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Liu S, Li N, Jin JJ, Yu YW. Double-edged sword of L-arginine in diabetes: Exploring anti-inflammatory and antioxidant strategies. World J Diabetes 2025; 16:104007. [PMID: 40236855 PMCID: PMC11947932 DOI: 10.4239/wjd.v16.i4.104007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/21/2025] [Accepted: 02/10/2025] [Indexed: 02/28/2025] Open
Abstract
The article by Mansouri et al provides a comprehensive investigation into the effects of L-arginine (L-Arg) on diabetic cardiomyopathy. The authors conclude that while a low dose (0.5 g/kg) of L-Arg improves lipid profiles and reduces body weight, higher doses (≥ 1 g/kg) exacerbate oxidative stress, inflammation, and myocardial damage. In this letter, we aim to expand on the potential role of anti-inflammatory and antioxidant strategies in mitigating these adverse effects. Specifically, we focus on nuclear factor erythroid 2-related factor 2 activation and nitric oxide synthase modulation. These strategies could enhance the clinical utility of L-Arg by preserving its metabolic benefits while reducing its cardiotoxic risks. We believe this perspective will stimulate future research on L-Arg-based therapies in patients with diabetes, with an emphasis on optimizing dosage and exploring synergistic co-therapies.
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Affiliation(s)
- Shuai Liu
- Department of Cardiology, The First People’s Hospital of Jiashan, Jiaxing 314100, Zhejiang Province, China
| | - Ning Li
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jia-Jia Jin
- Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yong-Wei Yu
- Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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2
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Stevens CM, Weeks K, Jain SK. Potential of Vitamin D and l-Cysteine Co-supplementation to Downregulate Mammalian Target of Rapamycin: A Novel Therapeutic Approach to Diabetes. Metab Syndr Relat Disord 2025; 23:13-22. [PMID: 39279596 PMCID: PMC12021770 DOI: 10.1089/met.2024.0146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2024] Open
Abstract
Diabetes, a metabolic disease associated with an increased health care burden and mortality, is currently on the rise. Both upregulation of the mammalian target of rapamycin (mTOR) and decreased levels of vitamin D (VD) and l-cysteine (LC) have been associated with diabetes. The overactivation of mTOR leads to insulin desensitization and metabolic dysfunction including uncontrolled hyperglycemia. This review summarizes various studies that have shown an inhibitory effect of VD or LC on mTOR activity. Findings from preclinical studies suggest that optimizing the VD and LC status in patients with diabetes can result in mTOR suppression, which has the potential to protect these individuals from microvascular and macrovascular complications while enhancing the regulation of their blood glucose. Given this information, finding ways to suppress mTOR signaling and also increasing VD and LC status is a possible therapeutic approach that might aid patients with diabetes. Future clinical trials are needed to investigate whether VD and LC co-supplementation can successfully downregulate mTOR and can be used as adjuvant therapy in patients with diabetes.
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Affiliation(s)
- Christopher M. Stevens
- Departments of Pediatrics and Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
| | - Kathrine Weeks
- Department of Chemistry, Centenary College of Louisiana, Shreveport, Louisiana, USA
| | - Sushil K. Jain
- Departments of Pediatrics and Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
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Levitt DE, Wohlgemuth KJ, Burnham EF, Conner MJ, Collier JJ, Mota JA. Hazardous alcohol use and cardiometabolic risk among firefighters. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2025; 49:392-406. [PMID: 39746845 PMCID: PMC11831616 DOI: 10.1111/acer.15517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 12/10/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Alcohol misuse is prevalent among firefighters, and associated adverse cardiometabolic health consequences could negatively impact readiness for duty. Mental health conditions may confer additional risk. Therefore, we aimed to determine whether alcohol misuse increases cardiometabolic risk among firefighters and whether mental health conditions modify these relationships. METHODS Deidentified data from firefighters (N = 2405; 95.8% males, 38 ± 9 years, 29.6 ± 4.6 kg/m2) included demographics, Alcohol Use Disorders Identification Test (AUDIT) and AUDIT-C scores, mental health screening scores, anthropometrics, metabolic panel, and cardiorespiratory testing results. Differences in cardiometabolic parameters between firefighters with low AUDIT-C (<3 [females] or <4 [males]; no or low-risk alcohol use) or high AUDIT-C (≥3 [females] or ≥4 [males]; hazardous alcohol use) were determined and odds ratios for clinical risk factors were calculated. Posttraumatic stress disorder (PTSD), insomnia, depression, and anxiety were assessed as moderators. RESULTS Firefighters with high AUDIT-C had significantly (p < 0.05) higher total cholesterol (TC), high-density lipoprotein (HDL-C), and systolic blood pressure (SBP) and diastolic blood pressure (DBP) and lower hemoglobin A1C (HbA1c) than those with low AUDIT-C. In unadjusted and/or adjusted analyses, those with high AUDIT-C had increased risk for overweight/obesity, hypercholesterolemia, and prehypertension/hypertension, and decreased risk for low HDL and elevated HbA1c. There were inverse moderation effects by posttraumatic stress disorder (PTSD), depression, and anxiety on relationships between AUDIT-C score and BP. Insomnia (directly) and anxiety (inversely) moderated relationships between AUDIT-C score and circulating lipids. CONCLUSIONS Firefighters with high AUDIT-C have differential cardiometabolic risk, with specific relationships altered by mental health status. Whether higher HDL and lower HbA1c with high AUDIT-C in firefighters is protective long-term remains to be explored. Overall, these results underscore the need for alcohol screening and intervention to maintain cardiometabolic health and long-term occupational readiness among firefighters.
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Affiliation(s)
- Danielle E. Levitt
- Metabolic Health and Muscle Physiology Laboratory, Department of Kinesiology & Sport Management, Texas Tech University, Lubbock, TX
| | - Kealey J. Wohlgemuth
- Neuromuscular and Occupational Performance Laboratory, Department of Kinesiology & Sport Management, Texas Tech University, Lubbock, TX
| | | | | | - J. Jason Collier
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Jacob A. Mota
- Neuromuscular and Occupational Performance Laboratory, Department of Kinesiology & Sport Management, Texas Tech University, Lubbock, TX
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Lu TL, Zheng AC, Suzuki K, Lu CC, Wang CY, Fang SH. Supplementation of L-glutamine enhanced mucosal immunity and improved hormonal status of combat-sport athletes. J Int Soc Sports Nutr 2024; 21:2300259. [PMID: 38193521 PMCID: PMC10783826 DOI: 10.1080/15502783.2023.2300259] [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: 06/21/2023] [Accepted: 12/21/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Maintaining proper immune function and hormone status is important for athletes to avoid upper respiratory tract infection (URTI) and insufficient recovery, which is detrimental to sport performance and health. The aim of this study was to evaluate whether three-week supplementation of L-glutamine could benefit the mucosal immunity and hormonal status of combat-sport athletes as well as their rates of upper respiratory tract infection (URTI) and subjective feelings of well-being after intensive training. METHODS Twenty-one combat-sport athletes from the National Taiwan University of Sport were recruited in this study. After intensive training, two groups of the participants were asked to consume powder form of 0.3 g/kg body weight of L-glutamine (GLU group) or maltodextrin (PLA group) with drinking water in a randomized design at the same time every day during 3 weeks. Saliva samples were collected to measure immunoglobulin A (IgA), nitric oxide (NO), testosterone (T) and cortisol (C) before and after three-week supplementation; moreover, Hooper's index questionnaires were completed for wellness assessment. The incidence and duration of URTI were recorded by using a health checklist throughout the entire study period. RESULTS Supplementation of L-glutamine significantly enhanced the concentrations of IgA and NO in saliva; additionally, the incidence of URTI was significantly reduced. Regarding hormones, T concentration was significantly decreased in the PLA group, whereas C concentration was significantly increased, resulting in a significant decrease of T/C ratio. In contrast, the GLU group showed a significant increase of T/C ratio, while the mood scores of the Hooper's index questionnaire were higher in the PLA group. CONCLUSIONS Three-week supplementation of L-glutamine after intensive training enhanced the mucosal immunity, improved hormonal status and reduced the rate of URTI of combat-sport athletes while feelings of well-being were also enhanced. Therefore, L-glutamine would be beneficial for the sports performance and recovery of athletes.
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Affiliation(s)
- Tung-Lin Lu
- Institute of Athletics, National Taiwan University of Sport, Taichung, Taiwan
| | - Ai-Chi Zheng
- Institute of Athletics, National Taiwan University of Sport, Taichung, Taiwan
| | | | - Chi-Cheng Lu
- Institute of Athletics, National Taiwan University of Sport, Taichung, Taiwan
| | - Chung-Yuan Wang
- Department of Combat Sports, National Taiwan University of Sport, Taichung, Taiwan
| | - Shih-Hua Fang
- Institute of Athletics, National Taiwan University of Sport, Taichung, Taiwan
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Li X, Zou J, Lin A, Chi J, Hao H, Chen H, Liu Z. Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus. Antioxid Redox Signal 2024; 40:968-989. [PMID: 38497734 PMCID: PMC11535463 DOI: 10.1089/ars.2023.0524] [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: 12/04/2023] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/19/2024]
Abstract
Significance: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) dysfunction with substantially increased risk for CVDs. Recent Advances: Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to EC dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In this review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in T2DM. Critical Issues: Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Future Directions: Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well-designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents and effective personalized strategies will be developed for the management of endothelial dysfunction in DM.
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Affiliation(s)
- Xin Li
- Department of Endocrinology, Ningbo No. 2 Hospital, Ningbo, China
| | - Junyong Zou
- Department of Respiratory Medicine, Ningbo No. 2 Hospital, Ningbo, China
| | - Aiping Lin
- Center for Precision Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Jingshu Chi
- Center for Precision Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Hong Hao
- Center for Precision Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Hong Chen
- Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Zhenguo Liu
- Center for Precision Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
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Cifù A, Janes F, Mio C, Domenis R, Pessa ME, Garbo R, Curcio F, Valente M, Fabris M. Brain Endothelial Cells Activate Neuroinflammatory Pathways in Response to Early Cerebral Small Vessel Disease (CSVD) Patients' Plasma. Biomedicines 2023; 11:3055. [PMID: 38002055 PMCID: PMC10669613 DOI: 10.3390/biomedicines11113055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/06/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
The pathogenesis of cerebral small vessel disease (CSVD) is largely unknown. Endothelial disfunction has been suggested as the turning point in CSVD development. In this study, we tested the effect of plasma from CSVD patients on human cerebral microvascular endothelial cells with the aim of describing the pattern of endothelial activation. Plasma samples from three groups of young subjects have been tested: PTs (subjects affected by early stage CSVD); CTRLs (control subjects without abnormalities at MRI scanning); BDs (blood donors). Human Brain Endothelial Cells 5i (HBEC5i) were treated with plasma and total RNA was extracted. RNAs were pooled to reduce gene expression-based variability and NGS analysis was performed. Differentially expressed genes were highlighted comparing PTs, CTRLs and BDs with HBEC5i untreated cells. No significantly altered pathway was evaluated in BD-related treatment. Regulation of p38 MAPK cascade (GO:1900744) was the only pathway altered in CTRL-related treatment. Indeed, 36 different biological processes turned out to be deregulated after PT treatment of HBEC5i, i.e., the cytokine-mediated signaling pathway (GO:0019221). Endothelial cells activate inflammatory pathways in response to stimuli from CSVD patients' plasma, suggesting the pathogenetic role of neuroinflammation from the early asymptomatic phases of cerebrovascular disease.
