Objective: The role of resistin in insulin sensitivity and obesity is controversial. Some authors suggest that increased serum resistin levels are associated with obesity, visceral fat, insulin resistance, type 2 diabetes and inflammation, while others failed to observe such correlations. The aim of the present study was to investigate the relationship of plasma resistin levels with markers of the metabolic syndrome and atherosclerosis in a large population-based study. Design and patients: Plasma resistin levels were determined in 1090 subjects free of any medication selected from the PLIC study (designed to verify the presence of atherosclerotic lesions and progression intimamedia thickness (IMT) in the common carotid artery in the general population) and related to the presence of obesity, metabolic syndrome, metabolic abnormalities, cardiovascular risk, and progression of IMT. Results: Plasma resistin levels were highly positively correlated with triglycerides, waist circumference, waist/hip ratio, systolic blood pressure, and ApoAI/ApoB ratio, while they were inversely correlated with high density lipoprotein and ApoAI levels. This finding was gender specific (mainly in women). Plasma resistin levels were significantly higher in women with the metabolic syndrome compared with controls (4.90 (0.24) ng/ml vs 3.90 (0.11) ng/ml; P!0.01), while no difference was observed in obese subjects. Finally, plasma resistin levels were significantly correlated with cardiovascular risk calculated according to the Framingham algorithm (P!0.01). Conclusion: Plasma resistin levels are increased in presence of the metabolic syndrome and are associated with increased cardiovascular risk.European Journal of Endocrinology 156 279-284

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Background and Purpose-Fractalkine receptor (CX3CR1) plays a key role during atherogenesis. CX3CR1 has 2 common coding polymorphisms, namely V249I and T280M, that have been associated with interindividual differences in susceptibility to atherosclerosis. In the present study, we investigated the possible association between CX3CR1variants and intima-media thickness (IMT). Methods-We genotyped 1256 samples from the Progression of Lesions in the Intima of the Carotid (PLIC) study (a prospective population-based study) for the presence of the V249 and the M280 variants of CX3CR1. Results-Significantly reduced IMT was observed in subjects with the MM280 genotype (0.57Ϯ0.12 mm) compared with subjects with the TT (0.65Ϯ0.14 mm) or the TM (0.65Ϯ0.13 mm) genotype. No difference in IMT was observed within carrier of the II249, VI249, or VV249 genotype. Subjects with combined genotype VI249/MM280 and II249/MM280 showed a reduced IMT. Conclusions-The presence of the M280 polymorphism of the fractalkine receptor is associated with a decreased common carotid artery IMT, whereas the presence of the I249 polymorphism does not play a major role on the progression of carotid atherosclerosis. CX3CR1 is believed to be a key mediator of atherogenesis and is expressed in atherosclerotic plaques 4,5 and in vessels from diabetic subjects. 6 The function of CX3CR1 in atherosclerosis was assessed by crossing CX3CR1 Ϫ/Ϫ mice into the apolipoprotein E (apoE) Ϫ/Ϫ background. Lesion formation throughout the aorta, including the aortic root, and macrophage accumulation were significantly reduced in the CX3CR1 Ϫ/Ϫ /apoE Ϫ/Ϫ animals, 7 suggesting a role for fractalkine in atherogenesis. 8 CX3CR1 has 2 common coding polymorphisms, namely V249I and T280M; I249 and M280 have been shown to be in linkage disequilibrium 9 -11 and have been associated with interindividual differences in susceptibility to HIV infection, atherosclerosis, and stroke. 9 -13 Despite these findings and the identification of CX3CR1 expression in atherosclerotic plaque, 4,5 the majority of the studies investigated the frequency of CX3CR1 polymorphisms in case-control studies, whereas no data are available on the possible role of these polymorphisms on early markers of atherosclerosis such as intima-media thickness (IMT) of the common carotid artery. We thus investigated the effect of the M280 and I249 variants of CX3CR1 on IMT in the PLIC study (a prospective population-based study) on the Progression of Lesions in the Intima of the Carotid. Materials and MethodsThe PLIC study was designed to investigate the presence and progression of atherosclerotic lesions and IMT in the common carotid artery in a local cohort (2141 subjects). The study was approved by the ethical committee for the Center for the Study of Atherosclerosis, University of Milan, and the participating subjects signed an informed consent. A detailed description of the study has been published previously 14 and as online supplement and includes the measurement of biochemical parameters and clinical outcome, ...

