Galectin-3 inhibition prevents adipose tissue remodelling in obesity.

Extracellular matrix remodelling of the adipose tissue has a pivotal role in the pathophysiology of obesity. Galectin-3 (Gal-3) is increased in obesity and mediates inflammation and fibrosis in the cardiovascular system. However, the effects of Gal-3 on adipose tissue remodelling associated with obesity remain unclear. Male Wistar rats were fed either a high-fat diet (33.5% fat) or a standard diet (3.5% fat) for 6 weeks. Half of the animals of each group were treated with the pharmacological inhibitor of Gal-3, modified citrus pectin (MCP; 100 mg kg(-1) per day) in the drinking water. In adipose tissue, obese animals presented an increase in Gal-3 levels that were accompanied by an increase in pericellular collagen. Obese rats exhibited higher adipose tissue inflammation, as well as enhanced differentiation degree of the adipocytes. Treatment with MCP prevented all the above effects. In mature 3T3-L1 adipocytes, Gal-3 (10(-8 )m) treatment increased fibrosis, inflammatory and differentiation markers. In conclusion, Gal-3 emerges as a potential therapeutic target in adipose tissue remodelling associated with obesity and could have an important role in the development of metabolic alterations associated with obesity.

MAG-EPA resolves lung inflammation in an allergic model of asthma.

BACKGROUND: Asthma is a chronic disease characterized by airways hyperresponsiveness, inflammation and airways remodelling involving reversible bronchial obstruction. Omega-3 fatty acids and their derivatives are known to reduce inflammation in several tissues including lung. OBJECTIVES: The effects of eicosapentaenoic acid monoacylglyceride (MAG-EPA), a newly synthesized EPA derivative, were determined on the resolution of lung inflammation and airway hyperresponsiveness in an in vivo model of allergic asthma. METHODS: Ovalbumin (OVA)-sensitized guinea-pigs were treated or not with MAG-EPA administered per os. Isometric tension measurements, histological analyses, homogenate preparation for Western blot experiments or total RNA extraction for RT-PCR were performed to assess the effect of MAG-EPA treatments. RESULTS: Mechanical tension measurements revealed that oral MAG-EPA treatments reduced methacholine (MCh)-induced bronchial hyperresponsiveness in OVA-sensitized guinea-pigs. Moreover, MAG-EPA treatments also decreased Ca(2+) hypersensitivity of bronchial smooth muscle. Histological analyses and leucocyte counts in bronchoalveolar lavages revealed that oral MAG-EPA treatments led to less inflammatory cell recruitment in the lung of OVA-sensitized guinea-pigs when compared with lungs from control animals. Results also revealed a reduction in mucin production and MUC5AC expression level in OVA-sensitized animals treated with MAG-EPA. Following MAG-EPA treatments, the transcript levels of pro-inflammatory markers such as IL-5, eotaxin, IL-13 and IL-4 were markedly reduced. Moreover, per os MAG-EPA administrations reduced COX2 over-expression in OVA-sensitized animals. CONCLUSION AND CLINICAL RELEVANCE: We demonstrate that MAG-EPA reduces airway hyperresponsiveness and lung inflammation in OVA-sensitized animals, a finding consistent with a decrease in IL-4, IL-5, IL-13, COX-2 and MUC5AC expression levels in the lung. The present data suggest that MAG-EPA represents a new potential therapeutic strategy for resolving inflammation in allergic asthma.

Improving the time to diagnosis after an abnormal screening mammogram.

INTRODUCTION: Five community-specific interventions to reduce the time to diagnosis after an abnormal breast screen have been evaluated. METHODS: Subjects with abnormal screening mammograms in 1998 were assessed through five community pilot projects (N = 1137) and a control random sample assessed elsewhere in BC (N = 1053). The number, types, dates and physician costs of breast-related interventions after an abnormal screen were compared between pilots and control. RESULTS: The median time to diagnosis for women without a biopsy was reduced from 23 days to 7 days (p = 0.001) in the pilot with facilitated referral to diagnosis. The median time to diagnosis for women with a biopsy was reduced from 57 days to 22-43 days in the pilots. Median physician costs per subject were lower (p = 0.02) in pilots that more frequently used core biopsy to obtain a diagnosis. CONCLUSIONS: Process changes can improve the time to diagnosis after an abnormal breast screen, with similar or lower physician costs per subject. Facilitating the referral process had the greatest impact.

