Although mast cell functions classically relate to allergic responses1–3, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm, and cancer4–8. This study presents evidence that mast cells contribute importantly to diet-induced obesity and diabetes. White adipose tissues (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Genetically determined mast cell deficiency and pharmacological stabilization of mast cells in mice reduce body weight gain and levels of inflammatory cytokines, chemokines, and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer of cytokine-deficient mast cells established that these cells contribute to mice adipose tissue cysteine protease cathepsin expression, apoptosis, and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance by production of IL6 and IFN-γ. Mast cell stabilizing agents in clinical use reduced obesity and diabetes in mice, suggesting the potential of developing novel therapies for these common human metabolic disorders.

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1.1. Types of Carbohydrates and Their Importance in the Chemical, Food, and Pharmaceutical Industries Carbohydrates used as large-scale feedstock in industry include starch, cellulose, sucrose, glucose, and fructose (Scheme 1); they provide a number of advantages for widespread application. Other important saccharides with promising properties for smallscale processes include chitin, chitosan, and uronic acidcontaining glycans. In this section, chemical, food, and pharmaceutical applications of these saccharides are reviewed.These carbohydrates are primarily obtained from renewable feedstocks made through photosynthetic pathways, that is, carbon fixation removing greenhouse gas from the environment. Furthermore, they do not contribute to fossil fuel consumption, therefore being greener than other raw materials. Cellulose and starch are among the most abundant polysaccharides in nature. The biological functions of cellulose and starch are very different, with starch acting as a reservoir of glucose storage for energy 8 and cellulose acting as a structural component in the cell. 9 The starch polymer has a backbone chain of α-D-(1→4)glucopyranose (amylose) with branches linked by α-D-(1→6)glucopyranose (amylopectin) that can be conveniently obtained from many important crops such as wheat, rice, maize, tapioca, potato, and sweet potato. 10 Starch is an economically important carbohydrate because of its partial solubility in water, digestibility by animals, and ability to be converted into other higher-value compounds (i.e., ethanol or Kojic acid) through fermentation. 11 Oxidation, esterification, hydroxyalkylation, hydrolysis, and cross-linking are the most common modifications for preparation of starch derivatives. 12 As a consequence, these derivatives have important applications in food, chemical, and energy industries, such as the preparation of plasticized films and composites, thickeners, and stabilizers for food preparation, and as a source of dextrins and glucose, prepared through enzymatic hydrolysis, for biofuel production. 13 Cellulose is a linear polymer composed entirely of β-D-(1→4)glucopyranose. It is the most abundant biopolymer on earth and the most environmentally friendly and sustainable raw material. It has been widely used as the primary source of paper and other applications including textiles, hydrogels for medical uses, films and thickeners, and bioethanol production. 9a,14 Chemical modifications of cellulose include oxidation, hydrolysis, alkylation, and composite synthesis with addition of other polymers. 15 Sucrose (β-D-fructofuranosyl-α-D-glucopyranoside) is a disaccharide widely found in plants and has been used as a sweetener for centuries. 16 Sucrose contains fructofuranose and glucopyranose that can be released by hydrolysis of its glycosidic bond. The enzymatic hydrolysis of sucrose produces a mixture of the two sugars, known as inverted sugars. Many research groups have put their efforts into optimizing new methods to obtain them. 17 These sugars are widely used in the foo...

The serine proteases of the intrinsic blood coagulation cascade are slowly neutralized by antithrombin (AT) 1 (reviewed in Ref. 1). This inhibition is secondary to the generation of 1:1 enzyme⅐AT complexes whose formation is dramatically enhanced by the mast cell product, heparin (2). Damus et al. (3) hypothesized that endothelial cell surface heparan sulfate proteoglycans (HSPGs) function in a similar fashion to accelerate coagulation enzyme inactivation by AT and therefore are responsible for the nonthrombogenic properties of blood vessels. We initially demonstrated that perfusion of the hind limbs of normal rodents and rodents deficient in mast cells with purified thrombin and AT leads to a greatly elevated rate of thrombin⅐AT complex formation and that the enzyme heparitinase as well as the natural heparin antagonist platelet factor 4 suppress the above acceleration (4, 5). We subsequently showed that cultured cloned bovine macrovascular and rodent microvascular endothelial cells synthesize both anticoagulant HSPG (HSPG act ) and nonanticoagulant HSPG (HSPG inact ) (6 -8). HSPG act bear glycosaminoglycan (GAG) chains that bind tightly to AT and accelerate thrombin⅐AT complex generation (6 -8).The biosynthesis of HSPG act requires generation of a core protein; assembly of a linkage region of four neutral sugars on specific serine attachment sites of the core protein; elongation of a GAG backbone composed of alternating N-acetylglu-

