-01-01
Summary Multiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARg, a and d ...
2010-01-01
Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory prope...
Oak Ridge National Laboratory REVIEW, Vol. 34, No. 1, 2001
2001-01-01
The titles in the table of contents from this journal are: Editorial: Unraveling Complex Biological Systems. Systems Biology: New Views of Life. Genes and Proteins: A Primer. Complex Biological Systems in Mice. Gene Chip Engineers. Searching for Mouse Models of Human Disorders. Mouse Models for the Human Disease of Chronic Hereditary Tyrosinemia. Obesity-related Gene in Mouse Discovered at ORNL. MicroCAT ''Sees'' Hidden Mouse Defects. Curing Cancer in Mice. Search for Signs of Inflammatory Disease. Surprises in the Mouse Genome. Protein Identification by Mass Spectrometry. Rapid Genetic Disease Screening Possible Using Laser Mass Spectrometry. Lab on a Chip Used for Protein Studies. The Mouse House: From Old to New. Human Genome Analyzed Using Supercomputer. Protein Prediction Tool Has Good Prospects. Microbe Probe: Studying Bacterial Genomes. SNS and Biological ...
Increased Prevalence of the Metabolic Syndrome in Patients with Psoriatic Arthritis
2010-01-01
Abstract Objectives: Psoriasis (PsO) is a common chronic T cellmediated inflammatory disorder traditionally thought to manifest in the skin and joints (psoriatic arthritis, PsA). Recently, it has been shown that these patients have an increased risk for myocardial infarction and this was greater with increasing severity of psoriasis. Patients with psoriasis have reported to have cardiometabolic disturbances including obesity, insulin resistance, and dyslipidemia. This constellation of risk factors, referred to as the metabolic syndrome, increases the risk for atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus. The aim of this study was to determine the prevalence of metabolic syndrome in PsA. Methods: In our study, we examined the records of 105 patients with Ps...
Heterocyclic indazole derivatives as SGK1 inhibitors, WO2008138448
2010-01-01
Heterocyclic indazole derivatives are claimed in patent WO2008138448 as inhibitors of the serum- and glucocorticoid-inducible-kinase 1 (SGK1) and drugs for the pharmacological treatment of SGK1-related diseases, such as diabetes, obesity, metabolic syndrome, systemic and pulmonary hypertension, cardiac fibrosis, hypertrophy and insufficiency, arteriosclerosis, glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, deranged electrolyte excretion, fibrosing and inflammatory disease (e.g., liver cirrhosis, lung fibrosis, rheumatism, arthrosis, Crohns disease, chronic bronchitis, radiation fibrosis, sclerodermia, cystic fibrosis, scar formation and Alzheimer' disease), tumor growth, peptic ulcers and some disorders hitherto not conclusively shown to involve SGK1. Most of the claims are s...
Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance
2010-10-14
Full Text Available.Non-alcoholic fatty liver disease (NAFLD), a further expression of metabolic syndrome, strictly linked to obesity and diabetes mellitus, is characterized by insulin resistance (IR), elevated serum levels of free fatty acids and fatty infiltration of the liver, which is known as hepatic steatosis. Hepatocyte apoptosis is a key feature of this disease and correlates with its severity. Free-fatty-acid-induced toxicity represents one of mechanisms for the pathogenesis of NAFLD and hormones, growth factors and adipokines influence also play a key role. This review highlights the various pathways that contribute to the development of hepatic steatosis. Circulating concentrations of inflammatory cytokines are reckoned to be the most important factor in causing and maintaining IR. Low-grade chronic inflammation is fundamental in the progression of NAFLD toward higher risk cirrhotic states.
Genetic variation in the visfatin (PBEF1/NAMPT) gene and type 2 diabetes in the Greek population
2010-01-01
Visfatin (NAMPT formerly known as PBEF1) is an adipokine that is strongly expressed in visceral fat and has caused much debate among researchers, regarding its involvement in glucose homeostasis and insulin resistance. It was initially isolated from bone marrow cells, and its involvement in inflammatory procedures such as sepsis and acute lung inflammation is now evident. Several studies have also reported an association of plasma visfatin levels with obesity. We undertook an evaluation of the involvement of the NAMPT gene in the development of type 2 diabetes (T2DM) in the Greek population. We studied 178 patients with T2DM and 177 controls that were matched for sex, age and body mass index. We genotyped three tagging SNPs selected from the HapMap II CEPH European population as reference ...
