|
1
|
Jang WB, Rethineswaran VK, Kwon SM. Targeting Mitochondrial Dysfunction to Prevent Endothelial Dysfunction and Atherosclerosis in Diabetes: Focus on the Novel Uncoupler BAM15. Int J Mol Sci 2025; 26:4603. [PMID: 40429748 PMCID: PMC12111197 DOI: 10.3390/ijms26104603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Revised: 05/02/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, leading to endothelial dysfunction and accelerated atherosclerosis. Mitochondrial dysfunction, oxidative stress, and dysregulated lipid metabolism contribute to endothelial cell (EC) injury, promoting plaque formation and increasing cardiovascular disease risk. Current lipid-lowering therapies have limited effectiveness in restoring endothelial function, highlighting the need for novel strategies. Mitochondrial uncoupling has emerged as a promising approach, with BAM15-a newly identified mitochondrial uncoupler-showing potential therapeutic benefits. BAM15 enhances fatty acid oxidation (FAO), reduces reactive oxygen species, and protects ECs from hyperglycemia-induced apoptosis. Unlike conventional uncouplers, BAM15 demonstrates improved tolerability and efficacy without severe off-target effects. It restores mitochondrial function, improves endothelial survival, and supports metabolic homeostasis under hyperglycemic conditions. This review uniquely integrates emerging evidence on mitochondrial dysfunction, endothelial metabolism, and FAO to highlight the novel role of BAM15 in restoring vascular function in diabetes. We provide the first focused synthesis of BAM15's mechanistic impact on EC bioenergetics and position it within the broader landscape of mitochondrial-targeted therapies for diabetic vascular complications. Further research is needed to elucidate the molecular mechanism through which BAM15 modulates EC metabolism and to evaluate its long-term vascular effects in diabetic models.
Collapse
Affiliation(s)
- Woong Bi Jang
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (W.B.J.); (V.K.R.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Vinoth Kumar Rethineswaran
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (W.B.J.); (V.K.R.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Sang-Mo Kwon
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (W.B.J.); (V.K.R.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| |
Collapse
|
|
2
|
Dai Y, Yang L, Cao G, Mo L, Yang C, Zhu Y, Guo Y, Hong Y, Xu H, Lu S, Du S, He J. Combination therapy and drug co-delivery systems for atherosclerosis. J Control Release 2025; 381:113543. [PMID: 39986476 DOI: 10.1016/j.jconrel.2025.02.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/25/2025] [Accepted: 02/15/2025] [Indexed: 02/24/2025]
Abstract
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of plaque within the arteries. Despite advances in therapeutic strategies including anti-inflammatory, antioxidant, and lipid metabolism modulation treatments over the past two decades, the treatment of atherosclerosis remains challenging, as arterial damage is the result of interconnected pathological factors. Therefore, current monotherapies often fail to address the complex nature of this disease, leading to insufficient therapeutic outcomes. This review addressed this paucity of effective treatment options by comprehensively exploring the potential for combination therapies and advanced drug co-delivery systems for the treatment of atherosclerosis. We investigated the pathological features of and risk factors for atherosclerosis, underscoring the importance of drug combination therapies for the treatment of atherosclerotic diseases. We discuss herein mathematical models for quantifying the efficacy of the combination therapies and provide a systematic summary of drug combinations for the treatment of atherosclerosis. We also provide a detailed review of the latest advances in nanoparticle-based drug co-delivery systems for the treatment of atherosclerosis, focusing on the design of carriers with high biocompatibility and efficacy. By exploring the possibilities and challenges inherent to this approach, we aim to highlight cutting-edge technologies that can foster the development of innovative strategies, optimize drug co-administration, improve treatment outcomes, and reduce the burden of atherosclerosis-related morbidity and mortality on the healthcare system.
Collapse
Affiliation(s)
- Yingxuan Dai
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Li Yang
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Guosheng Cao
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan 430065, PR China
| | - Liqing Mo
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Can Yang
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Yuxi Zhu
- Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH 43210, USA; Department of Pediatrics, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH 44106, USA
| | - Yujie Guo
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Yi Hong
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Hanlin Xu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China
| | - Shan Lu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China.
| | - Shi Du
- Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH 43210, USA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
| | - Jianhua He
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China.
| |
Collapse
|
|
3
|
Spitznagle JC, Kacha-Ochana A, Cook-Mills JM, Morgan GA, Pachman LM. Increased vascular deposition of oxidized LDL in untreated juvenile dermatomyositis. Pediatr Rheumatol Online J 2024; 22:73. [PMID: 39118148 PMCID: PMC11308466 DOI: 10.1186/s12969-024-01001-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Juvenile dermatomyositis (JDM) is a systemic vasculopathy associated with metabolic derangements and possible increased risk for premature atherosclerosis. Oxidation of low-density lipoprotein (LDL) in the endothelium is an early step in atherosclerotic plaque formation. It is not known if oxidized LDL is altered in children with untreated JDM. The deposition of oxidized LDL in the vasculature of muscle biopsies (MBx) from patients with untreated JDM and pediatric controls was assessed. FINDINGS Frozen tissue sections of MRI-directed MBx from 20 female children with untreated JDM and 5 female controls were stained with DAPI and fluorescently labeled antibodies against von Willebrand factor (vWF) and LDL oxidized by copper (oxLDL). Blood vessels were identified by positive vWF staining, and total fluorescence of oxLDL within the vessel walls was measured. Children with untreated JDM had increased deposition of oxLDL in the walls of muscle vasculature compared to healthy children (difference in means ± SEM = 19.86 ± 8.195, p = 0.03). Within the JDM cohort, there was a trend towards increased oxLDL deposition with longer duration of untreated disease (r = 0.43, p = 0.06). There was no significant correlation found between oxLDL deposition and markers of acute JDM disease activity including disease activity scores or muscle enzymes. CONCLUSIONS This study found increased deposition of oxLDL within blood vessels of children with untreated JDM supporting the concern that these children are at increased risk for premature atherosclerosis from chronic exposure to vascular oxLDL. This study highlights the importance of early diagnosis and treatment initiation to ameliorate cardiovascular damage.
Collapse
Affiliation(s)
- Jacob C Spitznagle
- Division of Pediatric Rheumatology, Children's Hospital Los Angeles, 4560 Sunset Blvd., #60, Los Angeles, CA, 90027, USA.
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Akadia Kacha-Ochana
- Division of Pediatric Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Box 50, Chicago, IL, 60611, USA
| | - Joan M Cook-Mills
- Herman B. Wells Center for Pediatric Research in Department of Pediatrics, Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gabrielle A Morgan
- Division of Pediatric Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Box 50, Chicago, IL, 60611, USA
| | - Lauren M Pachman
- Division of Pediatric Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Box 50, Chicago, IL, 60611, USA.
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| |
Collapse
|
|
4
|
Sobukawa Y, Hatta T, Funaki D, Nakatani E. Safety of Combined Statin and Fibrate Therapy: Risks of Liver Injury and Acute Kidney Injury in a Cohort Study from the Shizuoka Kokuho Database. Drugs Real World Outcomes 2024; 11:317-330. [PMID: 38727887 PMCID: PMC11176141 DOI: 10.1007/s40801-024-00426-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2024] [Indexed: 06/15/2024] Open
Abstract
INTRODUCTION Statins and fibrates are important means of preventing cardiovascular diseases, particularly when administered in combination as part of various therapeutic strategies. In this study, we explored the risks associated with various combinations of these drugs. OBJECTIVE We aimed to evaluate the risk of 1-year hospitalization with acute kidney injury, liver injury, pancreatitis, or rhabdomyolysis related to the concurrent administration of statins and fibrates. METHODS We performed a retrospective cohort study using data from the Shizuoka Kokuho Database, focusing on patients prescribed statins, fibrates, or a combination. Four drug exposure patterns were evaluated: adding statins to fibrates (exposure 1), switching from fibrates to statins (exposure 2), adding fibrates to statins (exposure 3), and switching from statins to fibrates (exposure 4). Hospitalization for the specified conditions within 1 year was the outcome. Propensity score matching was used to create balanced cohorts for comparison. RESULTS We studied 269,226 statin users and 16,282 fibrate users. After propensity score matching, there were 498 participants in the group of exposure 1, matched with 2988 in the fibrate-only group; 1180 in the group of exposure 2, matched with 7080 in the fibrate-only group; 1183 in group of exposure 3, matched with 11,830 in the statin only group; and 1356 in group of exposure 4, matched with 13,560 in the statin only group. The 1-year hospitalization rate with liver injury was higher in the group of exposure 1 than in the fibrate-only group (1.2% vs 0.3%, p < 0.01), in the group of exposure 2 than in the fibrate-only group (0.9% vs 0.3%, p < 0.01), and in the group of exposure 4 than in the statin-only group (0.6% vs 0.2%, p = 0.02). There was also a higher risk of 1-year hospitalization with acute kidney injury in group of exposure 1 than in the fibrate-only group (1.3% vs 0.3%, p = 0.01) but not in evaluations of exposure 2, 3, and 4. However, there were no differences in the risks of 1-year hospitalization with pancreatitis or rhabdomyolysis among the matched groups. CONCLUSIONS We have demonstrated higher risks of 1-year hospitalization with liver injury or acute kidney injury associated with the use of combinations of statins and fibrates. This underscores the need for a cautious approach to the prescribing of such drug combinations and the importance of monitoring patients for potential adverse events.
Collapse
Affiliation(s)
- Yohei Sobukawa
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, 4-27-2 Kitaando, Aoi-ku, Shizuoka, 420-0881, Japan
| | - Taichi Hatta
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, 4-27-2 Kitaando, Aoi-ku, Shizuoka, 420-0881, Japan
| | - Daito Funaki
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, 4-27-2 Kitaando, Aoi-ku, Shizuoka, 420-0881, Japan
| | - Eiji Nakatani
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, 4-27-2 Kitaando, Aoi-ku, Shizuoka, 420-0881, Japan.
| |
Collapse
|
|
5
|
Peng Z, Kan Q, Wang K, Deng T, Wang S, Wu R, Yao C. Deciphering smooth muscle cell heterogeneity in atherosclerotic plaques and constructing model: a multi-omics approach with focus on KLF15/IGFBP4 axis. BMC Genomics 2024; 25:490. [PMID: 38760675 PMCID: PMC11102212 DOI: 10.1186/s12864-024-10379-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 05/06/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND Ruptured atherosclerotic plaques often precipitate severe ischemic events, such as stroke and myocardial infarction. Unraveling the intricate molecular mechanisms governing vascular smooth muscle cell (VSMC) behavior in plaque stabilization remains a formidable challenge. METHODS In this study, we leveraged single-cell and transcriptomic datasets from atherosclerotic plaques retrieved from the gene expression omnibus (GEO) database. Employing a combination of single-cell population differential analysis, weighted gene co-expression network analysis (WGCNA), and transcriptome differential analysis techniques, we identified specific genes steering the transformation of VSMCs in atherosclerotic plaques. Diagnostic models were developed and validated through gene intersection, utilizing the least absolute shrinkage and selection operator (LASSO) and random forest (RF) methods. Nomograms for plaque assessment were constructed. Tissue localization and expression validation were performed on specimens from animal models, utilizing immunofluorescence co-localization, western blot, and reverse-transcription quantitative-polymerase chain reaction (RT-qPCR). Various online databases were harnessed to predict transcription factors (TFs) and their interacting compounds, with determination of the cell-specific localization of TF expression using single-cell data. RESULTS Following rigorous quality control procedures, we obtained a total of 40,953 cells, with 6,261 representing VSMCs. The VSMC population was subsequently clustered into 5 distinct subpopulations. Analyzing inter-subpopulation cellular communication, we focused on the SMC2 and SMC5 subpopulations. Single-cell subpopulation and WGCNA analyses revealed significant module enrichments, notably in collagen-containing extracellular matrix and cell-substrate junctions. Insulin-like growth factor binding protein 4 (IGFBP4), apolipoprotein E (APOE), and cathepsin C (CTSC) were identified as potential diagnostic markers for early and advanced plaques. Notably, gene expression pattern analysis suggested that IGFBP4 might serve as a protective gene, a hypothesis validated through tissue localization and expression analysis. Finally, we predicted TFs capable of binding to IGFBP4, with Krüppel-like family 15 (KLF15) emerging as a prominent candidate showing relative specificity within smooth muscle cells. Predictions about compounds associated with affecting KLF15 expression were also made. CONCLUSION Our study established a plaque diagnostic and assessment model and analyzed the molecular interaction mechanisms of smooth muscle cells within plaques. Further analysis revealed that the transcription factor KLF15 may regulate the biological behaviors of smooth muscle cells through the KLF15/IGFBP4 axis, thereby influencing the stability of advanced plaques via modulation of the PI3K-AKT signaling pathway. This could potentially serve as a target for plaque stability assessment and therapy, thus driving advancements in the management and treatment of atherosclerotic plaques.
