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Abaj F, Mirzababaei A, Gholizadeh M, Aali Y, Jadidi P, Amiri Khosroshahi R, Clark CCT, Mirzaei K. Associations of dietary insulin load and dietary insulin index with diabetic nephropathy and reduced kidney function among women: a case-control study. JOURNAL OF HEALTH, POPULATION, AND NUTRITION 2025; 44:173. [PMID: 40414858 PMCID: PMC12103775 DOI: 10.1186/s41043-025-00895-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 04/22/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Increased insulin levels lead to hyperinsulinemia and insulin resistance (IR). IR is one of the main causes of the onset and progression of Diabetic Nephropathy (DN) and kidney failure in type 2 diabetic patients. The present case-control study sought to investigate the relationship between dietary insulin load (DIL) and index (DII) and the odds of DN and kidney function decline. METHODS At the Kowsar Diabetes Clinic in Semnan, Iran, we enrolled 105 eligible women with DN and 105 controls (30-65 years old). Dietary insulin load (DIL) and index (DII) were assessed using a 147-item food frequency questionnaire (FFQ). Using standard protocols, biochemical variables and anthropometric measurements were evaluated for all patients. To investigate potential associations, binary logistic regression was used. RESULTS We found that higher DII was associated with 2.72 times higher odds of albuminuria (OR: 2.77; 95% CI 1.16, 6.63) and 1.92 times higher odds of DN (OR: 1.92; 95% CI 1.11, 3.32) compared to lower adherence. Additionally, DIL was found to be statistically highly connected with mild to severe reduction of glomerular filtration rate (GFR) in participants and 1.82 times greater odds of DN (OR = 1.82; 95% CI 1.01, 3.30). CONCLUSION The findings from this research showed that a higher odds of DN were related to a higher level of adherence to DIL and DII. Increased adherence to DIL was strongly correlated with the likelihood of a decreased GFR. To clarify our findings, more prospective research is necessary.
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Affiliation(s)
- Faezeh Abaj
- Department of Nutrition, Dietetics and Food, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
| | - Atieh Mirzababaei
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
| | - Mohammad Gholizadeh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Shahid Beheshti University of Medical Sciences (SBUMS), Tehran, Iran
| | - Yasaman Aali
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Paria Jadidi
- Electronic Health and Statistics Surveillance Research Center, SR.C., Islamic Azad University, Tehran, Iran
| | - Reza Amiri Khosroshahi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Cain C T Clark
- Institute for Health and Wellbeing, Coventry University, Coventry, CV1 5FB, UK
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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Wan B, Wang S, Hu S, Han W, Qiu S, Zhu L, Ruan L, Wei Y, Xu J. The comprehensive effects of high-sensitivity C-reactive protein and triglyceride glucose index on cardiometabolic multimorbidity. Front Endocrinol (Lausanne) 2025; 16:1511319. [PMID: 40235659 PMCID: PMC11996647 DOI: 10.3389/fendo.2025.1511319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/10/2025] [Indexed: 04/17/2025] Open
Abstract
Background The triglyceride-glucose index (TyG index) is one of the surrogate markers of insulin resistance, and high-sensitivity C-reactive protein (hsCRP) reflects systemic inflammation. Existing studies suggest that insulin resistance or systemic inflammation may be indicative of cardiometabolic disease, but few of the existing studies have combined the TyG index and inflammation levels before assessing cardiometabolic multimorbidity. Our study data came from the China Health and Retirement Longitudinal Study (CHARLS). Participants in this data were followed for 9 years, and we used these data to conduct a long-term analysis to assess the combined effects of the TyG index and hsCRP on cardiometabolic multimorbidity in Chinese adults over 45 years of age. Purpose To study the combined effect of TyG index and hsCRP on cardiometabolic multimorbidity in middle-aged as well as elderly Chinese. Method The study data came from the China Health and Retirement Longitudinal Study (CHARLS), which included a total of 4,483 middle-aged and elderly participants who did not have cardiovascular metabolic diseases at baseline, which was from CHARLS 2011, and the last survey was in 2020. A total of five cardiometabolic diseases were considered in this study: diabetes, hypertension, hyperlipidemia, heart disease and stroke. A person was defined as having cardiometabolic multimorbidity when he/she had two or more cardiometabolic diseases at the same time. TyG index (median as cut-off) and hsCRP (1mg/L as cut-off) were each divided into two groups and combined into four groups (Group L-L: TyG index=median & hsCRP<1mg/L; Group L-H: TyG index=1mg/L; Group H-H: TyG index>=median & hsCRP>=1mg/L). Multiple regression equations were fitted to analyse the combined influence of TyG index and hsCRP on cardiometabolic multimorbidity. Results TyG index increases the risk of CMM events independently of hsCRP, as does the reverse. When the TyG index is elevated and hsCRP is also elevated, this condition significantly increases the danger of cardiometabolic multimorbidity in middle-aged and elderly Chinese. Conclusion High levels of TyG index and hsCRP can enhance the danger of cardiometabolic multimorbidity in Chinese middle-aged and elderly people, and the joint use of hsCRP and TyG index assessment may be a better way to achieve primary prevention of cardiometabolic multimorbidity in Chinese middle-aged and elderly people.
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Affiliation(s)
| | | | | | | | | | | | | | - Yiping Wei
- Department of Thoracic Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jianjun Xu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
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Liu H, Wang L, Wang H, Hao X, Du Z, Li C, Hou X. Triglyceride-glucose index correlates with the incidences and prognoses of cardiac arrest following acute myocardial infarction: data from two large-scale cohorts. Cardiovasc Diabetol 2025; 24:108. [PMID: 40057710 PMCID: PMC11890517 DOI: 10.1186/s12933-025-02641-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/10/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND The triglyceride-glucose (TyG) index, renowned for its efficacy and convenience in assessing insulin resistance, has been validated as a reliable indicator for various cardiovascular conditions. The current study aims for clarifying the link of TyG with the incidences and prognoses of cardiac arrest (CA) following acute myocardial infarction (AMI). METHODS Our analysis is a multicenter, retrospective study utilizing data from the Medical Information Mart for Intensive Care IV and the eICU Collaborative Research Database. Patients with AMI for whom TyG could be calculated within the first 24 h after admission were included. The main endpoints were in-hospital and ICU mortalities. Correlations between TyG and outcomes were evaluated using logistic regression models, restricted cubic splines (RCS), as well as correlation and linear analyses. Overlap weighting (OW), inverse probability of treatment weighting (IPTW), and propensity score matching (PSM) methodologies were utilized to balance the cohorts, thereby minimizing potential biases. Subgroup analyses were performed in accordance with identified modifiers. RESULTS In total, 5208 individuals diagnosed with AMI, among whom 371 developed CA, were ultimately included. Higher TyG levels were observed among AMI populations with CA compared to those without [9.2 (8.7-9.7) vs. 9.0 (8.5-9.4)], and TyG demonstrated a moderate discriminatory capacity for identifying CA occurrences within entire AMI populations. Multivariate logistic regressions revealed TyG serves a significant risk indicator for both in-hospital (OR 1.711) and ICU mortalities (OR 1.520) in AMI-CA patients, and it is also associated with prolonged LOSs. RCS analyses confirmed linear relationships of ascending TyG with increased mortality risks for AMI-CA (P for nonlinearity: 0.592 and 0.816, respectively), which persisted following PSM, OW, and IPTW adjustments. Subgroup analyses further identified a strong link of the TyG with mortality rates among elders, females, individuals with BMI < 28 kg/m2, and those with hypertension. CONCLUSIONS Elevated TyG levels were found to apparently correlate with higher prevalence and adverse outcomes regarding CA in patients with AMI. Our findings point a fresh insight into the significance of the TyG in critically ill coronary conditions.
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Affiliation(s)
- Huiruo Liu
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People's Republic of China
| | - Liangshan Wang
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People's Republic of China
| | - Hong Wang
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People's Republic of China
| | - Xing Hao
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People's Republic of China
| | - Zhongtao Du
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People's Republic of China
| | - Chenglong Li
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People's Republic of China
| | - Xiaotong Hou
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People's Republic of China.
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Liu Z, Lu J, Sha W, Lei T. Comprehensive treatment of diabetic endothelial dysfunction based on pathophysiological mechanism. Front Med (Lausanne) 2025; 12:1509884. [PMID: 40093018 PMCID: PMC11906411 DOI: 10.3389/fmed.2025.1509884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/24/2025] [Indexed: 03/19/2025] Open
Abstract
Vascular endothelium is integral to the regulation of vascular homeostasis and maintenance of normal arterial function in healthy individuals. Endothelial dysfunction is a significant contributor to the advancement of atherosclerosis, which can precipitate cardiovascular complications. A notable correlation exists between diabetes and endothelial dysfunction, wherein chronic hyperglycemia and acute fluctuations in glucose levels exacerbate oxidative stress. This results in diminished nitric oxide synthesis and heightened production of endothelin-1, ultimately leading to endothelial impairment. In clinical settings, it is imperative to implement appropriate therapeutic strategies aimed at enhancing endothelial function to prevent and manage diabetes-associated vascular complications. Various antidiabetic agents, including insulin, GLP-1 receptor agonists, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, thiazolidinediones (TZDs), and metformin, are effective in mitigating blood glucose variability and improving insulin sensitivity by lowering postprandial glucose levels. Additionally, traditional Chinese medicinal compounds, such as turmeric extract, resveratrol, matrine alkaloids, tanshinone, puerarin, tanshinol, paeonol, astragaloside, berberine, and quercetin, exhibit hypoglycemic properties and enhance vascular function through diverse mechanisms. Consequently, larger randomized controlled trials involving both pharmacological and herbal interventions are essential to elucidate their impact on endothelial dysfunction in patients with diabetes. This article aims to explore a comprehensive approach to the treatment of diabetic endothelial dysfunction based on an understanding of its pathophysiology.
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Affiliation(s)
- Zhao Liu
- Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jun Lu
- Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Sha
- Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Lei
- Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Kim M, Cho S, Hwang DG, Shim IK, Kim SC, Jang J, Jang J. Bioprinting of bespoke islet-specific niches to promote maturation of stem cell-derived islets. Nat Commun 2025; 16:1430. [PMID: 39920133 PMCID: PMC11805982 DOI: 10.1038/s41467-025-56665-5] [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] [Received: 12/11/2023] [Accepted: 01/27/2025] [Indexed: 02/09/2025] Open
Abstract
Pancreatic islets are densely packed cellular aggregates containing various hormonal cell types essential for blood glucose regulation. Interactions among these cells markedly affect the glucoregulatory functions of islets along with the surrounding niche and pancreatic tissue-specific geometrical organization. However, stem cell (SC)-derived islets generated in vitro often lack the three-dimensional extracellular microenvironment and peri-vasculature, which leads to the immaturity of SC-derived islets, reducing their ability to detect glucose fluctuations and insulin release. Here, we bioengineer the in vivo-like pancreatic niches by optimizing the combination of pancreatic tissue-specific extracellular matrix and basement membrane proteins and utilizing bioprinting-based geometrical guidance to recreate the spatial pattern of islet peripheries. The bioprinted islet-specific niche promotes coordinated interactions between islets and vasculature, supporting structural and functional features resembling native islets. Our strategy not only improves SC-derived islet functionality but also offers significant potential for advancing research on islet development, maturation, and diabetic disease modeling, with future implications for translational applications.
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Affiliation(s)
- Myungji Kim
- Division of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Seungyeun Cho
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Dong Gyu Hwang
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - In Kyong Shim
- Asan Institute for Life Science, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Song Cheol Kim
- Asan Institute for Life Science, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Jiwon Jang
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Jinah Jang
- Division of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Republic of Korea.
