Alain Nicolay

HDLs activate ADAM17‐dependent shedding

The tumor necrosis factor‐alpha (TNF) converting enzyme (ADAM17) is a metalloprotease that cleaves several transmembrane proteins, including TNF and its receptors (TNFR1 and TNFR2). We recently showed that the shedding activity of ADAM17 is sequestered in lipid rafts and that cholesterol depletion increased the shedding of ADAM17 substrates. These data suggested that ADAM17 activity could be regulated by cholesterol movements in the cell membrane. We investigated if the membrane cholesterol efflux induced by high‐density lipoproteins (HDLs) was able to modify the shedding of ADAM17 substrates. HDLs added to different cell types, increased the ectodomain shedding of TNFR2, TNFR1, and TNF, an effect reduced by inhibitors active on ADAM17. The HDLs‐stimulated TNF release occurred also on cell‐free isolated plasma membranes. Purified apoA1 increased the shedding of TNF in an ABCA1‐dependent manner, suggesting a role for the cholesterol efflux in this phenomenon. HDLs reduced the cholesterol and proteins (including ADAM17) content of lipid rafts and triggered the ADAM17‐dependent cleavage of TNF in the non‐raft region of the membrane. In conclusion, these data demonstrate that HDLs alter the lipid raft structure, which in turn activates the ADAM17‐dependent processing of transmembrane substrates. J. Cell. Physiol. 214: 687–693, 2008.

Progression of atherosclerosis in ApoE-deficient mice that express distinct molecular forms of TNF-alpha†

TNFα (TNF) critically regulates inflammation‐driven atherosclerosis. Because the transmembrane (tmTNF) and soluble (sTNF) forms of TNF possess distinct immuno‐modulatory properties, we hypothesized that they might differentially regulate atherosclerosis progression. Three groups of male ApoE−/− mice were studied: one expressing wild‐type TNF (WT‐TNF); one expressing exclusively a mutated non‐cleavable form of TNF (KI‐TNF); and one deficient in TNF (KO‐TNF). Mice aged 5 weeks were fed the high‐fat diet for 5 (T5) and 15 weeks (T15) or a standard chow diet for 15 weeks. At T5, in mice fed the high‐fat diet, no significant differences in lesion area were observed among the three groups, either in valves or in aortas. At T15, lesion areas in valves were significantly lower in KO‐TNF mice compared with those in WT‐TNF mice, whereas in KI‐TNF mice, they were intermediate between KO‐ and WT‐TNF mice but not significantly different from these two groups. In aortas, lesions in KI‐TNF were comparable to those of KO‐TNF, both being significantly lower than those in WT‐TNF. Theses differences were not linked to circulating lipids, or to macrophage, actin, and collagen contents of lesions. At T15, in mice fed the chow diet, lesion areas in valves and the aortic arch were not significantly different between the three groups. Levels of IL‐6, IFNγ, IL‐10, and Foxp3 mRNAs in spleens and production of IL‐6, IL‐10, MCP‐1, RANTES, and TNFR‐2 by peritoneal macrophages at T15 of the high‐fat diet showed a decrease in pro‐inflammatory status, more marked in KO‐TNF than in KI‐TNF mice. Apoptosis was reduced only in KO‐TNF mice. In conclusion, these data show that TNF effects on atherosclerosis development are detectable at stages succeeding fatty streaks and that wild‐type TNF is superior to tmTNF alone in promoting atherosclerosis. TNF‐dependent progression of atherosclerosis is probably linked to the differential production of pro‐inflammatory mediators whether tmTNF is preponderant or essentially cleaved. Copyright

Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes

Objective—Overproduction of intestinally derived apoB-48-containing triglyceride-rich lipoproteins (TRLs) (chylomicrons) has recently been described in type 2 diabetes, as is known for hepatic TRL-apoB-100 (very-low-density lipoprotein) production. Furthermore, insulin acutely inhibits both intestinal and hepatic TRL production, whereas this acute inhibitory effect on very-low-density lipoprotein production is blunted in type 2 diabetes. It is not currently known whether this acute effect on chylomicron production is similarly blunted in humans with type 2 diabetes. Methods and Results—We investigated the effect of acute hyperinsulinemia on TRL metabolism in 18 type 2 diabetic men using stable isotope methodology. Each subject underwent 1 control (saline infusion [SAL]) lipoprotein turnover study followed by a second study, under 1 of the 3 following clamp conditions: (1) hyperinsulinemic-euglycemic, (2) hyperinsulinemic-hyperglycemic, or (3) hyperinsulinemic-euglycemic plus intralipid and heparin. TRL-apoB-48 and TRL-apoB-100 production and clearance rates were not different between SAL and clamp and between the different clamp conditions, except for significantly lower TRL-apoB-100 clearance and production rates in hyperinsulinemic-euglycemic plus intralipid and heparin clamp compared with SAL. Conclusion—This is the first demonstration in individuals with type 2 diabetes that chylomicron production is resistant to the normal acute suppressive effect of insulin. This phenomenon may contribute to the highly prevalent dyslipidemia of type 2 diabetes and potentially to atherosclerosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00950209.

Effects of Bariatric Surgery on Hepatic and Intestinal Lipoprotein Particle Metabolism in Obese, Nondiabetic Humans

Objective— The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100–containing very low-density lipoprotein) and intestinal (apoB-48–containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. Approach and Results— Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRL-apoB-48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of patients undergoing bariatric surgery. Conclusions— This is the first human lipoprotein kinetic study to explore the mechanism of improvement of TRL metabolism after bariatric surgery. These effects may contribute to the decrease of cardiovascular mortality after surgery. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01277068.

Parallel increase of plasma apoproteins C-II and C-III in Type 2 diabetic patients.

Aims  To determine plasma levels of apoprotein (apo) C‐II and apoprotein C‐III in Type 2 diabetic patients and to examine the clinical and biological factors that are associated with elevated apoC concentrations.

Hyperkalemia risks in hemodialysed patients consuming fluoride-rich water.

In order to observe the consequences of chronic ingestion of high fluoride-rich water on plasma potassium levels of hemodialysed subjects, we have conducted a retrospective study on 25 patients with chronic renal failure, treated with a substitute method, six of whom (consumers group, group C) were drinkers of a bicarbonate (about 4500 mg/l) and fluoride-rich (9 mg/l) mineral water, the Vichy Saint-Yorre water. With respect to sodium polystyrene sulfonate consumption (n = 17), there was no significant difference between group C and NC (non-consumers group). A significant correlation between plasma fluoride and potassium levels was observed only before dialysis (P < 1 x 10(-7)) but not after dialysis. A group by group analysis revealed that this correlation was linked to group C (P < 5 x 10(-6)), in which kalemia before dialysis was higher than that observed in group NC (P < 0.005). Moreover, it appeared that the higher fluoride levels were, the higher the kalemia was inclined to be. Thus, the risks of hyperkalemia in dialysed patients, who also drink Vichy St-Yorre water or other fluoride-rich waters, are more important, while not forgetting the risk of fluorosis. The mechanisms by which chronically administered fluoride could increase kalemia are also discussed.

Comparative In Vitro Performance of Three Small-Volume Valved Holding Chambers with Beclomethasone/Formoterol Pressurized Metered Dose Inhaler