Collapse
MESH Headings
- Animals
- Humans
- Male
- Gene Expression Profiling
- Gene Regulatory Networks
- Insulin-Like Growth Factor Binding Protein 4/metabolism
- Insulin-Like Growth Factor Binding Protein 4/genetics
- Kruppel-Like Transcription Factors/metabolism
- Kruppel-Like Transcription Factors/genetics
- Multiomics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/cytology
- Myocytes, Smooth Muscle/metabolism
- Plaque, Atherosclerotic/metabolism
- Plaque, Atherosclerotic/genetics
- Plaque, Atherosclerotic/pathology
- Single-Cell Analysis
- Transcriptome
- Rats
Collapse
Affiliation(s)
- Zhanli Peng
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Qinghui Kan
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Kangjie Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Tang Deng
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Shenming Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Ridong Wu
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
| | - Chen Yao
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, P.R. China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
| |
Collapse
|
|
6
|
Liu J, Pan S, Wang X, Liu Z, Zhang Y. Role of advanced glycation end products in diabetic vascular injury: molecular mechanisms and therapeutic perspectives. Eur J Med Res 2023; 28:553. [PMID: 38042909 PMCID: PMC10693038 DOI: 10.1186/s40001-023-01431-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/04/2023] [Indexed: 12/04/2023] Open
Abstract
BACKGROUND In diabetic metabolic disorders, advanced glycation end products (AGEs) contribute significantly to the development of cardiovascular diseases (CVD). AIMS This comprehensive review aims to elucidate the molecular mechanisms underlying AGE-mediated vascular injury. CONCLUSIONS We discuss the formation and accumulation of AGEs, their interactions with cellular receptors, and the subsequent activation of signaling pathways leading to oxidative stress, inflammation, endothelial dysfunction, smooth muscle cell proliferation, extracellular matrix remodeling, and impaired angiogenesis. Moreover, we explore potential therapeutic strategies targeting AGEs and related pathways for CVD prevention and treatment in diabetic metabolic disorders. Finally, we address current challenges and future directions in the field, emphasizing the importance of understanding the molecular links between AGEs and vascular injury to improve patient outcomes.
Collapse
Affiliation(s)
- Jing Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China
| | - Shuo Pan
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China.
- Affiliated Shaanxi Provincial People's Hospital, Medical Research Institute, Northwestern Polytechnical University, Xi'an, China.
| | - Yong Zhang
- Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China.
| |
Collapse
|
|
7
|
Rioux-Labrecque V, Cossette M, Rufiange M, Bilodeau D, Guertin MC, Tardif JC. Supplementation with a beta-glucan tablet has no effect on hyperlipidemia: a randomized, placebo-controlled clinical trial. Am J Clin Nutr 2023:S0002-9165(23)46841-4. [PMID: 37054888 DOI: 10.1016/j.ajcnut.2023.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/24/2023] [Accepted: 04/10/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Clinical evidence has suggested that the oat soluble fiber β-glucan might have lipid-lowering effects. OBJECTIVE The present clinical trial was conducted to evaluate the efficacy and safety of high-medium molecular weight β-glucan on serum low-density lipoprotein cholesterol (LDL-C) and other lipid subfractions in subjects with hyperlipidemia. METHODS A randomized double-blind trial was performed to assess the efficacy and safety of β-glucan supplementation in reducing lipid levels. Subjects with LDL-C above 3.37 mmol/L when treated or not with a statin were randomly assigned to receive one of three daily doses of a tableted formulation of β-glucan (1.5, 3 or 6 grams) or placebo. The primary efficacy endpoint was the change from baseline to 12 weeks in LDL-C. Secondary endpoints of lipid sub-fractions and safety were also assessed. RESULTS A total of 263 subjects were enrolled; 66 subjects were assigned to each of the 3 β-glucan groups and 65 subjects to the placebo group. The mean change from baseline to 12 weeks in serum LDL-C was 0.08, 0.11 and -0.04 mmol/L in the three β-glucan groups (P=0.23, 0.18 and 0.72 vs. placebo group, respectively) and -0.10 mmol/L in the placebo group. The changes in total cholesterol, small LDL-C subclass particle concentration, non-high-density lipoprotein cholesterol, apolipoprotein B, very low-density lipoprotein cholesterol and high sensitivity C-reactive protein were also not significant in the β-glucan groups when compared to placebo. Gastrointestinal adverse events were reported in 23.4, 34.8 and 66.7% of patients in the β-glucan groups and in 36.9% of patients in the placebo group (P<0.0001 for the overall comparison across the four groups). CONCLUSIONS In subjects with LDL-C above 3.37 mmol/L, a tablet formulation of β-glucan was not effective in reducing LDL-C concentration or other lipid sub-fractions when compared to placebo. CLINICALTRIALS GOV IDENTIFIER NCT03857256.
Collapse
Affiliation(s)
| | - Marieve Cossette
- Montreal Health Innovations Coordinating Center (MHICC), Montreal, Canada
| | - Marianne Rufiange
- Montreal Health Innovations Coordinating Center (MHICC), Montreal, Canada
| | | | | | - Jean-Claude Tardif
- Faculté de médecine, Université de Montréal, Montreal, Canada; Montreal Heart Institute (MHI), Montreal, Canada.
| |
Collapse
|
|
8
|
Qin Z, Duan S, Li Y, Li X, Xing H, Yao Z, Zhang X, Yao X, Yang J. Characterization of volatile organic compounds with anti-atherosclerosis effects in Allium macrostemon Bge. and Allium chinense G. Don by head space solid phase microextraction coupled with gas chromatography tandem mass spectrometry. Front Nutr 2023; 10:996675. [PMID: 36819690 PMCID: PMC9929146 DOI: 10.3389/fnut.2023.996675] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 01/04/2023] [Indexed: 02/04/2023] Open
Abstract
Introduction Allium macrostemon Bge. (AMB) and Allium chinense G. Don (ACGD) are both edible Allium vegetables and named officinal Xiebai (or Allii Macrostemonis Bulbus) in East Asia. Their medicinal qualities involve in lipid lowering and anti-atherosclerosis effects. And steroidal saponins, nitrogenous compounds and sulfur compounds are like the beneficial components responsible for medicinal functions. Sulfur compounds are the recognized main components both in the volatile oils of AMB and ACGD. Besides, few researches were reported about their holistic chemical profiles of volatile organic compounds (VOCs) and pharmacodynamic effects. Methods In this study, we first investigated the lipid-lowering and anti-atherosclerotic effects of volatile oils derived from AMB and ACGD in ApoE -/- mice with high fat and high cholesterol diets. Results The results showed the volatile oils of AMB and ACGD both could markedly reduce serum levels of TG, TC, and LDL-C (p < 0.05), and had no alterations of HDL-C, ALT, and AST levels (p > 0.05). Pathological results displayed they both could obviously improve the morphology of cardiomyocytes and the degree of myocardial fibrosis in model mice. Meanwhile, oil red O staining results also proved they could apparently decrease the lesion areas of plaques in the aortic intima (p < 0.05). Furthermore, head space solid phase microextraction coupled with gas chromatography tandem mass spectrometry combined with metabolomics analysis was performed to characterize the VOCs profiles of AMB and ACGD, and screen their differential VOCs. A total of 121 and 115 VOCs were identified or tentatively characterized in the volatile oils of AMB and ACGD, respectively. Relative-quantification results also confirmed sulfur compounds, aldehydes, and heterocyclic compounds accounted for about 85.6% in AMB bulbs, while approximately 86.6% in ACGD bulbs were attributed to sulfur compounds, ketones, and heterocyclic compounds. Multivariate statistical analysis showed 62 differentially expressed VOCs were observed between AMB and ACGD, of which 17 sulfur compounds were found to be closely associated with the garlic flavor and efficacy. Discussion Taken together, this study was the first analysis of holistic chemical profiles and anti-atherosclerosis effects of AMB and ACGD volatile oils, and would benefit the understanding of effective components in AMB and ACGD.
Collapse
Affiliation(s)
- Zifei Qin
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Henan Applied and Translational Center of Precision Clinical Pharmacy, Zhengzhou, China,College of Pharmacy, Jinan University, Guangzhou, China
| | - Shuyi Duan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuan Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinqiang Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Han Xing
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Henan Applied and Translational Center of Precision Clinical Pharmacy, Zhengzhou, China
| | - Zhihong Yao
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Henan Applied and Translational Center of Precision Clinical Pharmacy, Zhengzhou, China
| | - Xinsheng Yao
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jing Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Henan Applied and Translational Center of Precision Clinical Pharmacy, Zhengzhou, China,*Correspondence: Jing Yang,
| |
Collapse
|
|
9
|
Zhang L, Zhang Y, Chu C, Deng F, Zhou J, Yuan Z. Associations of pre-hospital statin treatment with in-hospital outcomes and severity of coronary artery disease in patients with first acute coronary syndrome-findings from the CCC-ACS project. Front Cardiovasc Med 2023; 9:1030108. [PMID: 36741846 PMCID: PMC9889368 DOI: 10.3389/fcvm.2022.1030108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/13/2022] [Indexed: 01/20/2023] Open
Abstract
Background The current burden of dyslipidemia, the pre-hospital application of statins and the association of pre-hospital statins with the severity of coronary artery disease (CAD) and in-hospital outcomes in Chinese patients with first acute coronary syndrome (ACS) are very significant and remain unclear. Methods A total of 41,183 patients who underwent coronary angiography and were diagnosed with ACS for the first time from a nationwide registry study (CCC-ACS) were enrolled. The severity of CAD was assessed using the CAD prognostic index (CADPI). The patients were classified into statin and non-statin groups according to their pre-hospital statin treatment status. Clinical characteristics, CADPI and in-hospital outcomes were compared, and a logistic regression analysis was performed to determine whether pre-hospital statin therapy is associated with in-hospital outcomes and CADPI. A sensitivity analysis was used to further explore the issues above. Results The non-statin group had more in-hospital all-cause deaths (1.2 vs. 0.8%, P = 0.010). However, no association exists between statin pretreatment and in-hospital major adverse cardiovascular events (MACEs) or all-cause deaths in the entire population and subgroups (all P > 0.05). Surprisingly, statin pretreatment was associated with an 8.9% higher risk of severely obstructive CAD (CADPI ≥ 37) (OR, 1.089; 95% CI, 1.010-1.175, P = 0.028), and similar results were observed in subgroups of females, those aged 50 to 75 years, and patients with hypertension. Conclusion Statin pretreatment was not related to MACEs or all-cause death during hospital stay, but it was associated with a higher risk of increased angiographic severity in patients with first ACS.