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Okita T, Kita S, Fukuda S, Kondo Y, Sakaue TA, Iioka M, Fukuoka K, Kawada K, Nagao H, Obata Y, Fujishima Y, Ebihara T, Matsumoto H, Nakagawa S, Kimura T, Nishizawa H, Shimomura I. Soluble T-cadherin secretion from endothelial cells is regulated via insulin/PI3K/Akt signalling. Biochem Biophys Res Commun 2024; 732:150403. [PMID: 39047402 DOI: 10.1016/j.bbrc.2024.150403] [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: 05/08/2024] [Revised: 06/27/2024] [Accepted: 07/12/2024] [Indexed: 07/27/2024]
Abstract
AIM AND OBJECTIVE Our recent report showed that soluble T-cadherin promotes pancreatic beta-cell proliferation. However, how and where the secretion of soluble T-cadherin is regulated remain unclear. METHODS AND RESULTS Soluble T-cadherin levels significantly increased in leptin receptor-deficient db/db mice with hypoinsulinaemia or in wild-type mice treated with insulin receptor blockade by S961. Similar results were observed in human subjects; Diabetic ketoacidosis patients at the time of hospitalization had increased plasma soluble T-cadherin levels, which decreased after insulin infusion therapy. Patients with recurrent ovarian cancer who were administered a phosphatidylinositol-3 kinase (PI3K)-alpha inhibitor (a new anticancer drug) had increased plasma soluble T-cadherin and plasma C-peptide levels. Endothelial cell-specific T-cadherin knockout mice, but not skeletal muscle- or cardiac muscle-specific T-cadherin knockout mice, showed a 26 % reduction in plasma soluble T-cadherin levels and a significant increase in blood glucose levels in streptozocin-induced diabetes. The secretion of soluble T-cadherin from human endothelial cells was approximately 20 % decreased by insulin and this decrease was canceled by blockade of insulin receptor/Akt signalling, not Erk signalling. CONCLUSION We conclude that insulin regulates soluble T-cadherin levels and soluble T-cadherin secretion from endothelial cells is positively regulated by insulin/insulin receptor/Akt signalling.
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Affiliation(s)
- Tomonori Okita
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shunbun Kita
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Shiro Fukuda
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Yuta Kondo
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Taka-Aki Sakaue
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masahito Iioka
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Keita Fukuoka
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Keitaro Kawada
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hirofumi Nagao
- Departments of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshinari Obata
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuya Fujishima
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takeshi Ebihara
- Departments of Traumatology and Acute Critical Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hisatake Matsumoto
- Departments of Traumatology and Acute Critical Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Satoshi Nakagawa
- Departments of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tadashi Kimura
- Departments of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hitoshi Nishizawa
- Departments of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Iichiro Shimomura
- Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
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Liu H, Wang L, Zhou X, Wang H, Hao X, Du Z, Li C, Hou X. Triglyceride-glucose index correlates with the occurrence and prognosis of acute myocardial infarction complicated by cardiogenic shock: data from two large cohorts. Cardiovasc Diabetol 2024; 23:337. [PMID: 39261816 PMCID: PMC11391630 DOI: 10.1186/s12933-024-02423-8] [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: 08/16/2024] [Accepted: 08/27/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND Triglyceride-glucose (TyG) index, a dependable indicator of insulin resistance, has been identified as a valid marker regarding multiple cardiovascular diseases. Nevertheless, the correlation of TyG index with acute myocardial infarction complicated by cardiogenic shock (AMICS) remains uncertain. Our study aims for elucidating this relationship by comprehensively analyzing two large-scale cohorts. METHODS Utilizing records from the eICU Collaborative Research Database and the Medical Information Mart for Intensive Care IV, the link between TyG and the incidence and prognosis of AMICS was assessed multicentrally and retrospectively by logistic and correlation models, as well as restricted cubic spline (RCS). Propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting (OW) were employed to balance the potential confounders. Subgroup analyses were performed according to potential modifiers. RESULTS Overall, 5208 AMI patients, consisting of 375 developing CS were finally included. The TyG index exhibited an apparently higher level in AMI populations developing CS than in those who did not experienced CS [9.2 (8.8-9.7) vs. 9.0 (8.5-9.5)], with a moderate discrimination ability to recognize AMICS from the general AMI (AUC: 0.604). Logistic analyses showed that the TyG index was significantly correlated with in-hospital and ICU mortality. RCS analysis demonstrated a linear link between elevated TyG and increased risks regarding in-hospital and ICU mortality in the AMICS population. An increased mortality risk remains evident in PSM-, OW- and IPTW-adjusted populations with higher TyG index who have undergone CS. Correlation analyses demonstrated an apparent link between TyG index and APS score. Subgroup analyses presented a stable link between elevated TyG and mortality particularly in older age, females, those who are overweight or hypertensive, as well as those without diabetes. CONCLUSIONS Elevated TyG index was related to the incidence of CS following AMI and higher mortality risks in the population with AMICS. Our findings pointed a previously undisclosed role of TyG index in regard to AMICS that still requires further validation.
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Affiliation(s)
- Huiruo Liu
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Liangshan Wang
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xing Zhou
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Hong Wang
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xing Hao
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zhongtao Du
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Chenglong Li
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xiaotong Hou
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
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Content VG, Williams AC, Alexander LM. Inhibition of nuclear factor-κB activation improves non-nitric oxide-mediated cutaneous microvascular function in reproductive-aged healthy women. Am J Physiol Heart Circ Physiol 2024; 327:H364-H369. [PMID: 38847757 PMCID: PMC11444226 DOI: 10.1152/ajpheart.00204.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/28/2024] [Accepted: 06/05/2024] [Indexed: 07/17/2024]
Abstract
The transcriptional regulator nuclear factor-κB (NF-κB) is a mediator of endothelial dysfunction. Inhibiting NF-κB with salsalate is used to investigate inflammatory mechanisms contributing to accelerated cardiovascular disease risk. However, in the absence of disease, inhibition of NF-κB can impact redox mechanisms, resulting in paradoxically decreased endothelial function. This study aimed to measure microvascular endothelial function during inhibition of the transcriptional regulator NF-κB in reproductive-aged healthy women. In a randomized, single-blind, crossover, placebo-controlled design, nine healthy women were randomly assigned oral salsalate (1,500 mg, twice daily) or placebo treatments for 5 days. Subjects underwent graded perfusion with the endothelium-dependent agonist acetylcholine (ACh, 10-10 to 10-1 M, 33°C) alone and in combination with 15 mM NG-nitro-l-arginine methyl ester [l-NAME; nonselective nitric oxide (NO) synthase inhibitor] through intradermal microdialysis. Laser-Doppler flux was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated as flux divided by mean arterial pressure and normalized to site-specific maximum (CVC%max; 28 mM sodium nitroprusside + 43°C). The l-NAME sensitive component was calculated as the difference between the areas under the dose-response curves. During the placebo and salsalate treatments, the l-NAME sites were reduced compared with the control sites (both P < 0.0001). Across treatments, there was a significant difference between the control and l-NAME sites, where both sites shifted upward following salsalate treatment (both P < 0.0001), whereas the l-NAME-sensitive component was not different (P = 0.94). These data demonstrate that inhibition of the transcriptional regulator NF-κB improves cutaneous microvascular function in reproductive-aged healthy women through non-NO-dependent mechanisms.NEW & NOTEWORTHY The transcription factor nuclear factor-κB (NF-κB) regulates multiple aspects of innate and adaptive immunity by encoding for genes that participate in inflammation and impact endothelial function following NF-κB inhibition with salsalate treatment. Our results show that cutaneous microvascular function is increased through non-nitric oxide (NO)-dependent mechanisms following salsalate treatment in reproductive-aged healthy women.
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Affiliation(s)
- Virginia G Content
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
| | - Auni C Williams
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
| | - Lacy M Alexander
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
- Center for Healthy Aging, The Pennsylvania State University, University Park, Pennsylvania, United States
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Gladding JM, Rafiei N, Mitchell CS, Begg DP. Excision of the endothelial blood-brain barrier insulin receptor does not alter spatial cognition in mice fed either a chow or high-fat diet. Neurobiol Learn Mem 2024; 212:107938. [PMID: 38772444 DOI: 10.1016/j.nlm.2024.107938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 05/02/2024] [Accepted: 05/15/2024] [Indexed: 05/23/2024]
Abstract
Insulin is transported across the blood-brain barrier (BBB) endothelium to regulate aspects of metabolism and cognition. Brain insulin resistance often results from high-fat diet (HFD) consumption and is thought to contribute to spatial cognition deficits. To target BBB insulin function, we used Cre-LoxP genetic excision of the insulin receptor (InsR) from endothelial cells in adult male mice. We hypothesized that this excision would impair spatial cognition, and that high-fat diet consumption would exacerbate these effects. Excision of the endothelial InsR did not impair performance in two spatial cognition tasks, the Y-Maze and Morris Water Maze, in tests held both before and after 14 weeks of access to high-fat (or chow control) diet. The HFD increased body weight gain and induced glucose intolerance but did not impair spatial cognition. Endothelial InsR excision tended to increase body weight and reduce sensitivity to peripheral insulin, but these metabolic effects were not associated with impairments to spatial cognition and did not interact with HFD exposure. Instead, all mice showed intact spatial cognitive performance regardless of whether they had been fed chow or a HFD, and whether the InsR had been excised or not. Overall, the results indicate that loss of the endothelial InsR does not impact spatial cognition, which is in line with pharmacological evidence that other mechanisms at the BBB facilitate insulin transport and allow it to exert its pro-cognitive effects.
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Affiliation(s)
- Joanne M Gladding
- School of Psychology, Faculty of Science, University of New South Wales, Australia.
| | - Neda Rafiei
- School of Psychology, Faculty of Science, University of New South Wales, Australia
| | - Caitlin S Mitchell
- School of Psychology, Faculty of Science, University of New South Wales, Australia
| | - Denovan P Begg
- School of Psychology, Faculty of Science, University of New South Wales, Australia
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Liu H, Wang L, Wang H, Hao X, Du Z, Li C, Hou X. The association of triglyceride-glucose index with major adverse cardiovascular and cerebrovascular events after acute myocardial infarction: a meta-analysis of cohort studies. Nutr Diabetes 2024; 14:39. [PMID: 38844442 PMCID: PMC11156940 DOI: 10.1038/s41387-024-00295-1] [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: 11/22/2023] [Revised: 05/02/2024] [Accepted: 05/15/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Insulin resistance (IR) is indicated to be linked with adverse outcomes of acute myocardial infarction (AMI), for its pro-inflammatory and pro-thromboplastic function. The triglyceride-glucose (TyG) index is a newly developed substitute marker for IR. The aim of this pooled analysis was to provide a summary of the relationship of TyG index with occurrences of major adverse cardiovascular and cerebrovascular events (MACCEs) among populations suffering from AMI. METHODS Cohorts reporting multivariate-adjusted hazard ratios of TyG index with MACCEs or its independent events were identified through systematically searching PubMed, MEDLINE, Web of science, Embase and Cochrane databases. Results were combined using a random-effects model. RESULTS 21 cohorts comprising 20403 individuals were included. Compared to individuals in the lowest TyG category, patients in the highest TyG category exhibited elevated risks of both MACCEs (P < 0.00001) and all-cause death (P < 0.00001). These findings were in line with the results as TyG analyzed as continuous variables (MACCEs: P = 0.006; all-cause death: P < 0.00001). Subgroup analysis demonstrated that diabetic status, type of AMI, nor the reperfusion therapy did not destruct this correlation (for subgroups, all P < 0.05). CONCLUSION All these indicated that higher TyG index could potentially predict MACCEs and all-cause death in patients with AMI as an independent indicator.