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Affiliation(s)
- Adriana Cifù
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (A.C.); (C.M.); (R.D.); (F.C.); (M.V.); (M.F.)
| | - Francesco Janes
- Department of Head, Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), 33100 Udine, Italy; (M.E.P.); (R.G.)
| | - Catia Mio
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (A.C.); (C.M.); (R.D.); (F.C.); (M.V.); (M.F.)
| | - Rossana Domenis
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (A.C.); (C.M.); (R.D.); (F.C.); (M.V.); (M.F.)
| | - Maria Elena Pessa
- Department of Head, Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), 33100 Udine, Italy; (M.E.P.); (R.G.)
| | - Riccardo Garbo
- Department of Head, Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), 33100 Udine, Italy; (M.E.P.); (R.G.)
- Neurology Unit of Gorizia-Monfalcone, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), 34100 Gorizia, Italy
| | - Francesco Curcio
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (A.C.); (C.M.); (R.D.); (F.C.); (M.V.); (M.F.)
- Institute of Clinical Pathology, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), 33100 Udine, Italy
| | - Mariarosaria Valente
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (A.C.); (C.M.); (R.D.); (F.C.); (M.V.); (M.F.)
- Department of Head, Neck and Neuroscience, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), 33100 Udine, Italy; (M.E.P.); (R.G.)
| | - Martina Fabris
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (A.C.); (C.M.); (R.D.); (F.C.); (M.V.); (M.F.)
- Institute of Clinical Pathology, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), 33100 Udine, Italy
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Manzano M, Girón MD, Salto R, Burgio C, Reinoso A, Cabrera E, Rueda R, López-Pedrosa JM. Arginine and Lysine Supplementation Potentiates the Beneficial β-Hydroxy ß-Methyl Butyrate (HMB) Effects on Skeletal Muscle in a Rat Model of Diabetes. Nutrients 2023; 15:4706. [PMID: 38004100 PMCID: PMC10674618 DOI: 10.3390/nu15224706] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/02/2023] [Accepted: 11/04/2023] [Indexed: 11/26/2023] Open
Abstract
Skeletal muscle is the key tissue for maintaining protein and glucose homeostasis, having a profound impact on the development of diabetes. Diabetes causes deleterious changes in terms of loss of muscle mass, which will contribute to reduced glucose uptake and therefore progression of the disease. Nutritional approaches in diabetes have been directed to increase muscle glucose uptake, and improving protein turnover has been at least partially an oversight. In muscle, β-hydroxy β-methyl butyrate (HMB) promotes net protein synthesis, while arginine and lysine increase glucose uptake, albeit their effects on promoting protein synthesis are limited. This study evaluates if the combination of HMB, lysine, and arginine could prevent the loss of muscle mass and function, reducing the progression of diabetes. Therefore, the combination of these ingredients was tested in vitro and in vivo. In muscle cell cultures, the supplementation enhances glucose uptake and net protein synthesis due to an increase in the amount of GLUT4 transporter and stimulation of the insulin-dependent signaling pathway involving IRS-1 and Akt. In vivo, using a rat model of diabetes, the supplementation increases lean body mass and insulin sensitivity and decreases blood glucose and serum glycosylated hemoglobin. In treated animals, an increase in GLUT4, creatine kinase, and Akt phosphorylation was detected, demonstrating the synergic effects of the three ingredients. Our findings showed that nutritional formulations based on the combination of HMB, lysine, and arginine are effective, not only to control blood glucose levels but also to prevent skeletal muscle atrophy associated with the progression of diabetes.
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Affiliation(s)
- Manuel Manzano
- Abbott Nutrition R&D, E18004 Granada, Spain; (M.M.); (R.R.); (J.M.L.-P.)
| | - María D. Girón
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, E18071 Granada, Spain; (M.D.G.); (C.B.); (A.R.); (E.C.)
| | - Rafael Salto
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, E18071 Granada, Spain; (M.D.G.); (C.B.); (A.R.); (E.C.)
| | - Chiara Burgio
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, E18071 Granada, Spain; (M.D.G.); (C.B.); (A.R.); (E.C.)
| | - Antonio Reinoso
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, E18071 Granada, Spain; (M.D.G.); (C.B.); (A.R.); (E.C.)
| | - Elena Cabrera
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, E18071 Granada, Spain; (M.D.G.); (C.B.); (A.R.); (E.C.)
| | - Ricardo Rueda
- Abbott Nutrition R&D, E18004 Granada, Spain; (M.M.); (R.R.); (J.M.L.-P.)
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Karimi E, Abaj F, Gholizadeh M, Asbaghi O, Amini M, Ghaedi E, Hadi A. Watermelon consumption decreases risk factors of cardiovascular diseases: A systematic review and meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2023:110801. [PMID: 37369281 DOI: 10.1016/j.diabres.2023.110801] [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] [Received: 10/18/2022] [Revised: 06/16/2023] [Accepted: 06/21/2023] [Indexed: 06/29/2023]
Abstract
This meta-analysis was conducted to examine the effects of watermelon supplementation on cardiovascular diseases (CVDs) risk factors in randomized controlled trials (RCTs). The comprehensive search was done in Cochrane Library databases, ISI Web of Science, PubMed, and Scopus up to March 2022. A random-effect model was used for computing weighted mean differences (WMD). Standard methods were applied to examine publication bias, sensitivity analysis, and heterogeneity. Of the 8962 identified studies, 9 RCTs were included in the final analysis. Watermelon consumption significantly decreased systolic blood pressure (SBP), total cholesterol (TC) and low-density lipoprotein (LDL). In addition, watermelon consumption led to a significant increase in fasting blood sugar (FBS). However, there was not any significant difference in other outcomes of interest including diastolic blood pressure (DBP), heart rate (HR), BMI, body fat, and serum levels of arginine, insulin, and CRP after watermelon supplementation. The current findings provide promising evidence of the antihypertensive effect of watermelon. However, due to the lack of evidence in human research, the result regarding the remaining outcomes needs to be used with caution. Furter RCTs with longer follow-ups and larger sample sizes should be done to confirm the current findings.
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Affiliation(s)
- Elmira Karimi
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Victoria, Australia
| | - Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Gholizadeh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Omid Asbaghi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Ehsan Ghaedi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
| | - Amir Hadi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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Argaev-Frenkel L, Rosenzweig T. Redox Balance in Type 2 Diabetes: Therapeutic Potential and the Challenge of Antioxidant-Based Therapy. Antioxidants (Basel) 2023; 12:antiox12050994. [PMID: 37237860 DOI: 10.3390/antiox12050994] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/19/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Oxidative stress is an important factor in the development of type 2 diabetes (T2D) and associated complications. Unfortunately, most clinical studies have failed to provide sufficient evidence regarding the benefits of antioxidants (AOXs) in treating this disease. Based on the known complexity of reactive oxygen species (ROS) functions in both the physiology and pathophysiology of glucose homeostasis, it is suggested that inappropriate dosing leads to the failure of AOXs in T2D treatment. To support this hypothesis, the role of oxidative stress in the pathophysiology of T2D is described, together with a summary of the evidence for the failure of AOXs in the management of diabetes. A comparison of preclinical and clinical studies indicates that suboptimal dosing of AOXs might explain the lack of benefits of AOXs. Conversely, the possibility that glycemic control might be adversely affected by excess AOXs is also considered, based on the role of ROS in insulin signaling. We suggest that AOX therapy should be given in a personalized manner according to the need, which is the presence and severity of oxidative stress. With the development of gold-standard biomarkers for oxidative stress, optimization of AOX therapy may be achieved to maximize the therapeutic potential of these agents.
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Affiliation(s)
| | - Tovit Rosenzweig
- Department of Molecular Biology, Ariel University, Ariel 4070000, Israel
- Adison School of Medicine, Ariel University, Ariel 4070000, Israel
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Forzano I, Avvisato R, Varzideh F, Jankauskas SS, Cioppa A, Mone P, Salemme L, Kansakar U, Tesorio T, Trimarco V, Santulli G. L-Arginine in diabetes: clinical and preclinical evidence. Cardiovasc Diabetol 2023; 22:89. [PMID: 37072850 PMCID: PMC10114382 DOI: 10.1186/s12933-023-01827-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/06/2023] [Indexed: 04/20/2023] Open
Abstract
L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic.
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Affiliation(s)
- Imma Forzano
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Roberta Avvisato
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Fahimeh Varzideh
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Stanislovas S Jankauskas
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | - Angelo Cioppa
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
- Montevergine Clinic, Mercogliano (AV), Italy
| | - Pasquale Mone
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | | | - Urna Kansakar
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
| | | | - Valentina Trimarco
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA
- Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University, Naples, Italy
| | - Gaetano Santulli
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research, Fleischer Institute for Diabetes Research (FIDAM), Einstein - Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein University College of Medicine, New York, NY, USA.
- Department of Molecular Pharmacology, Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY, USA.
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Nandi S, Ahmed S, Saxena AK. Exploring the Role of Antioxidants to Combat Oxidative Stress in Malaria Parasites. Curr Top Med Chem 2022; 22:2029-2044. [PMID: 35382719 DOI: 10.2174/1568026622666220405121643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 02/06/2022] [Accepted: 02/18/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Malaria, a global challenge, is a parasitic disease caused by Plasmodium species. Approximately 229 million cases of malaria were reported in 2019. Major incidences occur in various continents, including African and Eastern Mediterranean Continents and South-East Asia. INTRODUCTION Despite the overall decline in global incidence from 2010 to 2018, the rate of decline has been almost constant since 2014. The morbidity and mortality have been accelerated due to reactive oxygen species (ROS) caused by oxidative stress generated by the parasite responsible for the destruction of host metabolism and cell nutrients. METHODS The excessive release of free radicals is associated with the infection in the animal or human body by the parasites. This may be related to a reduction in nutrients required for the generation of antioxidants and the destruction of cells by parasite activity. Therefore, an intensive literature search has been carried out to find the natural antioxidants used to neutralize the free radicals generated during malarial infection. RESULTS The natural antioxidants may be useful as an adjuvant treatment along with the antimalarial chemotherapeutics to reduce the death rate and enhance the success rate of malaria treatment. CONCLUSION In this manuscript, an attempt has been made to provide significant insight into the antioxidant activities of herbal extracts against malaria parasites.