Collapse
Affiliation(s)
- Lisha Zhang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,*Correspondence: Lisha Zhang,
| | - Yan Zhang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Chao Chu
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Fuxue Deng
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Juan Zhou
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Zuyi Yuan
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,Zuyi Yuan,
| |
Collapse
|
|
10
|
Abstract
Systemic inflammation has been suggested to have a pivotal role in atherothrombosis, but the factors that trigger systemic inflammation have not been fully elucidated. Lipopolysaccharide (LPS) is a component of the membrane of Gram-negative bacteria present in the gut that can translocate into the systemic circulation, causing non-septic, low-grade endotoxaemia. Gut dysbiosis is a major determinant of low-grade endotoxaemia via dysfunction of the intestinal barrier scaffold, which is a prerequisite for LPS translocation into the systemic circulation. Experimental studies have demonstrated that LPS is present in atherosclerotic arteries but not in normal arteries. In atherosclerotic plaques, LPS promotes a pro-inflammatory status that can lead to plaque instability and thrombus formation. Low-grade endotoxaemia affects several cell types, including leukocytes, platelets and endothelial cells, leading to inflammation and clot formation. Low-grade endotoxaemia has been described in patients at risk of or with overt cardiovascular disease, in whom low-grade endotoxaemia was associated with atherosclerotic burden and its clinical sequelae. In this Review, we describe the mechanisms favouring the development of low-grade endotoxaemia, focusing on gut dysbiosis and changes in gut permeability; the plausible biological mechanisms linking low-grade endotoxaemia and atherothrombosis; the clinical studies suggesting that low-grade endotoxaemia is a risk factor for cardiovascular events; and the potential therapeutic tools to improve gut permeability and eventually eliminate low-grade endotoxaemia.
Collapse
|
|
11
|
Zhang G, Liu Z, Deng J, Liu L, Li Y, Weng S, Guo C, Zhou Z, Zhang L, Wang X, Liu G, Guo J, Bai J, Wang Y, Du Y, Li TS, Tang J, Zhang J. Smooth muscle cell fate decisions decipher a high-resolution heterogeneity within atherosclerosis molecular subtypes. J Transl Med 2022; 20:568. [PMID: 36474294 PMCID: PMC9724432 DOI: 10.1186/s12967-022-03795-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mounting evidence has revealed the dynamic variations in the cellular status and phenotype of the smooth muscle cell (SMC) are vital for shaping the atherosclerotic plaque microenvironment and ultimately mapping onto heterogeneous clinical outcomes in coronary artery disease. Currently, the underlying clinical significance of SMC evolutions remains unexplored in atherosclerosis. METHODS The dissociated cells from diseased segments within the right coronary artery of four cardiac transplant recipients and 1070 bulk samples with atherosclerosis from six bulk cohorts were retrieved. Following the SMC fate trajectory reconstruction, the MOVICS algorithm integrating the nearest template prediction was used to develop a stable and robust molecular classification. Subsequently, multi-dimensional potential biological implications, molecular features, and cell landscape heterogeneity among distinct clusters were decoded. RESULTS We proposed an SMC cell fate decision signature (SCFDS)-based atherosclerosis stratification system and identified three SCFDS subtypes (C1-C3) with distinguishing features: (i) C1 (DNA-damage repair type), elevated base excision repair (BER), DNA replication, as well as oxidative phosphorylation status. (ii) C2 (immune-activated type), stronger immune activation, hyper-inflammatory state, the complex as well as varied lesion microenvironment, advanced stage, the most severe degree of coronary stenosis severity. (iii) C3 (stromal-rich type), abundant fibrous content, stronger ECM metabolism, immune-suppressed microenvironment. CONCLUSIONS This study uncovered atherosclerosis complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying SMC. The novel high-resolution stratification system could improve clinical outcomes and facilitate individualized management.
Collapse
Affiliation(s)
- Ge Zhang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Zaoqu Liu
- grid.412633.10000 0004 1799 0733Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Jinhai Deng
- grid.13097.3c0000 0001 2322 6764Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London, London, UK
| | - Long Liu
- grid.412633.10000 0004 1799 0733Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yu Li
- grid.260463.50000 0001 2182 8825Medical College, Nanchang University, Nanchang, 330006 Jiangxi China
| | - Siyuan Weng
- grid.412633.10000 0004 1799 0733Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Chunguang Guo
- grid.412633.10000 0004 1799 0733Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Zhaokai Zhou
- grid.412633.10000 0004 1799 0733Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Li Zhang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Xiaofang Wang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Gangqiong Liu
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Jiacheng Guo
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Jing Bai
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Yunzhe Wang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Youyou Du
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Tao-Sheng Li
- grid.174567.60000 0000 8902 2273Department of Stem Cell Biology, Atomic Bomb Diseases Institute, Nagasaki University, Nagasaki, 852-8523 Japan
| | - Junnan Tang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Jinying Zhang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| |
Collapse
|
|
12
|
Nsaibia MJ, Devendran A, Goubaa E, Bouitbir J, Capoulade R, Bouchareb R. Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail? J Clin Med 2022; 11:jcm11123331. [PMID: 35743402 PMCID: PMC9225514 DOI: 10.3390/jcm11123331] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 12/12/2022] Open
Abstract
Calcific Aortic Valve Disease (CAVD) is a fibrocalcific disease. Lipoproteins and oxidized phospholipids play a substantial role in CAVD; the level of Lp(a) has been shown to accelerate the progression of valve calcification. Indeed, oxidized phospholipids carried by Lp(a) into the aortic valve stimulate endothelial dysfunction and promote inflammation. Inflammation and growth factors actively promote the synthesis of the extracellular matrix (ECM) and trigger an osteogenic program. The accumulation of ECM proteins promotes lipid adhesion to valve tissue, which could initiate the osteogenic program in interstitial valve cells. Statin treatment has been shown to have the ability to diminish the death rate in subjects with atherosclerotic impediments by decreasing the serum LDL cholesterol levels. However, the use of HMG-CoA inhibitors (statins) as cholesterol-lowering therapy did not significantly reduce the progression or the severity of aortic valve calcification. However, new clinical trials targeting Lp(a) or PCSK9 are showing promising results in reducing the severity of aortic stenosis. In this review, we discuss the implication of lipids in aortic valve calcification and the current findings on the effect of lipid-lowering therapy in aortic stenosis.
Collapse
Affiliation(s)
- Mohamed J. Nsaibia
- Department of Cell Biology and Molecular Medicine, Rutgers University, Newark, NJ 07103, USA;
| | - Anichavezhi Devendran
- Department of Medicine, Cardiovascular Research Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Eshak Goubaa
- Thomas Jefferson University East Falls, Philadelphia, PA 19144, USA;
| | - Jamal Bouitbir
- Department of Pharmaceutical Sciences, Division of Molecular and Systems Toxicology, University of Basel, 4056 Basel, Switzerland;
| | - Romain Capoulade
- L’institut Du Thorax, Nantes Université, CNRS, INSERM, F-44000 Nantes, France;
| | - Rihab Bouchareb
- Department of Medicine, Division of Nephrology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Correspondence: or ; Tel.: +1-(212)-241-8471
| |
Collapse
|
|
13
|
Bugiardini R, Yoon J, Mendieta G, Kedev S, Zdravkovic M, Vasiljevic Z, Miličić D, Manfrini O, van der Schaar M, Gale CP, Bergami M, Badimon L, Cenko E. Reduced Heart Failure and Mortality in Patients Receiving Statin Therapy Before Initial Acute Coronary Syndrome. J Am Coll Cardiol 2022; 79:2021-2033. [PMID: 35589164 DOI: 10.1016/j.jacc.2022.03.354] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 02/09/2022] [Accepted: 03/10/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND There is uncertainty regarding the impact of statins on the risk of atherosclerotic cardiovascular disease (ASCVD) and its major complication, acute heart failure (AHF). OBJECTIVES The aim of this study was to investigate whether previous statin therapy translates into lower AHF events and improved survival from AHF among patients presenting with an acute coronary syndrome (ACS) as a first manifestation of ASCVD. METHODS Data were drawn from the International Survey of Acute Coronary Syndromes Archives. The study participants consisted of 14,542 Caucasian patients presenting with ACS without previous ASCVD events. Statin users before the index event were compared with nonusers by using inverse probability weighting models. Estimates were compared by test of interaction on the log scale. Main outcome measures were the incidence of AHF according to Killip class and the rate of 30-day all-cause mortality in patients presenting with AHF. RESULTS Previous statin therapy was associated with a significantly decreased rate of AHF on admission (4.3% absolute risk reduction; risk ratio [RR]: 0.72; 95% CI: 0.62-0.83) regardless of younger (40-75 years) or older age (interaction P = 0.27) and sex (interaction P = 0.22). Moreover, previous statin therapy predicted a lower risk of 30-day mortality in the subset of patients presenting with AHF on admission (5.2 % absolute risk reduction; RR: 0.71; 95% CI: 0.50-0.99). CONCLUSIONS Among adults presenting with ACS as a first manifestation of ASCVD, previous statin therapy is associated with a reduced risk of AHF and improved survival from AHF. (International Survey of Acute Coronary Syndromes [ISACS] Archives; NCT04008173).
Collapse
Affiliation(s)
- Raffaele Bugiardini
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy.
| | - Jinsung Yoon
- Google Cloud AI, Sunnyvale, California, USA; Department of Electrical and Computer Engineering, University of California, Los Angeles, Los Angeles, California, USA
| | - Guiomar Mendieta
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - Sasko Kedev
- University Clinic of Cardiology, Faculty of Medicine Ss. Cyril and Methodius University, Skopje, Macedonia
| | - Marija Zdravkovic
- University Hospital Medical Center Bezanijska Kosa, Belgrade, Serbia
| | | | - Davor Miličić
- Department of Cardiovascular Diseases, University Hospital Center Zagreb, University of Zagreb, Zagreb, Croatia
| | - Olivia Manfrini
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Mihaela van der Schaar
- Department of Electrical and Computer Engineering, University of California, Los Angeles, Los Angeles, California, USA; Cambridge Centre for Artificial Intelligence in Medicine, Department of Applied Mathematics and Theoretical Physics and Department of Population Health, University of Cambridge, Cambridge, United Kingdom
| | - Chris P Gale
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
| | - Maria Bergami
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Lina Badimon
- Cardiovascular Research Program ICCC, IR-IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, CiberCV-Institute Carlos III, Barcelona, Spain
| | - Edina Cenko
- Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy
| |
Collapse
|
|
14
|
Belce A, Ozkan BN, Dumlu FS, Sisman BH, Guler EM. Evaluation of Oxidative Stress and Inflammatory Biomarkers Pre and Post-Treatment in New Diagnosed Atherosclerotic Patients. Clin Exp Hypertens 2022; 44:320-325. [PMID: 35172655 DOI: 10.1080/10641963.2022.2036993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Atherosclerosis is a chronic vascular inflammatory disease associated to oxidative stress and endothelial dysfunction. It is characterized by lipid accumulation in the arterial wall, increased hyperlipidemia, oxidative stress, lipid peroxidation, and protein oxidation. Our study included 45 patients ages of 40-60 and 45 healthy volunteers with similar demographic characteristics without any chronic disease as well. Fasting plasma glucose, BUN, creatinine, LDL-cholesterol, HDL-cholesterol, triglyceride, total cholesterol, HbA1c, and C-reactive protein (CRP) levels were measured using commercial kits by autoanalyzer. The oxidative stress biomarkers total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), native thiol (NT), catalase (CAT), paraoxonase (PON1), and arylesterase (ARES) enzyme activities were measured using photometric methods. The inflammatory biomarkers interleukin 1 beta (IL-1β), tumor necrosis factor-α (TNF-α), presepsin (PSPN), and raftlin (RFTN1) levels were measured with ELISA Kits. Oxidative stress index (OSI) and disulfide (DIS) were calculated. The clinical, biochemical biomarkers such as BUN, creatinine, HDL, LDL, total cholesterol, triglyceride, and CRP levels were found to be higher than the control group and lower post-treatment compared to the pre-treatment group (p <0.001). The oxidative stress parameters, TOS, OSI, and DIS levels were found to be higher than the control group, and the levels before the treatment were statistically significantly higher than after the treatment (p < 0.001). Antioxidant biomarkers TAS, TT, and NT levels were low in the patient group. Inflammatory biomarkers were highest before treatment and decreased with treatment. Oxidative stress and inflammation, which increased in atherosclerosis patients may guide disease prognosis and treatment strategies.