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Affiliation(s)
- Huiruo Liu
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Liangshan Wang
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Hong Wang
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xing Hao
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zhongtao Du
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Chenglong Li
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xiaotong Hou
- Centre for Cardiac Intensive Care, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
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11
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Mbara KC, Fotsing MC, Ndinteh DT, Mbeb CN, Nwagwu CS, Khan R, Mokhetho KC, Baijnath H, Nlooto M, Mokhele S, Leonard CM, Tembu VJ, Tarirai C. Endoplasmic reticulum stress in pancreatic β-cell dysfunction: The potential therapeutic role of dietary flavonoids. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2024; 6:100184. [PMID: 38846008 PMCID: PMC11153890 DOI: 10.1016/j.crphar.2024.100184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/09/2024] Open
Abstract
Diabetes mellitus (DM) is a global health burden that is characterized by the loss or dysfunction of pancreatic β-cells. In pancreatic β-cells, endoplasmic reticulum (ER) stress is a fact of life that contributes to β-cell loss or dysfunction. Despite recent advances in research, the existing treatment approaches such as lifestyle modification and use of conventional therapeutics could not prevent the loss or dysfunction of pancreatic β-cells to abrogate the disease progression. Therefore, targeting ER stress and the consequent unfolded protein response (UPR) in pancreatic β-cells may be a potential therapeutic strategy for diabetes treatment. Dietary phytochemicals have therapeutic applications in human health owing to their broad spectrum of biochemical and pharmacological activities. Flavonoids, which are commonly obtained from fruits and vegetables worldwide, have shown promising prospects in alleviating ER stress. Dietary flavonoids including quercetin, kaempferol, myricetin, isorhamnetin, fisetin, icariin, apigenin, apigetrin, vitexin, baicalein, baicalin, nobiletin hesperidin, naringenin, epigallocatechin 3-O-gallate hesperidin (EGCG), tectorigenin, liquiritigenin, and acacetin have shown inhibitory effects on ER stress in pancreatic β-cells. Dietary flavonoids modulate ER stress signaling components, chaperone proteins, transcription factors, oxidative stress, autophagy, apoptosis, and inflammatory responses to exert their pharmacological effects on pancreatic β-cells ER stress. This review focuses on the role of dietary flavonoids as potential therapeutic adjuvants in preserving pancreatic β-cells from ER stress. Highlights of the underlying mechanisms of action are also presented as well as possible strategies for clinical translation in the management of DM.
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Affiliation(s)
- Kingsley C. Mbara
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Marthe C.D. Fotsing
- Drug Discovery and Smart Molecules Research Laboratory, Centre for Natural Products Research (CNPR), Department of Chemical Sciences, University of Johannesburg, Doornfontein, Johannesburg, 2028, South Africa
| | - Derek T. Ndinteh
- Drug Discovery and Smart Molecules Research Laboratory, Centre for Natural Products Research (CNPR), Department of Chemical Sciences, University of Johannesburg, Doornfontein, Johannesburg, 2028, South Africa
| | - Claudine N. Mbeb
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Chinekwu S. Nwagwu
- Drug Delivery and Nanomedicines Research Laboratory, Department of Pharmaceutics, University of Nigeria, Nsukka, Enugu State, Nigeria
| | - Rene Khan
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, South Africa
| | - Kopang C. Mokhetho
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Himansu Baijnath
- Ward Herbarium, School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, KwaZulu-Natal, South Africa
| | - Manimbulu Nlooto
- Department of Pharmaceutical Sciences, Healthcare Sciences, University of Limpopo, South Africa
| | - Shoeshoe Mokhele
- Department of Pharmaceutical Sciences, School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, 0208, South Africa
| | - Carmen M. Leonard
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Vuyelwa J. Tembu
- Natural Products Chemistry Research Laboratory, Department of Chemistry, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
| | - Clemence Tarirai
- Nanomedicines Manufacturing, Biopharmaceutics and Diagnostics Research Laboratory, Department of Pharmaceutical Sciences, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa
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12
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Chacar S, Abdi A, Almansoori K, Alshamsi J, Al Hageh C, Zalloua P, Khraibi AA, Holt SG, Nader M. Role of CaMKII in diabetes induced vascular injury and its interaction with anti-diabetes therapy. Rev Endocr Metab Disord 2024; 25:369-382. [PMID: 38064002 PMCID: PMC10943158 DOI: 10.1007/s11154-023-09855-9] [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] [Accepted: 11/16/2023] [Indexed: 03/16/2024]
Abstract
Diabetes mellitus is a metabolic disorder denoted by chronic hyperglycemia that drives maladaptive structural changes and functional damage to the vasculature. Attenuation of this pathological remodeling of blood vessels remains an unmet target owing to paucity of information on the metabolic signatures of this process. Ca2+/calmodulin-dependent kinase II (CaMKII) is expressed in the vasculature and is implicated in the control of blood vessels homeostasis. Recently, CaMKII has attracted a special attention in view of its chronic upregulated activity in diabetic tissues, yet its role in the diabetic vasculature remains under investigation.This review highlights the physiological and pathological actions of CaMKII in the diabetic vasculature, with focus on the control of the dialogue between endothelial (EC) and vascular smooth muscle cells (VSMC). Activation of CaMKII enhances EC and VSMC proliferation and migration, and increases the production of extracellular matrix which leads to maladaptive remodeling of vessels. This is manifested by activation of genes/proteins implicated in the control of the cell cycle, cytoskeleton organization, proliferation, migration, and inflammation. Endothelial dysfunction is paralleled by impaired nitric oxide signaling, which is also influenced by CaMKII signaling (activation/oxidation). The efficiency of CaMKII inhibitors is currently being tested in animal models, with a focus on the genetic pathways involved in the regulation of CaMKII expression (microRNAs and single nucleotide polymorphisms). Interestingly, studies highlight an interaction between the anti-diabetic drugs and CaMKII expression/activity which requires further investigation. Together, the studies reviewed herein may guide pharmacological approaches to improve health-related outcomes in patients with diabetes.
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Affiliation(s)
- Stephanie Chacar
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates.
| | - Abdulhamid Abdi
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Khalifa Almansoori
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Jawaher Alshamsi
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Cynthia Al Hageh
- Department of Molecular Biology and Genetics, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Pierre Zalloua
- Department of Molecular Biology and Genetics, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates
| | - Ali A Khraibi
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates
| | - Stephen G Holt
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- SEHA Kidney Care, SEHA, Abu Dhabi, UAE
| | - Moni Nader
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
- Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates.
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Zhao Y, Gu Y, Zhang B. Associations of triglyceride-glucose (TyG) index with chest pain incidence and mortality among the U.S. population. Cardiovasc Diabetol 2024; 23:111. [PMID: 38555461 PMCID: PMC10981836 DOI: 10.1186/s12933-024-02209-y] [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: 12/25/2023] [Accepted: 03/20/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND The triglyceride and glucose (TyG) index, a simple surrogate marker of insulin resistance, is related to cardiovascular disease. However, there is a lack of evidence for the relationship between the TyG index and chest pain. This study aimed to investigate the association of the TyG index with chest pain and to evaluate the relationship between the TyG index and all-cause mortality in participants with or without chest pain. METHODS The present study utilized data from the 2001-2012 National Health and Nutrition Examination Survey (NHANES), employing a combination of cross-sectional and cohort study designs. The association between the TyG index and chest pain was investigated using weighted logistic regression models. Weighted Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause mortality. Restricted cubic spline analysis was used to explore linear or nonlinear relationships between the TyG index and chest pain or all-cause mortality. RESULTS The findings revealed a positive correlation between the TyG index and chest pain, even after adjusting for potential confounding factors (quartile 4 versus quartile 1, odds ratio [OR] 1.42, 95% confidence interval [CI] 1.14-1.77, P = 0.002). During a mean follow-up time of 139 months, a total of 2286 individuals (27.43%) experienced mortality. Weighted multivariate Cox regression models indicated that for each one-unit increase in the TyG index, the adjusted hazard ratio (HR) for mortality was 1.14 (95% CI = 0.94-1.37) for participants with chest pain and 1.25 (95% CI = 1.09-1.43) for those without chest pain. Furthermore, restricted cubic spline analysis revealed a linear relationship between the TyG index and chest pain (P for nonlinearity = 0.902), whereas a nonlinear relationship was shown between the TyG index and all-cause mortality among populations regardless of chest pain (all P for nonlinearity < 0.01). CONCLUSION The TyG index was positively linked to a higher incidence of chest pain. Moreover, the TyG index was associated with all-cause mortality not only in participants with chest pain but also in those without chest pain.
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Affiliation(s)
- Yao Zhao
- Department of Cardiovascular Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, 200433, China
- Department of Cardiovasology, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yu Gu
- Department of Neonatology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Bili Zhang
- Department of Cardiovasology, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, China.
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14
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Parker J, O’Brien CL, Yeoh C, Gersh FL, Brennecke S. Reducing the Risk of Pre-Eclampsia in Women with Polycystic Ovary Syndrome Using a Combination of Pregnancy Screening, Lifestyle, and Medical Management Strategies. J Clin Med 2024; 13:1774. [PMID: 38541997 PMCID: PMC10971491 DOI: 10.3390/jcm13061774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/12/2024] [Accepted: 03/17/2024] [Indexed: 05/04/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is a multisystem disorder that presents with a variety of phenotypes involving metabolic, endocrine, reproductive, and psychological symptoms and signs. Women with PCOS are at increased risk of pregnancy complications including implantation failure, miscarriage, gestational diabetes, fetal growth restriction, preterm labor, and pre-eclampsia (PE). This may be attributed to the presence of specific susceptibility features associated with PCOS before and during pregnancy, such as chronic systemic inflammation, insulin resistance (IR), and hyperandrogenism, all of which have been associated with an increased risk of pregnancy complications. Many of the features of PCOS are reversible following lifestyle interventions such as diet and exercise, and pregnant women following a healthy lifestyle have been found to have a lower risk of complications, including PE. This narrative synthesis summarizes the evidence investigating the risk of PE and the role of nutritional factors in women with PCOS. The findings suggest that the beneficial aspects of lifestyle management of PCOS, as recommended in the evidence-based international guidelines, extend to improved pregnancy outcomes. Identifying high-risk women with PCOS will allow targeted interventions, early-pregnancy screening, and increased surveillance for PE. Women with PCOS should be included in risk assessment algorithms for PE.
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Affiliation(s)
- Jim Parker
- School of Medicine, University of Wollongong, Wollongong 2522, Australia
| | - Claire Louise O’Brien
- Faculty of Science and Technology, University of Canberra, Canberra 2617, Australia;
| | - Christabelle Yeoh
- Next Practice Genbiome, 2/2 New McLean Street, Edgecliff 2027, Australia;
| | - Felice L. Gersh
- College of Medicine, University of Arizona, Tucson, AZ 85004, USA;
| | - Shaun Brennecke
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, The Royal Women’s Hospital, Melbourne 3052, Australia;
- Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne 3052, Australia
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15
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Engin A. Endothelial Dysfunction in Obesity and Therapeutic Targets. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:489-538. [PMID: 39287863 DOI: 10.1007/978-3-031-63657-8_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter β, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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16
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Wu Q, Jiao Y, Luo M, Wang J, Li J, Ma Y, Liu C. Detection of Various Traditional Chinese Medicinal Metabolites as Angiotensin-Converting Enzyme Inhibitors: Molecular Docking, Activity Testing, and Surface Plasmon Resonance Approaches. Molecules 2023; 28:7131. [PMID: 37894610 PMCID: PMC10609061 DOI: 10.3390/molecules28207131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/09/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Angiotensin-converting enzyme 1 (ACE1) is a peptide involved in fluid and blood pressure management. It regulates blood pressure by converting angiotensin I to angiotensin II, which has vasoconstrictive effects. Previous studies have shown that certain compounds of natural origin can inhibit the activity of angiotensin-converting enzymes and exert blood pressure-regulating effects. Surface Plasmon Resonance (SPR) biosensor technology is the industry standard method for observing biomolecule interactions. In our study, we used molecular simulation methods to investigate the docking energies of various herbal metabolites with ACE1 proteins, tested the real-time binding affinities between various herbal metabolites and sACE1 by SPR, and analyzed the relationship between real-time binding affinity and docking energy. In addition, to further explore the connection between inhibitor activity and real-time binding affinity, several herbal metabolites' in vitro inhibitory activities were tested using an ACE1 activity test kit. The molecular docking simulation technique's results and the real-time affinity tested by the SPR technique were found to be negatively correlated, and the virtual docking technique still has some drawbacks as a tool for forecasting proteins' affinities to the metabolites of Chinese herbal metabolites. There may be a positive correlation between the enzyme inhibitory activity and the real-time affinity detected by the SPR technique, and the results from the SPR technique may provide convincing evidence to prove the interaction between herbal metabolites and ACE1 target proteins.