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Affiliation(s)
- Sisir Nandi
- Global Institute of Pharmaceutical Education and Research, Kashipur, 244713, India
| | - Sarfaraz Ahmed
- Global Institute of Pharmaceutical Education and Research, Kashipur, 244713, India
| | - Anil Kumar Saxena
- Global Institute of Pharmaceutical Education and Research, Kashipur, 244713, India
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12
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Lizzo G, Migliavacca E, Lamers D, Frézal A, Corthesy J, Vinyes-Parès G, Bosco N, Karagounis LG, Hövelmann U, Heise T, von Eynatten M, Gut P. A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage. FRONTIERS IN AGING 2022; 3:852569. [PMID: 35821844 PMCID: PMC9261343 DOI: 10.3389/fragi.2022.852569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/08/2022] [Indexed: 01/23/2023]
Abstract
Glycine and cysteine are non-essential amino acids that are required to generate glutathione, an intracellular tripeptide that neutralizes reactive oxygen species and prevents tissue damage. During aging glutathione demand is thought to increase, but whether additional dietary intake of glycine and cysteine contributes towards the generation of glutathione in healthy older adults is not well understood. We investigated supplementation with glycine and n-acetylcysteine (GlyNAC) at three different daily doses for 2 weeks (low dose: 2.4 g, medium dose: 4.8 g, or high dose: 7.2 g/day, 1:1 ratio) in a randomized, controlled clinical trial in 114 healthy volunteers. Despite representing a cohort of healthy older adults (age mean = 65 years), we found significantly higher baseline levels of markers of oxidative stress, including that of malondialdehyde (MDA, 0.158 vs. 0.136 µmol/L, p < 0.0001), total cysteine (Cysteine-T, 314.8 vs. 276 µM, p < 0.0001), oxidized glutathione (GSSG, 174.5 vs. 132.3 µmol/L, p < 0.0001), and a lower ratio of reduced to oxidized glutathione (GSH-F:GSSG) (11.78 vs. 15.26, p = 0.0018) compared to a young reference group (age mean = 31.7 years, n = 20). GlyNAC supplementation was safe and well tolerated by the subjects, but did not increase levels of GSH-F:GSSG (end of study, placebo = 12.49 vs. 7.2 g = 12.65, p-value = 0.739) or that of total glutathione (GSH-T) (end of study, placebo = 903.5 vs. 7.2 g = 959.6 mg/L, p-value = 0.278), the primary endpoint of the study. Post-hoc analyses revealed that a subset of subjects characterized by high oxidative stress (above the median for MDA) and low baseline GSH-T status (below the median), who received the medium and high doses of GlyNAC, presented increased glutathione generation (end of study, placebo = 819.7 vs. 4.8g/7.2 g = 905.4 mg/L, p-value = 0.016). In summary GlyNAC supplementation is safe, well tolerated, and may increase glutathione levels in older adults with high glutathione demand. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05041179, NCT05041179.
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Affiliation(s)
- Giulia Lizzo
- Nestlé Institute of Health Sciences, Lausanne, Switzerland
| | | | | | - Adrien Frézal
- Nestlé Institute of Food Safety and Analytical Sciences, Lausanne, Switzerland
| | - John Corthesy
- Nestlé Institute of Food Safety and Analytical Sciences, Lausanne, Switzerland
| | | | - Nabil Bosco
- Nestlé Institute of Health Sciences, Lausanne, Switzerland
| | - Leonidas G Karagounis
- Nestlé Health Science, Vevey, Switzerland.,Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | | | | | | | - Philipp Gut
- Nestlé Institute of Health Sciences, Lausanne, Switzerland
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R-spondin 3 Inhibits High Glucose-Induced Endothelial Activation Through Leucine-Rich G Protein-Coupled Receptor 4/Wnt/β-catenin Pathway. J Cardiovasc Pharmacol 2022; 80:70-81. [PMID: 35767713 DOI: 10.1097/fjc.0000000000001295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/22/2022] [Indexed: 11/26/2022]
Abstract
ABSTRACT High glucose-induced endothelial activation plays critical roles in the development of diabetic vascular complications. R-spondin 3 could inhibit inflammatory damage, and diabetic vascular inflammation is secondary to endothelial activation. In this article, we identify R-spondin 3 as a novel regulator of high glucose-induced endothelial activation. We found that the serum levels of R-spondin 3 were significantly reduced in type 2 diabetic patients and db/db mice. We observed that the increased expressions of vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, and monocyte chemoattractant protein-1 (endothelial activation makers) in high glucose-stimulated human umbilical vein endothelial cell lines (HUVECs) could be inhibited by overexpressing R-spondin 3 or human R-spondin 3 recombinant protein. Subsequently, high glucose-induced adhesion and migration of human myeloid leukemia mononuclear cells (THP-1 cells) to HUVECs were markedly suppressed by the overexpression of R-spondin 3 in HUVECs. Moreover, the inhibitory effect of R-spondin 3 on the expressions of vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, and monocyte chemoattractant protein-1 in high glucose-treated HUVECs could be blocked by knockdown of leucine-rich G protein-coupled receptor 4 (R-spondin 3 receptor) or the specific inhibitor of Wnt/β-catenin pathway. Taken together, R-spondin 3 could suppress high glucose-induced endothelial activation through leucine-rich G protein-coupled receptor 4/Wnt/β-catenin pathway.
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Zhu Q, Liu X, Zhu Q, Liu Z, Yang C, Wu H, Zhang L, Xia X, Wang M, Hao H, Cui Y, Zhang G, Hill MA, Flaker GC, Zhou S, Liu Z. N-Acetylcysteine Enhances the Recovery of Ischemic Limb in Type-2 Diabetic Mice. Antioxidants (Basel) 2022; 11:antiox11061097. [PMID: 35739993 PMCID: PMC9219773 DOI: 10.3390/antiox11061097] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/16/2022] Open
Abstract
Critical limb ischemia (CLI) is a severe complication of diabetes mellitus that occurs without effective therapy. Excessive reactive oxygen species (ROS) production and oxidative stress play critical roles in the development of diabetic cardiovascular complications. N-acetylcysteine (NAC) reduces ischemia-induced ROS production. The present study aimed to investigate the effect of NAC on the recovery of ischemic limb in an experimental model of type-2 diabetes. TALLYHO/JngJ diabetic and SWR/J non-diabetic mice were used for developing a CLI model. For NAC treatment, mice received NAC (1 mg/mL) in their drinking water for 24 h before initiating CLI, and continuously for the duration of the experiment. Blood flow, mechanical function, histology, expression of antioxidant enzymes including superoxide dismutase (SOD)-1, SOD-3, glutathione peroxidase (Gpx)-1, catalase, and phosphorylated insulin receptor substrate (IRS)-1, Akt, and eNOS in ischemic limb were evaluated in vivo or ex vivo. Body weight, blood glucose, plasma advanced glycation end-products (AGEs), plasma insulin, insulin resistance index, and plasma TNF-a were also evaluated during the experiment. NAC treatment effectively attenuated ROS production with preserved expressions of SOD-1, Gpx-1, catalase, phosphorylated Akt, and eNOS, and enhanced the recovery of blood flow and function of the diabetic ischemic limb. NAC treatment also significantly decreased the levels of phosphorylated IRS-1 (Ser307) expression and plasma TNF-α in diabetic mice without significant changes in blood glucose and AGEs levels. In conclusion, NAC treatment enhanced the recovery of blood flow and mechanical function in ischemic limbs in T2D mice in association with improved tissue redox/inflammatory status and insulin resistance.
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Affiliation(s)
- Qiang Zhu
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
- Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha 410011, China;
| | - Xuanyou Liu
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Qingyi Zhu
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
- Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha 410011, China;
| | - Zehao Liu
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Chunlin Yang
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Hao Wu
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Linfang Zhang
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Xiujuan Xia
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Meifang Wang
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Hong Hao
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Yuqi Cui
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Guangsen Zhang
- Institute of Molecular Hematopathy, Second Xiangya Hospital, Central South University, Changsha 410011, China;
| | - Michael A. Hill
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA;
| | - Gregory C. Flaker
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
| | - Shenghua Zhou
- Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha 410011, China;
| | - Zhenguo Liu
- Center for Precision Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; (Q.Z.); (X.L.); (Q.Z.); (Z.L.); (C.Y.); (H.W.); (L.Z.); (X.X.); (M.W.); (H.H.); (Y.C.); (G.C.F.)
- Correspondence: ; Tel.: +1-573-884-3278; Fax: +1-573-884-7743
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Yang P, Zhou L, Chen M, Zeng L, Ouyang Y, Zheng X, Chen X, Yang Z, Tian Z. Supplementation of amino acids and organic acids prevents the increase in blood pressure induced by high salt in Dahl salt-sensitive rats. Food Funct 2022; 13:891-903. [PMID: 34994761 DOI: 10.1039/d1fo03577k] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A high-salt (HS) diet leads to metabolic disorders in Dahl salt-sensitive (SS) rats, and promotes the development of hypertension. According to the changes in the metabolites of SS rats, a set of combined dietary supplements containing amino acids and organic acids (AO) were designed. The purpose of the present study was to evaluate the effect of AO supplementation on the blood pressure of SS rats after the HS diet and clarify the mechanism of AO by metabolomics and biochemical analyses. The results showed that AO supplementation avoided the elevation of blood pressure induced by the HS diet in SS rats, increased the renal antioxidant enzyme activities (catalase, superoxide dismutase, glutathione reductase, and glutathione S-transferase), reduced the H2O2 and MDA levels, and restored the normal antioxidant status of the serum and kidneys. AO also reversed the decrease in the nitric oxide (NO) levels and NO synthase activity induced by the HS feed, which involved the L-arginine/NO pathway. Metabolomics analysis showed that AO administration increased the levels of amino acids such as cysteine, glycine, hypotaurine, and lysine in the renal medulla and the levels of leucine, isoleucine, and serine in the renal cortex. Of note, lysine, hypotaurine and glycine had higher metabolic centrality in the metabolic correlation network of the renal medulla after AO administration. In conclusion, AO intervention could prevent HS diet-induced hypertension in SS rats by restoring the metabolic homeostasis of the kidneys. Hence, AO has the potential to become a functional food additive to improve salt-sensitive hypertension.