Collapse
Affiliation(s)
- Ahmet Belce
- Department of Medical Biochemistry, Biruni University, Faculty of Medicine, Zeytinburnu, Istanbul
| | - Beyza Nur Ozkan
- Department of Medical Biochemistry, University of Health Science Turkey, Hamidiye Faculty of Medicine, Uskudar, Istanbul
| | - Fatma Sena Dumlu
- Department of Medical Biochemistry, University of Health Science Turkey, Hamidiye Faculty of Medicine, Uskudar, Istanbul
| | - Behice Hande Sisman
- Department of Cardiology, Bezmialem Vakıf University, Faculty of Medicine, Fatih, Istanbul
| | - Eray Metin Guler
- Department of Medical Biochemistry, University of Health Sciences Turkey, Haydarpasa Numune Health Application and Research Center, Uskudar, Istanbul
| |
Collapse
|
|
15
|
Kwon SJ, Hong KW, Choi S, Hong JS, Kim JW, Kim JW, Lee HJ, Jang HB, Yum KS. Association of 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene polymorphism with obesity and lipid metabolism in children and adolescents with autism spectrum disorder. Metab Brain Dis 2022; 37:319-328. [PMID: 34806144 DOI: 10.1007/s11011-021-00877-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/14/2021] [Indexed: 11/25/2022]
Abstract
The prevalence of obesity among children and adolescents with autism spectrum disorder (ASD) is higher than that among typically developing children and adolescents. However, very few studies have explored the genetic factors associated with obesity in children and adolescents with ASD. Thus, the aim of this study was to examine the associations between 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) gene polymorphisms and obesity among children and adolescents with ASD. The study participants consisted of 33 children and adolescents with ASD and 271 age- and sex-matched typically developing controls. We compared the metabolic traits (body mass index, blood pressure, triglyceride, high-density lipoprotein, and fasting glucose levels) between the ASD and control group. Furthermore, we assessed the genotypes of rs12654264 in the HMGCR gene within the participants with ASD, and compared metabolic traits among the different allele subgroups. The mean body mass index (BMI) and triglyceride level of the ASD group were significantly higher than those of the control group. Within the ASD group, the triglyceride level of participants with rs12654264-T alleles was significantly higher than that of participants with A-alleles. A pattern of increasing values in the BMI and fasting glucose was also observed in participants with T allele. This is the first study to show that obesity in children and adolescents with ASD is associated with the cholesterol synthesis pathway. Future studies are needed to further clarify the molecular mechanisms by which the HMGCR gene influences metabolic traits.
Collapse
Affiliation(s)
- Si Jin Kwon
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | - Silvia Choi
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ji Su Hong
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine/Center for Autism and Related Disorders, Kennedy Kreger Institute, Baltimore, MD, USA
| | - Jung Won Kim
- Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ju Whi Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye-Ja Lee
- Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Chungcheongbuk-do, Republic of Korea
| | - Han Byul Jang
- Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Chungcheongbuk-do, Republic of Korea
| | - Keun-Sang Yum
- Department of Family Medicine, Uijeongbu St. Mary's Hospital, The Catholic University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
16
|
Bland AR, Payne FM, Ashton JC, Jamialahmadi T, Sahebkar A. The cardioprotective actions of statins in targeting mitochondrial dysfunction associated with myocardial ischaemia-reperfusion injury. Pharmacol Res 2022; 175:105986. [PMID: 34800627 DOI: 10.1016/j.phrs.2021.105986] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 12/24/2022]
Abstract
During cardiac reperfusion after myocardial infarction, the heart is subjected to cascading cycles of ischaemia reperfusion injury (IRI). Patients presenting with this injury succumb to myocardial dysfunction resulting in myocardial cell death, which contributes to morbidity and mortality. New targeted therapies are required if the myocardium is to be protected from this injury and improve patient outcomes. Extensive research into the role of mitochondria during ischaemia and reperfusion has unveiled one of the most important sites contributing towards this injury; specifically, the opening of the mitochondrial permeability transition pore. The opening of this pore occurs during reperfusion and results in mitochondria swelling and dysfunction, promoting apoptotic cell death. Activation of mitochondrial ATP-sensitive potassium channels (mitoKATP) channels, uncoupling proteins, and inhibition of glycogen synthase kinase-3β (GSK3β) phosphorylation have been identified to delay mitochondrial permeability transition pore opening and reduce reactive oxygen species formation, thereby decreasing infarct size. Statins have recently been identified to provide a direct cardioprotective effect on these specific mitochondrial components, all of which reduce the severity of myocardial IRI, promoting the ability of statins to be a considerate preconditioning agent. This review will outline what has currently been shown in regard to statins cardioprotective effects on mitochondria during myocardial IRI.
Collapse
Affiliation(s)
- Abigail R Bland
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Fergus M Payne
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - John C Ashton
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
17
|
Morais TMF, Melo TS, Dantas MB, Ferreira JM, Sousa DFD, Magalhães EP, Menezes RRPPBD, Pessoa ODL, Feitosa ML, Sousa FCFD, Sampaio TL, Queiroz MGRD. Tyramine exerts hypolipidemic and anti-obesity effects in vivo. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e201191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
|
|
18
|
Pillai SC, Borah A, Jacob EM, Kumar DS. Nanotechnological approach to delivering nutraceuticals as promising drug candidates for the treatment of atherosclerosis. Drug Deliv 2021; 28:550-568. [PMID: 33703990 PMCID: PMC7954496 DOI: 10.1080/10717544.2021.1892241] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/14/2021] [Accepted: 02/15/2021] [Indexed: 12/25/2022] Open
Abstract
Atherosclerosis is Caesar's sword, which poses a huge risk to the present generation. Understanding the atherosclerotic disease cycle would allow ensuring improved diagnosis, better care, and treatment. Unfortunately, a highly effective and safe way of treating atherosclerosis in the medical community remains a continuous challenge. Conventional treatments have shown considerable success, but have some adverse effects on the human body. Natural derived medications or nutraceuticals have gained immense popularity in the treatment of atherosclerosis due to their decreased side effects and toxicity-related issues. In hindsight, the contribution of nutraceuticals in imparting enhanced clinical efficacy against atherosclerosis warrants more experimental evidence. On the other hand, nanotechnology and drug delivery systems (DDS) have revolutionized the way therapeutics are performed and researchers have been constantly exploring the positive effects that DDS brings to the field of therapeutic techniques. It could be as exciting as ever to apply nano-mediated delivery of nutraceuticals as an additional strategy to target the atherosclerotic sites boasting high therapeutic efficiency of the nutraceuticals and fewer side effects.
Collapse
Affiliation(s)
- Sindhu C. Pillai
- Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Saitama, Japan
| | - Ankita Borah
- Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Saitama, Japan
| | - Eden Mariam Jacob
- Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Saitama, Japan
| | - D. Sakthi Kumar
- Bio-Nano Electronics Research Centre, Graduate School of Interdisciplinary New Science, Toyo University, Saitama, Japan
| |
Collapse
|
|
19
|
A Systematic Review and Meta-Analysis of the Effect of Statins on Glutathione Peroxidase, Superoxide Dismutase, and Catalase. Antioxidants (Basel) 2021; 10:antiox10111841. [PMID: 34829712 PMCID: PMC8614838 DOI: 10.3390/antiox10111841] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 12/22/2022] Open
Abstract
Statins may exert protective effects against oxidative stress by upregulating specific antioxidant mechanisms. We conducted a systematic review and meta-analysis of the effect of statins on three key antioxidant enzymes: glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. The electronic databases PubMed, Web of Science, and Scopus were searched from inception to July 2021. The risk of bias was assessed with the Joanna Briggs Institute Critical Appraisal Checklist and certainty of evidence was assessed using the GRADE framework. In 15 studies, reporting 17 treatment arms in 773 patients (mean age 53 years, 54% males), statins significantly increased the concentrations of both GPx (standardized mean difference, SMD = 0.80, 95% confidence interval, CI 0.13 to 1.46, p = 0.018; high certainty of evidence) and SOD (SMD = 1.54, 95% CI 0.71 to 2.36, p < 0.001; high certainty of evidence), but not catalase (SMD = −0.16, 95% CI −0.51 to 0.20, p = 0.394; very low certainty of evidence). The pooled SMD values were not altered in sensitivity analysis. There was no publication bias. In conclusion, statin treatment significantly increases the circulating concentrations of GPx and SOD, suggesting an antioxidant effect of these agents (PROSPERO registration number: CRD42021271589).
Collapse
|
|
20
|
Rey-García J, Townsend RR. Large Artery Stiffness: A Companion to the 2015 AHA Science Statement on Arterial Stiffness. Pulse (Basel) 2021; 9:1-10. [PMID: 34722350 DOI: 10.1159/000518613] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/15/2021] [Indexed: 11/19/2022] Open
Abstract
Large artery stiffness (LAS) has proven to be an independent risk factor for cardiovascular disease and mortality. Nevertheless, the position of current hypertension guidelines regarding the usefulness of assessing LAS differs across different continents. In general, European Guidelines recognize pulse wave velocity (PWV) as a marker of target organ damage but do not recommend its systematic use in general population. Asian guidelines consider PWV as a recommended test at diagnosis of hypertension, in contrast to North American guidelines that do not state any position about its usefulness. However, PWV predicts cardiovascular events, and several studies have shown that it improves risk classification adjusting for established risk factors especially for intermediate-risk patients. Finally, some advances have been made related to treatments affecting LAS. Dietary interventions such as sodium restriction and exercise-based interventions have a modest effect in reducing LAS. Pharmacological interventions, such as statins, or more recent advances with mineralocorticoid blocker seem to have a beneficial effect. Last, controversial effects of renal denervation on LAS have been found. Our goal here is to update the reader on LAS on these areas since the 2015 American Heart Association Scientific Statement.