Fish oils for cardiovascular disease: Impact on diabetes
2010-01-01
The increasing prevalence of overweight and obesity has led to an epidemic of type 2 diabetes mellitus (T2DM), and is likely to be followed by an epidemic of patients with complications of T2DM such as cardiovascular diseases, neuropathy, retinopathy, and nephropathy. Nutritional interventions that incorporate functional foods, such fish oils - in particular n-3 polyunsaturated fatty acids (n-3 PUFAs) - may be a novel strategy to reduce insulin insensitivity, dyslipidemia, hypertension and pro-inflammatory state. The purpose of this article is to examine the impact of fish oil supplementation on blood lipids, glycemic control, blood pressure and inflammation in subjects with T2DM. Overall, the literature suggests that n-3 PUFA supplementation in diet presents many benefits in T2DM manageme...
2010-01-01
Ethnopharmacological relevance: Cordia ecalyculata Vell. and Echinodorus grandiflorus (Cham. & Schltdl.) Micheli are extensively used in Brazil as therapeutic preparations for indigenous groups and the general population. These plants have been used in the folk medicine as: tonic, diuretic, anti-inflammatory, appetite suppressants, for the treatment of snake bites, and weight loss. Aim of the study: In this study, it was verified the possible cytotoxic and genotoxic effects of the crude extracts of. Cordia ecalyculata and Echinodorus grandiflorus, as well as their effectiveness in treating obesity. Materials and methods: The Micronucleus Test was used for the evaluation of possible clastogenic and aneugenic effects, and the Comet Assay was used for the evaluation of single-strand and doubl...
2007-01-01
Statins exert anti-inflammatory, anti-atherogenic actions. The mechanisms responsible for these effects remain only partially elucidated. Diabetes and obesity are characterized by low-grade inflammation. Metabolic and endocrine adipocyte dysfunction is known to play a crucial role in the development of these disorders and the related cardiovascular complications. Thus, direct modulation of adipocyte function may represent a mechanism of pleiotropic statin actions. We investigated effects of atorvastatin on apoptosis, differentiation, endocrine, and metabolic functions in murine white and brown adipocyte lines. Direct exposure of differentiating preadipocytes to atorvastatin strongly reduced lipid accumulation and diminished protein expression of the differentiation marker CCAAT/enhancer bi...
At the crossroad between immunity and metabolism: focus on leptin
2010-01-01
White adipose tissue is currently considered to be an active endocrine organ that secretes a plethora of factors named adipokines, most of them proinflammatory in nature, which probably contribute to low-level systemic inflammation; a state that is often present in metabolic syndrome-associated chronic pathologies such as obesity and atherosclerosis. Leptin is historically and indisputably one of the most important adipokines secreted by fat cells, with a variety of physiological roles related to the control of metabolism, energy homeostasis and inflammatory response. One of these functions is the connection between nutritional status and immune competence. Indeed, leptin has been shown to modulate both the innate and adaptive immune responses in both normal and pathological conditions. It...
2010-01-01
Hirsutism is a common endocrine disorder, defined as increased growth of terminal hairs in a male pattern. Hirsutism is most often caused by polycystic ovary syndrome (PCOS), whereas only 5% patients are diagnosed with rare endocrine diseases. PCOS may be considered a multiorgan disease causing not only increased adrenal and ovarian sex hormone secretion but also changed secretion of gonadotrophins, growth hormone, and adrenocorticotrophic hormone (ACTH) from the pituitary. The majority of patients with PCOS are insulin resistant and PCOS is characterized by an increased inflammatory state with abdominal obesity and increased secretion of interleukins, chemokines, and adipokines. PCOS is therefore associated with an increased risk of the metabolic syndrome and type 2 diabetes (T2D). Patien...
Adiponectin in health and diseases: from metabolic syndrome to tissue regeneration
2010-01-01
Importance of the field: Adiponectin's importance as a regulator of metabolic functions has been assessed after observation of its downregulation in obese and diabetic patients. Decreased plasma adiponectin has been correlated with the onset of metabolic syndrome. Adiponectin has been proposed as an anti-inflammatory factor involved in protection of microvascular endothelium from inflammation insults. Areas covered in this review: The pleiotropic role of adiponectin in health and disease, with the double aim of describing the complex network of molecules engaged in its signaling in different tissues and underlining the gaps in the available data which need further investigation. What the reader will gain: Recent studies suggest that adiponectin can act as a paracrine/autocrine factor durin...
2005-01-01
SummaryThe metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular diseases such as visceral obesity, hypertension, and diabetes. There is a growing body of evidence to show that nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of insulin resistant patients with the metabolic syndrome. Indeed, insulin resistance increases adipocyte lipolysis and subsequently elevates circulating free fatty acids, thus stimulating the accumulation of fatty acids in the liver (hepatic steatosis). Fatty acids elicit reactive oxygen species generation, thereby promoting disease progression to NASH by both lipid peroxidation and inflammatory cytokine production. Postprandial hyperglycemia, one of the characteristic...
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