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Affiliation(s)
- Pengfei Yang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Luxin Zhou
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Meng Chen
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Li Zeng
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Yanan Ouyang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Xuewei Zheng
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Xiangbo Chen
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Zhe Yang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Zhongmin Tian
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
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16
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Alves Porto A, Almeida Gonzaga L, Benjamim C, Garner D, Adami F, Valenti V. Effect of oral l-arginine supplementation on post-exercise blood pressure in hypertensive adults: A systematic review with meta-analysis of randomized double-blind, placebo-controlled studies. Sci Sports 2022. [DOI: 10.1016/j.scispo.2021.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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17
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Schwalfenberg GK. N-Acetylcysteine: A Review of Clinical Usefulness (an Old Drug with New Tricks). J Nutr Metab 2021; 2021:9949453. [PMID: 34221501 PMCID: PMC8211525 DOI: 10.1155/2021/9949453] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/26/2021] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE To review the clinical usefulness of N-acetylcysteine (NAC) as treatment or adjunctive therapy in a number of medical conditions. Use in Tylenol overdose, cystic fibrosis, and chronic obstructive lung disease has been well documented, but there is emerging evidence many other conditions would benefit from this safe, simple, and inexpensive intervention. Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. This study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented. Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. These conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn's disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles. There are also a number of other conditions that may show benefit; however, the evidence is not as robust. CONCLUSION The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.
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Affiliation(s)
- Gerry K. Schwalfenberg
- Department of Family Medicine, University of Alberta, No. 301, 9509-156 Street, Edmonton T5P 4J5, AB, Canada
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18
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Finsen SH, Hansen MR, Hansen PBL, Mortensen SP. Aldosterone Induces Vasoconstriction in Individuals with Type 2 Diabetes: Effect of Acute Antioxidant Administration. J Clin Endocrinol Metab 2021; 106:e1262-e1270. [PMID: 33247722 DOI: 10.1210/clinem/dgaa867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Indexed: 11/19/2022]
Abstract
CONTEXT Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species-dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone. OBJECTIVE We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared with healthy controls and if infusion of an antioxidant (n-acetylcysteine [NAC]) would alter the vascular response. METHODS In a case-control design, 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min-1 [L leg volume]-1) for 10 minutes into the femoral artery with and without coinfusion of NAC (125 mg kg-1 hour-1 followed by 25 mg kg-1 hour-1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected. RESULTS Compared with the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in individuals with type 2 diabetes, whereas coinfusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions. CONCLUSION These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response.
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Affiliation(s)
- Stine Høyer Finsen
- Department of Cardiovascular and Renal Research, University of Southern Denmark, Denmark
| | - Mie Rytz Hansen
- Department of Cardiovascular and Renal Research, University of Southern Denmark, Denmark
| | | | - Stefan P Mortensen
- Department of Cardiovascular and Renal Research, University of Southern Denmark, Denmark
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Venkatakrishnan K, Chiu HF, Wang CK. Impact of functional foods and nutraceuticals on high blood pressure with a special focus on meta-analysis: review from a public health perspective. Food Funct 2021; 11:2792-2804. [PMID: 32248209 DOI: 10.1039/d0fo00357c] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In recent times many researchers are expressing immense interest in nutraceuticals and functional foods for combating various diseases or abnormal conditions, especially against hypertension (HT). Persistent HT is medically referred to as chronic high blood pressure (BP) and considered to be one of the major risk factors for the deadliest diseases including cardiovascular disease (CVD) and cerebrovascular diseases. Hence HT poses a serious socio-economic burden worldwide, particularly to developing countries. The current treatment strategy for HT includes standard anti-hypertensive drugs, which are associated with many adverse effects and lower drug adherence rates. Therefore, an alternative or complementary natural therapy (functional foods or nutraceuticals or dietary supplements) would be the alternate choice along with a modified lifestyle pattern that might help to manage or combat HT and its related complications. During this review, the author would like to shed light on the basic science behind HT including pathophysiology and the impact of dietary salt on HT and the impact of various functional foods or nutraceuticals against HT in humans (meta-analysis and systemic review). This contribution gives a better idea (public health perspective) for choosing the best functional foods/nutraceuticals for the prevention, management or delaying the onset of HT and its associated conditions along with modified lifestyle patterns and standard anti-hypertensive drugs.
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Affiliation(s)
- Kamesh Venkatakrishnan
- School of Nutrition, Chung Shan Medical University, 110, Sec. 1, Jianguo North Road, Taichung City-40201, Taiwan, Republic of China.
| | - Hui-Fang Chiu
- Department of Chinese Medicine, Taichung Hospital Ministry of Health and Welfare, Taichung-40301, Taiwan, Republic of China
| | - Chin-Kun Wang
- School of Nutrition, Chung Shan Medical University, 110, Sec. 1, Jianguo North Road, Taichung City-40201, Taiwan, Republic of China.
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20
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Morris G, Bortolasci CC, Puri BK, Olive L, Marx W, O'Neil A, Athan E, Carvalho A, Maes M, Walder K, Berk M. Preventing the development of severe COVID-19 by modifying immunothrombosis. Life Sci 2021; 264:118617. [PMID: 33096114 PMCID: PMC7574725 DOI: 10.1016/j.lfs.2020.118617] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/01/2020] [Accepted: 10/13/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. MAIN BODY The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail.
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Affiliation(s)
- Gerwyn Morris
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Chiara C Bortolasci
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia
| | | | - Lisa Olive
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; School of Psychology, Deakin University, Geelong, Australia
| | - Wolfgang Marx
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Adrienne O'Neil
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Melbourne School of Population and Global Health, Melbourne, Australia
| | - Eugene Athan
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Barwon Health, Geelong, Australia
| | - Andre Carvalho
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, University of Toronto, Toronto, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, Canada
| | - Michael Maes
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Ken Walder
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia
| | - Michael Berk
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.
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Hamill MJ, Afeyan R, Chakravarthy MV, Tramontin T. Endogenous Metabolic Modulators: Emerging Therapeutic Potential of Amino Acids. iScience 2020; 23:101628. [PMID: 33103071 PMCID: PMC7569218 DOI: 10.1016/j.isci.2020.101628] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Multifactorial disease pathophysiology is complex and incompletely addressed by existing targeted pharmacotherapies. Amino acids (AAs) and related metabolites and precursors are a class of endogenous metabolic modulators (EMMs) that have diverse biological functions and, thus, have been explored for decades as potential multifactorial disease treatments. Here, we review the literature on this class of EMMs in disease treatment, with a focus on the emerging clinical studies on AAs and related metabolites and precursors as single- and combination-agents targeted to a single biology. These clinical research insights, in addition to increasing understanding of disease metabolic profiles and combinatorial therapeutic design principles, highlight an opportunity to develop EMM compositions with AAs and related metabolites and precursors to target multifactorial disease biology. EMM compositions are uniquely designed to enable a comprehensive approach, with potential to simultaneously and safely target pathways underlying multifactorial diseases and to regulate biological processes that promote overall health.
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Hallajzadeh J, Milajerdi A, Reiner Ž, Kolahdooz F, Asemi Z. The Effects of N-acetylcysteine on Inflammatory Markers and Homocysteine: A Systematic Review and Meta-analysis of Randomized Controlled Trials. PHARMACEUTICAL SCIENCES 2020. [DOI: 10.34172/ps.2020.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Jamal Hallajzadeh
- Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Alireza Milajerdi
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Community Nutrition, School of Nutritional Scienes and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Fariba Kolahdooz
- Indigenous and Global Health Research, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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23
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Effect of N-Acetylcysteine on Metabolic Profile in Metabolic Syndrome Patients. Metab Syndr Relat Disord 2020; 18:341-346. [DOI: 10.1089/met.2020.0017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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Gambardella J, Khondkar W, Morelli MB, Wang X, Santulli G, Trimarco V. Arginine and Endothelial Function. Biomedicines 2020; 8:277. [PMID: 32781796 PMCID: PMC7460461 DOI: 10.3390/biomedicines8080277] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 12/15/2022] Open
Abstract
Arginine (L-arginine), is an amino acid involved in a number of biological processes, including the biosynthesis of proteins, host immune response, urea cycle, and nitric oxide production. In this systematic review, we focus on the functional role of arginine in the regulation of endothelial function and vascular tone. Both clinical and preclinical studies are examined, analyzing the effects of arginine supplementation in hypertension, ischemic heart disease, aging, peripheral artery disease, and diabetes mellitus.
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Affiliation(s)
- Jessica Gambardella
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine—Montefiore University Hospital, New York City, NY 10461, USA; (J.G.); (W.K.); (M.B.M.); (X.W.)
- Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, NY 10461, USA
- Department of Advanced Biomedical Sciences, “Federico II” University, 80131 Naples, Italy
- International Translational Research and Medical Education (ITME), 80100 Naples, Italy
| | - Wafiq Khondkar
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine—Montefiore University Hospital, New York City, NY 10461, USA; (J.G.); (W.K.); (M.B.M.); (X.W.)
| | - Marco Bruno Morelli
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine—Montefiore University Hospital, New York City, NY 10461, USA; (J.G.); (W.K.); (M.B.M.); (X.W.)
- Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, NY 10461, USA
| | - Xujun Wang
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine—Montefiore University Hospital, New York City, NY 10461, USA; (J.G.); (W.K.); (M.B.M.); (X.W.)
| | - Gaetano Santulli
- Department of Medicine (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine—Montefiore University Hospital, New York City, NY 10461, USA; (J.G.); (W.K.); (M.B.M.); (X.W.)
- Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, NY 10461, USA
- Department of Advanced Biomedical Sciences, “Federico II” University, 80131 Naples, Italy
- International Translational Research and Medical Education (ITME), 80100 Naples, Italy
| | - Valentina Trimarco
- Department of Neuroscience, “Federico II” University, 80131 Naples, Italy;
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25
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Chiu HF, Venkatakrishnan K, Wang CK. Nutraceuticals and functional foods in the prevention of hypertension induced by excessive intake of dietary salt. DIETARY SUGAR, SALT AND FAT IN HUMAN HEALTH 2020:423-450. [DOI: 10.1016/b978-0-12-816918-6.00020-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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26
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Cuevas S, Villar VAM, Jose PA. Genetic polymorphisms associated with reactive oxygen species and blood pressure regulation. THE PHARMACOGENOMICS JOURNAL 2019; 19:315-336. [PMID: 30723314 PMCID: PMC6650341 DOI: 10.1038/s41397-019-0082-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 10/19/2018] [Accepted: 12/21/2018] [Indexed: 02/08/2023]
Abstract
Hypertension is the most prevalent cause of cardiovascular disease and kidney failure, but only about 50% of patients achieve adequate blood pressure control, in part, due to inter-individual genetic variations in the response to antihypertensive medication. Significant strides have been made toward the understanding of the role of reactive oxygen species (ROS) in the regulation of the cardiovascular system. However, the role of ROS in human hypertension is still unclear. Polymorphisms of some genes involved in the regulation of ROS production are associated with hypertension, suggesting their potential influence on blood pressure control and response to antihypertensive medication. This review provides an update on the genes associated with the regulation of ROS production in hypertension and discusses the controversies on the use of antioxidants in the treatment of hypertension, including the antioxidant effects of antihypertensive drugs.