Collapse
Affiliation(s)
- Jimena Rey-García
- Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid, Madrid, Spain.,Internal Medicine Department, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
| | - Raymond R Townsend
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
21
|
Kim SY, Lee SM, Kwon GE, Kim BJ, Koo JN, Oh IH, Kim SM, Shin S, Kim W, Joo SK, Norwitz ER, Jung YM, Park CW, Jun JK, Choi MH, Park JS. Maternal dyslipidemia and altered cholesterol metabolism in early pregnancy as a risk factor for small for gestational age neonates. Sci Rep 2021; 11:21066. [PMID: 34702839 PMCID: PMC8548295 DOI: 10.1038/s41598-021-00270-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022] Open
Abstract
We evaluated the relationship between maternal cholesterol levels and its biologically active precursors and metabolites in the first trimester and subsequent risk for small-for-gestational-age birthweight (SGA). This is a secondary analysis of a prospective cohort study which enrolled healthy singleton pregnancies (n = 1337). Maternal fasting blood was taken in the first trimester and followed up till delivery. The lipid parameters were compared between women who delivered SGA neonates (SGA-group, birthweight < 10th percentile, n = 107) and women who did not (non-SGA-group, n = 1230). In addition, metabolic signatures of cholesterol were evaluated in a subset consisting of propensity-score matched SGA (n = 56) and control group (n = 56). Among lipid parameters, maternal high-density lipoprotein cholesterol (HDL-C) levels were significantly lower in SGA-group than in non-SGA-group (p = 0.022). The risk for SGA was negatively correlated with maternal serum HDL-C quartiles (p = 0.003), and this association remained significant after adjustment for confounding variables. In metabolic signatures of cholesterol, the cholesterol/lathosterol ratio in SGA-group was significantly higher than non-SGA-group [(2.7 (1.6-3.7) vs. 2.1 (1.5-2.9), respectively; p = 0.034)], suggesting increased endogenous cholesterol biosynthesis. We demonstrated that dyslipidemia and increased cholesterol biosynthesis led to delivery of SGA neonates even in early pregnancy.
Collapse
Affiliation(s)
- So Yeon Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.,Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seung Mi Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Go Eun Kwon
- Molecular Recognition Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seoul, 02792, Korea
| | - Byoung Jae Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.,Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | | | | | - Sun Min Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.,Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Sue Shin
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Laboratory Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Sae Kyung Joo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Errol R Norwitz
- Department of Obstetrics and Gynecology, Tufts University School of Medicine, Boston, MA, USA
| | - Young Mi Jung
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Chan-Wook Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Jong Kwan Jun
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Man Ho Choi
- Molecular Recognition Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seoul, 02792, Korea.
| | - Joong Shin Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.
| |
Collapse
|
|
22
|
Alternative Splicing in Cardiovascular Disease-A Survey of Recent Findings. Genes (Basel) 2021; 12:genes12091457. [PMID: 34573439 PMCID: PMC8469243 DOI: 10.3390/genes12091457] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/11/2021] [Accepted: 09/16/2021] [Indexed: 12/22/2022] Open
Abstract
Alternative splicing, a driver of posttranscriptional variance, differs from canonical splicing by arranging the introns and exons of an immature pre-mRNA transcript in a multitude of different ways. Although alternative splicing was discovered almost half a century ago, estimates of the proportion of genes that undergo alternative splicing have risen drastically over the last two decades. Deep sequencing methods and novel bioinformatic algorithms have led to new insights into the prevalence of spliced variants, tissue-specific splicing patterns and the significance of alternative splicing in development and disease. Thus far, the role of alternative splicing has been uncovered in areas ranging from heart development, the response to myocardial infarction to cardiac structural disease. Circular RNAs, a product of alternative back-splicing, were initially discovered in 1976, but landmark publications have only recently identified their regulatory role, tissue-specific expression, and transcriptomic abundance, spurring a renewed interest in the topic. The aim of this review is to provide a brief insight into some of the available findings on the role of alternative splicing in cardiovascular disease, with a focus on atherosclerosis, myocardial infarction, heart failure, dilated cardiomyopathy and circular RNAs in myocardial infarction.
Collapse
|
|
23
|
Selected 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors. A look into their use and potential in pre-diabetes and type 2 diabetes. Endocr Regul 2021; 55:182-192. [PMID: 34523296 DOI: 10.2478/enr-2021-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Objectives. This review assesses the comparative safety and efficacy of selected 3-hydroxy-3-methylglutaric acid coenzyme A inhibitors (statins, cinnamic acids. 3-hydroxy-3-methyl glutaric acid) on the pre-onset type 2 diabetes (PT2D) and post-onset type 2 diabetes (T2D)-related cluster of seven features (central obesity, hyperglycemia, hypertension, dyslipidemia, pro-thrombosis, oxidation and inflammation). Methods. Google scholar and PubMed were searched for statin*, flaxseed lignan complex (FLC), cinnamic acid (CA)*, and 3-hydroxy-3-methylglutaric acid (HMGA) in conjunction with each of PT2D, T2D and the cluster of seven. An introduction was followed by findings or absence thereof on the impacts of each of statins, FLC, CAs and HMGA on each member of the cluster of seven. Results. Pravastatin manages three features in PT2D, while a number of the statins improve five in T2D. FLC is negative in PT2D but controls four in T2D; it is not clear if the CAs and HMGA in FLC play a role in this success. CAs have potential in six and HMGA has potential in three of the cluster of seven though yet CAs and HMGA are untested in PT2D and T2D in humans. There are safety concerns with some statins and HMGA but FLC and CAs appear safe in the doses and durations tested. Conclusions. Selected statins, FLC, CAs and HMGA can manage or have a potential to manage at least three features of the cluster of seven. Most of the literature-stated concerns are with select statins but there are concerns (one actual and two potential) with HMGA.
Collapse
|
|
24
|
Wang J, Dong PK, Xu XF, Huang T, Mao S, Wang QG, Hao J, Liu XH, Sun XD, Kang K, Zhang Q, Li JT, Wang T. Identification of tRNA-derived Fragments and Their Potential Roles in Atherosclerosis. Curr Med Sci 2021; 41:712-721. [PMID: 34403096 DOI: 10.1007/s11596-021-2406-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/30/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Atherosclerosis (AS), a chronic inflammatory disease, is the basis of cardiovascular disease (CVD). Although the treatment has been greatly improved, AS still imposes a large burden on human health and the medical system, and we still need to further study its pathogenesis. As a novel biomolecule, transfer RNA-derived fragments (tRFs) play a key role in the progression of various disease. However, whether tRFs contribute to atherosclerosis pathogenesis remains unexplored. METHODS With deep sequencing technology, the change of tRFs expression profiles in patients with AS compared to healthy control group was identified. The accuracy of the sequencing data was validated using RT qPCR. Subsequently, we predicted the potential target genes of tRFs by online miRNA target prediction algorithms. The potential functions of tRFs were evaluated with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. RESULTS There were 13 tRFs differentially expressed between patients with AS and healthy controls, of which 2 were up-regulated and 11 were down-regulated. Validation by RT-qPCR analysis confirmed the sequencing results, and tRF-Gly-GCC-009 was highly up-regulated in the AS group based on the results of sequencing which was confirmed by RT-qPCR analysis. Furthermore, GO enrichment and KEGG pathway analyses indicated that 10 signaling pathways were related to tRF-Gly-GCC-009. These pathways might be physiopathological fundamentals of AS, mainly involving in Apelin signaling, Notch signaling and calcium signaling. CONCLUSION The results of our study provide important novel insight into the underlying pathogenesis and demonstrate that tRFs might be potential biomarkers and therapeutic targets for AS in the future.
Collapse
Affiliation(s)
- Jian Wang
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Pei-Kang Dong
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Xiu-Feng Xu
- Department of Neurology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Tao Huang
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Shuai Mao
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Qing-Guo Wang
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Jie Hao
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Xiao-Hong Liu
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Xiao-Dong Sun
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Kai Kang
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Quan Zhang
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
| | - Jing-Tian Li
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China.
| | - Tao Wang
- Department of Cardiology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China.
| |
Collapse
|
|
25
|
Anti-inflammatory potential of simvastatin loaded nanoliposomes in 2D and 3D foam cell models. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 37:102434. [PMID: 34214684 DOI: 10.1016/j.nano.2021.102434] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/10/2021] [Accepted: 05/31/2021] [Indexed: 12/17/2022]
Abstract
Atherosclerosis is a multifactorial disease triggered and sustained by risk factors such as high cholesterol, high blood pressure and unhealthy lifestyle. Inflammation plays a pivotal role in atherosclerosis pathogenesis. In this study, we developed a simvastatin (STAT) loaded nanoliposomal formulation (LIPOSTAT) which can deliver the drug into atherosclerotic plaque, when administered intravenously. This formulation is easily prepared, stable, and biocompatible with minimal burst release for effective drug delivery. 2D and 3D in vitro models were examined towards anti-inflammatory effects of STAT, both free and in combination with liposomes. LIPOSTAT induced greater cholesterol efflux in the 2D foam cells and significantly reduced inflammation in both 2D and 3D models. LIPOSTAT alleviated inflammation by reducing the secretion of early and late phase pro-inflammatory cytokines, monocyte adherence marker, and lipid accumulation cytokines. Additionally, the 3D foam cell spheroid model is a convenient and practical approach in testing various anti-atherosclerotic drugs without the need for human tissue.
Collapse
|
|
26
|
Mohankumari HP, Naidu KA, Narasimhamurthy K, Vijayalakshmi G. Bioactive Pigments of Monascus purpureus Attributed to Antioxidant, HMG-CoA Reductase Inhibition and Anti-atherogenic Functions. FRONTIERS IN SUSTAINABLE FOOD SYSTEMS 2021. [DOI: 10.3389/fsufs.2021.590427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Monascus purpureus is known to produce pigment molecules. The pigments were extracted from M. purpureus fermented rice. In-vitro antioxidant effects of pigments were observed and presumed to alleviate oxidative stress related atherosclerosis effect in rats fed with high fat diet (HFD) for 14 weeks. The formation of lipid peroxide due to the oxidation of serum lipid was higher in rats fed with HFD. While, the feeding of fermented rice (groups III-V) significantly lowered the formation of lipid peroxide (27.1–51.7%) in serum of rats, indicated antioxidative effect of pigments. In addition, feeding of fermented rice lowered serum cholesterol and triacylglycerol by 44.82 and 45.30%, respectively. Whereas, LDL-cholesterol levels were decreased by 70.12% and HDL-cholesterol increased by 34.58%. The atherogenic indices (LDL/HDL and TC/HDL) were reduced by 77.80 and 61.05%, respectively, in rats fed with fermented rice. These data confirmed the anti-atherosclerotic effect of pigments. Further liver enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was significantly inhibited up to 54%. The identification of statins, sterols and fatty acids in fermented rice revealed the HMG-CoA reductase inhibitory activity. This was confirmed by synthesis of lower levels of cholesterol and triacylglycerol in liver of rats fed with fermented rice. Accordingly antioxidant, inhibition of HMG-CoA reductase, anti-atherogenic functions of M. purpureus fermented rice is attributed to the collective effect of bioactive metabolites.
Collapse
|
|
27
|
Nicolosi M, Bellia F, Giuffrida ML, Zimbone S, Oliveri V, Vecchio G. Synthesis and biological evaluation of novel β-cyclodextrin-fluvastatin conjugates. RESULTS IN CHEMISTRY 2021. [DOI: 10.1016/j.rechem.2021.100230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
|
|
28
|
Statins, toxicity, and their adverse effects via oxidative imbalance. Toxicology 2021. [DOI: 10.1016/b978-0-12-819092-0.00026-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
29
|
Pan H, Xue C, Auerbach BJ, Fan J, Bashore AC, Cui J, Yang DY, Trignano SB, Liu W, Shi J, Ihuegbu CO, Bush EC, Worley J, Vlahos L, Laise P, Solomon RA, Connolly ES, Califano A, Sims PA, Zhang H, Li M, Reilly MP. Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human. Circulation 2020; 142:2060-2075. [PMID: 32962412 DOI: 10.1161/circulationaha.120.048378] [Citation(s) in RCA: 384] [Impact Index Per Article: 76.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive. METHODS To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro. RESULTS We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed "SEM" cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary artery disease risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans RA, an anticancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden, and promoted fibrous cap stability. CONCLUSIONS Integration of cell-specific fate mapping, single-cell genomics, and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.
