Hollander K.S.,Minerva Center for Cholesterol |
Konikoff F.M.,Minerva Center for Cholesterol |
Fainaru M.,Tel Aviv University |
Leikin-Frenkel A.,Minerva Center for Cholesterol |
And 2 more authors.
Archives of Physiology and Biochemistry | Year: 2014
Objective: Our objective was to test the contribution of dietary enrichment in essential or saturated fatty acids, in normocaloric diets, on the lipid accumulation and insulin resistance in the adult offspring in a C57Bl6/J mice model. Methods: Pregnant mothers were fed normocaloric diets containing 6% fat enriched in essential fatty acids (EFA): alpha-linolenic (ALA-18:3, n-3), linoleic (LA-18:2, n-6), or saturated fatty acids (SFA). After a washing-out period with regular diet, the offspring received a high-fat diet before euthanization. Results: Adult mice fed maternal ALA showed lower body weight gain and lower liver fat accumulation, lower HOMA index and lower stearoyl-CoA desaturase (SCD1) activity than those fed maternal SFA. Conclusion: The results observed using this novel model suggest that ALA in maternal diet may have the potential to inhibit insulin resistance in adult offspring. © 2014 Informa UK Ltd.
Yahalom G.,Parkinson Disease and Movement Disorders Clinic |
Yahalom G.,Sagol Neuroscience Center |
Tsabari R.,Sagol Neuroscience Center |
Tsabari R.,Stroke Center |
And 8 more authors.
Clinical Neuropharmacology | Year: 2013
OBJECTIVE: To present the long-term neurological outcome of Jewish Israeli patients with cerebrotendinous xanthomatosis (CTX) after several years of chenodeoxycholic acid (CDCA) treatment. METHODS: A cross sectional observational study of all patients with a diagnosis of CTX followed in a referral outpatient clinic during the years 2003-2012. RESULTS: Eighteen patients (10 men) from 11 families were enrolled. Sixteen patients were included in the analysis (2 patients had low compliance for treatment). The mean ± SD age at last evaluation was 35.0 ± 9.2 years (range, 16-45 years). After their diagnosis, at age 22.6 ± 10.8 years, all patients were treated with CDCA. Patients who started treatment after the age of 25 years had worse outcome and were significantly more limited in ambulation (P = 0.004) and more cognitively impaired (P = 0.047). Five patients who started treatment after 25 years of age continued to deteriorate despite CDCA treatment. CONCLUSIONS: Beginning CDCA treatment as early as possible is crucial to preventing neurological damage and deterioration in CTX. After significant neurological pathology is established, the effect of treatment is limited and deterioration may continue. Copyright © 2013 by Lippincott Williams & Wilkins.
Cohen H.,Bert rassburger Lipid Center |
Cohen H.,Tel Aviv University |
Bielorai B.,Safra Childrens Hospital |
Bielorai B.,Tel Aviv University |
And 6 more authors.
Pediatric Blood and Cancer | Year: 2010
Objective. To determine the incidence and clinical consequences of asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia (ALL). Methods. Sixty-five newly diagnosed children and adolescents aged 0.4-21 years with ALL or lymphoblastic lymphoma were retrospectively evaluated for lipid abnormalities. They were treated according to the ALLIC-BFM 2002 protocol between 2002 and 2005. Fasting cholesterol levels were measured in all patients and triglycerides (TG) in 42/65 patients. Results. Prior to treatment, mean cholesterol level was 149 ± 50 mg/dl, and increased to maximal level 274 ± 124 mg/dl during treatment. Mean TG level during treatment was 459 ± 526 mg/dl (range 54-3,009). Twelve patients (28%) had TG levels <200 mg/dl, 18 (43%) had 200-400 mg/dl, 3 (7%) had 400-600 mg/dl, 4 (10%) between 600 and 1,000 mg/dl, and 5 (12%) patients had >1,000 mg/dl. No association was found between TG levels and age or gender. One of the 12 patients with TG >400 mg/dl developed left saggital sinus thrombosis and left frontal lobe infarct. TG level at the time of the event was 2,640 mg/dl. None of the five patients with TG levels >1,000 mg/dl developed pancreatitis. Children with TG levels between 400 and 600 mg/dl were treated by fasting. Fibrates and heparin were added to those with levels >600 mg/dl. Lipid abnormalities normalized in all children upon completion of asparaginase treatment. Conclusions. Abnormalities of lipid profile in children with ALL during asparaginase therapy are relatively common. We recommend measuring TG before and during asparaginase treatment. Initiation of conservative treatment could prevent further increase of TG and decrease the risk of potential complications. © 2010 Wiley-Liss, Inc.
Ben-David U.,Hebrew University of Jerusalem |
Gan Q.-F.,Hoffmann-La Roche |
Golan-Lev T.,Hebrew University of Jerusalem |
Arora P.,Hoffmann-La Roche |
And 9 more authors.