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Affiliation(s)
- Santiago Cuevas
- Center for Translational Science, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC, 20010, USA.
| | - Van Anthony M Villar
- Department of Medicine, Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, Walter G. Ross Hall, Suite 738, 2300 I Street, NW, Washington, DC, 20052, USA
| | - Pedro A Jose
- Department of Medicine, Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, Walter G. Ross Hall, Suite 738, 2300 I Street, NW, Washington, DC, 20052, USA
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27
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Hagen DM, Ekena JL, Geesaman BM, Viviano KR. Antioxidant supplementation during illness in dogs: effect on oxidative stress and outcome, an exploratory study. J Small Anim Pract 2019; 60:543-550. [PMID: 31292973 DOI: 10.1111/jsap.13050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 03/08/2019] [Accepted: 05/09/2019] [Indexed: 12/24/2022]
Abstract
OBJECTIVES To assess whether combination antioxidant supplementation for 30 days in systemically ill dogs alters antioxidant status, degree of lipid peroxidation, clinical score and survival. MATERIALS AND METHODS Forty client-owned systemically-ill hospitalised dogs were eligible for inclusion. Dogs were randomised to no supplementation (NS; n=19) or supplementation with N-acetylcysteine/S-adenosylmethionine/silybin and vitamin E (AS; n=20) for 30 days. Clinical score and oxidative biomarkers including glutathione, cysteine, vitamin E, selenium and urine isoprostanes/creatinine (F2 -IsoPs/Cr) were determined on days 0 and 30. Glutathione, cysteine, vitamin E and urine F2 -IsoPs/Cr were quantified by high-performance liquid chromatography, and selenium concentrations determined using atomic absorption spectroscopy. RESULTS Thirty-two dogs completed the study (NS, n=16; AS, n=16). Vitamin E concentrations were significantly greater in the supplemented compared to the non-supplemented group. No other markers of oxidative stress significantly changed with supplementation. There was no difference in Day 30 clinical scores or survival between the two groups. CLINICAL SIGNIFICANCE In this population of systemically-ill hospitalised dogs, combination antioxidant supplementation did not alter redox state or clinical outcome.
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Affiliation(s)
- D M Hagen
- VCA Bay Area Veterinary Specialists & Emergency Hospital, San Leandro, California, 94578, USA
| | - J L Ekena
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, USA
| | - B M Geesaman
- Carolina Veterinary Specialist, Winston-Salem, North Carolina, 27103, USA
| | - K R Viviano
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, USA
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Kanikarla-Marie P, Micinski D, Jain SK. Hyperglycemia (high-glucose) decreases L-cysteine and glutathione levels in cultured monocytes and blood of Zucker diabetic rats. Mol Cell Biochem 2019; 459:151-156. [PMID: 31172369 DOI: 10.1007/s11010-019-03558-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 05/27/2019] [Indexed: 02/05/2023]
Abstract
L-Cysteine (LC) is an essential precursor of GSH biosynthesis. GSH is a major physiological antioxidant, and its depletion increases oxidative stress. Diabetes is associated with lower blood levels of LC and GSH. The mechanisms leading to a decrease in LC in diabetes are not entirely known. This study reports a significant decrease in LC in human monocytes exposed to high glucose (HG) concentrations as well as in the blood of type 2 diabetic rats. Thus, a significant decrease in the level of LC in response to exposure to HG supports the assertion that uncontrolled hyperglycemia contributes to a reduction of blood levels of LC and GSH seen in diabetic patients. Increased requirement of LC to replace GSH needed to scavenge excess ROS generated by hyperglycemia can result in lower levels of LC and GSH. Animal and human studies report that LC supplementation improves GSH biosynthesis and is beneficial in lowering oxidative stress and insulin resistance. This suggests that hyperglycemia has a direct role in the impairment of LC and GSH homeostasis in diabetes.
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Affiliation(s)
- Preeti Kanikarla-Marie
- Departments of Pediatrics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA
| | - David Micinski
- Departments of Pediatrics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA
| | - Sushil K Jain
- Departments of Pediatrics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA.
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Šalamon Š, Kramar B, Marolt TP, Poljšak B, Milisav I. Medical and Dietary Uses of N-Acetylcysteine. Antioxidants (Basel) 2019; 8:antiox8050111. [PMID: 31035402 PMCID: PMC6562654 DOI: 10.3390/antiox8050111] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/09/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
N-acetylcysteine (NAC), a plant antioxidant naturally found in onion, is a precursor to glutathione. It has been used as a drug since the 1960s and is listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote in poisonings. There are numerous other uses or proposed uses in medicine that are still in preclinical and clinical investigations. NAC is also used in food supplements and cosmetics. Despite its abundant use, there are projections that the NAC global market will grow in the next five years; therefore, the purpose of this work is to provide a balanced view of further uses of NAC as a dietary supplement. Although NAC is considered a safe substance, the results among clinical trials are sometimes controversial or incomplete, like for many other antioxidants. More clinical trials are underway that will improve our understanding of NAC applicability.
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Affiliation(s)
- Špela Šalamon
- Center for human molecular genetics and pharmacogenomics, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia.
| | - Barbara Kramar
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.
| | - Tinkara Pirc Marolt
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.
| | - Borut Poljšak
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Oxidative Stress Research, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia.
| | - Irina Milisav
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia.
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Oxidative Stress Research, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia.
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Association of l-Arginine Supplementation with Markers of Endothelial Function in Patients with Cardiovascular or Metabolic Disorders: A Systematic Review and Meta-Analysis. Nutrients 2018; 11:nu11010015. [PMID: 30577559 PMCID: PMC6357192 DOI: 10.3390/nu11010015] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/16/2018] [Accepted: 11/17/2018] [Indexed: 12/18/2022] Open
Abstract
l-Arginine supplementation is a potential therapy for treating cardiovascular and metabolic diseases. However, the use of distinct l-arginine sources, intervened populations, and treatment regimens may have yielded confusion about their efficacy. This research constitutes a systematic review and meta-analysis summarizing the effects of l-arginine supplementation compared to placebo in individuals with cardiovascular disease (CVD), obesity, or diabetes. Eligibility criteria included randomized clinical trials and interventions based on oral supplementation of l-arginine with a minimum duration of three days; comparison groups consisted of individuals with the same disease condition receiving an oral placebo substance. The primary outcome was flow-mediated dilation, and secondary outcomes were nitrite/nitrate (NOx) rate and asymmetric dimethylarginine (ADMA). Statistical heterogeneity among studies included in the meta-analyses was assessed using the inconsistency index (I2). Fifty-four full-text articles from 3761 retrieved references were assessed for eligibility. After exclusions, 13 studies were included for data extraction. There was no difference in blood flow after post-ischemic hyperemia between the supplementation of l-arginine and placebo groups before and after the intervention period (standardized mean difference (SMD) = 0.30; 95% confidence intervals (CIs) = −0.85 to 1.46; I2 = 96%). Sensitivity analysis showed decreased heterogeneity when the studies that most favor arginine and placebo were removed, and positive results in favor of arginine supplementation were found (SMD = 0.59; 95% CIs = 0.10 to 1.08; I2 = 75%). No difference was found in meta-analytical estimates of NOx and ADMA responses between arginine or placebo treatments. Overall, the results indicated that oral l-arginine supplementation was not associated with improvements on selected variables in these patients (PROSPERO Registration: CRD42017077289).
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Haghikia A, Landmesser U. Lipoproteins and Cardiovascular Redox Signaling: Role in Atherosclerosis and Coronary Disease. Antioxid Redox Signal 2018; 29:337-352. [PMID: 28817963 DOI: 10.1089/ars.2017.7052] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
SIGNIFICANCE Lipoproteins, such as low-density lipoprotein, play a causal role in the development of atherosclerosis and coronary disease. Recent Advances: Lipoproteins can stimulate vascular production of reactive oxygen species, which act as important signaling molecules in the cardiovascular system contributing to the pathophysiology of endothelial dysfunction, hypertension, and atherosclerosis. CRITICAL ISSUES Modified lipoproteins have emerged as important regulators of redox signaling, such as oxidized or carbamylated low-density lipoprotein or modified high-density lipoproteins, that contain oxidized lipids, an altered protein cargo, and associated small molecules, such as symmetric dimethylarginine. FUTURE DIRECTIONS In this review, we provide an overview on signaling pathways stimulated by modified lipoproteins in the cardiovascular system and their potential role in cardiovascular disease development. Moreover, we highlight novel aspects of how gut microbiome-related mechanisms-a growing research field-may contribute to lipoprotein modification with subsequent impact on cardiovascular redox signaling. Antioxid. Redox Signal. 29, 337-352.
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Affiliation(s)
- Arash Haghikia
- 1 Department of Cardiology, Charité Universitätsmedizin Berlin , Berlin, Germany
- 2 German Center for Cardiovascular Research (DZHK) , partner site Berlin, Berlin, Germany
| | - Ulf Landmesser
- 1 Department of Cardiology, Charité Universitätsmedizin Berlin , Berlin, Germany
- 2 German Center for Cardiovascular Research (DZHK) , partner site Berlin, Berlin, Germany
- 3 Berlin Institute of Health (BIH) , Berlin, Germany
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Abstract
Cardiovascular disease (CVD) is traditionally treated through medications and lifestyle modifications, yet adherence to these treatments is often poor. The use of complementary therapies is increasing, and it is vital for physicians to be aware of the risks and benefits of these options. This article summarizes the current evidence base on integrative therapies for the prevention and treatment of CVD, including hypertension, hyperlipidemia, coronary artery disease, heart failure, and arrhythmias. Where applicable, recommendations are included for therapies that may be used as an adjunct to traditional medical care to improve cardiovascular health and quality of life.