Collapse
Affiliation(s)
- Huize Pan
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Chenyi Xue
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Benjamin J Auerbach
- Graduate Group in Genomics and Computational Biology (B.J.A.), University of Pennsylvania, Philadelphia
| | - Jiaxin Fan
- Department of Biostatistics, Epidemiology, and Informatics (J.F., M.L.), University of Pennsylvania, Philadelphia
| | - Alexander C Bashore
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Jian Cui
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Dina Y Yang
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Sarah B Trignano
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Wen Liu
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Jianting Shi
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Chinyere O Ihuegbu
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Erin C Bush
- Department of Systems Biology (E.C.B., J.W., L.V., P.L. A.C., P.A.S.), Columbia University Irving Medical Center, New York
| | - Jeremy Worley
- Department of Systems Biology (E.C.B., J.W., L.V., P.L. A.C., P.A.S.), Columbia University Irving Medical Center, New York
| | - Lukas Vlahos
- Department of Systems Biology (E.C.B., J.W., L.V., P.L. A.C., P.A.S.), Columbia University Irving Medical Center, New York
| | - Pasquale Laise
- Department of Systems Biology (E.C.B., J.W., L.V., P.L. A.C., P.A.S.), Columbia University Irving Medical Center, New York
| | - Robert A Solomon
- Department of Neurologic Surgery, New York-Presbyterian Hospital/Columbia University Irving Medical Center (R.A.S., E.S.C.)
| | - Edward S Connolly
- Department of Neurologic Surgery, New York-Presbyterian Hospital/Columbia University Irving Medical Center (R.A.S., E.S.C.)
| | - Andrea Califano
- Department of Systems Biology (E.C.B., J.W., L.V., P.L. A.C., P.A.S.), Columbia University Irving Medical Center, New York.,Herbert Irving Comprehensive Cancer Center (A.C.), Columbia University Irving Medical Center, New York.,JP Sulzberger Columbia Genome Center (A.C.), Columbia University Irving Medical Center, New York.,Department of Biomedical Informatics (A.C.), Columbia University Irving Medical Center, New York.,Department of Biochemistry and Molecular Biophysics (A.C., P.A.S.), Columbia University Irving Medical Center, New York
| | - Peter A Sims
- Department of Systems Biology (E.C.B., J.W., L.V., P.L. A.C., P.A.S.), Columbia University Irving Medical Center, New York.,Department of Biochemistry and Molecular Biophysics (A.C., P.A.S.), Columbia University Irving Medical Center, New York
| | - Hanrui Zhang
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York
| | - Mingyao Li
- Department of Biostatistics, Epidemiology, and Informatics (J.F., M.L.), University of Pennsylvania, Philadelphia
| | - Muredach P Reilly
- Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York.,Irving Institute for Clinical and Translational Research, Columbia University, New York (M.P.R.)
| |
Collapse
|
|
30
|
She L, Yao H, He L, Li Y, Cao J. GPR146: an emerging therapeutic target for hypercholesterolemia and atherosclerosis. Acta Biochim Biophys Sin (Shanghai) 2020; 52:914-915. [PMID: 32491159 DOI: 10.1093/abbs/gmaa058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 01/18/2020] [Accepted: 04/07/2020] [Indexed: 12/31/2022] Open
Affiliation(s)
- Lan She
- Department of Medical College, Hunan Polytechnic of Environment and Biology, Hengyang 421001, China
| | - Hailun Yao
- Department of Medical College, Hunan Polytechnic of Environment and Biology, Hengyang 421001, China
| | - Lingzhi He
- Department of Medical College, Hunan Polytechnic of Environment and Biology, Hengyang 421001, China
| | - Yajun Li
- Department of Medical College, Hunan Polytechnic of Environment and Biology, Hengyang 421001, China
| | - Jianping Cao
- Department of Medical College, Hunan Polytechnic of Environment and Biology, Hengyang 421001, China
| |
Collapse
|
|
31
|
Zhao Y, Wu TY, Zhao MF, Li CJ. The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease. J Biol Chem 2020; 295:5152-5162. [PMID: 32139507 DOI: 10.1074/jbc.rev119.008897] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate or geranylgeranyl diphosphate as substrates, respectively. Geranylgeranyl diphosphate synthase is a branch point enzyme in the mevalonate pathway that affects the ratio of farnesyl diphosphate to geranylgeranyl diphosphate. Abnormal geranylgeranyl diphosphate synthase expression and activity can therefore disrupt the balance of farnesylation and geranylgeranylation and alter the ratio between farnesylated and geranylgeranylated proteins. This change is associated with the progression of nonalcoholic fatty liver disease (NAFLD), a condition characterized by hepatic fat overload. Of note, differential accumulation of farnesylated and geranylgeranylated proteins has been associated with differential stages of NAFLD and NAFLD-associated liver fibrosis. In this review, we summarize key aspects of protein prenylation as well as advances that have uncovered the regulation of associated metabolic patterns and signaling pathways, such as Ras GTPase signaling, involved in NAFLD progression. Additionally, we discuss unique opportunities for targeting prenylation in NAFLD/hepatocellular carcinoma with agents such as statins and bisphosphonates to improve clinical outcomes.
Collapse
Affiliation(s)
- Yue Zhao
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China.,MOE Key Laboratory of Model Animal for Disease Study, Model Animals Research Center, Nanjing University, Nanjing 210093, China
| | - Tian-Yu Wu
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - Meng-Fei Zhao
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - Chao-Jun Li
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China .,MOE Key Laboratory of Model Animal for Disease Study, Model Animals Research Center, Nanjing University, Nanjing 210093, China
| |
Collapse
|
|
32
|
lotfi M, azizi M, tahmasebi W, bashiri P, Msc of exercise physiology, ssistant professor, ssistant professor, ssistant professor. Efficacy of Beetroot Juice Consumption on the Lipid Profile of Female Soccer Players. MEDICAL LABORATORY JOURNAL 2020. [DOI: 10.29252/mlj.14.2.26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
|
|
33
|
Gao JH, Yu XH, Tang CK. CXC chemokine ligand 12 (CXCL12) in atherosclerosis: An underlying therapeutic target. Clin Chim Acta 2019; 495:538-544. [PMID: 31145896 DOI: 10.1016/j.cca.2019.05.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 12/27/2022]
Abstract
CXC chemokine ligand 12 (CXCL12) is a specific chemokine ligand and plays a significant role in cell chemotaxis. Upon binding to CXC chemokine receptor 4 (CXCR4) or CXCR7, CXCL12 can activate different signaling cascades to regulate cell proliferation, migration, and metabolism. CXCL12 exerts a pro-atherogenic action by aggravating multiple pathogenesis of atherogenesis, including dyslipidemia, inflammation, neointima hyperplasia, angiogenesis, and insulin resistance. Serum CXCL12 levels are also markedly increased in patients with atherosclerosis-associated disease. The present review focuses on recent advances in CXCL12 research in the pathogenesis of atherosclerosis together with its clinical values. This may provide insight into potential novel therapies for atherosclerosis.
Collapse
Affiliation(s)
- Jia-Hui Gao
- Institute of Cardiovascular Disease, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Hua Yu
- Institute of Cardiovascular Disease, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China.
| |
Collapse
|
|
34
|
Jiang C, Qi Z, Tang Y, Jia H, Li Z, Zhang W, Liu J. Rational Design of Lovastatin-Loaded Spherical Reconstituted High Density Lipoprotein for Efficient and Safe Anti-Atherosclerotic Therapy. Mol Pharm 2019; 16:3284-3291. [DOI: 10.1021/acs.molpharmaceut.9b00445] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Cuiping Jiang
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Zitong Qi
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Yuqi Tang
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Hengbo Jia
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Zhuoting Li
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Wenli Zhang
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| | - Jianping Liu
- Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
| |
Collapse
|
|
35
|
Yandrapalli S, Gupta S, Andries G, Cooper HA, Aronow WS. Drug Therapy of Dyslipidemia in the Elderly. Drugs Aging 2019; 36:321-340. [PMID: 30613912 DOI: 10.1007/s40266-018-00632-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Abnormal lipoprotein metabolism is an important and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD), which has been shown in numerous studies to lead to adverse cardiovascular outcomes. As cardiovascular disease (CVD) remains the major cause of morbidity and mortality globally, management of dyslipidemia is a key component of primary and secondary risk-reduction strategies. Because ASCVD risk increases with age, as the population ages, many more people-particularly the elderly-will meet guideline criteria for drug treatment. Statins (HMG-CoA reductase inhibitors) have an unequivocal benefit in reducing ASCVD risk across age groups for secondary prevention. However, the benefit of these drugs for primary prevention in those > 75 years of age remains controversial. We strongly believe that statins should be offered for primary prevention to all older individuals after a shared decision-making process that takes polypharmacy, frailty, and potential adverse effects into consideration. When considering statin therapy in the very old, competing risks of death, and therefore the likelihood that patients will live long enough to benefit from drug therapy, should inform this process. Combination therapies with ezetimibe or proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors should be considered to facilitate the use of tolerable doses of statins. Future investigations of dyslipidemia therapies must appropriately include this at-risk population to identify optimal drugs and drug combinations that have a high benefit:risk ratio for the prevention of ASCVD in the elderly.
Collapse
Affiliation(s)
- Srikanth Yandrapalli
- Cardiology Division, Westchester Medical Center and New York Medical College, Macy Pavilion, Room 141, Valhalla, NY, 10595, USA
| | - Shashvat Gupta
- Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Gabriela Andries
- Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Howard A Cooper
- Cardiology Division, Westchester Medical Center and New York Medical College, Macy Pavilion, Room 141, Valhalla, NY, 10595, USA
| | - Wilbert S Aronow
- Cardiology Division, Westchester Medical Center and New York Medical College, Macy Pavilion, Room 141, Valhalla, NY, 10595, USA.
| |
Collapse
|
|
36
|
Kadir NAAA, Azlan A, Abas F, Ismail IS. Beneficial Effect of Supercritical Carbon Dioxide Extracted (SC-CO2) Dabai (Canarium odontophyllum) Pulp Oil in Hypercholesterolemia-Induced SPF Sprague-Dawley Rats. Nat Prod Commun 2018. [DOI: 10.1177/1934578x1801301205] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Production of dabai ( Canarium odontophyllum) pulp oil by supercritical carbon dioxide extraction is still relatively new and should be investigated. The objective of this study was to investigate the effects of supercritical carbon dioxide (SC-CO2) extracted dabai pulp oil (DPO) on rats induced with hypercholesterolemia. Male-specific pathogen free (SPF) Sprague-Dawley rats were fed with diets with high cholesterol contents for 4 weeks to induce hypercholesterolemia. Afterwards, the hypercholesterolemia rats were divided into groups namely: positive control group (PG), low dose group (LG), high dose group (HG), and statin group (SG). 0.5% and 2% of SC-CO2 DPO were administered to the LG and HG groups respectively for another 4 weeks. Changes in body weight and biochemistry profiles were measured. When compared with the normal rats that were fed with a normal basal diet, the hypercholesterolemia rats had elevated body weights and major increments in total cholesterol and LDL levels(NG) ( p<0.05). Paired-samples t-tests showed that the LG group exhibited a notable reduction in total cholesterol, triglyceride and LDL levels ( p<0.05) and an 8.26% increment in HDL level. Meanwhile, diminishing levels of total cholesterol, triglyceride and LDL levels were found in the HG group. Notable differences in AST and ALT levels were not detected in LG and HG groups when compared with the NG group. These results indicated that SC-CO2dabai pulp oil contains vital elements which contribute to cholesterol-loweringeffects and which can be used as special oils for health promotion and disease prevention.