BACKGROUND The use of valved holding chambers (VHCs) with pressurized metered dose inhalers (pMDIs) is reported to reduce the oral deposition of inhaled drugs and to facilitate the handling of these devices by patients, especially children. Although the number of commercially available VHCs is increasing, the correct choice of VHC in clinical practice is important, because VHCs are not equally effective regarding medication delivery. Hence, we aimed to evaluate the use of three small-volume VHCs-Vortex(®), AeroChamber(®) Plus (ACP), and Able Spacer™ (AS)-along with a commercial pMDI containing a combination of beclomethasone and formoterol (Innovair(®)) frequently used by asthma patients. METHODS Evaluation of the delivered dose of both drugs and analysis of particle size distribution of aerosols emitted for the inhaler were performed using the Next Generation Impactor with and without the tested VHCs. RESULTS The VHCs retained significant quantities of both drugs and dramatically reduced the quantity of drugs deposited in the throat of the impactor, indicating that particles with large size were preferably retained in the VHCs. Interestingly, although the delivered dose of both drugs was reduced by the use of VHCs, the use of the Vortex and the ACP resulted in comparable fine particle doses (FPDs) to that obtained when the pMDI was used alone, whereas the AS VHC significantly reduced the FPDs of both drugs. This may be due to the fact that, unlike the AS VHC, the Vortex and the ACP VHCs are made of antistatic materials that minimize the electrostatic interaction with emitted aerosols, enhancing medication delivery. CONCLUSION The Vortex and the ACP VHCs present interesting advantages over the AS VHC to be used with Innovair pMDI. However, these results are based on an in vitro evaluation and need to be validated in an in vivo study in order to clinically assess the performance of these VHCs.

Chemical composition and variability of the essential oil of Thymus numidicus Poir. from Algeria

Abstract In a previous study, Thymus numidicus has showed a high antifungal activity. Here, GC/MS analysis was used for the chemical determination of the essential oil from T. numidicus. Samples were obtained by hydrodistillation from plants gathered in three different places during the biological cycle. Essential oils were high in phenolic monoterpens and in their precursors, and in non—phenolic oxygenated and non—oxygenated monoterpens. The arrangement of several statistical tools has enabled a relation between the chemical composition variation of essential oils during the biological cycle and the abiotic conditions of each place. Essential oils collected during the periods: end of March and end of April were low in monoterpens, high in oxygenated monoterpens and phenols. The periods corresponding to July were typical from the biological cycle end, with high level in p—cymene and low level in phenols and linalool.

Plasma adiponectin in heart transplant recipients

Abstract:  Background:  The association between plasma adiponectin and metabolic syndrome may be impaired in heart transplant recipients, since renal failure is frequent among these patients. Thus, we studied the relationship between metabolic syndrome and plasma adiponectin in transplanted heart recipients.

Cholesterol-Absorber Status Modifies the LDL Cholesterol–Lowering Effect of a Mediterranean-Type Diet in Adults with Moderate Cardiovascular Risk Factors

LDL-cholesterol (LDL-C) reduction may be achieved by various types of prudent diets, but their effects on surrogate markers of cholesterol absorption and synthesis have not been well studied in humans. We aimed to assess whether the extent of cholesterol absorption or synthesis, and cholesterol concentrations, are modified in adults when they shift from a Western-type diet (WD) to a combined low-fat, low-cholesterol/Mediterranean-type diet (LFCMD). Cholestanol and sitosterol, as well as desmosterol and lathosterol, surrogate markers of cholesterol absorption or synthesis, respectively, were quantified in the serum of 125 fasting, middle-aged participants at moderate cardiovascular risk. They habitually consumed a WD and then consumed a LFCMD during the 3-mo intervention. The group was stratified by serum cholestanol concentration and classified as high, intermediate, or low absorbers of cholesterol. When they consumed the WD, participants had comparable total and LDL-C concentrations, independent of absorber group and sex. After 3 mo of consuming the LFCMD, absorption and synthesis did not change or changed only slightly. The cholestanol concentration increased in low absorbers by 18% (P < 0.02) and decreased in high absorbers by 14% (P < 0.001), but these variations did not change the high- or low-absorber status. In male and female low absorbers, plasma total (-7%) and LDL-C (-9%) concentrations decreased after the 3-mo intervention and changes were 2.3- and 2.4-fold greater, respectively, than in high absorbers, independent of sex. Cholesterol synthesis/absorption status was not markedly altered by diet, but the decrease in plasma LDL-C due to the Mediterranean-type diet occurred only in low absorbers of cholesterol. This should be considered during further dietary interventions.