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Murr J.,Center Dexcellence Sur Le Vieillissement Of Quebec | Murr J.,Laval University | Carmichael P.-H.,Center Dexcellence Sur Le Vieillissement Of Quebec | Julien P.,Laval University | And 3 more authors.
Neurobiology of Aging | Year: 2014

This study examines the association of plasma oxidized low-density lipoprotein (OxLDL) levels with all-cause dementia, including Alzheimer's disease (AD) and vascular dementia. Data are taken from the Canadian Study of Health and Aging, a population-based study of a representative sample of persons aged more than 65 years conducted from 1991 to 2002. The present study sample included 670 subjects of which, 155 developed all-cause dementia with 109 cases of AD and 32 of vascular dementia. In Cox regression models, no association between OxLDL and risks of dementia or subtypes was found. A triple interaction between OxLDL, sex, and history of cardiovascular disease on the risk of AD (p= 0.0077) was found. Increased levels of OxLDL were significantly associated with an increased risk of AD in men with a history of cardiovascular disease (hazard ratio= 1.11; 95% confidence interval 1.04-1.19); no association in women was found. These findings suggest that increased levels of OxLDL are not associated with the risk of dementia, AD, and vascular dementia. The association of OxLDL with AD in men with a history of cardiovascular disease merits further investigation. © 2014 Elsevier Inc.

Thibault V.,Endocrinology and Nephrology Unit | Morisset A.-S.,Endocrinology and Nephrology Unit | Brown C.,Universite de Sherbrooke | Carpentier A.C.,Universite de Sherbrooke | And 5 more authors.
British Journal of Nutrition | Year: 2015

Serum 25-hydroxyvitamin D (25(OH)D) concentrations have been reported to increase following weight loss. Moreover, both weight loss and higher serum 25(OH)D concentrations have been associated with a lower risk of developing type 2 diabetes. The objective of the present study was to determine whether the increase in serum 25(OH)D concentration following weight loss is associated with improved insulin sensitivity, insulin secretion and disposition index (β-cell function). Data from two prospective lifestyle modification studies had been combined. Following a lifestyle-modifying weight loss intervention for 1 year, eighty-four men and women with prediabetes and a BMI ≥ 27 kg/m2 were divided based on weight loss at 1 year: < 5 % (non-responders, n 56) and ≥ 5 % (responders, n 28). The association between the change in serum 25(OH)D concentration and changes in insulin sensitivity (homeostasis model assessment of insulin sensitivity (HOMA%S) and Matsuda), insulin secretion (AUC of C-peptide) and disposition index after adjustment for weight loss was examined. Participants in the responders' group lost on average 9·5 % of their weight when compared with non-responders who lost only 0·8 % of weight. Weight loss in responders resulted in improved insulin sensitivity (HOMA%S, P= 0·0003) and disposition index (P= 0·02); however, insulin secretion remained unchanged. The rise in serum 25(OH)D concentration following weight loss in responders was significantly higher than that in non-responders (8·9 (sd 12·5) v. 3·6 (sd 10·7) nmol/l, P= 0·05). However, it had not been associated with amelioration of insulin sensitivity and β-cell function, even after adjustment for weight loss and several confounders. In conclusion, the increase in serum 25(OH)D concentration following weight loss does not contribute to the improvement in insulin sensitivity or β-cell function. © The Authors 2015.

Kenmogne L.C.,Endocrinology and Nephrology Unit | Kenmogne L.C.,Laval University | Ayan D.,Endocrinology and Nephrology Unit | Roy J.,Endocrinology and Nephrology Unit | And 3 more authors.
PLoS ONE | Year: 2015

Ovarian and pancreatic cancers are two of the most aggressive and lethal cancers, whose management faces only limited therapeutic options. Typically, these tumors spread insidiously accompanied first with atypical symptoms, and usually shift to a drug resistance phenotype with the current pharmaceutical armamentarium. Thus, the development of new drugs acting via a different mechanism of action represents a clear priority. Herein, we are reporting for the first time that the aminosteroid derivative RM-133, developed in our laboratory, displays promising activity on two models of aggressive cancers, namely ovarian (OVCAR-3) and pancreatic (PANC-1) cancers. The IC50 value of RM-133 was 0.8 ÎM and 0.3 ÎM for OVCAR-3 and PANC-1 cell lines in culture, respectively. Based on pharmacokinetic studies on RM-133 using 11 different vehicles, we selected two main vehicles: aqueous 0.4% methylcellulose:ethanol (92:8) and sunflower oil:ethanol (92:8) for in vivo studies. Using subcutaneous injection of RM-133 with the methylcellulose-based vehicle, growth of PANC-1 tumors xenografted to nude mice was inhibited by 63%. Quite interestingly, RM- 133 injected subcutaneously with the methylcellulose-based or sunflower-based vehicles reduced OVCAR-3 xenograft growth by 122% and 100%, respectively. After the end of RM- 133 treatment using the methylcellulose-based vehicle, OVCAR-3 tumor growth inhibition was maintained for > 1 week. RM-133 was also well tolerated in the whole animal, no apparent sign of toxicity having been detected in the xenograft studies. © 2015 Kenmogne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Ouellet C.,Endocrinology and Nephrology Unit | Ouellet C.,Laval University | Ouellet E.,Endocrinology and Nephrology Unit | Ouellet E.,Laval University | And 2 more authors.
Investigational New Drugs | Year: 2015