Collapse
Affiliation(s)
- Noor Atiqah Aizan Abdul Kadir
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, 43400 UPM Serdang, Selangor, Malaysia
| | - Azrina Azlan
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, 43400 UPM Serdang, Selangor, Malaysia
- Research Centre for Excellence for Nutrition and Non-Communicable Disease, Faculty of Medicine and Health Sciences, 43400 UPM Serdang, Selangor, Malaysia
| | - Faridah Abas
- Department of Food Sciences, Faculty of Food Science and Technology, 43400 UPM Serdang, Selangor, Malaysia
| | - Intan Safinar Ismail
- Department of Chemistry, Faculty of Science, 43400 UPM Serdang, Selangor, Malaysia
| |
Collapse
|
|
37
|
Yue Y, Yan S, Li H, Zong Y, Yue J, Zeng L. The role of oral fluvastatin on postoperative peritoneal adhesion formation in an experimental rat model. Acta Chir Belg 2018; 118:372-379. [PMID: 29482467 DOI: 10.1080/00015458.2018.1444549] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND Postoperative peritoneal adhesions are a momentousness complication after abdominal surgery. Although varied means have been used to prevent and treat adhesions, the effects have not been satisfactory. Fluvastatin, a HMG-CoA reductase inhibitors, exhibits a variety of pharmacological effects. Aim of this study was to evaluate the effect of fluvastatin on postoperative peritoneal adhesion formation. METHODS Seventy-five male Wistar rats weighting 220-250g were randomly assigned equally to three groups. Group A was given sham operation without treatment, Group B was the model group in which postoperative peritoneal adhesion model was created without medication, and Group C was given oral fluvastatin treatment after postoperative peritoneal adhesion model created. After laparotomy on day 7, macroscopic and pathological assessment were evaluated, IL-1β and t-PA in plasma were performed to measure, and tissue samples were taken to measure MMP-9 protein. RESULTS There were significant differences between the groups on adhesion grade (p < .05), IL-1β content of the plasma and t-PA activity of the adhesions (p < .05). The grading of adhesion demonstrated significant differences between all groups. The levels of the IL-1β content of plasma, t-PA activity and MMP-9 of adhesion showed pivotal changes in Group B compared with Group A and C, while the difference between Group A and C was not statistically significant. CONCLUSION Oral fluvastatin application could reduce formation of intra-abdominal adhesion by promoting expression of MMP-9 level, lowering the levels of IL-1β and increasing the activity of t-PA after abdominal surgery.
Collapse
Affiliation(s)
- Yinzi Yue
- Suzhou Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Shuai Yan
- Suzhou Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Huan Li
- First Clinical Medical College of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yang Zong
- Suzhou Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Jin Yue
- Yancheng Hospital of Traditional Chinese Medicine, Yancheng, China
| | - Li Zeng
- First Clinical Medical College of Nanjing University of Traditional Chinese Medicine, Nanjing, China
| |
Collapse
|
|
38
|
Effects of Icariin on Atherosclerosis and Predicted Function Regulatory Network in ApoE Deficient Mice. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9424186. [PMID: 30533443 PMCID: PMC6247691 DOI: 10.1155/2018/9424186] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/02/2018] [Accepted: 10/21/2018] [Indexed: 12/13/2022]
Abstract
Objective. Icariin plays a pivotal role in ameliorating atherosclerosis for animal models although its comprehensive biological role remains largely unexplored. This study aimed to fully understand the effects of icariin on atherosclerosis in high-fat diet-induced ApoE-/- mice and investigate mRNA-miRNA regulation based on microarray and bioinformatics analysis. Methods. The areas of atherosclerotic lesions in en face aorta were evaluated. Microarray analysis was performed on atherosclerotic aortic tissues. The integrative analysis of mRNA and miRNA profiling was utilized to suggest specific functions of gene and supply an integrated and corresponding method to study the protective effect of icariin on atherosclerosis. Results. Icariin attenuated the development of atherosclerosis that the mean atherosclerotic lesion area was reduced by 5.8% (P < 0.05). Significant changes were observed in mRNA and miRNA expression patterns. Several miRNAs obtained from the miRNA-Gene-Network might play paramount part in antiatherosclerotic effect of icariin, such as mmu-miR-6931-5p, mmu-miR-3547-5p, mmu-miR-5107-5p, mmu-miR-6368, and mmu-miR-7118-5p. Specific miRNAs and GO terms associated with icariin in the pathogenesis of atherosclerosis were validated using GO analysis and miRNA-GO-Network. MiRNA-Pathway-Network indicated that icariin induced miRNAs mainly regulate the signaling pathways of PI3K/Akt signaling pathway, Ras signaling pathway, ErbB signaling pathway, and VEGF signaling pathway in aorta atherosclerotic lesion. Conclusions. Our data provides evidence that icariin is able to exhibit one antiatherosclerotic action by mediating multiple biological processes or cascades, suggesting the pleiotropic effects of icariin in atherosclerosis alleviation. The identified gene functional categories and pathways are potentially valuable targets for future development of RNA-guided gene regulation to fight disease.
Collapse
|
|
39
|
Tan CX, Chong GH, Hamzah H, Ghazali HM. Hypocholesterolaemic and hepatoprotective effects of virgin avocado oil in diet-induced hypercholesterolaemia rats. Int J Food Sci Technol 2018. [DOI: 10.1111/ijfs.13880] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Chin Xuan Tan
- Department of Food Science; Faculty of Food Science and Technology; Universiti Putra Malaysia; Serdang Selangor 43400 UPM Malaysia
| | - Gun Hean Chong
- Department of Food Technology; Faculty of Food Science and Technology; Universiti Putra Malaysia; Serdang Selangor 43400 UPM Malaysia
| | - Hazilawati Hamzah
- Department of Veterinary Pathology and Microbiology; Faculty of Veterinary Medicine; Universiti Putra Malaysia; Serdang Selangor 43400 UPM Malaysia
| | - Hasanah Mohd Ghazali
- Department of Food Science; Faculty of Food Science and Technology; Universiti Putra Malaysia; Serdang Selangor 43400 UPM Malaysia
| |
Collapse
|
|
40
|
Viktorinova A, Jurkovicova I, Fabryova L, Kinova S, Koren M, Stecova A, Svitekova K. Abnormalities in the relationship of paraoxonase 1 with HDL and apolipoprotein A1 and their possible connection to HDL dysfunctionality in type 2 diabetes. Diabetes Res Clin Pract 2018; 140:174-182. [PMID: 29626583 DOI: 10.1016/j.diabres.2018.03.055] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/09/2018] [Accepted: 03/29/2018] [Indexed: 10/17/2022]
Abstract
AIMS Lipid parameters, lipid risk indexes and lipid-related oxidative stress markers (paraoxonase 1 [PON1] and lipid peroxides [LPO]) reflect the actual status of lipid metabolism in type 2 diabetes (T2DM). We hypothesized that relationships of high-density lipoprotein cholesterol (HDL-c) with PON1 and apolipoprotein A1 (ApoA1) and/or PON1 with ApoA1 under conditions of hyperglycaemia and oxidative stress might reveal HDL functionality. We investigated relationships between PON1, LPO, and lipid risk markers in T2DM subjects and compared them with those in healthy subjects. METHODS A total of 107 Caucasian subjects, 67 T2DM outpatients (mean age 52.2 ± 6.9 years) and 40 healthy subjects (mean age 48.1 ± 7.5 years) were included in the study. Serum levels of total cholesterol (CHOL-T), HDL-c, low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), apolipoprotein B (ApoB), ApoA1, LPO, and PON1 activity were measured. Non-HDL-c, ApoB/ApoA1 and non-HDL/HDL (lipid risk indexes) were calculated. RESULTS Higher levels of TG, LPO (P < 0.0001), nonHDL/HDL and ApoB/ApoA1 (P < 0.001, 0.05, respectively), and lower levels of HDL-c, ApoA1, and PON1 (P < 0.0001) were observed in T2DM subjects than in controls. There is a lack of relationship among PON1, HDL-c, and ApoA1 in T2DM patients. PON1 activity positively correlated with these parameters (P < 0.0001) in controls. Strong correlations between non-HDL-c and ApoB (r = 0.956 vs. 0.756; P < 0.0001), LPO and TG (r = 0.831 vs. 0.739; P < 0.0001) were recorded in both study groups (P < 0.0001). CONCLUSIONS Impaired anti-oxidant and anti-atherogenic HDL properties associated with weakened PON1 function and lipid peroxidation may contribute to the development of atherosclerosis-related diseases in T2DM.
Collapse
Affiliation(s)
- Alena Viktorinova
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - Ingrid Jurkovicova
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Lubomira Fabryova
- Department of Diabetology and Metabolic Diseases, Metabol Klinik, Lipid Clinic, MED PED centre, Bratislava, Slovakia
| | - Sona Kinova
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Michal Koren
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Anna Stecova
- Department of Laboratory Diagnostics, Central Laboratory of Medirex, Bratislava, Slovakia
| | - Klara Svitekova
- National Blood Transfusion Service of Slovak Republic in Bratislava, Bratislava, Slovakia
| |
Collapse
|
|
41
|
Soulaidopoulos S, Nikiphorou E, Dimitroulas T, Kitas GD. The Role of Statins in Disease Modification and Cardiovascular Risk in Rheumatoid Arthritis. Front Med (Lausanne) 2018; 5:24. [PMID: 29473041 PMCID: PMC5809441 DOI: 10.3389/fmed.2018.00024] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 01/24/2018] [Indexed: 01/22/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune, inflammatory disorder associated with excess cardiovascular morbidity and mortality. A complex interplay between traditional risk factors (dyslipidemia, insulin resistance, arterial hypertension, obesity, smoking) and chronic inflammation is implicated in the development of premature atherosclerosis and consequently in the higher incidence of cardiovascular events observed in RA patients. Despite the acknowledgment of elevated cardiovascular risk among RA individuals, its management remains suboptimal. While statin administration has a crucial role in primary and secondary cardiovascular disease prevention strategies as lipid modulating factors, there are limited data concerning the precise benefit of such therapy in patients with RA. Systemic inflammation and anti-inflammatory treatments influence lipid metabolism, leading to variable states of dyslipidemia in RA. Hence, the indications for statin therapy for cardiovascular prevention may differ between RA patients and the general population and the precise role of lipid lowering treatment in RA is yet to be established. Furthermore, some evidence supports a potential beneficial impact of statins on RA disease activity, attributable to their anti-inflammatory and immunomodulatory properties. This review discusses existing data on the efficacy of statins in reducing RA-related cardiovascular risk as well as their potential beneficial effects on disease activity.