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Affiliation(s)
| | | | | | | | | | | | - Changzhen Liu
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
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17
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Shetti AU, Ramakrishnan A, Romanova L, Li W, Vo K, Volety I, Ratnayake I, Stephen T, Minshall RD, Cologna SM, Lazarov O. Reduced endothelial caveolin-1 underlies deficits in brain insulin signalling in type 2 diabetes. Brain 2023; 146:3014-3028. [PMID: 36731883 PMCID: PMC10316766 DOI: 10.1093/brain/awad028] [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] [Received: 08/05/2022] [Revised: 01/07/2023] [Accepted: 01/17/2023] [Indexed: 02/04/2023] Open
Abstract
Patients with type 2 diabetes exhibit severe impairments in insulin signalling in the brain and are five times more likely to develop Alzheimer's disease. However, what leads to these impairments is not fully understood. Here, we show reduced expression of endothelial cell caveolin-1 (Cav-1) in the db/db (Leprdb) mouse model of type 2 diabetes. This reduction correlated with alterations in insulin receptor expression and signalling in brain microvessels as well as brain parenchyma. These findings were recapitulated in the brains of endothelial cell-specific Cav-1 knock-out (Tie2Cre; Cav-1fl/fl) mice. Lack of Cav-1 in endothelial cells led to reduced response to insulin as well as reduced insulin uptake. Furthermore, we observed that Cav-1 was necessary for the stabilization of insulin receptors in lipid rafts. Interactome analysis revealed that insulin receptor interacts with Cav-1 and caveolae-associated proteins, insulin-degrading enzyme and the tight junction protein Zonula Occludence-1 in brain endothelial cells. Restoration of Cav-1 in Cav-1 knock-out brain endothelial cells rescued insulin receptor expression and localization. Overall, these results suggest that Cav-1 regulates insulin signalling and uptake by brain endothelial cells by modulating IR-α and IR-β localization and function in lipid rafts. Furthermore, depletion of endothelial cell-specific Cav-1 and the resulting impairment in insulin transport leads to alteration in insulin signalling in the brain parenchyma of type 2 diabetics.
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Affiliation(s)
- Aashutosh U Shetti
- Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Abhirami Ramakrishnan
- Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Liudmila Romanova
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Wenping Li
- Department of Chemistry, College of Liberal Arts and Sciences, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Khanh Vo
- Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Ipsita Volety
- Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Ishara Ratnayake
- Electron Microscopy Core, Research Resource Center, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Terilyn Stephen
- Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Richard D Minshall
- Department of Pharmacology and Regenerative Medicine, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
- Department of Anesthesiology, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Stephanie M Cologna
- Department of Chemistry, College of Liberal Arts and Sciences, The University of Illinois Chicago, Chicago, IL 60612, USA
| | - Orly Lazarov
- Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois Chicago, Chicago, IL 60612, USA
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18
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Mima A, Murakami A, Lee R, Lee S. Predictive significance of glomerular insulin receptor substrate-1 in patients with diabetic kidney disease. Metabol Open 2023; 18:100240. [PMID: 37025096 PMCID: PMC10070893 DOI: 10.1016/j.metop.2023.100240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
Background In rodents, glomerular expression of insulin receptor substrate 1 (IRS1) is decreased in diabetic kidney disease (DKD) and reduced associated functioning is involved in the development and progression of DKD. This study aimed to evaluate the significance of glomerular IRS1 expression in DKD patients, and investigated whether glomerular IRS1 expression can reflect renal pathology and predict renal outcomes. Methods This study included 10 patients who underwent renal biopsy and were diagnosed with DKD or minor glomerular abnormality (MGA). IRS1-positive cells were determined based on renal biopsy and immunostaining, and the associations of the number of these cells with baseline and prognostic parameters were analyzed. Results IRS1-positive cells were significantly decreased in DKD than in MGA. IRS1 positivity tended to be negatively correlated with global glomerulosclerosis and tubulointerstitial fibrosis. The rate of change in estimated glomerular filtration rate before and 12 months after renal biopsy was positively correlated to the number of IRS1-positive cells. Furthermore, a tendency towards negative correlation was observed between the number of glomerular IRS1-positive cells and the proteinuria. Conclusions This study shows the glomerular IRS1-positive cell count was significantly decreased in DKD, and that the degree IRS1 positivity was partially correlated with renal pathology and function.
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Pakdeechote P, Poasakate A, Prasatthong P, Potue P, Khamseekaew J, Maneesai P. Mitigation effect of galangin against aortic dysfunction and hypertrophy in rats with metabolic syndrome. Heliyon 2023; 9:e16500. [PMID: 37251824 PMCID: PMC10213349 DOI: 10.1016/j.heliyon.2023.e16500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 05/08/2023] [Accepted: 05/18/2023] [Indexed: 05/31/2023] Open
Abstract
Vascular alterations induced by a high-fat diet (HFD) are involved in the development of hypertension. Galangin, a flavonoid, is the major active compound isolated from galangal and propolis. The objective of this study was to investigate the effect of galangin on aortic endothelial dysfunction and hypertrophy, and the mechanisms involved in HFD-induced metabolic syndrome (MS) in rats. Male Sprague-Dawley rats (220-240 g) were separated into three groups: control + vehicle, MS + vehicle, and MS + galangin (50 mg/kg). Rats with MS received HFD plus 15% fructose solution for 16 weeks. Galangin or vehicle was orally administered daily for the final four weeks. Galangin reduced body weight and mean arterial pressure in HFD rats (p < 0.05). It also reduced circulating fasting blood glucose, insulin, and total cholesterol levels (p < 0.05). Impaired vascular responses to the exogenous acetylcholine observed in the aortic ring of HFD rats were restored by galangin (p < 0.05). However, the response to sodium nitroprusside did not differ between the groups. Galangin enhanced the expression of the aortic endothelial nitric oxide synthase (eNOS) protein and increased circulating nitric oxide (NO) levels in the MS group (p < 0.05). Aortic hypertrophy in HFD rats was alleviated by galangin (p < 0.05). Increases in tumour necrosis factor-alpha (TNF-α), interleukin (IL)-6 levels, angiotensin-converting enzyme activity and angiotensin II (Ang II) concentrations in rats with MS were suppressed in galangin treated group (p < 0.05). Furthermore, galangin reduced the upregulation of angiotensin II type I receptor (AT1R) and transforming growth factor-beta (TGF-β) expression in rats with MS (p < 0.05). In conclusion, galangin alleviates metabolic disorders and improves aortic endothelial dysfunction and hypertrophy in the MS group. These effects were consistent with increased NO availability, reduced inflammation, and suppressing Ang II/AT1R/TGF-β signalling pathway.
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Affiliation(s)
- Poungrat Pakdeechote
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Anuson Poasakate
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Patoomporn Prasatthong
- Department of Health Science, Faculty of Science and Technology, Nakhon Sawan Rajabhat University, Nakhon Sawan 60000, Thailand
| | - Prapassorn Potue
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Juthamas Khamseekaew
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Putcharawipa Maneesai
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
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20
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Fessel J. Cure of Alzheimer's Dementia in Many Patients by Using Intranasal Insulin to Augment an Inadequate Counter-Reaction, Edaravone to Scavenge ROS, and 1 or 2 Other Drugs to Address Affected Brain Cells. J Clin Med 2023; 12:jcm12093151. [PMID: 37176592 PMCID: PMC10178959 DOI: 10.3390/jcm12093151] [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: 03/09/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The goal of treatment for Alzheimer's dementia (AD) is the restoration of normal cognition. No drug regimen has ever achieved this. This article suggests that curing AD may be achieved by combination therapy as follows. First, with intranasal insulin to augment the body's natural counter-reaction to the changes in brain cell-types that produced the dementia. Second, with edaravone to decrease free radicals, which are increased and causal in AD. Third, as described elsewhere, with one or two drugs from among pioglitazone, fluoxetine, and lithium, which address the brain cell-types whose changed functions cause the dementia. Insulin restores cerebral glucose, which is the main nutrient for brain neurons whose depletion is responsible for the dementia; and edaravone decreases ROS, which are intrinsic causes of neuropathology in AD. This combination of drugs is a potential cure for many patients with AD, and should be tested in a clinical trial.
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Affiliation(s)
- Jeffrey Fessel
- Department of Medicine, University of California San Francisco, 2069 Filbert Street, San Francisco, CA 94123, USA
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21
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Kale A, Rogers NM. No Time to Die-How Islets Meet Their Demise in Transplantation. Cells 2023; 12:cells12050796. [PMID: 36899932 PMCID: PMC10000424 DOI: 10.3390/cells12050796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Islet transplantation represents an effective treatment for patients with type 1 diabetes mellitus (T1DM) and severe hypoglycaemia unawareness, capable of circumventing impaired counterregulatory pathways that no longer provide protection against low blood glucose levels. The additional beneficial effect of normalizing metabolic glycaemic control is the minimisation of further complications related to T1DM and insulin administration. However, patients require allogeneic islets from up to three donors, and the long-term insulin independence is inferior to that achieved with solid organ (whole pancreas) transplantation. This is likely due to the fragility of islets caused by the isolation process, innate immune responses following portal infusion, auto- and allo-immune-mediated destruction and β-cell exhaustion following transplantation. This review covers the specific challenges related to islet vulnerability and dysfunction that affect long-term cell survival following transplantation.
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Affiliation(s)
- Atharva Kale
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Natasha M. Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Renal and Transplant Unit, Westmead Hospital, Westmead, NSW 2145, Australia
- Correspondence:
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Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice. Biomedicines 2023; 11:biomedicines11030662. [PMID: 36979641 PMCID: PMC10045486 DOI: 10.3390/biomedicines11030662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 02/24/2023] Open
Abstract
Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.
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23
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Chook CYB, Cheung YM, Ma KY, Leung FP, Zhu H, Niu QJ, Wong WT, Chen ZY. Physiological concentration of protocatechuic acid directly protects vascular endothelial function against inflammation in diabetes through Akt/eNOS pathway. Front Nutr 2023; 10:1060226. [PMID: 37025617 PMCID: PMC10070727 DOI: 10.3389/fnut.2023.1060226] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 03/06/2023] [Indexed: 04/08/2023] Open
Abstract
Background Cardiovascular diseases (CVDs) have been the major cause of mortality in type 2 diabetes. However, new approaches are still warranted since current diabetic medications, which focus mainly on glycemic control, do not effectively lower cardiovascular mortality rate in diabetic patients. Protocatechuic acid (PCA) is a phenolic acid widely distributed in garlic, onion, cauliflower and other plant-based foods. Given the anti-oxidative effects of PCA in vitro, we hypothesized that PCA would also have direct beneficial effects on endothelial function in addition to the systemic effects on vascular health demonstrated by previous studies. Methods and results Since IL-1β is the major pathological contributor to endothelial dysfunction in diabetes, the anti-inflammatory effects of PCA specific on endothelial cells were further verified by the use of IL-1β-induced inflammation model. Direct incubation of db/db mouse aortas with physiological concentration of PCA significantly ameliorated endothelium-dependent relaxation impairment, as well as reactive oxygen species overproduction mediated by diabetes. In addition to the well-studied anti-oxidative activity, PCA demonstrated strong anti-inflammatory effects by suppressing the pro-inflammatory cytokines MCP1, VCAM1 and ICAM1, as well as increasing the phosphorylation of eNOS and Akt in the inflammatory endothelial cell model induced by the key player in diabetic endothelial dysfunction IL-1β. Upon blocking of Akt phosphorylation, p-eNOS/eNOS remained low and the inhibition of pro-inflammatory cytokines by PCA ceased. Conclusion PCA exerts protection on vascular endothelial function against inflammation through Akt/eNOS pathway, suggesting daily acquisition of PCA may be encouraged for diabetic patients.