Abstract. Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, Maggi FM, Catapano AL (University of Milan; and Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo; Italy). Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J Intern Med 2005; 258: 21-27.Objectives. Toll-like receptor 4 (TLR-4) is believed to contribute to the initiation and progression of atherosclerosis. The association of the D299G polymorphism of the TLR-4 gene with the progression of coronary and carotid atherosclerosis, risk of cardiovascular events and myocardial infarction is controversial. We have investigated whether the presence of the D299G polymorphism and the co-segregated T399I polymorphism affects the intima-media thickness (IMT) in the general population. Subjects. The PLIC study population (n ¼ 1256) was genotyped for the D299G and the T399I polymorphisms. Results. The presence of both the D299G and T399I alleles was observed in the 13.0% of the population, carriers of the T399I alone were 1.8% and of the D299G alone were 0.9%. No difference in IMT was detected within the carriers of the D299G and T399I alleles and the wild-type subjects in the PLIC population. Furthermore, we investigated whether monocyte from D299G to T399I subjects present a defective response to CD40, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, cyclooxygenase (COX)-2 and PTX3 expression induced by lipopolysaccharide (LPS). When the monocytederived macrophages of these subjects were challenged with LPS (1 lg mL )1 ), no impact of the polymorphisms on the induction of CD40, MCP-1 and PTX3 was observed. Only IL-6 and COX-2 induction by LPS resulted reduced in the D299G/ T399I carriers. Conclusion. The presence of the D299G and T399I polymorphisms of the TLR-4 gene does not play a major role on the progression of carotid atherosclerosis. Macrophages from the subjects carrying the polymorphisms show an impaired response to LPS limited only to a IL-6 and COX-2.

The online version of this article has a Supplementary Appendix. BackgroundBoth the multi-kinase inhibitor sorafenib and the small molecule inhibitor of the MDM2/p53 interaction, nutlin-3, used alone, have shown promising anti-leukemic activity in acute myeloid leukemia cells. Thus, in this study we investigated the effect of the combination of sorafenib plus nutlin-3 in acute myeloid leukemia. Design and MethodsPrimary acute myeloid leukemia blasts (n=13) and FLT3 wildtype /p53 mutated (NB4) acute myeloid cell lines were exposed to sorafenib, used alone or in association with nutlin-3 at a 1:1 ratio, in a range of clinically achievable concentrations (1-10 mM). Induction of apoptosis and autophagy was evaluated by transmission electron microscopy and by specific flow cytometry analyses. The levels of Mcl-1, p53 and Bak proteins were analyzed by western blotting. Knock-down of Bax and Bak gene expression was performed in transfection experiments with specific short interfering RNA. ResultsThe sorafenib+nutlin-3 drug combination exhibits synergistic cytotoxicity in primary acute myeloid leukemia blasts and in acute myeloid leukemia cell lines with maximal cytotoxicity in FLT3 mutated MV4-11 and MOLM, followed by the FLT3 wild-type OCI-AML3, HL60 and NB4 cell lines. The cytotoxic activity of sorafenib+nutlin-3 was characterized by an increase of both apoptosis and autophagy. Moreover, Bax and Bak showed prominent roles in mediating the decrease of cell viability in response to the drug combination in p53wild-type OCI-AML3 and p53 deleted HL-60 cells, respectively, as demonstrated in transfection experiments performed with specific short interfering RNA. ConclusionsOur data demonstrate that acute myeloid leukemia cells show a variable but overall good susceptibility to the innovative therapeutic combination of sorafenib+nutlin-3, which differentially involves the pro-apoptotic Bcl-2 family members Bax and Bak in p53wild-type and p53 deleted cells.