Cell Stem Cell | Year: 2013
The use of human pluripotent stem cells (hPSCs) in cell therapy is hindered by the tumorigenic risk from residual undifferentiated cells. Here we performed a high-throughput screen of over 52,000 small molecules and identified 15 pluripotent cell-specific inhibitors (PluriSIns), nine of which share a common structural moiety. The PluriSIns selectively eliminated hPSCs while sparing a large array of progenitor and differentiated cells. Cellular and molecular analyses demonstrated that the most selective compound, PluriSIn #1, induces ER stress, protein synthesis attenuation, and apoptosis in hPSCs. Close examination identified this molecule as an inhibitor of stearoyl-coA desaturase (SCD1), the key enzyme in oleic acid biosynthesis, revealing a unique role for lipid metabolism in hPSCs. PluriSIn #1 was also cytotoxic to mouse blastocysts, indicating that the dependence on oleate is inherent to the pluripotent state. Finally, application of PluriSIn #1 prevented teratoma formation from tumorigenic undifferentiated cells. These findings should increase the safety of hPSC-based treatments. © 2013 Elsevier Inc.
Zolberg Relevy N.,Bert rassburger Lipid Center |
Zolberg Relevy N.,Tel Aviv University |
Bechor S.,Bert rassburger Lipid Center |
Bechor S.,Tel Aviv University |
And 7 more authors.
PLoS ONE | Year: 2015
Atherosclerosis is a major cause of morbidity and mortality in developed societies, and begins when activated endothelial cells recruit monocytes and T-cells from the bloodstream into the arterial wall. Macrophages that accumulate cholesterol and other fatty materials are transformed into foam cells. Several epidemiological studies have demonstrated that a diet rich in carotenoids is associated with a reduced risk of heart disease; while previous work in our laboratory has shown that the 9-cis β-carotene rich alga Dunaliella inhibits atherogenesis in mice. The effect of 9-cis β-carotene on macrophage foam cell formation has not yet been investigated. In the present work, we sought to study whether the 9-cis β-carotene isomer, isolated from the alga Dunaliella, can inhibit macrophage foam cell formation upon its conversion to retinoids. The 9-cis β-carotene and Dunaliella lipid extract inhibited foam cell formation in the RAW264.7 cell line, similar to 9-cis retinoic acid. Furthermore, dietary enrichment with the algal powder in mice resulted in carotenoid accumulation in the peritoneal macrophages and in the inhibition of foam cell formation ex-vivo and in-vivo. We also found that the β-carotene cleavage enzyme β-carotene 15,15′-monooxygenase (BCMO1) is expressed and active in macrophages. Finally, 9-cis β-carotene, as well as the Dunaliella extract, activated the nuclear receptor RXR in hepa1-6 cells. These results indicate that dietary carotenoids, such as 9-cis β-carotene, accumulate in macrophages and can be locally cleaved by endogenous BCMO1 to form 9-cis retinoic acid and other retinoids. Subsequently, these retinoids activate the nuclear receptor RXR that, along with additional nuclear receptors, can affect various metabolic pathways, including those involved in foam cell formation and atherosclerosis. © 2015 Zolberg Relevy et al.
Kamari Y.,Bert rassburger Lipid Center |
Kamari Y.,Tel Aviv University |
Shaish A.,Bert rassburger Lipid Center |
Vax E.,Bert rassburger Lipid Center |
And 15 more authors.
Journal of Hepatology | Year: 2011
Background & Aims: The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1α and IL-1β in steatohepatitis remains elusive. Methods: We employed IL-1α and IL-1β-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis. Results: Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 fold-elevations in mRNA levels of hepatic IL-1α and IL-1β, respectively. In mice deficient in either IL-1α or IL-1β the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1α-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1α markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, and TNFα) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFβ levels (p = 0.004). IL-1α mRNA levels were two-folds lower in IL-1β-deficient mice, and IL-1β transcripts were three-folds lower in IL-1α-deficient compared to wild-type mice. Hepatic cell derived IL-1α rather than from recruited bone marrow-derived cells was required for steatohepatitis development. Conclusions: These data demonstrate the critical role of IL-1α and IL-1β in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1α and/or IL-1β to inhibit the development of steatohepatitis should be explored. © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Kamari Y.,Hypertension Unit |
Kamari Y.,Bert rassburger Lipid Center |
Kamari Y.,Tel Aviv University |
Peleg E.,Hypertension Unit |
And 4 more authors.
American Journal of Hypertension | Year: 2012
Background Premenopausal women have lower blood pressure (BP) levels than men of similar age. Adiponectin has been shown to play a role in the pathogenesis of hypertension. The aim of the present study was to compare the effect of various stress stimuli on BP and plasma adiponectin levels in male and female Sprague Dawley (SD) rats. Methods In three experimental models of hypertension, fructose-enriched diet, high salt diet, or L-NAME, were administered for up to 4 weeks. BP, metabolic parameters, and plasma adiponectin were measured at baseline and during the studies. The fructose diet protocol was repeated in female rats for 2 weeks with the addition of testosterone injections or vehicle. Results Females, in contrast to males, did not develop fructose-induced hypertension. Total plasma triglycerides (TGs) were half in females at baseline (P < 0.001) and a third at 4 weeks (P < 0.05). Plasma insulin levels were 23% lower in females than in males at baseline (P < 0.05) and 42% lower after 4 weeks of fructose-enriched diet (P = 0.001). Plasma adiponectin levels were 65% higher in females than in males at baseline (P = 0.001) and 45% higher after 4 weeks of fructose-enriched diet (P < 0.05). Furthermore, female rats showed blunted BP response and elevated plasma adiponectin in the salt-induced and L-NAME-induced hypertension models. Testosterone injection to female rats reduced plasma adiponectin and reversed the blunted BP response. Conclusions Elevated plasma adiponectin levels, perhaps due to lack of suppression by testosterone, are associated with a blunting of BP response in female compared to male SD rats. © 2012 American Journal of Hypertension, Ltd.