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Affiliation(s)
- Monica Aggarwal
- Division of Cardiology, University of Florida, 1600 Southwest Archer Road, PO Box 100288, Gainesville, FL 32610, USA.
| | - Brooke Aggarwal
- Division of Cardiology, Department of Medicine, Columbia University Medical Center, 51 Audubon Avenue, Suite 505, New York, NY 10032, USA
| | - Jyothi Rao
- Shakthi Health and Wellness Center, 2702 Back Acre Circle Suite 290C, Mt. Airy, MD 21771, USA
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de Melo LGP, Nunes SOV, Anderson G, Vargas HO, Barbosa DS, Galecki P, Carvalho AF, Maes M. Shared metabolic and immune-inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry 2017; 78:34-50. [PMID: 28438472 DOI: 10.1016/j.pnpbp.2017.04.027] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/27/2017] [Accepted: 04/08/2017] [Indexed: 02/08/2023]
Abstract
This review examines the shared immune-inflammatory, oxidative and nitrosative stress (IO&NS) and metabolic pathways underpinning metabolic syndrome (MetS), bipolar disorder (BD) and major depressive disorder (MDD). Shared pathways in both MetS and mood disorders are low grade inflammation, including increased levels of pro-inflammatory cytokines and acute phase proteins, increased lipid peroxidation with formation of malondialdehyde and oxidized low density lipoprotein cholesterol (LDL-c), hypernitrosylation, lowered levels of antioxidants, most importantly zinc and paraoxonase (PON1), increased bacterial translocation (leaky gut), increased atherogenic index of plasma and Castelli risk indices; and reduced levels of high-density lipoprotein (HDL-c) cholesterol. Insulin resistance is probably not a major factor associated with mood disorders. Given the high levels of IO&NS and metabolic dysregulation in BD and MDD and the high comorbidity with the atherogenic components of the MetS, mood disorders should be viewed as systemic neuro-IO&NS-metabolic disorders. The IO&NS-metabolic biomarkers may have prognostic value and may contribute to the development of novel treatments targeting neuro-immune, neuro-oxidative and neuro-nitrosative pathways.
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Affiliation(s)
- Luiz Gustavo Piccoli de Melo
- Department of Clinical Medicine, Londrina State University (UEL), Health Sciences Centre, Londrina, Paraná, Brazil; Center of Approach and Treatment for Smokers, University Hospital, Londrina State University, University Campus, Londrina, Paraná, Brazil; Health Sciences Graduation Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Sandra Odebrecht Vargas Nunes
- Department of Clinical Medicine, Londrina State University (UEL), Health Sciences Centre, Londrina, Paraná, Brazil; Center of Approach and Treatment for Smokers, University Hospital, Londrina State University, University Campus, Londrina, Paraná, Brazil; Health Sciences Graduation Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil
| | | | - Heber Odebrecht Vargas
- Department of Clinical Medicine, Londrina State University (UEL), Health Sciences Centre, Londrina, Paraná, Brazil; Center of Approach and Treatment for Smokers, University Hospital, Londrina State University, University Campus, Londrina, Paraná, Brazil; Health Sciences Graduation Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Décio Sabbattini Barbosa
- Health Sciences Graduation Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Clinical and Toxicological Analysis, State University of Londrina, Londrina, Paraná, Brazil
| | - Piotr Galecki
- Department of Adult Psychiatry, University of Lodz, Lodz, Poland
| | - André F Carvalho
- Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Michael Maes
- Health Sciences Graduation Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand; Department of Psychiatry, Plovdiv University, Plovdiv, Bulgaria; Revitalis, Waalre, The Netherlands; Impact Strategic Research Center, Deakin University, Geelong, Australia.
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35
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van de Vyver M. Intrinsic Mesenchymal Stem Cell Dysfunction in Diabetes Mellitus: Implications for Autologous Cell Therapy. Stem Cells Dev 2017; 26:1042-1053. [DOI: 10.1089/scd.2017.0025] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Mari van de Vyver
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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N-Acetylcysteine-induced vasodilatation is modulated by K ATP channels, Na +/K +-ATPase activity and intracellular calcium concentration: An in vitro study. Pharmacol Rep 2017; 69:738-745. [PMID: 28577450 DOI: 10.1016/j.pharep.2017.03.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/28/2017] [Accepted: 03/29/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND In this study, we aimed to investigate the role of ATP-sensitive potassium (KATP) channel, Na+/K+-ATPase activity, and intracellular calcium levels on the vasodilatory effect of N-acetylcysteine (NAC) in thoracic aorta by using electrophysiological and molecular techniques. METHODS Rat thoracic aorta ring preparations and cultured thoracic aorta cells were divided into four groups as control, 2mM NAC, 5mM NAC, and 10mM NAC. Thoracic aorta rings were isolated from rats for measurements of relaxation responses and Na+/K+-ATPase activity. In the cultured thoracic aorta cells, we measured the currents of KATP channel, the concentration of intracellular calcium and mRNA expression level of KATP channel subunits (KCNJ8, KCNJ11, ABCC8 and ABCC9). RESULTS The relaxation rate significantly increased in all NAC groups compared to control. Similarly, Na+/K+- ATPase activity also significantly decreased in NAC groups. Outward KATP channel current significantly increased in all NAC groups compared to the control group. Intracellular calcium concentration decreased significantly in all groups with compared control. mRNA expression level of ABCC8 subunit significantly increased in all NAC groups compared to the control group. Pearson correlation analysis showed that relaxation rate was significantly associated with KATP current, intracellular calcium concentration, Na+/K+-ATPase activity and mRNA expression level of ABCC8 subunit. CONCLUSION Our findings suggest that NAC relaxes vascular smooth muscle cells through a direct effect on KATP channels, by increasing outward K+ flux, partly by increasing mRNA expression of KATP subunit ABCC8, by decreasing in intracellular calcium and by decreasing in Na+/K+-ATPase activity.
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Pahlavani N, Entezari MH, Nasiri M, Miri A, Rezaie M, Bagheri-Bidakhavidi M, Sadeghi O. The effect of l-arginine supplementation on body composition and performance in male athletes: a double-blinded randomized clinical trial. Eur J Clin Nutr 2017; 71:544-548. [PMID: 28120856 DOI: 10.1038/ejcn.2016.266] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 11/20/2016] [Accepted: 12/01/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND/OBJECTIVE Athletes used a lot of dietary supplements to achieve the more muscle mass and improve their athletic performance. The objective of this study was to investigate the effect of l-arginine supplementation on sport performance and body composition in male soccer players. SUBJECTS/METHODS This double-blinded, randomized and placebo-controlled trial was conducted on 56 male soccer players, with age range of 16-35, who referred to sport clubs in Isfahan, Iran. Subjects were randomly assigned to either l-arginine or placebo groups. Athletes received daily either 2 g per day l-arginine supplement or the same amount of placebo (maltodextrin) for 45 days. Sport performance and also body mass index (BMI), body fat mass (BFM) and lean body mass (LBM) were measured at the beginning and end of the study. Also, 3-day dietary records were collected at three different time points (before, in the middle of, and at the end of the study). RESULTS The mean age of subjects was 20.85±4.29 years. Sport performance (VO2 max) significantly increased in l-arginine supplementation group (4.12±6.07) compared with placebo group (1.23±3.36) (P=0.03). This increase remained significant even after adjustment of baseline values, physical activity and usual dietary intake of subjects throughout the study. No significant effect of l-arginine supplementation was found on weight, BMI, BFM and LBM. CONCLUSIONS l-arginine supplementation (2 g per day) could increase the sport performance in male athletes, but had no effect on anthropometric measurements, including BMI, BFM and LBM. So, further studies are needed to shed light our findings.
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Affiliation(s)
- N Pahlavani
- Food Security Research Center and Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.,Department of Nutrition, Faculty of Medicine, Mashad University of Medical Sciences, Mashhad, Iran
| | - M H Entezari
- Food Security Research Center and Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - M Nasiri
- Department of Operating Room Technology, School of Paramedicine, Qom University of Medical Sciences, Qom, Iran
| | - A Miri
- Department of Nutrition, School of Health, Zabol University of Medical Sciences, Zabol, Iran
| | - M Rezaie
- Department of Nursing, School of Nursing and Midwifery, Isfahan University of Medical Sciences, Isfahan, Iran
| | - M Bagheri-Bidakhavidi
- Department of Nutrition, School of Health, Kerman University of Medical Sciences, Kerman, Iran
| | - O Sadeghi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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Shatnawi A, Shafer A, Ahmed H, Elbarbry F. Complementary and Alternative Medicine Use in Hypertension. ADVANCES IN MEDICAL DIAGNOSIS, TREATMENT, AND CARE 2017:255-287. [DOI: 10.4018/978-1-5225-2092-4.ch015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Thirty six percent of people in USA and Canada regularly use complementary and alternative medicine (CAM) for the prevention and treatment of different diseases, including hypertension. Generally, majority of the hypertensive patients do not disclose the use of such remedies, and also health care providers do not usually ask their hypertensive patients if they use CAM. The widespread consumption of CAM in hypertension requires clear understanding of their underlying mechanism of action, efficacy and safety. This chapter will provide a comprehensive list of CAM commonly used by Americans for the prevention and treatment of hypertension as well as their postulated mechanism of action. Modulation of drug metabolizing enzymes and their safety will also be covered along with the clinical consequences, i.e. drug-herb or herb-disease interactions. patients and healthcare providers should also be careful with using CAM therapies, because not only is there minimal evidence that several CAM products work to treat hypertension, but their safety hasn't been well-established.
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D'Elia JA, Bayliss G, Gleason RE, Weinrauch LA. Cardiovascular-renal complications and the possible role of plasminogen activator inhibitor: a review. Clin Kidney J 2016; 9:705-12. [PMID: 27679717 PMCID: PMC5036907 DOI: 10.1093/ckj/sfw080] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 07/20/2016] [Indexed: 12/14/2022] Open
Abstract
Since angiotensin increases the expression of plasminogen activator inhibitor (PAI), mechanisms associated with an actively functioning renin–angiotensin–aldosterone system can be expected to be associated with increased PAI-1 expression. These mechanisms are present not only in common conditions resulting in glomerulosclerosis associated with aging, diabetes or genetic mutations, but also in autoimmune disease (like scleroderma and lupus), radiation injury, cyclosporine toxicity, allograft nephropathy and ureteral obstruction. While the renin–angiotensin–aldosterone system and growth factors, such as transforming growth factor-beta (TGF-β), are almost always part of the process, there are rare experimental observations of PAI-1 expression without their interaction. Here we review the literature on PAI-1 and its role in vascular, fibrotic and oxidative injury as well as work suggesting potential areas of intervention in the pathogenesis of multiple disorders.