EETs relax airway smooth muscle via an EpDHF effect: BK(Ca) channel activation and hyperpolarization.

Epoxyeicosatrienoic acids (EETs) are produced from arachidonic acid via the cytochrome P-450 epoxygenase pathway. EETs are able to modulate smooth muscle tone by increasing K(+) conductance, hence generating hyperpolarization of the tissues. However, the molecular mechanisms by which EETs induce smooth muscle relaxation are not fully understood. In the present study, the effects of EETs on airway smooth muscle (ASM) were investigated using three electrophysiological techniques. 8,9-EET and 14,15-EET induced concentration-dependent relaxations of the ASM precontracted with a muscarinc agonist (carbamylcholine chloride), and these relaxations were partly inhibited by 10 nM iberiotoxin (IbTX), a specific large-conductance Ca(2+)-activated K(+) (BK(Ca)) channel blocker. Moreover, 3 microM 8,9- or 14,15-EET induced hyperpolarizations of -12 +/- 3.5 and -16 +/- 3 mV, with EC(50) values of 0.13 and 0.14 microM, respectively, which were either reversed or blocked on addition of 10 nM IbTX. These results indicate that BK(Ca) channels are involved in hyperpolarization and participate in the relaxation of ASM. In addition, complementary experiments demonstrated that 8,9- and 14,15-EET activate reconstituted BK(Ca) channels at low free Ca(2+) concentrations without affecting their unitary conductance. These increases in channel activity were IbTX sensitive and correlated well with the IbTX-sensitive hyperpolarization and relaxation of ASM. Together these results support the view that, in ASM, the EETs act through an epithelium-derived hyperpolarizing factorlike effect.

Putative anticarcinogenic actions of carotenoids: nutritional implications.

This review provides an update on nutritional aspects of carotenoids (as distinct from retinoids), with specific relevance to anticarcinogenesis. Critical gaps remain in our knowledge of the nutritional functions of carotenoids despite an overwhelming accumulation of research data in areas tangential to human nutrition. In addition to their roles as precursors of retinol and retinoids, carotenoids have distinct functions of their own in animals and humans. In vitro they are antioxidants with a broad range of potencies. In vivo, they protect porphyrics against sunlight. The evidence for anticarcinogenic actions of beta-carotene in certain specified test situations is persuasive. Nevertheless, despite a large number of studies demonstrating protection by carotenoids, the characteristics that render a given carotenoid effective and the relative efficacy of the individual carotenoids are not known. Moreover, dose-response and pharmacokinetic relationships remain virtually unexplored. Research to uncover mechanisms of protection by carotenoids is, for technical reasons, painfully slow. Epidemiological studies reveal associations but not cause and effect. To explore cause and effect, intervention trials are underway, hampered by the paucity of data regarding optimal choice of carotenoid, dosage, and regimen. The in vitro test systems that would provide this information are not available because the molecular sites relevant to the chemopreventive action of carotenoids are obscure. Each of these problems has a solution, but not a simple one. Until these are resolved, blanket recommendations regarding supplementation will remain problematic. To this point, health authorities have not recommended dietary supplementation with carotenoids. Instead, they recommend increased consumption of yellow and dark green carotenoid-rich vegetables. In the future, an individual at risk for a particular carcinogenic process may be recommended a supplement of the most appropriate anticarcinogen, specific to their individual endowment of genetic and environmental risk factors. This review emphasizes not only what is known but also what is not known. Consequently we identify priorities for research that, if undertaken, will allow such recommendations to be made or discounted with more confidence.

Hemolytic uremic syndrome: urate nephropathy superimposed on an acute glomerulopathy? An hypothesis.

The oligo-anuria of the hemolytic uremic syndrome is attributed to the presence of a renal lesion which is predominantly glomerulopathic but which may have a vasculopathic component of varying severity. Fourteen children, four of whom had anuric, four oliguric and six non oliguric acute renal failure were treated with intravenous fluids and high dose intravenous furosemide therapy. Polyuria was induced in all, obviating the need for dialysis. We hypothesize that oligo-anuria in this syndrome may be due to the previously recognized hyperuricemia causing a urate nephropathy superimposed on the glomerulopathy thus explaining its possible amenability to fluid and diuretic therapy.