Membrane fusion induced by herpes simplex virus (HSV) is required for both entry and cell-to-cell spread. It is mediated by the viral glycoprotein gB, gD, gH-gL and gD receptors. Although 3-O-sulfated heparan sulfate (3-OS HS) is a receptor for HSV-1 entry, the requirement for heparan sulfate in the fusion process has been ruled out. Here, it is demonstrated that cells expressing 3-OS HS, generated by D-glucosaminyl 3-O-sulfotransferase isoforms-3 and/or -5 (3-OST-3 and 3-OST-5), fused with cells expressing the four glycoproteins. The cell fusion observed exhibited similar requirements but was independent of protein receptors, HVEM or nectin-1. Additionally, removal of 3-OS HS from the cell surface by heparinase-I treatment and, in separate experiments, the presence of soluble 3-OST-3-and 3-OST-5-modified HS, significantly inhibited fusion. Taken together, these results indicate that 3-OS HS can play a crucial role in virus entry and cell fusion.

The present report analyzes the prevalence of the cluster of metabolic abnormalities defined as syndrome X (high blood glucose, high blood pressure, low high density lipoprotein (HDL) cholesterol, and high triglycerides) and its impact on cardiovascular disease mortality in a large cohort of men and women (22,561 men and 18,495 women). These individuals were participants in a series of epidemiologic investigations of cardiovascular disease conducted in Italy between 1978 and 1987. They were followed for an average of 7 years, during which time a total of 1,218 deaths occurred (1,003 in men and 215 in women). Deaths were coded according to the International Classification of Diseases, 9th Revision (ICD-9). The prevalence of the full cluster of metabolic abnormalities (syndrome X) was low in the population as a whole, with only 3.0 percent of men and 3.4 percent of women exhibiting the full cluster of abnormalities that comprise syndrome X. The risk of death from all causes and cardiovascular disease increased with increased numbers of metabolic abnormalities in both men and women. Mortality from cancer was significantly increased in women (but not in men) with syndrome X, compared with women with no metabolic abnormalities. Population attributable risks for all cause mortality and cardiovascular disease mortality were 0.06 and 0.09 in men and 0.04 and 0.48 in women when assessed by population cutpoints. These data from a large population-based epidemiologic investigation indicate that the presence of a full cluster of metabolic abnormalities from syndrome X is an important risk factor for cardiovascular disease and all-cause mortality in both men and women, but that the low prevalence of such a cluster in the population reduces the public health impact of syndrome X. The majority of individuals who die from cardiovascular disease present elevations in any one, two, or three of the metabolic abnormalities. The notion of the cluster of metabolic abnormalities (syndrome X) should not distract our attention from established individual risk factors that have been proven to be major causes of cardiovascular disease death and disability in our society.

DCLK1 up-regulation may play a contributory role in CRC metastasis and poor prognosis via activation of EMT. DCLK1 may serve as an independent predictor for CRC prognosis.

Abstract-Peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPAR␤/␦ activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPAR␤/␦ in adult mice using a tamoxifen-inducible transgenic approach with Cre-LoxP recombination. The expression of PPAR␤/␦ mRNA and protein in cardiomyocytes of adult mice was substantially increased after short-term induction. In these mice, the cardiac expression of key factors involved in mitochondrial biogenesis, such as PPAR␥ coactivator-1, endogenous antioxidants Cu/Zn superoxide dismutase, and catalase, fatty acid, and glucose metabolism, such as carnitine palmitoyltransferase Ib, carnitine palmitoyltransferase II, and glucose transporter 4, were upregulated. Subsequently, myocardial oxidative metabolism was elevated concomitant with an increased mitochondrial DNA copy number and an enhanced cardiac performance. Moreover, activation of PPAR␤/␦ in the adult heart improved cardiac function and resisted progression to pathological development in mechanical stress condition. We conclude that PPAR␤/␦ activation in the adult heart will promote cardiac performance along with transcriptional upregulation of mitochondrial biogenesis and defense, as well as oxidative metabolism at basal and pressure-overload conditions. (Hypertension. 2011;57:223-230.) • Online Data Supplement