Targeting the Wnt pathway in cancer: The emerging role of Dickkopf-3

Aberrant activation of the Wnt signaling pathway is a major trait of many human cancers. Due to its vast implications in tumorigenesis and progression, the Wnt pathway has attracted considerable attention at several molecular levels, also with respect to developing novel cancer therapeutics. Indeed, research in Wnt biology has recently provided numerous clues, and evidence is accumulating that the secreted Wnt antagonist Dickkopf-related protein 3 (Dkk-3) and its regulators may constitute interesting therapeutic targets in the most important human cancers. Based on the currently available literature, we here review the knowledge on the biological role of Dkk-3 as an antagonist of the Wnt signaling pathway, the involvement of Dkk-3 in several stages of tumor development, the genetic and epigenetic mechanisms disrupting DKK3 gene function in cancerous cells, and the potential clinical value of Dkk-3 expression/DKK3 promoter methylation as a biomarker and molecular target in cancer diseases.In conclusion, Dkk-3 rapidly emerges as a key player in human cancer with auspicious tumor suppressive capacities, most of all affecting apoptosis and proliferation. Its gene expression is frequently downregulated by promoter methylation in almost any solid and hematological tumor entity. Clinically, evidence is accumulating of Dkk-3 being both a potential tumor biomarker and effective anti-cancer agent. Although further research is needed, re-establishing Dkk-3 expression in cancer cells holds promise as novel targeted molecular tumor therapy.     

The use of small subcutaneous transponders for quantifying thermal biology and torpor in small mammals

Remote measurements of body temperature (T_b) in animals require implantation of relatively large temperature-sensitive radio-transmitters or data loggers, whereas rectal temperature (T_rec) measurements require handling and therefore may bias the results. We investigated whether ∼0.1 g temperature-sensitive subcutaneously implanted transponders can be reliably used to quantify thermal biology and torpor use in small mammals. We examined (i) the precision of transponder readings as a function of temperature and (ii) whether subcutaneous transponders can be used to remotely record subcutaneous temperature (T_sub). Five adult male dunnarts (Sminthopsis macroura, body mass 24 g) were implanted with subcutaneous transponders to determine T_sub as a function of time and ambient temperature (T_a), and in comparison to thermocouple readings of T_rec. Transponder temperature was highly correlated with water bath temperature (r²=0.96–0.99) over a range of approximately 10.0–40.0 °C. Transponders provided reliable data (±0.6 °C) over the T_sub of 21.4–36.9 °C and could be read from a distance of up to 5 cm. Below 21.4 °C, accuracy was reduced to ±2.8 °C, but individual transponder accuracy varied. Consequently, small subcutaneous transponders are useful to remotely quantify thermal physiology and torpor patterns without having to disturb the animal and disrupt torpor. Even at T_sub<21.4 °C where the accuracy of the temperature readings was reduced, transponders do provide reliable data on whether and when torpor is used.     

Relationship of Anterior and Posterior Subcutaneous Abdominal Fat to Insulin Sensitivity in Nondiabetic Men

Recent studies from our group reveal that adipose tissue (AT) in the subcutaneous abdominal region is the most important determinant of peripheral and hepatic insulin sensitivity. Because of different anatomic and physiologic characteristics of anterior and posterior subcutaneous abdominal AT, we investigated the relationship of the masses of each compartment, as determined by magnetic resonance imaging, to insulin sensitivity (using euglycemic hyperinsulinemic glucose clamp technique), and other anthropometric variables. Thirty-four healthy men with varying ranges of obesity were recruited for the study. The mass of posterior subcutaneous abdominal AT was ～1.6 times more than that of the anterior compartment, and these masses accounted for 12.9% and 8.2% of the total body fat mass, respectively. All anthropometric variables, including body mass index (BMI), waist-to-hip circumference ratio (WHR), skinfold thicknesses, and intraperitoneal AT mass were more significantly related to the posterior than the anterior subcutaneous abdominal AT mass. Compared to the anterior compartment mass, the posterior compartment mass displayed stronger relationship with insulin-mediated glucose disposal (Rd) (r=-0.44, p=0.009, and r=-0.76, p=0.0001, respectively) as well as with residual hepatic glucose output during the 40 mU.^?2.min-¹ insulin infusion (r=0.39, p=0.02, and r=0.53, p=0.001, respectively). After adjusting for total body fat, the Rd values showed a significant partial correlation with the posterior subcutaneous abdominal AT mass (r=-0.52, p=0.002). To conclude, posterior subcutaneous abdominal AT mass is a more important determinant of peripheral and hepatic insulin sensitivity than the anterior subcutaneous abdominal AT.     

Effect of T. chebula on mitochondrial alterations in experimental myocardial injury

Mitochondria play a central role in molecular events leading to tissue damage in ischemia. The present study examines the role of the alcoholic extract of T. chebula (TCE) pretreatment (50 mg/100 g body weight) to attenuate the isoproterenol (ISO) (20mg/100g body wt, sc) induced alterations on heart mitochondrial ultrastucture and function in experimental rats. ISO induced cardiotoxicity was evidenced by a significant rise in the level of lactate, decrease in enzyme activities of tricarboxylic acid cycle (TCA), mitochondrial respiration, levels of adenosine triphosphate (ATP) and oxidative phosphorylation. TCE intervention significantly attenuated the above alterations by ISO and retained near normal function of the mitochondria. Electron microscopic studies of the mitochondria further support the isoproterenol induced deleterious changes and accredit the protective effect of TCE on mitochondrial structure and energy metabolism.     