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Affiliation(s)
- Chui Yiu Bamboo Chook
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yiu Ming Cheung
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ka Ying Ma
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Fung Ping Leung
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Hanyue Zhu
- School of Food Science and Engineering, Foshan University, Foshan, Guangdong, China
| | - Qingshan Jason Niu
- Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China
| | - Wing Tak Wong
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Wing Tak Wong,
| | - Zhen-Yu Chen
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Zhen-Yu Chen,
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24
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Love KM, Barrett EJ, Horton WB. Metformin's Impact on the Microvascular Response to Insulin. Endocrinology 2022; 163:bqac162. [PMID: 36201598 PMCID: PMC10233257 DOI: 10.1210/endocr/bqac162] [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: 07/28/2022] [Indexed: 11/19/2022]
Abstract
Metformin improves insulin's action on whole-body glucose metabolism in various insulin-resistant populations. The detailed cellular mechanism(s) for its metabolic actions are multiple and still incompletely understood. Beyond metabolic actions, metformin also impacts microvascular function. However, the effects of metformin on microvascular function and microvascular insulin action specifically are poorly defined. In this mini-review, we summarize what is currently known about metformin's beneficial impact on both microvascular function and the microvascular response to insulin while highlighting methodologic issues in the literature that limit straightforward mechanistic understanding of these effects. We examine potential mechanisms for these effects based on pharmacologically dosed studies and propose that metformin may improve human microvascular insulin resistance by attenuating oxidative stress, inflammation, and endothelial dysfunction. Finally, we explore several important evidence gaps and discuss avenues for future investigation that may clarify whether metformin's ability to improve microvascular insulin sensitivity is linked to its positive impact on vascular outcomes.
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Affiliation(s)
- Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - William B Horton
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
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25
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Zaharia OP, Schön M, Löffler L, Strassburger K, Möser C, Yurchenko I, Bódis K, Antoniou S, Karusheva Y, Szendroedi J, Burkart V, Roden M. Metabolic Factors Predict Changes in Endothelial Function During the Early Course of Type 1 and Type 2 Diabetes. J Clin Endocrinol Metab 2022; 107:e4167-e4176. [PMID: 35965389 PMCID: PMC9516081 DOI: 10.1210/clinem/dgac480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Endothelial dysfunction may occur early in the development of cardiovascular and metabolic diseases; however, it remains often underestimated and studies rarely discriminate between diabetes types. We have examined endothelial function and its determinants during the early course of type 1 and type 2 diabetes. METHODS Caucasian participants of the prospective German Diabetes Study (GDS) with known diabetes duration <1 year (n = 398) or without diabetes, but of similar age, body mass index (BMI) and sex distribution (n = 109), underwent measurements of flow-mediated dilation (FMD) and nitroglycerin-mediated dilatation (NMD). Whole-body insulin sensitivity (M-value) was assessed by hyperinsulinemic-euglycemic clamps and physical fitness (VO2max) by spiroergometry. A subset of individuals with type 1 or type 2 diabetes (n = 108) was re-evaluated after 5 years. RESULTS At baseline, neither FMD nor NMD differed between people with diabetes and the matched glucose-tolerant groups. At the 5-year follow-up, decline in FMD (-13.9%, P = .013) of persons with type 2 diabetes was independent of age, sex, and BMI, but associated with baseline adipose tissue insulin resistance and indices of liver fibrosis. The M-value decreased in both type 1 and type 2 diabetes groups by 24% and 15% (both P < .001, respectively) over 5 years. Higher HbA1c, lower M-value, and lower VO2max at baseline was associated with lower FMD in both type 1 and type 2 diabetes. CONCLUSION Endothelial function decreases during the early course of type 2 diabetes. In addition to age and BMI, insulin sensitivity at diagnosis was the best predictor of progressive impairment in endothelial function in type 2 diabetes.
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Affiliation(s)
| | | | - Luca Löffler
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Klaus Strassburger
- German Center for Diabetes Research (DZD e. V.), Partner Düsseldorf, Neuherberg, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Clara Möser
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e. V.), Partner Düsseldorf, Neuherberg, Germany
| | - Iryna Yurchenko
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e. V.), Partner Düsseldorf, Neuherberg, Germany
| | - Kálmán Bódis
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e. V.), Partner Düsseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany
| | - Sofia Antoniou
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Yanislava Karusheva
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e. V.), Partner Düsseldorf, Neuherberg, Germany
| | - Julia Szendroedi
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e. V.), Partner Düsseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany
| | - Volker Burkart
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e. V.), Partner Düsseldorf, Neuherberg, Germany
| | - Michael Roden
- Correspondence: Michael Roden, Prof, Dr, Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University Düsseldorf, Germany, c/o Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany. E-mail:
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Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options. Biomedicines 2022; 10:biomedicines10092274. [PMID: 36140374 PMCID: PMC9496134 DOI: 10.3390/biomedicines10092274] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/04/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of this microvascular complication is complex and not completely known, involving several alterations among which hyperglycemia and insulin resistance play particularly central roles leading to oxidative stress, inflammatory activation and altered barrier function of endothelium. CMD significantly contributes to cardiac events such as angina or infarction without obstructive coronary artery disease, as well as heart failure, especially the phenotype associated with preserved ejection fraction, which greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target this vascular damage, but recent experimental studies and some clinical investigations have produced data in favor of potential beneficial effects on coronary micro vessels caused by two classes of glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy and inhibitors of sodium-glucose cotransporter-2 (SGLT2). The purpose of this review is to describe pathophysiological mechanisms, clinical manifestations of CMD with particular reference to diabetes, and to summarize the protective effects of antidiabetic drugs on the myocardial microvascular compartment.
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27
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Hydrogen sulfide donor GYY4137 attenuates vascular complications in mesenteric bed of streptozotocin-induced diabetic rats. Eur J Pharmacol 2022; 933:175265. [PMID: 36108734 DOI: 10.1016/j.ejphar.2022.175265] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/26/2022] [Accepted: 09/06/2022] [Indexed: 01/06/2023]
Abstract
Hydrogen sulfide (H2S) has been reported to have beneficial effects in different pathological conditions. OBJECTIVES the effects of chronic treatment of diabetic rats with GYY4137 (slow releasing H2S donor) or NaHS (fast releasing H2S donor) on the reactivity of the mesenteric bed to vasoactive agonists and the changes in its downstream effectors, ERK1/2 and p38 MAP Kinase have been investigated. In addition, the levels of nitric oxide (NO) and H2S in all groups were measured. METHODS diabetes was induced by a single intraperitoneal (ip) injection of streptozotocin (STZ; 55 mg/kg). Sprague Dawley (SD; n = 10-12/group) rats were randomly divided into six groups: control, STZ-induced diabetic rats, GYY4137-treated control, NaHS-treated control, GYY4137-treated diabetic, and NaHS-treated diabetic. After 28 days of treatment, rats were sacrificed and mesenteric beds were isolated for functional or biochemical studies. The vascular reactivity of the perfused mesenteric bed to norepinephrine, carbachol and sodium nitroprusside were determined by measurement of changes in perfusion pressure. Western blotting was performed to measure the protein expression of ERK1/2, p38, eNOS, and H2S biosynthesizing enzymes cystathionine-β-synthase and cystathionine-γ-lyase. NO and H2S levels were measured in all groups in isolated mesenteric tissues or plasma. RESULTS diabetes resulted in a significant increase in vasoconstrictor responses to norepinephrine (e.g., 129.6 ± 6.77 mmHg in diabetic vs 89.3 ± 8.48 mmHg in control at 10-7 dose), and carbachol-induced vasodilation was significantly reduced in diabetic mesenteric bed (e.g., 68.9 ± 4.8 mmHg in diabetic vs 90.6 ± 2.2 mmHg in control at 10-7 dose). Chronic treatment of the diabetic rats with GYY4137 resulted in a significant improvement in the response to norepinephrine (e.g., 86.66 ± 8.04 mmHg in GYY4137-treated diabetic vs 129.6 ± 6.77 mmHg in untreated diabetic at 10-7 dose) or carbachol (e.g., 84.90 ± 2.48 mmHg in GYY4137-treated diabetic vs 68.9 ± 4.8 mmHg in untreated diabetic at 10-7 dose). The biochemical studies showed a marked reduction of the protein expression of ERK and p38 and a significant upregulation of the expression of eNOS and H2S synthesizing enzymes after chronic treatment with GYY4137. Plasma levels of NO and H2S were significantly elevated after treatment with GYY4137. However, H2S production in the mesenteric bed showed a marginal elevation in diabetic tissues compared to controls. CONCLUSION the results indicate that GYY4137 may be a novel therapeutic tool to prevent diabetes-associated vascular dysfunction.
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28
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Sowa PW, Winzer EB, Hommel J, Männel A, van Craenenbroeck EM, Wisløff U, Pieske B, Halle M, Linke A, Adams V. Impact of different training modalities on high-density lipoprotein function in HFpEF patients: a substudy of the OptimEx trial. ESC Heart Fail 2022; 9:3019-3030. [PMID: 35747946 DOI: 10.1002/ehf2.14032] [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: 02/02/2022] [Revised: 05/18/2022] [Accepted: 06/09/2022] [Indexed: 11/12/2022] Open
Abstract
AIMS In heart failure with preserved ejection fraction (HFpEF), the reduction of nitric oxide (NO)-bioavailability and consequently endothelial dysfunction leads to LV stiffness and diastolic dysfunction of the heart. Besides shear stress, high-density lipoprotein (HDL) stimulates endothelial cells to increased production of NO via phosphorylation of endothelial nitric oxide synthase (eNOS). For patients with heart failure with reduced ejection fraction, earlier studies demonstrated a positive impact of exercise training (ET) on HDL-mediated eNOS activation. The study aims to investigate the influence of ET on HDL-mediated phosphorylation of eNOS in HFpEF patients. METHODS AND RESULTS The present study is a substudy of the OptimEx-Clin trial. The patients were randomized to three groups: (i) HIIT (high-intensity interval training; (ii) MCT (moderate-intensity continuous training); and (iii) CG (control group). Supervised training at study centres was offered for the first 3 months. From months 4-12, training sessions were continued at home with the same exercise protocol as performed during the in-hospital phase. Blood was collected at baseline, after 3, and 12 months, and HDL was isolated by ultracentrifugation. Human aortic endothelial cells were incubated with isolated HDL, and HDL-induced eNOS phosphorylation at Ser1177 and Thr495 was assessed. Subsequently, the antioxidative function of HDL was evaluated by measuring the activity of HDL-associated paraoxonase-1 (Pon1) and the concentration of thiobarbituric acid-reactive substances (TBARS). After 3 months of supervised ET, HIIT resulted in increased HDL-mediated eNOS-Ser1177 phosphorylation. This effect diminished after 12 months of ET. No effect of HIIT was observed on HDL-mediated eNOS-Thr495 phosphorylation. MCT had no effect on HDL-mediated eNOS phosphorylation at Ser1177 and Thr495 . HIIT also increased Pon1 activity after 12 months of ET and reduced the concentration of TBARS in the serum after 3 and 12 months of ET. A negative correlation was observed between TBARS concentration and HDL-associated Pon1 activity in the HIIT group (r = -0.61, P < 0.05), and a trend was evident for the correlation between the change in HDL-mediated eNOS-Ser1177 phosphorylation and the change in peak V̇O2 after 3 months in the HIIT group (r = 0.635, P = 0.07). CONCLUSIONS The present study documented that HIIT but not MCT exerts beneficial effects on HDL-mediated eNOS phosphorylation and HDL-associated Pon1 activity in HFpEF patients. These beneficial effects of HIIT were reduced as soon as the patients switched to home-based ET.