Collapse
Affiliation(s)
- Stergios Soulaidopoulos
- 4th Department of Internal Medicine, Hippokration University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Elena Nikiphorou
- Department of Academic Rheumatology, King’s College London, London, United Kingdom
- Department of Rheumatology, Whittington NHS Health, London, United Kingdom
| | - Theodoros Dimitroulas
- 4th Department of Internal Medicine, Hippokration University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - George D. Kitas
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, United Kingdom
- Department of Rheumatology, Dudley Group NHS Fountation Trust, Dudley, United Kingdom
| |
Collapse
|
|
42
|
Jiang C, Zhao Y, Yang Y, He J, Zhang W, Liu J. Evaluation of the Combined Effect of Recombinant High-Density Lipoprotein Carrier and the Encapsulated Lovastatin in RAW264.7 Macrophage Cells Based on the Median-Effect Principle. Mol Pharm 2018; 15:1017-1027. [DOI: 10.1021/acs.molpharmaceut.7b00923] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Cuiping Jiang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210008, PR China
| | - Yi Zhao
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210008, PR China
| | - Yun Yang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210008, PR China
| | - Jianhua He
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210008, PR China
| | - Wenli Zhang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210008, PR China
| | - Jianping Liu
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210008, PR China
| |
Collapse
|
|
43
|
Pechlivani N, Ajjan RA. Thrombosis and Vascular Inflammation in Diabetes: Mechanisms and Potential Therapeutic Targets. Front Cardiovasc Med 2018; 5:1. [PMID: 29404341 PMCID: PMC5780411 DOI: 10.3389/fcvm.2018.00001] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/03/2018] [Indexed: 12/14/2022] Open
Abstract
Cardiovascular disease remains the main cause of morbidity and mortality in patients with diabetes. The risk of vascular ischemia is increased in this population and outcome following an event is inferior compared to individuals with normal glucose metabolism. The reasons for the adverse vascular profile in diabetes are related to a combination of more extensive atherosclerotic disease coupled with an enhanced thrombotic environment. Long-term measures to halt the accelerated atherosclerotic process in diabetes have only partially addressed vascular pathology, while long-term antithrombotic management remains largely similar to individuals without diabetes. We address in this review the pathophysiological mechanisms responsible for atherosclerosis with special emphasis on diabetes-related pathways. We also cover the enhanced thrombotic milieu, characterized by increased platelet activation, raised activity of procoagulant proteins together with compromised function of the fibrinolytic system. Potential new therapeutic targets to reduce the risk of atherothrombosis in diabetes are explored, including alternative use of existing therapies. Special emphasis is placed on diabetes-specific therapeutic targets that have the potential to reduce vascular risk while keeping an acceptable clinical side effect profile. It is now generally acknowledged that diabetes is not a single clinical entity but a continuum of various stages of the condition with each having a different vascular risk. Therefore, we propose that future therapies aiming to reduce vascular risk in diabetes require a stratified approach with each group having a "stage-specific" vascular management strategy. This "individualized care" in diabetes may prove to be essential to improve vascular outcome in this high risk population.
Collapse
Affiliation(s)
- Nikoletta Pechlivani
- School of Medicine, Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
| | - Ramzi A Ajjan
- School of Medicine, Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
| |
Collapse
|
|
44
|
Fang J, Zhang Y. Icariin, an Anti-atherosclerotic Drug from Chinese Medicinal Herb Horny Goat Weed. Front Pharmacol 2017; 8:734. [PMID: 29075193 PMCID: PMC5644024 DOI: 10.3389/fphar.2017.00734] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 09/29/2017] [Indexed: 12/16/2022] Open
Abstract
Icariin is a major bioactive pharmaceutical constituent isolated from Chinese medicine Horny Goat Weed (Ying Yang Huo) with potent cardiovascular protective functions. Emerging evidence in the past decade has shown that Icariin possesses multiple atheroprotective functions, through multiple mechanisms, including attenuating DNA damage, correcting endothelial dysfunction, inhibiting the proliferation and migration of smooth muscle cells, repressing macrophage-derived foam cell formation and inflammatory responses, as well as preventing platelet activation. All of these protective effects, combined with its lipid-modulatory effects, contribute to the broad atheroprotective effects of Icariin. In this review, we will summarize the anti-atherosclerotic properties of Icariin and highlight future perspectives in developing Icariin as a promising anti-atherosclerotic drug.
Collapse
Affiliation(s)
- Jian Fang
- Department of Pharmacy, Huadu District People's Hospital, Southern Medical University, Guangzhou, China
| | - Yongjun Zhang
- Department of Gastroenterology, Huadu District People's Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
45
|
Akin I, Nienaber CA. Is there evidence for statins in the treatment of aortic valve stenosis? World J Cardiol 2017; 9:667-672. [PMID: 28932355 PMCID: PMC5583539 DOI: 10.4330/wjc.v9.i8.667] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 02/21/2017] [Accepted: 06/06/2017] [Indexed: 02/06/2023] Open
Abstract
Research revealed that the pathogenesis of aortic stenosis (AS) not merely comprises of a mechanical wear and tear process yet that active biological processes, similar to those of coronary artery disease are involved, a promising role for statins in disease-modifying therapy was suggested. However, recently, many prospective studies could not observe decreased progression nor regression of the disease. Here, we review the current knowledge on the pathomechanisms of AS and its similarities and differences with atherosclerosis. Moreover, we discuss whether there is still a place for statins in the treatment of particular AS patient subgroups.
Collapse
Affiliation(s)
- Ibrahim Akin
- Medical Faculty Mannheim, University Heidelberg, 68167 Mannheim, Germany
| | | |
Collapse
|
|
46
|
Detrimental effects of atherogenic and high fat diet on bone and aortic calcification rescued by an isoflavonoid Caviunin β-d-glucopyranoside. Biomed Pharmacother 2017; 92:757-771. [DOI: 10.1016/j.biopha.2017.05.120] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 05/23/2017] [Accepted: 05/24/2017] [Indexed: 02/06/2023] Open
|
|
47
|
Makay O, Isik D, Erol V, Yenisey C, Kose T, Icoz G, Ertan Y, Ozutemiz O, Akyildiz M. Efficacy of simvastatin in reducing postoperative adhesions after thyroidectomy: an experimental study. Acta Chir Belg 2017; 117:77-83. [PMID: 27735220 DOI: 10.1080/00015458.2016.1242292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND We aimed to investigate whether simvastatin had any impact on the prevention of adhesion formation after thyroidectomy in a rat model. METHODS This study was performed in 66 Wistar albino rats randomized into three experimental groups. A right hemithyroidectomy was carried out in all the rats. Simvastatin was administered locally at a dose of 0.5 mg/kg and 0.8 mg/kg. Control rats received a saline solution only. Changes during the 1st week, 1st month and 3rd month were evaluated. Efficacy of the treatment was assessed by using a scoring system. RESULTS The severity of adhesions in low-dose simvastatin group was significantly less than the control and high-dose groups during the 1st and 3rd month (p < .05). In addition, adhesions were less in the high dose group during the 3rd month, when compared to the control group (p < .05). Moreover, fibrosis and fibroblast scores, which represent adhesions, were significantly lower in low-dose and high-dose groups at 3rd month, compared to controls (p < .05). CONCLUSIONS We investigated the influence of simvastatin application on post-thyroidectomy adhesion formation in rats. Whether adhesions, causing technical difficulties during neck redo surgery, can be reduced by the use of simvastatin in human, needs to be studied.
Collapse
Affiliation(s)
- Ozer Makay
- Department of General Surgery, School of Medicine, Ege University, Bornova, Izmir, Turkey
| | - Dilek Isik
- Department of General Surgery, School of Medicine, Ege University, Bornova, Izmir, Turkey
| | - Varlik Erol
- Department of General Surgery, Zubeyde Hanim Practice and Research Center, Baskent University, Izmir, Turkey
| | - Cigdem Yenisey
- Department of Biochemistry, School of Medicine, Adnan Menderes University, Aydın, Turkey
| | - Timur Kose
- Department of Biostatistics, School of Medicine, Ege University, Bornova, Izmir, Turkey
| | - Gokhan Icoz
- Department of General Surgery, School of Medicine, Ege University, Bornova, Izmir, Turkey
| | - Yesim Ertan
- Department of Pathology, School of Medicine, Ege University, Bornova, Izmir, Turkey
| | - Omer Ozutemiz
- Department of Gastroenterology, School of Medicine, Ege University, Bornova, Izmir, Turkey
| | - Mahir Akyildiz
- Department of General Surgery, School of Medicine, Ege University, Bornova, Izmir, Turkey
| |
Collapse
|
|
48
|
Upala S, Wirunsawanya K, Jaruvongvanich V, Sanguankeo A. Effects of statin therapy on arterial stiffness: A systematic review and meta-analysis of randomized controlled trial. Int J Cardiol 2016; 227:338-341. [PMID: 27839806 DOI: 10.1016/j.ijcard.2016.11.073] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 11/05/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND Arterial stiffness has been observed to be an independent predictor for cardiovascular events. Effects of cholesterol lowering agents (statins) on arterial stiffness are inconsistent. We conducted a systematic review with a meta-analysis of all RCTs investigating the impact of statin therapy on arterial properties. METHODS We comprehensively searched the databases of MEDLINE, EMBASE, and Cochrane from their dates of inception through April 2016. The inclusion criteria were published RCTs comparing change in arterial stiffness between statin administration and active control or placebo groups. Arterial stiffness is determined by aortic pulse wave velocity (PWV). We used a random-effects model and calculated pooled standardized mean difference (SMD) with 95% confidence intervals (CI) comparing change in PWV between the statin and control groups. RESULTS Six studies were included in the meta-analysis. Statin therapy includes simvastatin, rosuvastatin, lovastatin, fluvastatin, and atorvastatin. Compared with the active control or placebo group, the statin therapy group had lower aPWV (SMD=2.31, 95% CI: 1.15-3.45, Pheterogeneity=0.07, I2=93%). CONCLUSION Our meta-analysis demonstrates that statin therapy has a beneficial effect on aortic arterial stiffness. Further studies should be conducted to assess the effects of this therapy on arterial stiffness at various sites and conditions.
Collapse
Affiliation(s)
- Sikarin Upala
- Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA; Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | | | - Veeravich Jaruvongvanich
- Department of Internal Medicine, University of Hawaii, Honolulu, HI, USA; Department of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
| | - Anawin Sanguankeo
- Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA; Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| |
Collapse
|
|
49
|
Olivares AL, González Ballester MA, Noailly J. Virtual exploration of early stage atherosclerosis. Bioinformatics 2016; 32:3798-3806. [DOI: 10.1093/bioinformatics/btw551] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 08/10/2016] [Accepted: 08/21/2016] [Indexed: 01/09/2023] Open
|
|
50
|
Krakauer T, Pradhan K, Stiles BG. Staphylococcal Superantigens Spark Host-Mediated Danger Signals. Front Immunol 2016; 7:23. [PMID: 26870039 PMCID: PMC4735405 DOI: 10.3389/fimmu.2016.00023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 01/18/2016] [Indexed: 12/19/2022] Open
Abstract
Staphylococcal enterotoxin B (SEB) of Staphylococcus aureus, and related superantigenic toxins produced by myriad microbes, are potent stimulators of the immune system causing a variety of human diseases from transient food poisoning to lethal toxic shock. These protein toxins bind directly to specific Vβ regions of T-cell receptors (TCR) and major histocompatibility complex (MHC) class II on antigen-presenting cells, resulting in hyperactivation of T lymphocytes and monocytes/macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. Because of superantigen-induced T cells skewed toward TH1 helper cells, and the induction of proinflammatory cytokines, superantigens can exacerbate autoimmune diseases. Upon TCR/MHC ligation, pathways induced by superantigens include the mitogen-activated protein kinase cascades and cytokine receptor signaling, resulting in activation of NFκB and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Various mouse models exist to study SEB-induced shock including those with potentiating agents, transgenic mice and an “SEB-only” model. However, therapeutics to treat toxic shock remain elusive as host response genes central to pathogenesis of superantigens have only been identified recently. Gene profiling of a murine model for SEB-induced shock reveals novel molecules upregulated in multiple organs not previously associated with SEB-induced responses. The pivotal genes include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, immunoproteasome components, as well as antiviral and IFN-stimulated genes. The host-wide induction of these, and other, antimicrobial defense genes provide evidence that SEB elicits danger signals resulting in multi-organ damage and toxic shock. Ultimately, these discoveries might lead to novel therapeutics for various superantigen-based diseases.
Collapse
Affiliation(s)
- Teresa Krakauer
- Department of Immunology, Molecular Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick , Frederick, MD , USA
| | - Kisha Pradhan
- Biology Department, Wilson College , Chambersburg, PA , USA
| | | |
Collapse
|