Rotenstreich Y.,Maurice and Gabriela Goldschleger Eye Research Institute |
Rotenstreich Y.,Tel Aviv University |
Harats D.,Bert rassburger Lipid Center |
Harats D.,Tel Aviv University |
And 5 more authors.
British Journal of Ophthalmology | Year: 2010
Background: Fundus albipunctatus is a retinal dystrophy caused by a mutation in the gene encoding 11-cis-retinol dehydrogenase which delays the recovery of rod photoreceptor cells from light stimulation leading to night blindness. A recent study of a mouse model of fundus albipunctatus treated with 9-cis-retinal showed an improvement in visual function and structure. Methods: Seven patients with fundus albipunctatus were given a daily food supplement of four capsules containing high-dose 9-cis-β-carotene for 90 days. The subjects were tested before and after treatment by visual field and electroretinogram in both eyes. This nonrandomised prospective phase I study was registered at http://www.clinicaltrials.gov (NCT00478530). Results: All patients showed significant improvements in peripheral visual field (mean deviation improved from -4.7762.0 to -3.28±2.28, p=0.009, t test) and a highly significant improvement in rod recovery rates measured electroretinographically (maximal scotopic bwave amplitude responses, improved from 197±49 μV to 292±48 μV, p<0.001, t test). No complications or side effects were observed. Conclusion: Oral treatment with 9-cis-β-carotene led to reversal of a human retinal dystrophy. This potential therapy is readily available and should be evaluated in retinal dystrophies of similar mechanisms such as various types of retinitis pigmentosa.
Uri-Belapolsky S.,Bert rassburger Lipid Center |
Uri-Belapolsky S.,Tel Aviv University |
Shaish A.,Bert rassburger Lipid Center |
Eliyahu E.,Genetics and Genomic science |
And 11 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014
Oocyte endowment dwindles away during prepubertal and adult life until menopause occurs, and apoptosis has been identified as a central mechanism responsible for oocyte elimination. A few recent reports suggest that uncontrolled inflammation may adversely affect ovarian reserve. We tested the possible role of the proinflammatory cytokine IL-1 in the age-related exhaustion of ovarian reserve using IL-1α and IL-1β-KO mice. IL-1α-KO mice showed a substantially higher pregnancy rate and litter size compared with WT mice at advanced age. The number of secondary and antral follicles was significantly higher in 2.5-mo-old IL-1α-KO ovaries compared withWT ovaries. Serum anti-Müllerian hormone, a putative marker of ovarian reserve, was markedly higher in IL-1α-KO mice from 2.5 mo onward, along with a greater ovarian response to gonadotropins. IL-1β-KO mice displayed a comparable but more subtle prolongation of ovarian lifespan compared with IL-1α-KO mice. The protein and mRNA of both IL-1α and IL-1β mice were localized within the developing follicles (oocytes and granulosa cells), and their ovarian mRNA levels increased with age. Molecular analysis revealed decreased apoptotic signaling [higher B-cell lymphoma 2 (BCL-2) and lower BCL-2-associated X protein levels], along with a marked attenuation in the expression of genes coding for the proinflammatory cytokines IL-1β, IL-6, and TNF-α in ovaries of IL-1α-KO mice compared with WT mice. Taken together, IL-1 emerges as an important participant in the age-related exhaustion of ovarian reserve in mice, possibly by enhancing the expression of inflammatory genes and promoting apoptotic pathways.
Bitzur R.,Bert rassburger Lipid Center
Diabetes Care | Year: 2016
The issue of statin-associated cognitive impairment has been a hot topic among both patients and health care providers, especially since the U.S. Food and Drug Administration (FDA) issued a statement regarding rare postmarketing reports of ill-defined cognitive impairment associated with statin use. This statement was based on case reports, and no objectivemeasures of cognitive functionwere used. Nevertheless,many patients at high risk of cardiovascular disease have expressed concerns about possible cognitive decline and may have opted to forgo statin therapy. In this overview, the evidence leading to the statement by the FDA is reviewed. Potential mechanisms of the effect of LDL cholesterol reduction and statin therapy on cognition are discussed. Evidence from observational and prospective randomized trials is summarized, leading to the conclusion that as for now, there is no good evidence that statins cause cognitive impairment to a significant degree. Reported cases seem to be rare, and a causal relationship has not been established.