Selective estrogen receptor modulators (SERMs) are currently in use in the hormonal therapy of breast cancer. In that respect, a new hormone-related approach is the therapeutical inhibition of steroid sulfatase (STS), which converts inactive, sulfated steroids into active hormones. We investigated the potential of 6-EO-14, a non-steroidal STS inhibitor with SERM potential. The latter compound, which exhibits a sulfamate moiety, releases the phenol derivative 8-EO-14 after the irreversible inhibition of STS. STS was inhibited by 6-EO-14 (IC50=0.3 μM), but not 8-EO-14, in HEK-293 cells transfected with an STS expression vector. The SERM potential of 8-EO-14 was assessed in osteoblast-like Saos-2 cells by investigating its effect on cell proliferation and on the activity of alkaline phosphatase (ALP), a specific differentiation marker. Saos-2 cell proliferation was increased by 21 % following 8-EO-14 addition (1 μM), and 8-EO-14 induced ALP activity (31 % increase at 0.1 nM) via estrogen receptor alpha (ERα) similarly to the SERM raloxifene. As compared to estradiol (E2) (100 %), the relative binding affinity of 6-EO-14 and 8-EO-14) for ERα was found to be weak (0.09 and 0.01 %, respectively). When assessed in two estrogen-dependent human breast cancer cell lines (MCF-7 and T-47D), 8-EO-14 did not support MCF-7 cell proliferation, whereas both 8-EO-14 and 6-EO-14 exhibited estrogen-like growth stimulation in T-47D cells. These two compounds were also unable to block E2-induced cell proliferation, suggesting their lack of antiestrogenic activity. Despite the known potency of 6-EO-14 as an STS inhibitor, the observed trophic activity of this new scaffold towards ERα-positive cells needs to be carefully considered prior to its potential utilization as a therapeutic agent. © 2014 Springer Science+Business Media New York.

Roy P.,Laval University | Nadeau M.,Laval University | Nadeau M.,Quebec Heart and Lung Institute Research Center | Nadeau M.,Endocrinology and Nephrology Unit | And 15 more authors.
Steroids | Year: 2015

Context Both Vitamin D deficiency and inflammation have been associated with insulin resistance and type 2 diabetes risk. In vitro Vitamin D treatment of subcutaneous (SC) adipose tissue (AT) may reduce inflammation, but data are conflicting. Objectives To evaluate the effects of Vitamin D (25(OH)D3 and 1,25(OH)2D3) on the secretion of inflammatory cytokines (TNF-α and IL-6) in omental (OM) and SC human AT and to explore factors that could correlate with the individual response to Vitamin D including age, smoking status, BMI, comorbidities, medication, HbA1c, apolipoprotein B, serum 25-hydroxyVitamin D and high sensitivity C-reactive protein. Patients 7 men and 8 women with severe obesity undergoing bariatric surgery. Intervention Fresh OM and SC AT explants sampled during surgery (n = 15) were incubated for 24 h in a control, 25(OH)D3 (150 nM) or 1,25(OH)2D3 (1 nM) medium. Lipopolysaccharide (LPS) (10 ng/ml) was added for another 24 h. Main outcome measure Change in TNF-α and IL-6 levels in collected media after Vitamin D treatment (ELISA). Results Mean age and BMI of the patients were 46.4 ± 10.9 years and 48.8 ± 7.5 kg/m2, respectively. Eleven patients had type 2 diabetes. 25(OH)D3 and 1,25(OH)2D3 reduced the LPS-induced increases in cytokine levels in OM AT of women but not in men. No effect was observed in SC AT. Apart from gender, none of the factors analyzed correlated with Vitamin D response. Conclusion We showed that 25(OH)D3 and 1,25(OH)2D3 can lower cytokine release from OM but not SC AT explants and only in women. © 2015 Elsevier Inc.

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