Depot-specific effects of the PPAR�� agonist rosiglitazone on adipose tissue glucose uptake and metabolism

We investigated mechanisms whereby peroxisome proliferator-activated receptor γ (PPARγ) agonism redistributes lipid from visceral (VF) toward subcutaneous fat (SF) by studying the impact of PPARγ activation on VF and SF glucose uptake and metabolism, lipogenesis, and enzymes involved in triacylglycerol (TAG) synthesis. VF (retroperitoneal) and SF (inguinal) of rats treated or not for 7 days with rosiglitazone (15 mg/kg/day) were evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (or lipin-1), and diacylglycerol acyltransferase. Rosiglitazone increased SF glucose uptake, GLUT4 mRNA, and insulin-stimulated glucose oxidation, conversion to lactate, glycogen, and the glycerol and fatty acid components of TAG. In VF, only glucose incorporation into TAG-glycerol was stimulated by rosiglitazone and less so than in SF (1.5- vs. 3-fold). mRNA levels of proteins involved in glycolysis, Krebs cycle, glycogen synthesis, and lipogenesis were markedly upregulated by rosiglitazone in SF and again less so in VF. Rosiglitazone activated TAG-glycerol synthesis in vivo (2.8- vs. 1.9-fold) and lipin activity (4.6- vs. 1.5-fold) more strongly in SF than VF, whereas GPAT activity was increased similarly in both depots. The preferential increase in glucose uptake and intracellular metabolism in SF contributes to the PPARγ-mediated redistribution of TAG from VF to SF, which in turn favors global insulin sensitization.     

Body fat influences departure from stopover sites in migratory birds: evidence from whole-island telemetry

Migration remains one of the great mysteries of animal life. Small migratory birds rely on refuelling stopovers after crossing ecological barriers such as deserts or seas. Previous studies have suggested that fuel reserves may determine stopover duration but this hypothesis could not be tested because of methodological limitations. Here, we provide evidence that subcutaneous fat stores determine stopover duration by measuring the permanence of migratory garden warblers (Sylvia borin) on a small Mediterranean island during spring migration with telemetry methods. Garden warblers with large amounts of fat stores departed the island significantly sooner than lean birds. All except one fat bird left the island on the same evening after capture, with a mean total stopover estimate of 8.8 hours. In contrast, the mean estimated total stopover duration of lean birds was 41.3 hours. To our knowledge, this is the first study that measures the true minimum stopover duration of a songbird during migration.     

Fatness and Physical Fitness of Girls 7 to 17 Years

A two-fold approach was used to investigate the association between fatness and fitness of girls 7 to 17 years of age: first, age-specific correlations between fatness and measures of health-related and motor fitness, and second, comparisons of fitness levels of girls classified as fat and lean. A representative sample of 6700 between 7 to 17 years was surveyed. Adiposity (fatness) was estimated as the sum of five skinfolds (biceps, triceps, subscapular, suprailiac, medial calf). Physical fitness included health-related items (step test, PWC₁₇₀ the sit and reach, sit-ups and leg lifts, flexed arm hang) and motor performance items (standing long jump, vertical jump, arm pull strength, flamingo stand, shuttle run, plate tapping). Age-specific partial correlations between fatness and each fitness item, controlling for stature and weight, were calculated. In addition, in each age group the fattest 5% (presumably the obese) and the leanest 5% were compared on each fitness test. After controlling for stature and weight, subcutaneous fatness accounts for variable percentages of the variance in each fitness item. Estimates for health-related fitness items are: cardiorespiratory endurance - step test (3% to 5%) and PWC₁₇₀ (0% to 16%), flexibility - sit and reach (3% to 8%), functional strength - flexed arm hang (6% to 17%) and abdominal strength - sit-ups/leg lifts (1% to 8%). Corresponding estimates for motor fitness items are more variable: speed of limb movement -plate tapping (0% to 3%), balance - flamingo stand (0% to 5%), speed and agility - shuttle run (2% to 12 %), static strength - arm pull (4% to 12%), explosive strength - standing long jump/vertical jump (11% to 18%). At the extremes, the fattest girls have generally poorer levels of health-related and motor fitness.     

Review of animal mycoses in Australia

This review covers the available literature on the mycoses of animals in Australia since the last review published in 1967. Of the cutaneous infections, dermatophytoses have been recorded in a wide range of animals: cattle, horses, goats, pigs, sheep, cats, dogs, mice, guinea-pigs, rabbits, a lion, kangaroos, a camel, koalas and wallabies. These infections were caused by several species and varieties of the genera,Microsporum andTrichophyton. Eight agents of ringworms have been recorded in the horse. Two subcutaneous mycoses, phaeohyphomycosis and sporotrichosis have been reported. Phaeohyphomycosis is becoming more common but sporotrichosis is rare having been recorded only once in a cat.The following systemic mycoses have been recorded: adiaspiromycosis, aspergillosis, candidiasis, cryptococcosis, dactylariosis, fusariomycosis, histoplasmosis, miscellaneous mycoses, mycotic abortion and related conditions, zygomycosis, pythiosis, protothecosis and green algal infections. Cryptococcosis has affected 11 different animal species. Mycotic abortion is a serious disease in Victoria. Pythiosis of horses has been extensively studied in northern Australia.