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Affiliation(s)
- Pamela W Sowa
- Laboratory of Molecular and Experimental Cardiology, Technische Universität Dresden, Heart Center Dresden, Dresden, Germany
| | - Ephraim B Winzer
- Laboratory of Molecular and Experimental Cardiology, Technische Universität Dresden, Heart Center Dresden, Dresden, Germany
| | - Jennifer Hommel
- Laboratory of Molecular and Experimental Cardiology, Technische Universität Dresden, Heart Center Dresden, Dresden, Germany
| | - Anita Männel
- Laboratory of Molecular and Experimental Cardiology, Technische Universität Dresden, Heart Center Dresden, Dresden, Germany
| | - Emeline M van Craenenbroeck
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium.,Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Ulrik Wisløff
- The Cardiac Exercise Research Group at Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Burkert Pieske
- Department Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Martin Halle
- Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Axel Linke
- Laboratory of Molecular and Experimental Cardiology, Technische Universität Dresden, Heart Center Dresden, Dresden, Germany
| | - Volker Adams
- Laboratory of Molecular and Experimental Cardiology, Technische Universität Dresden, Heart Center Dresden, Dresden, Germany.,Dresden Cardiovascular Research Institute and Core Laboratories GmbH, Dresden, Germany
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29
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Sabe SA, Feng J, Sellke FW, Abid MR. Mechanisms and clinical implications of endothelium-dependent vasomotor dysfunction in coronary microvasculature. Am J Physiol Heart Circ Physiol 2022; 322:H819-H841. [PMID: 35333122 PMCID: PMC9018047 DOI: 10.1152/ajpheart.00603.2021] [Citation(s) in RCA: 27] [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: 11/15/2021] [Revised: 03/21/2022] [Accepted: 03/21/2022] [Indexed: 12/16/2022]
Abstract
Coronary microvascular disease (CMD), which affects the arterioles and capillary endothelium that regulate myocardial perfusion, is an increasingly recognized source of morbidity and mortality, particularly in the setting of metabolic syndrome. The coronary endothelium plays a pivotal role in maintaining homeostasis, though factors such as diabetes, hypertension, hyperlipidemia, and obesity can contribute to endothelial injury and consequently arteriolar vasomotor dysfunction. These disturbances in the coronary microvasculature clinically manifest as diminished coronary flow reserve, which is a known independent risk factor for cardiac death, even in the absence of macrovascular atherosclerotic disease. Therefore, a growing body of literature has examined the molecular mechanisms by which coronary microvascular injury occurs at the level of the endothelium and the consequences on arteriolar vasomotor responses. This review will begin with an overview of normal coronary microvascular physiology, modalities of measuring coronary microvascular function, and clinical implications of CMD. These introductory topics will be followed by a discussion of recent advances in the understanding of the mechanisms by which inflammation, oxidative stress, insulin resistance, hyperlipidemia, hypertension, shear stress, endothelial cell senescence, and tissue ischemia dysregulate coronary endothelial homeostasis and arteriolar vasomotor function.
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Affiliation(s)
- Sharif A Sabe
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island
| | - Jun Feng
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island
| | - Frank W Sellke
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island
| | - M Ruhul Abid
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island
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30
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Lv W, Jin S, Cao D, Wang N, Jin X, Zhang Y. Effects of Luteinizing Hormone Releasing Hormone A2 on Gonad Development in Juvenile Amur Sturgeon, Acipenser schrenckii, Revealed by Transcriptome Profiling Analysis. Front Genet 2022; 13:859965. [PMID: 35401695 PMCID: PMC8989137 DOI: 10.3389/fgene.2022.859965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 02/22/2022] [Indexed: 11/15/2022] Open
Abstract
Acipenser schrenckii is an economically important aquatic species whose gonads require particularly long times to reach sexual maturity. Luteinizing hormone plays important roles in gonad development, and luteinizing hormone releasing hormone A2 (LH-A2) is used as an oxytocin to promote ovulation in aquaculture of A. schrenckii. In this study, we aimed to determine the effects of LH-A2 on gonad development in juvenile A. schrenckii through transcriptome profiling analysis of the pituitary and gonads after LH-A2 treatment at a dose of 3 μg/kg. The 17β-estradiol (E2) levels gradually increased with LH-A2 treatment time, and significantly differed from those of the control group on days 5 and 7 (p < 0.01). However, the content of testosterone (Testo) gradually decreased with LH-A2 treatment time and showed significant differences on day 3 (p < 0.05), and on days 5 and 7 (p < 0.01), compared to those in the control group. Thus, LH-A2 promotes the secretion of E2 and inhibits the secretion of Testo. Transcriptome profiling analysis revealed a total of 2,883 and 8,476 differentially expressed genes (DEGs) in the pituitary and gonads, respectively, thus indicating that LH-A2 has more regulatory effects on the gonads than the pituitary in A. schrenckii. Signal transduction, global and overview maps, immune system, endocrine system and lipid metabolism were the main enriched metabolic pathways in both the pituitary and gonads. Sixteen important genes were selected from these metabolic pathways. Seven genes were co-DEGs enriched in both signal transduction and endocrine system metabolic pathways. The other co-DEGs were selected from the immune system and lipid metabolism metabolic pathways, and showed mRNA expression changes of >7.0. The expression of five DEGs throughout LH-A2 treatment was verified to show the same patterns of change as those observed with RNA-seq, indicating the accuracy of the RNA-seq in this study. Our findings provide valuable evidence of the regulation of gonad development of juvenile A. schrenckii by LH-A2 and may enable the establishment of artificial techniques to regulate gonad development in this species.
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Affiliation(s)
- Weihua Lv
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Shubo Jin
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Dingchen Cao
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Nianmin Wang
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Xing Jin
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Ying Zhang
- Key Open Laboratory of Cold Water Fish Germplasm Resources and Breeding of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
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31
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Teimouri M, Hosseini H, ArabSadeghabadi Z, Babaei-Khorzoughi R, Gorgani-Firuzjaee S, Meshkani R. The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications. J Physiol Biochem 2022; 78:307-322. [PMID: 34988903 DOI: 10.1007/s13105-021-00860-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/16/2021] [Indexed: 01/16/2023]
Abstract
Insulin resistance, the most important characteristic of the type 2 diabetes mellitus (T2DM), is mostly caused by impairment in the insulin receptor (IR) signal transduction pathway. Protein tyrosine phosphatase 1B (PTP1B), one of the main negative regulators of the IR signaling pathway, is broadly expressed in various cells and tissues. PTP1B decreases the phosphorylation of the IR resulting in insulin resistance in various tissues. The evidence for the physiological role of PTP1B in regulation of metabolic pathways came from whole-body PTP1B-knockout mice. Whole-body and tissue-specific PTP1B-knockout mice showed improvement in adiposity, insulin resistance, and glucose tolerance. In addition, the key role of PTP1B in the pathogenesis of T2DM and its complications was further investigated in mice models of PTP1B deficient/overexpression. In recent years, targeting PTP1B using PTP1B inhibitors is being considered an attractive target to treat T2DM. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. We herein summarized the biological functions of PTP1B in different tissues in vivo and in vitro. We also describe the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat T2DM.
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Affiliation(s)
- Maryam Teimouri
- Department of Clinical Biochemistry, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra ArabSadeghabadi
- Department of Clinical Sciences, Faculty of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran
| | - Reyhaneh Babaei-Khorzoughi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sattar Gorgani-Firuzjaee
- Department of Medical Laboratory Sciences, School of Allied Health Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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32
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Dhanya R. Quercetin for managing type 2 diabetes and its complications, an insight into multitarget therapy. Biomed Pharmacother 2021; 146:112560. [PMID: 34953390 DOI: 10.1016/j.biopha.2021.112560] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Quercetin, a bioflavonoid abundant in grapefruit, onion, berries, etc., has vast therapeutic potential, especially against Type 2 diabetes and its complications. Quercetin showed similar effects as that of metformin, (widely prescribed antidiabetic drug) in cell lines models (Sajan et al., 2010; Dhanya et al., 2017). In vivo findings also showcase it as a promising agent against diabetes and its pathophysiological complications. SCOPE AND APPROACH Quercetin can be produced on a large scale through a novel fermentation-based glycosylation strategy from cheap substrates and can be utilized as a dietary supplement. The review focuses on the mounting evidence pointing to Quercetin as a promising candidate for managing type 2 diabetes and its oxidative stress mediated pathophysiological complications. CONCLUSION Quercetin acts on multiple targets of diabetes and regulates key signalling pathways which improve the symptoms as well as the complications of Type 2 diabetes. However further studies are needed to improve the bioavailability and to establish a dosing regimen for Quercetin.
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Affiliation(s)
- R Dhanya
- Cardiovascular Diseases and Diabetes Biology Division, Rajiv Gandhi Centre for Biotechnology (RGCB), Thycaud Post, Poojappura, Trivandrum 695014, Kerala, India.
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Salvatore T, Caturano A, Galiero R, Di Martino A, Albanese G, Vetrano E, Sardu C, Marfella R, Rinaldi L, Sasso FC. Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function. Biomedicines 2021; 9:biomedicines9101356. [PMID: 34680473 PMCID: PMC8533063 DOI: 10.3390/biomedicines9101356] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/15/2021] [Accepted: 09/26/2021] [Indexed: 12/23/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a known independent risk factor for atherosclerotic cardiovascular disease (CVD) and solid epidemiological evidence points to heart failure (HF) as one of the most common complications of diabetes. For this reason, it is imperative to consider the prevention of CV outcomes as an effective goal for the management of diabetic patients, as important as lowering blood glucose. Endothelial dysfunction (ED) is an early event of atherosclerosis involving adhesion molecules, chemokines, and leucocytes to enhance low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. This abnormal vascular phenotype represents an important risk factor for the genesis of any complication of diabetes, contributing to the pathogenesis of not only macrovascular disease but also microvascular damage. Gliflozins are a novel class of anti-hyperglycemic agents used for the treatment of Type 2 diabetes mellitus (T2DM) that selectively inhibit the sodium glucose transporter 2 (SGLT2) in the kidneys and have provoked large interest in scientific community due to their cardiovascular beneficial effects, whose underlying pathophysiology is still not fully understood. This review aimed to analyze the cardiovascular protective mechanisms of SGLT2 inhibition in patients T2DM and their impact on endothelial function.
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Affiliation(s)
- Teresa Salvatore
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via De Crecchio 7, I-80138 Naples, Italy;
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Anna Di Martino
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Gaetana Albanese
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Erica Vetrano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy; (A.C.); (R.G.); (A.D.M.); (G.A.); (E.V.); (C.S.); (R.M.); (L.R.)
- Correspondence: ; Tel.: +39-081-566-5010
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Copur S, Rossing P, Afsar B, Sag AA, Siriopol D, Kuwabara M, Ortiz A, Kanbay M. A primer on metabolic memory: why existing diabesity treatments fail. Clin Kidney J 2021; 14:756-767. [PMID: 34512957 PMCID: PMC8422888 DOI: 10.1093/ckj/sfaa143] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Indexed: 11/28/2022] Open
Abstract
Despite massive government and private sector investments into prevention of cardiovascular disease, diabetes mellitus and obesity, efforts have largely failed, and the burden of cost remains in the treatment of downstream morbidity and mortality, with overall stagnating outcomes. A new paradigm shift in the approach to these patients may explain why existing treatment strategies fail, and offer new treatment targets. This review aims to provide a clinician-centred primer on metabolic memory, defined as the sum of irreversible genetic, epigenetic, cellular and tissue-level alterations that occur with long-time exposure to metabolic derangements.
