PMID- 29128090 OWN - NLM STAT- MEDLINE DCOM- 20190528 LR - 20190528 IS - 1879-1484 (Electronic) IS - 0021-9150 (Linking) VI - 268 DP - 2018 Jan TI - Crocus sativus L. aqueous extract reduces atherogenesis, increases atherosclerotic plaque stability and improves glucose control in diabetic atherosclerotic animals. PG - 207-214 LID - S0021-9150(17)31370-9 [pii] LID - 10.1016/j.atherosclerosis.2017.10.032 [doi] AB - BACKGROUND AND AIMS: We aimed to evaluate a possible atheroprotective effect of saffron aqueous extract (SFE), and its potential anti-inflammatory mechanisms, in apoE knockout (ApoE(-/-)) mice. METHODS: Fifty male, ApoE(-/-) mice, fed a high-fat diet (HFD) for 12 weeks, were randomized into 5 groups: (1) baseline group, euthanatized, without intervention, (2) three saffron groups, receiving HFD and 30,60,90 mg/kg/day of SFE, respectively, for four weeks, per os through gavage, after reconstitution in water for injection (WFI), (3) control group (COG), receiving daily HFD and the same volume of WFI (four weeks). After blood sampling and euthanasia, aortic roots were excised and analyzed for gene expression and/or percentage of aortic stenosis, relative content of macrophages, smooth muscle cells (SMCs), connective tissue, tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases-2,-3,-9 (MMP-2,-3,-9) and their inhibitor (TIMP-2) and IL-6. SFE doses were determined by a pilot serum pharmacokinetic study in C57BL/6J wild-type mice. RESULTS: SFE did not affect body weight and total cholesterol levels (p > 0.05), while high SFE dose significantly ameliorated glucose and triglycerides profiles compared to other groups (p < 0.05). SFE considerably decreased aortic stenosis in a dose-dependent manner (p < 0.05). Furthermore, increasing SFE doses proportionally reduced macrophages content and increased within plaques content of collagen, elastin, and SMCs, promoting more stable plaque phenotype compared to COG (p < 0.05). Those effects seemed to be associated with a considerable reduction (>30%) in IL-6, TNF-alpha, MCP-1, MMP-2,-3,-9 (p < 0.05) and MMP-2/TIMP-2 ratio. CONCLUSIONS: SFE exerted dose-dependent anti-atherosclerotic and plaque-stabilizing effects in Apo-E(-/-) mice, probably mediated by a favorable modification of inflammatory mechanisms, which requires further investigation. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Christodoulou, Ei AU - Christodoulou E AD - National & Kapodistrian University of Athens, School of Health Sciences, Department of Pharmacy, Laboratory of Biopharmaceutics-Pharmacokinetics, Athens, Greece. FAU - Kadoglou, N P E AU - Kadoglou NPE AD - Oxford University, Oxford, United Kingdom. FAU - Stasinopoulou, M AU - Stasinopoulou M AD - Biomedical Research Foundation of the Academy of Athens, Centre of Clinical, Experimental Surgery and Translational Research, Athens, Greece. FAU - Konstandi, O A AU - Konstandi OA AD - National & Kapodistrian University of Athens, School of Sciences, Department of Biology, Section of Cell Biology and Biophysics, Athens, Greece. FAU - Kenoutis, C AU - Kenoutis C AD - National & Kapodistrian University of Athens, School of Sciences, Department of Biology, Section of Cell Biology and Biophysics, Athens, Greece. FAU - Kakazanis, Z I AU - Kakazanis ZI AD - Biomedical Research Foundation of the Academy of Athens, Centre of Clinical, Experimental Surgery and Translational Research, Athens, Greece. FAU - Rizakou, A AU - Rizakou A AD - National & Kapodistrian University of Athens, School of Health Sciences, Department of Pharmacy, Laboratory of Biopharmaceutics-Pharmacokinetics, Athens, Greece. FAU - Kostomitsopoulos, N AU - Kostomitsopoulos N AD - Biomedical Research Foundation of the Academy of Athens, Centre of Clinical, Experimental Surgery and Translational Research, Athens, Greece. FAU - Valsami, G AU - Valsami G AD - National & Kapodistrian University of Athens, School of Health Sciences, Department of Pharmacy, Laboratory of Biopharmaceutics-Pharmacokinetics, Athens, Greece. Electronic address: valsami@pharm.uoa.gr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171101 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Crocus vernus agglutinin) RN - 0 (Hypoglycemic Agents) RN - 0 (Inflammation Mediators) RN - 0 (Mannose-Binding Lectins) RN - 0 (Plant Extracts) RN - 0 (Plant Lectins) RN - 0 (Triglycerides) RN - EC 3.4.24.- (Matrix Metalloproteinases) SB - IM CIN - Atherosclerosis. 2018 Jan;268:193-195. PMID: 29198557 MH - Animals MH - Anti-Inflammatory Agents/isolation & purification/pharmacokinetics/*pharmacology MH - Aorta/*drug effects/metabolism/pathology MH - Aortic Diseases/blood/genetics/pathology/*prevention & control MH - Atherosclerosis/blood/genetics/pathology/*prevention & control MH - Biomarkers/blood MH - Blood Glucose/*drug effects/metabolism MH - Diabetes Mellitus, Experimental/blood/*drug therapy/etiology MH - Diet, High-Fat MH - Dose-Response Relationship, Drug MH - Hypoglycemic Agents/isolation & purification/pharmacokinetics/*pharmacology MH - Inflammation Mediators/metabolism MH - Male MH - *Mannose-Binding Lectins/chemistry MH - Matrix Metalloproteinases/metabolism MH - Mice, Inbred C57BL MH - Mice, Knockout, ApoE MH - Plant Extracts/isolation & purification/pharmacokinetics/*pharmacology MH - *Plant Lectins/chemistry MH - *Plaque, Atherosclerotic MH - Rupture, Spontaneous MH - Triglycerides/blood OTO - NOTNLM OT - ApoE(-/-) mice OT - Atherosclerosis OT - Crocetin OT - Inflammation OT - Matrix metalloproteinases OT - Saffron EDAT- 2017/11/13 06:00 MHDA- 2019/05/29 06:00 CRDT- 2017/11/13 06:00 PHST- 2017/05/16 00:00 [received] PHST- 2017/10/12 00:00 [revised] PHST- 2017/10/26 00:00 [accepted] PHST- 2017/11/13 06:00 [pubmed] PHST- 2019/05/29 06:00 [medline] PHST- 2017/11/13 06:00 [entrez] AID - S0021-9150(17)31370-9 [pii] AID - 10.1016/j.atherosclerosis.2017.10.032 [doi] PST - ppublish SO - Atherosclerosis. 2018 Jan;268:207-214. doi: 10.1016/j.atherosclerosis.2017.10.032. Epub 2017 Nov 1.