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Affiliation(s)
- John A D'Elia
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - George Bayliss
- Division ofKidney Diseases and Hypertension, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA; The Miriam Hospital, Providence, RI, USA; Alpert Medical School, Brown University, Providence, RI, USA
| | - Ray E Gleason
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; EP Joslin Research Laboratory, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
| | - Larry A Weinrauch
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; EP Joslin Research Laboratory, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
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Effectiveness of N-acetylcysteine for preserving residual renal function in patients undergoing maintenance hemodialysis: multicenter randomized clinical trial. Clin Exp Nephrol 2016; 21:342-349. [PMID: 27206513 DOI: 10.1007/s10157-016-1277-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 05/05/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND To investigate the efficacy and safety of oral N-acetylcysteine (NAC) for preserving residual renal function in patients undergoing hemodialysis. METHODS Randomized, multi-center, parallel-group, open-label clinical trial (Registration No. IRCT 2014071418482N1). 54 patients who have been undergoing hemodialysis for at least 3 months and had residual urine volume >100 ml/24 h were randomly allocated to NAC or no medication. Residual renal function evaluated by (1) estimated glomerular filtration rate (GFR), (2) 24 h urine volume, and (3) renal Kt/V. GFR and Kt/V was determined at baseline and after 3 months. 24 h urine volume was measured at baseline, after 1, 2, and 3 months. RESULTS Intention-to-treat analysis was performed on 47 patients (NAC = 26, control = 21). GFR in patients receiving NAC improved, whereas in the control arm a decline of 1.0 ml/min/1.73 m2 was recorded (3.59 vs. 2.11 ml/min/1.73 m2, effect size = 17.0 %, p = 0.004). For 24 h urine volume, the between-group difference after 1 month was significant (669 vs. 533 ml/24 h, effect size = 15.4 %, p = 0.004). After 3 months, 24 h urine volume in the NAC arm was on average 137 ml higher than in the control group, and the difference reached near significance (673 vs. 536 ml/24 h, p = 0.072). In the follow-up visit, Kt/V was higher in the NAC arm but the difference did not reach statistical significance (0.81 vs. 0.54, p = 0.152). CONCLUSION Three months treatment with NAC appears to be effective in preserving renal function in patients undergoing hemodialysis and the medication is generally well-tolerated.
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Szkudlinska MA, von Frankenberg AD, Utzschneider KM. The antioxidant N-Acetylcysteine does not improve glucose tolerance or β-cell function in type 2 diabetes. J Diabetes Complications 2016; 30:618-22. [PMID: 26922582 PMCID: PMC4834245 DOI: 10.1016/j.jdiacomp.2016.02.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 02/02/2016] [Accepted: 02/02/2016] [Indexed: 01/25/2023]
Abstract
UNLABELLED Hyperglycemia induces oxidative stress and thereby may exacerbate β-cell dysfunction in type 2 diabetes (T2DM). Notably, glutathione (GSH), synthesized from N-Acetylcysteine (NAC), neutralizes reactive oxygen species within cells and is low in individuals with diabetes. AIM Determine if NAC supplementation improves β-cell function and glucose tolerance by decreasing oxidative stress in T2DM. METHODS Thirteen subjects (6M/7F) with T2DM (duration: 0-13 years, median: 2 years), treated with diet/exercise alone (n=7) or metformin (n=6), underwent a 2-h oral glucose tolerance test (OGTT) at baseline, after 2 weeks supplementation with 600 mg NAC orally twice daily, and again after 2 weeks supplementation with 1200 mg NAC twice daily. The following measurements were made: fasting glucose and fructosamine for glycemic control, incremental AUC glucose (0-120 min) for glucose tolerance, and Δ insulin/Δ glucose (0-30 min) for the early insulin response to glucose. Fasting erythrocyte GSH and GSSG (oxidized glutathione) levels, plasma thiobarbituric acid reactive substances (TBARS), and urine F2α isoprostanes were measured to assess oxidative status. RESULTS Subjects were middle aged (mean ± SEM: 53.9 ± 3.2 years), obese (BMI 37.3 ± 2.8 kg/m(2)), and relatively well-controlled (HbA1c 6.7 ± 0.3%, 50 mmol/mol). Glycemic control, glucose tolerance, insulin release, and oxidative markers did not change with either dose of NAC. CONCLUSIONS Based on the lack of any short-term benefit from NAC supplementation on markers of glucose metabolism, β-cell response, and oxidative status, it is unlikely to be a valuable therapeutic approach for treatment of type 2 diabetes.
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Affiliation(s)
- Magdalena A Szkudlinska
- Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, WA.
| | - Anize D von Frankenberg
- Post-Graduate Endocrinology Program, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Kristina M Utzschneider
- Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, WA.
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Dashtabi A, Mazloom Z, Fararouei M, Hejazi N. Oral L-Arginine Administration Improves Anthropometric and Biochemical Indices Associated With Cardiovascular Diseases in Obese Patients: A Randomized, Single Blind Placebo Controlled Clinical Trial. Res Cardiovasc Med 2015; 5:e29419. [PMID: 26889456 PMCID: PMC4750008 DOI: 10.5812/cardiovascmed.29419] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 06/27/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Recently, the potential of L-arginine supplementation as a novel and effective strategy for weight loss and improving biochemical parameters in obese patients has been under consideration. OBJECTIVES To evaluate the influence of 8-week oral L-arginine supplementation on body mass index (BMI), waist circumference (WC), triceps skinfold (TS), subscapular skinfold (SS), systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma fasting blood sugar (FBS), glycated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and malondialdehyde (MDA) in patients with BMI values > 29.9 or visceral obesity (WC > 102 cm in men or > 88 cm in women). PATIENTS AND METHODS Ninety obese patients were included in a single-blind randomized controlled trial. Patients were randomized to receive either L-arginine (3 or 6 g thrice daily) or placebo for 8 weeks. Anthropometric and biochemical indices, dietary intake, and blood pressure values were measured at the baseline and after the 8-week intervention. RESULTS Significant decreases in anthropometric parameters, blood pressure (SBP, DBP), FBS, HbA1c, LDL, MDA (P < 0.001), TG (P = 0.02), and TC (P = 0.002) and a significant increase in HDL (P < 0.001) were observed in the intervention group, compared to the control group. In the control group, no significant differences were found between the baseline and end-of-intervention measurements. CONCLUSIONS In conclusion, oral L-Arginine supplementation appears to improve anthropometric parameters, blood pressure values, and some blood biochemical indices associated with cardiovascular disease prevention.
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Affiliation(s)
- Arash Dashtabi
- School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Zohreh Mazloom
- School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, IR Iran
- Corresponding author: Zohreh Mazloom, School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, IR Iran. Tel: +98-9171111527, Fax: +98-7137251001, E-mail:
| | | | - Najmeh Hejazi
- Nutrition and Food Science Research Center, School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, IR Iran
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Hildebrandt W, Sauer R, Bonaterra G, Dugi KA, Edler L, Kinscherf R. Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status. Am J Clin Nutr 2015; 102:1014-24. [PMID: 26447155 DOI: 10.3945/ajcn.114.101964] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 08/27/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Elevated total plasma homocysteine (tHcy) is considered to be an independent cardiovascular disease risk factor, although tHcy lowering by B-vitamins improves only certain clinical endpoints. N-acetylcysteine (NAC), a thiol-containing antioxidant, acutely lowers tHcy and possibly also blood pressure. However, to our knowledge, at present no conclusive long-term evaluation exists that controls for factors such as hyperlipidemia, smoking, medication, and disease stage, all of which affect the thiol redox state, including tHcy. OBJECTIVE We reanalyzed 2 double-blind, placebo-controlled trials in unmedicated middle-aged men, one in a hyperlipidemic group (HYL group; n = 40) and one in a normolipidemic group (NOL group; n = 42), each stratified for smokers and nonsmokers. DESIGN We evaluated the effect of 4 wk of oral NAC (1.8 g/d) on tHcy (primary endpoint), plasma thiol (cysteine), and intracellular glutathione concentrations as well as on blood pressure. The HYL group had total cholesterol >220 mg/dL or triglycerides >150 mg/dL. RESULTS NAC treatment significantly (P = 0.001, multivariate analysis of variance for repeated measures) lowered postabsorptive plasma concentrations of tHcy by -11.7% ± 3.0% (placebo: 4.1% ± 3.6%) while increasing those of cysteine by 28.1% ± 5.7% (placebo: 4.0% ± 3.4%) with no significant impact of hyperlipidemia or smoking. Moreover, NAC significantly decreased systolic (P = 0.003) and diastolic (P = 0.017) blood pressure within all subjects with a significant reduction in diastolic pressure in the HYL group (P = 0.008) but not in the NOL group. An explorative stepwise multiple regression analysis identified 1) post-treatment cysteine as well as 2) pretreatment tHcy and 3) albumin plasma concentrations as being significant contributors to tHcy reduction. CONCLUSIONS Four weeks of oral NAC treatment significantly decreased plasma tHcy concentrations, irrespective of lipid or smoking status, and lowered systolic blood pressure in both normolipidemic and hyperlipidemic men, with significant diastolic blood pressure reductions in the HYL group only. Increased oral intake of cysteine may therefore be considered for primary or secondary prevention of vascular events with regard to the 2 independent risk factors of hyperhomocysteinemia and arterial hypertension.