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Affiliation(s)
- Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Baris Afsar
- Department of Internal Medicine, Division of Nephrology, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Alan A Sag
- Department of Radiology, Division of Vascular and Interventional Radiology, Duke University Medical Center, Durham, NC, USA
| | - Dimitrie Siriopol
- Nephrology Clinic, Dialysis and Renal Transplant Center, 'C.I. PARHON' University Hospital, 'Grigore T. Popa' University of Medicine, Iasi, Romania
| | | | - Alberto Ortiz
- School of Medicine, Dialysis Unit, IIS-Fundacion Jimenez Diaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
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35
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Yao C, Huang K, Shen R, Chen Q, Tian Z, Xia Z, Lin X, Wu G, Chen Z. Insulin product decreases risk of varicose vein: Evidence from a Mendelian randomization study. VASCULAR INVESTIGATION AND THERAPY 2021. [DOI: 10.4103/2589-9686.323983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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36
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He A, Hu S, Pi Q, Guo Y, Long Y, Luo S, Xia Y. Regulation of O-GlcNAcylation on endothelial nitric oxide synthase by glucose deprivation and identification of its O-GlcNAcylation sites. Sci Rep 2020; 10:19364. [PMID: 33168911 PMCID: PMC7652922 DOI: 10.1038/s41598-020-76340-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 10/20/2020] [Indexed: 12/18/2022] Open
Abstract
As an energy-sensitive post-translational modification, O-GlcNAcylation plays a major role in endothelial nitric oxide synthase (eNOS) activity regulation. However, effects of glucose deprivation on eNOS O-GlcNAcylation and the presence of novel O-GlcNAcylation sites of eNOS under glucose deprivation remain unknown. Hence, we aim to determine the effects of glucose deprivation on O-GlcNAcylation and novel O-GlcNAcylation sites of eNOS. Bovine aortic endothelial cells (BAECs) and Sprague-Dawley rats were induced by glucose deprivation and their eNOS O-GlcNAcylation was subjected to immunoblotting. eNOS and transfected eNOS were purified by pull-down assay and immunoprecipitation respectively. Novel O-GlcNAcylation sites of eNOS were predicted by HPLC-MS and MS/MS Ion and determined by immunoblotting. eNOS activity was detected by Elisa and isotope labeling method. In BAECs and rat thoracic aorta, low glucose-associated activation of eNOS was accompanied by elevated O-GlcNAcylation, which did not affect O-linked serine phosphorylation at 1179/1177 residues. Changes in this post-translational modification were associated with increased O-GlcNAc transferase (OGT) expression and were reversed by AMPK knockdown. Immunoblot analysis of cells expressing His-tagged wild-type human eNOS and human eNOS carrying a mutation at the Ser1177 phosphorylation site confirmed an increase in O-GlcNAcylation by glucose deprivation. A marked increase in O-GlcNAcylation indicated that eNOS contained novel O-GlcNAcylation sites that were activated by glucose deprivation. Immunoblot analysis of cells expressing His-tagged human eNOS carrying a mutation at Ser738 and Ser867 confirmed an increase in O-GlcNAcylation by glucose deprivation. Conversely, in His-tagged human eNOS carrying a mutation at Thr866, O-GlcNAcylation was unaffected by glucose deprivation. Differences in culture conditions were identified using two-way analysis of variance (ANOVA), one-way ANOVA, and unpaired Student's t-test. Glucose deprivation increases O-GlcNAcylation and activity of eNOS, potentially by the AMPK-OGT pathway, suggesting that Thr866 is a novel O-GlcNAcylation site involved in glucose-deprivation mediated eNOS activation.
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Affiliation(s)
- An He
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Shupeng Hu
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Qiangzhong Pi
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yongzheng Guo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yang Long
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Suxin Luo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yong Xia
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China.
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Mancusi C, Izzo R, di Gioia G, Losi MA, Barbato E, Morisco C. Insulin Resistance the Hinge Between Hypertension and Type 2 Diabetes. High Blood Press Cardiovasc Prev 2020; 27:515-526. [PMID: 32964344 PMCID: PMC7661395 DOI: 10.1007/s40292-020-00408-8] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 09/05/2020] [Indexed: 12/19/2022] Open
Abstract
Epidemiological studies have documented a high incidence of diabetes in hypertensive patients.Insulin resistance is defined as a less than expected biologic response to a given concentration of the hormone and plays a pivotal role in the pathogenesis of diabetes. However, over the last decades, it became evident that insulin resistance is not merely a metabolic abnormality, but is a complex and multifaceted syndrome that can also affect blood pressure homeostasis. The dysregulation of neuro-humoral and neuro-immune systems is involved in the pathophysiology of both insulin resistance and hypertension. These mechanisms induce a chronic low grade of inflammation that interferes with insulin signalling transduction. Molecular abnormalities associated with insulin resistance include the defects of insulin receptor structure, number, binding affinity, and/or signalling capacity. For instance, hyperglycaemia impairs insulin signalling through the generation of reactive oxygen species, which abrogate insulin-induced tyrosine autophosphorylation of the insulin receptor. Additional mechanisms have been described as responsible for the inhibition of insulin signalling, including proteasome-mediated degradation of insulin receptor substrate 1/2, phosphatase-mediated dephosphorylation and kinase-mediated serine/threonine phosphorylation of both insulin receptor and insulin receptor substrates. Insulin resistance plays a key role also in the pathogenesis and progression of hypertension-induced target organ damage, like left ventricular hypertrophy, atherosclerosis and chronic kidney disease. Altogether these abnormalities significantly contribute to the increase the risk of developing type 2 diabetes.
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Affiliation(s)
- Costantino Mancusi
- Department of Advanced Biomedical Sciences, Federico II University of Naples, Via S. Pansini n. 5, 80131, Naples, Italy
| | - Raffaele Izzo
- Department of Advanced Biomedical Sciences, Federico II University of Naples, Via S. Pansini n. 5, 80131, Naples, Italy
| | - Giuseppe di Gioia
- Department of Advanced Biomedical Sciences, Federico II University of Naples, Via S. Pansini n. 5, 80131, Naples, Italy
| | - Maria Angela Losi
- Department of Advanced Biomedical Sciences, Federico II University of Naples, Via S. Pansini n. 5, 80131, Naples, Italy
| | - Emanuele Barbato
- Department of Advanced Biomedical Sciences, Federico II University of Naples, Via S. Pansini n. 5, 80131, Naples, Italy
| | - Carmine Morisco
- Department of Advanced Biomedical Sciences, Federico II University of Naples, Via S. Pansini n. 5, 80131, Naples, Italy.
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Pirri D, Fragiadaki M, Evans PC. Diabetic atherosclerosis: is there a role for the hypoxia-inducible factors? Biosci Rep 2020; 40:BSR20200026. [PMID: 32816039 PMCID: PMC7441368 DOI: 10.1042/bsr20200026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 07/28/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022] Open
Abstract
Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors, including diabetes. Diabetes is associated with either an insulin deficiency in its juvenile form or with insulin resistance and obesity in Type 2 diabetes mellitus, and the latter is clustered with other comorbidities to define the metabolic syndrome. Diabetes and metabolic syndrome are complex pathologies and are associated with cardiovascular risk via vascular inflammation and other mechanisms. Several transcription factors are activated upon diabetes-driven endothelial dysfunction and drive the progression of atherosclerosis. In particular, the hypoxia-inducible factor (HIF) transcription factor family is a master regulator of endothelial biology and is raising interest in the field of atherosclerosis. In this review, we will present an overview of studies contributing to the understanding of diabetes-driven atherosclerosis, integrating the role of HIF in this disease with the knowledge of its functions in metabolic syndrome and diabetic scenario.
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Affiliation(s)
- Daniela Pirri
- Department of Infection, Immunity and Cardiovascular disease, The University of Sheffield, U.K
- Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Maria Fragiadaki
- Department of Infection, Immunity and Cardiovascular disease, The University of Sheffield, U.K
| | - Paul C. Evans
- Department of Infection, Immunity and Cardiovascular disease, The University of Sheffield, U.K
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39
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Grunewald ZI, Ramirez-Perez FI, Woodford ML, Morales-Quinones M, Mejia S, Manrique-Acevedo C, Siebenlist U, Martinez-Lemus LA, Chandrasekar B, Padilla J. TRAF3IP2 (TRAF3 Interacting Protein 2) Mediates Obesity-Associated Vascular Insulin Resistance and Dysfunction in Male Mice. Hypertension 2020; 76:1319-1329. [PMID: 32829657 DOI: 10.1161/hypertensionaha.120.15262] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Insulin resistance in the vasculature is a characteristic feature of obesity and contributes to the pathogenesis of vascular dysfunction and disease. However, the molecular mechanisms underlying obesity-associated vascular insulin resistance and dysfunction remain poorly understood. We hypothesized that TRAF3IP2 (TRAF3 interacting protein 2), a proinflammatory adaptor molecule known to activate pathological stress pathways and implicated in cardiovascular diseases, plays a causal role in obesity-associated vascular insulin resistance and dysfunction. We tested this hypothesis by employing genetic-manipulation in endothelial cells in vitro, in isolated arteries ex vivo, and diet-induced obesity in a mouse model of TRAF3IP2 ablation in vivo. We show that ectopic expression of TRAF3IP2 blunts insulin signaling in endothelial cells and diminishes endothelium-dependent vasorelaxation in isolated aortic rings. Further, 16 weeks of high fat/high sucrose feeding impaired glucose tolerance, aortic insulin-induced vasorelaxation, and hindlimb postocclusive reactive hyperemia, while increasing blood pressure and arterial stiffness in wild-type male mice. Notably, TRAF3IP2 ablation protected mice from such high fat/high sucrose feeding-induced metabolic and vascular defects. Interestingly, wild-type female mice expressed markedly reduced levels of TRAF3IP2 mRNA independent of diet and were protected against high fat/high sucrose diet-induced vascular dysfunction. These data indicate that TRAF3IP2 plays a causal role in vascular insulin resistance and dysfunction. Specifically, the present findings highlight a sexual dimorphic role of TRAF3IP2 in vascular control and identify it as a promising therapeutic target in vasculometabolic derangements associated with obesity, particularly in males.