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Affiliation(s)
| | - Roland Sauer
- Immunochemistry and Department of Neurology, University Hospital Erlangen, Erlangen, Germany
| | | | - Klaus A Dugi
- Internal Medicine I, University of Heidelberg, Heidelberg, Germany; Departments of
| | - Lutz Edler
- Biostatistics, Deutsches Krebsforschungszentrum, Heidelberg, Germany; and
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McCarty MF, DiNicolantonio JJ. An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly. AGE (DORDRECHT, NETHERLANDS) 2015; 37:96. [PMID: 26362762 PMCID: PMC5005830 DOI: 10.1007/s11357-015-9823-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 07/28/2015] [Indexed: 06/05/2023]
Abstract
Restricted dietary intakes of protein or essential amino acids tend to slow aging and boost lifespan in rodents, presumably because they downregulate IGF-I/Akt/mTORC1 signaling that acts as a pacesetter for aging and promotes cancer induction. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) III cohort has revealed that relatively low protein intakes in mid-life (under 10 % of calories) are indeed associated with decreased subsequent risk for mortality. However, in those over 65 at baseline, such low protein intakes were associated with increased risk for mortality. This finding accords well with other epidemiology correlating relatively high protein intakes with lower risk for loss of lean mass and bone density in the elderly. Increased efficiency of protein translation reflecting increased leucine intake and consequent greater mTORC1 activity may play a role in this effect; however, at present there is little solid evidence that leucine supplementation provides important long-term benefits to the elderly. Aside from its potential pro-anabolic impact, higher dietary protein intakes may protect the elderly in another way-by providing increased amino acid substrate for synthesis of key protective factors. There is growing evidence, in both rodents and humans, that glutathione synthesis declines with increasing age, likely reflecting diminished function of Nrf2-dependent inductive mechanisms that boost expression of glutamate cysteine ligase (GCL), rate-limiting for glutathione synthesis. Intracellular glutathione blunts the negative impact of reactive oxygen species (ROS) on cell health and functions both by acting as an oxidant scavenger and by opposing the pro-inflammatory influence of hydrogen peroxide on cell signaling. Fortunately, since GCL's K m for cysteine is close to intracellular cysteine levels, increased intakes of cysteine-achieved from whole proteins or via supplementation with N-acetylcysteine (NAC)-can achieve a compensatory increase in glutathione synthesis, such that more youthful tissue levels of this compound can be restored. Supplementation with phase 2 inducers-such as lipoic acid-can likewise increase glutathione levels by promoting increased GCL expression. In aging humans and/or rodents, NAC supplementation has exerted favorable effects on vascular health, muscle strength, bone density, cell-mediated immunity, markers of systemic inflammation, preservation of cognitive function, progression of neurodegeneration, and the clinical course of influenza-effects which could be expected to lessen mortality and stave off frailty. Hence, greater cysteine availability may explain much of the favorable impact of higher protein intakes on mortality and frailty risk in the elderly, and joint supplementation with NAC and lipoic acid could be notably protective in the elderly, particularly in those who follow plant-based diets relatively low in protein. It is less clear whether the lower arginine intake associated with low-protein diets has an adverse impact on vascular health.
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Affiliation(s)
- Mark F McCarty
- Catalytic Longevity, 7831 Rush Rose Dr., Apt. 316, Carlsbad, CA, 92009, USA.
| | - James J DiNicolantonio
- Preventive Cardiology Department, St. Luke's Mid America Heart Institute, Kansas City, MO, USA.
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Kawase Ishihara K, Kokubo Y, Yokota C, Hida E, Miyata T, Toyoda K, Matsumoto M, Minematsu K, Miyamoto Y. Effect of Plasma Fibrinogen, High-Sensitive C-Reactive Protein, and Cigarette Smoking on Carotid Atherosclerosis: The Suita Study. J Stroke Cerebrovasc Dis 2015; 24:2385-9. [DOI: 10.1016/j.jstrokecerebrovasdis.2015.06.039] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 06/24/2015] [Accepted: 06/25/2015] [Indexed: 02/05/2023] Open
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Oledzka E, Sawicka A, Sobczak M, Nalecz-Jawecki G, Skrzypczak A, Kolodziejski W. Prazosin-Conjugated Matrices Based on Biodegradable Polymers and α-Amino Acids--Synthesis, Characterization, and in Vitro Release Study. Molecules 2015; 20:14533-51. [PMID: 26274943 PMCID: PMC6332215 DOI: 10.3390/molecules200814533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 07/24/2015] [Accepted: 08/05/2015] [Indexed: 11/16/2022] Open
Abstract
Novel and promising macromolecular conjugates of the α1-adrenergic blocker prazosin were directly synthesized by covalent incorporation of the drug to matrices composed of biodegradable polymers and α-amino acids for the development of a polymeric implantable drug delivery carrier. The cyto- and genotoxicity of the synthesized matrices were evaluated using a bacterial luminescence test, protozoan assay, and Salmonella typhimurium TA1535. A new urethane bond was formed between the hydroxyl end-groups of the synthesized polymer matrices and an amine group of prazosin, using 1,1'-carbonyldiimidazole (CDI) as a coupling agent. The structure of the polymeric conjugates was characterized by various spectroscopy techniques. A study of hydrogen nuclear magnetic resonance ((1)H-NMR) and differential scanning calorimetry (DSC) thermodiagrams indicated that the presence of prazosin pendant groups in the macromolecule structures increased the polymer's rigidity alongside increasing glass transition temperature. It has been found that the kinetic release of prazosin from the obtained macromolecular conjugates, tested in vitro under different conditions, is strongly dependent on the physicochemical properties of polymeric matrices. Furthermore, the presence of a urethane bond in the macromolecular conjugates allowed for obtaining a relatively controlled release profile of the drug. The obtained results confirm that the pharmacokinetics of prazosin might be improved through the synthesis of polymeric conjugates containing biomedical polymers and α-amino acids in the macromolecule.
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Affiliation(s)
- Ewa Oledzka
- Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, Warsaw 02-097, Poland.
| | - Anna Sawicka
- Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, Warsaw 02-097, Poland.
| | - Marcin Sobczak
- Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, Warsaw 02-097, Poland.
| | - Grzegorz Nalecz-Jawecki
- Department of Environmental Health Science, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, Warsaw 02-097, Poland.
| | - Agata Skrzypczak
- Department of Environmental Health Science, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, Warsaw 02-097, Poland.
| | - Waclaw Kolodziejski
- Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, Warsaw 02-097, Poland.
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Goszcz K, Deakin SJ, Duthie GG, Stewart D, Leslie SJ, Megson IL. Antioxidants in Cardiovascular Therapy: Panacea or False Hope? Front Cardiovasc Med 2015; 2:29. [PMID: 26664900 PMCID: PMC4671344 DOI: 10.3389/fcvm.2015.00029] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 06/10/2015] [Indexed: 12/31/2022] Open
Abstract
Oxidative stress is a key feature of the atherothrombotic process involved in the etiology of heart attacks, ischemic strokes, and peripheral arterial disease. It stands to reason that antioxidants represent a credible therapeutic option to prevent disease progression and thereby improve outcome, but despite positive findings from in vitro studies, clinical trials have failed to consistently show benefit. The aim of this review is to re-appraise the concept of antioxidants in the prevention and management of cardiovascular disease. In particular, the review will explore the reasons behind failed antioxidant strategies with vitamin supplements and will evaluate how flavonoids might improve cardiovascular function despite bioavailability that is not sufficiently high to directly influence antioxidant capacity. As well as reaching conclusions relating to those antioxidant strategies that might hold merit, the major myths, limitations, and pitfalls associated with this research field are explored.
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Affiliation(s)
- Katarzyna Goszcz
- Department of Diabetes and Cardiovascular Science, Centre for Health Science, University of the Highlands and Islands , Inverness , UK ; James Hutton Institute , Dundee , UK
| | - Sherine J Deakin
- Department of Diabetes and Cardiovascular Science, Centre for Health Science, University of the Highlands and Islands , Inverness , UK
| | - Garry G Duthie
- Rowett Institute of Health and Nutrition , Aberdeen , UK
| | - Derek Stewart
- James Hutton Institute , Dundee , UK ; School of Life Sciences, Heriot Watt University , Edinburgh , UK
| | - Stephen J Leslie
- Department of Diabetes and Cardiovascular Science, Centre for Health Science, University of the Highlands and Islands , Inverness , UK ; Cardiology Unit, Raigmore Hospital , Inverness , UK
| | - Ian L Megson
- Department of Diabetes and Cardiovascular Science, Centre for Health Science, University of the Highlands and Islands , Inverness , UK
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NADPH Oxidase Activity in Cerebral Arterioles Is a Key Mediator of Cerebral Small Vessel Disease-Implications for Prevention. Healthcare (Basel) 2015; 3:233-51. [PMID: 27417759 PMCID: PMC4939544 DOI: 10.3390/healthcare3020233] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 03/21/2015] [Accepted: 04/08/2015] [Indexed: 02/05/2023] Open
Abstract
Cerebral small vessel disease (SVD), a common feature of brain aging, is characterized by lacunar infarcts, microbleeds, leukoaraiosis, and a leaky blood-brain barrier. Functionally, it is associated with cognitive decline, dementia, depression, gait abnormalities, and increased risk for stroke. Cerebral arterioles in this syndrome tend to hypertrophy and lose their capacity for adaptive vasodilation. Rodent studies strongly suggest that activation of Nox2-dependent NADPH oxidase activity is a crucial driver of these structural and functional derangements of cerebral arterioles, in part owing to impairment of endothelial nitric oxide synthase (eNOS) activity. This oxidative stress may also contribute to the breakdown of the blood-brain barrier seen in SVD. Hypertension, aging, metabolic syndrome, smoking, hyperglycemia, and elevated homocysteine may promote activation of NADPH oxidase in cerebral arterioles. Inhibition of NADPH oxidase with phycocyanobilin from spirulina, as well as high-dose statin therapy, may have potential for prevention and control of SVD, and high-potassium diets merit study in this regard. Measures which support effective eNOS activity in other ways-exercise training, supplemental citrulline, certain dietary flavonoids (as in cocoa and green tea), and capsaicin, may also improve the function of cerebral arterioles. Asian epidemiology suggests that increased protein intakes may decrease risk for SVD; conceivably, arginine and/or cysteine-which boosts tissue glutathione synthesis, and can be administered as N-acetylcysteine-mediate this benefit. Ameliorating the risk factors for SVD-including hypertension, metabolic syndrome, hyperglycemia, smoking, and elevated homocysteine-also may help to prevent and control this syndrome, although few clinical trials have addressed this issue to date.
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Larsson SC, Håkansson N, Wolk A. Dietary Cysteine and Other Amino Acids and Stroke Incidence in Women. Stroke 2015; 46:922-6. [DOI: 10.1161/strokeaha.114.008022] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Susanna C. Larsson
- From the Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Niclas Håkansson
- From the Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Alicja Wolk
- From the Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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Cicero AFG, Colletti A. Nutraceuticals and Blood Pressure Control: Results from Clinical Trials and Meta-Analyses. High Blood Press Cardiovasc Prev 2015; 22:203-13. [PMID: 25788027 DOI: 10.1007/s40292-015-0081-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 03/03/2015] [Indexed: 12/16/2022] Open
Abstract
Beyond the well-known effects on blood pressure (BP) of the dietary approaches to stop hypertension (DASH) and the Mediterranean diets, a large number of studies has investigated the possible BP lowering effect of different dietary supplements and nutraceuticals, the most part of them being antioxidant agents with a high tolerability and safety profile. In particular relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, beetroot juice, coenzyme Q10, controlled-release melatonin, and aged garlic extract. However there is a need for data about the long-term safety of a large part of the above discussed products. Moreover further clinical research is advisable to identify between the available active nutraceuticals those with the best cost-effectiveness and risk-benefit ratio for a large use in general population with low-added cardiovascular risk related to uncomplicated hypertension.
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Affiliation(s)
- Arrigo F G Cicero
- Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy,
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