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Affiliation(s)
- Zachary I Grunewald
- From the Department of Nutrition and Exercise Physiology (Z.I.G., M.L.W., J.P.), University of Missouri, Columbia.,Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia
| | - Francisco I Ramirez-Perez
- Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia.,Department of Biological Engineering (F.I.R.-P., L.A.M.-L.), University of Missouri, Columbia
| | - Makenzie L Woodford
- From the Department of Nutrition and Exercise Physiology (Z.I.G., M.L.W., J.P.), University of Missouri, Columbia.,Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia
| | - Mariana Morales-Quinones
- Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia
| | - Salvador Mejia
- Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia
| | - Camila Manrique-Acevedo
- Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia.,Division of Endocrinology and Metabolism, Department of Medicine (C.M.-A.), University of Missouri, Columbia.,Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (C.M.-A., B.C.)
| | | | - Luis A Martinez-Lemus
- Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia.,Department of Biological Engineering (F.I.R.-P., L.A.M.-L.), University of Missouri, Columbia.,Department of Medical Pharmacology and Physiology (L.A.M.-L., B.C.), University of Missouri, Columbia
| | - Bysani Chandrasekar
- Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia.,Division of Cardiovascular Medicine, Department of Medicine (B.C.), University of Missouri, Columbia.,Department of Medical Pharmacology and Physiology (L.A.M.-L., B.C.), University of Missouri, Columbia.,Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (C.M.-A., B.C.)
| | - Jaume Padilla
- From the Department of Nutrition and Exercise Physiology (Z.I.G., M.L.W., J.P.), University of Missouri, Columbia.,Dalton Cardiovascular Research Center (Z.I.G., F.I.R.-P., M.L.W., M.M.-Q., S.M., C.M.-A., L.A.M.-L., B.C., J.P.), University of Missouri, Columbia
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de Oliveira PGFP, Bonfante EA, Bergamo ETP, de Souza SLS, Riella L, Torroni A, Benalcazar Jalkh EB, Witek L, Lopez CD, Zambuzzi WF, Coelho PG. Obesity/Metabolic Syndrome and Diabetes Mellitus on Peri-implantitis. Trends Endocrinol Metab 2020; 31:596-610. [PMID: 32591106 DOI: 10.1016/j.tem.2020.05.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/08/2020] [Accepted: 05/26/2020] [Indexed: 12/27/2022]
Abstract
Literature has reported that up to 50% of dental implants may be affected by peri-implantitis, a bacteria-induced chronic inflammatory process, which promotes osteoclast-mediated bone resorption and inhibits bone formation, leading to progressive bone loss around implants. Current evidence points toward an increased risk for the development of peri-implantitis in both obesity/metabolic syndrome (MetS) and diabetes mellitus (DM) conditions relative to the healthy population. Currently, there is no effective treatment for peri-implantitis and the 50% prevalence in MetS and DM, along with its predicted increase in the worldwide population, presents a major concern in implant dentistry as hyperglycemic conditions are associated with bone-healing impairment; this may be through dysfunction of osteocalcin-induced glucose metabolism. The MetS/DM proinflammatory systemic condition and altered immune/microbiome response affect both catabolic and anabolic events of bone-healing that include increased osteoclastogenesis and compromised osteoblast activity, which could be explained by the dysfunction of insulin receptor that led to activation of signals related with osteoblast differentiation. Furthermore, chronic hyperglycemia along with associated micro- and macro-vascular ailments leads to delayed/impaired wound healing due to activation of pathways that are particularly important in initiating events linked to inflammation, oxidative stress, and cell apoptosis; this may be through deactivation of AKT/PKB protein, which possesses a pivotal role in drive survival and eNOS signaling. This review presents an overview of the local and systemic mechanisms synergistically affecting bone-healing impairment in MetS/DM individuals, as well as a rationale for hierarchical animal model selection, in an effort to characterize peri-implantitis disease and treatment.
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Affiliation(s)
- Paula Gabriela Faciola Pessôa de Oliveira
- Department of Biomaterials and Biomimetics, New York University College of Dentistry, New York, NY, USA; Department of Oral and Maxillofacial Surgery and Periodontology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil; Department of Periodontology, School of Dentistry, University Center of State of Para, Belem, PA, Brazil
| | - Estevam A Bonfante
- Department of Prosthodontics and Periodontology, Bauru School of Dentistry, University of Sao Paulo, Bauru, SP, Brazil
| | - Edmara T P Bergamo
- Department of Prosthodontics and Periodontology, Bauru School of Dentistry, University of Sao Paulo, Bauru, SP, Brazil
| | - Sérgio Luis Scombatti de Souza
- Department of Oral and Maxillofacial Surgery and Periodontology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Leonardo Riella
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrea Torroni
- Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health School of Medicine, New York, NY, USA
| | - Ernesto B Benalcazar Jalkh
- Department of Biomaterials and Biomimetics, New York University College of Dentistry, New York, NY, USA; Department of Prosthodontics and Periodontology, Bauru School of Dentistry, University of Sao Paulo, Bauru, SP, Brazil
| | - Lukasz Witek
- Department of Biomaterials and Biomimetics, New York University College of Dentistry, New York, NY, USA; Department of Biomedical Engineering, NYU Tandon School of Engineering, New York University, Brooklyn, NY, USA
| | - Christopher D Lopez
- Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine Baltimore, MD, USA
| | - Willian Fernando Zambuzzi
- Department of Chemical and Biological Sciences, Bioscience Institute (IBB), UNESP - São Paulo State University, Botucatu, São Paulo, Brazil
| | - Paulo G Coelho
- Department of Biomaterials and Biomimetics, New York University College of Dentistry, New York, NY, USA; Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health School of Medicine, New York, NY, USA; Department of Mechanical and Aerospace Engineering, NYU Tandon School of Engineering, Brooklyn, NY, USA.
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41
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Sanches E, Topal B, Proczko M, Stepaniak PS, Severin R, Phillips SA, Sabbahi A, Pujol Rafols J, Pouwels S. Endothelial function in obesity and effects of bariatric and metabolic surgery. Expert Rev Cardiovasc Ther 2020; 18:343-353. [DOI: 10.1080/14779072.2020.1767594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Elijah Sanches
- Department of Surgery, Haaglanden Medical Center, The Hague, The Netherlands
| | - Besir Topal
- Department of Cardiothoracic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Monika Proczko
- Department of General, Endocrine and Transplant Surgery, University Medical Center, Gdansk University, Gdansk, Poland
| | - Pieter S. Stepaniak
- Department of Operating Rooms, Catharina Hospital, Eindhoven, The Netherlands
| | - Rich Severin
- Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA
- Doctor of Physical Therapy Program, Robbins College of Health and Human Sciences, Baylor University, Waco, TX, USA
| | - Shane A. Phillips
- Department of Physical Therapy, Integrative Physiologic Laboratory, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Ahmad Sabbahi
- Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA
- Department of Physical Therapy, Integrative Physiologic Laboratory, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Sjaak Pouwels
- Department of Intensive Care Medicine, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands
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42
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Hernandez M, Harrington A, Ma Y, Galdanes K, Halzack B, Zhong M, Vaughan J, Sebasco E, Gordon T, Lippmann M, Chen LC. World Trade Center Dust induces airway inflammation while promoting aortic endothelial dysfunction. Toxicol Appl Pharmacol 2020; 400:115041. [PMID: 32428593 DOI: 10.1016/j.taap.2020.115041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 10/24/2022]
Abstract
Respiratory ailments have plagued occupational and public health communities exposed to World Trade Center (WTC) dust since the September 11, 2001 attack on the Twin Towers in Lower Manhattan. We proposed that these ailments were proposed to be induced by inhalation exposure to WTC particulate matter (WTCPM), that was released during the collapse of the buildings and its subsequent resuspension during cleanup. We investigated this hypothesis using both an in vitro and an in vivo mouse intranasal (IN) exposure models to identify the inflammatory potential of WTCPM with specific emphasis on respiratory and endothelial tissue responses. The in vitro exposure studies found WTCPM exposure to be positively correlated with cytotoxicity and increased NO2- production in both BEAS-2B pulmonary epithelial cells and THP-1 macrophage cells. The in vivo C57BL/6 mouse studies found significant increases in inflammatory markers including increases in polymorphonuclear neutrophil (PMN) influx into nasal and bronchoalveolar lavage fluids (NLF and BALF), as well as increased levels of total protein and cytokine/chemokines levels. Concurrently, NLF, BALF, and serum NO2- levels exhibited significant homeostatic temporal deviations as well as temporal myograohic aortic dysfunction in myography studies. Respiratory exposure to- and evidence -based retention of- WTCPM may have contributed to chronic systemic effects in exposed mice that r resembled to observed effects in WTCPM-exposed human populations. Collectively, these findings are reflective of WTCPM exposure and its effect(s) on respiratory and aortic tissues, highlighting potential dysfunctional pathways that may precipitate inflammatory events, while simultaneously altering homeostatic balances. The tight interplay between these balances, when chronically altered, may contribute to- or result in- chronically diseased pathological states.
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Affiliation(s)
- Michelle Hernandez
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Andrea Harrington
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Yanqin Ma
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Karen Galdanes
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Beth Halzack
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Mianhua Zhong
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Joshua Vaughan
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Ethan Sebasco
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Terry Gordon
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Morton Lippmann
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
| | - Lung Chi Chen
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA.
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Abdul-Ghani MA, Jayyousi A, DeFronzo RA, Asaad N, Al-Suwaidi J. Insulin Resistance the Link between T2DM and CVD: Basic Mechanisms and Clinical Implications. Curr Vasc Pharmacol 2020; 17:153-163. [PMID: 29032755 DOI: 10.2174/1570161115666171010115119] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 09/05/2017] [Accepted: 09/27/2017] [Indexed: 01/04/2023]
Abstract
Insulin resistance (IR) is a cardinal feature of type 2 diabetes mellitus (T2DM). It also is associated with multiple metabolic abnormalities which are known cardiovascular disease (CVD) risk factors. Thus, IR not only contributes to the development of hyperglycemia in T2DM patients, but also to the elevated CVD risk. Improving insulin sensitivity is anticipated to both lower the plasma glucose concentration and decrease CVD risk in T2DM patients, independent of glucose control. We review the molecular mechanisms and metabolic consequences of IR in T2DM patients and discuss the importance of addressing IR in the management of T2DM.
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Affiliation(s)
- Muhammad A Abdul-Ghani
- Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States.,Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Amin Jayyousi
- Cardio-Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Ralph A DeFronzo
- Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States
| | - Nidal Asaad
- Cardio-Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
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Südy R, Schranc Á, Fodor GH, Tolnai J, Babik B, Peták F. Lung volume dependence of respiratory function in rodent models of diabetes mellitus. Respir Res 2020; 21:82. [PMID: 32272932 PMCID: PMC7146915 DOI: 10.1186/s12931-020-01334-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 03/09/2020] [Indexed: 12/16/2022] Open
Abstract
Background Diabetes mellitus causes the deterioration of smooth muscle cells and interstitial matrix proteins, including collagen. Collagen and smooth muscle cells are abundant in the lungs, but the effect of diabetes on airway function and viscoelastic respiratory tissue mechanics has not been characterized. This study investigated the impact of diabetes on respiratory function, bronchial responsiveness, and gas exchange parameters. Methods Rats were allocated randomly to three groups: a model of type 1 diabetes that received a high dose of streptozotocin (DM1, n = 13); a model of type 2 diabetes that received a low dose of streptozotocin with a high-fat diet (DM2, n = 14); and a control group with no treatment (C, n = 14). Forced oscillations were applied to assess airway resistance (Raw), respiratory tissue damping (G), and elastance (H). The arterial partial pressure of oxygen to the inspired oxygen fraction (PaO2/FiO2) and intrapulmonary shunt fraction (Qs/Qt) were determined from blood gas samples at positive end-expiratory pressures (PEEPs) of 0, 3, and 6 cmH2O. Lung responsiveness to methacholine was also assessed. Collagen fibers in lung tissue were quantified by histology. Results The rats in groups DM1 and DM2 exhibited elevated Raw, G, H, and Qs/Qt, compromised PaO2/FiO2, and diminished airway responsiveness. The severity of adverse tissue mechanical change correlated with excessive lung collagen expression. Increased PEEP normalized the respiratory mechanics, but the gas exchange abnormalities remained. Conclusions These findings indicate that diabetes reduces airway and lung tissue viscoelasticity, resulting in alveolar collapsibility that can be compensated by increasing PEEP. Diabetes also induces persistent alveolo-capillary dysfunction and abnormal adaptation ability of the airways to exogenous constrictor stimuli.
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Affiliation(s)
- Roberta Südy
- Department of Medical Physics and Informatics, University of Szeged, 9 Koranyi fasor, Szeged, H-6720, Hungary.,Department of Anaesthesiology and Intensive Therapy, University of Szeged, 6 Semmelweis Street, Szeged, H 6725, Hungary
| | - Álmos Schranc
- Department of Medical Physics and Informatics, University of Szeged, 9 Koranyi fasor, Szeged, H-6720, Hungary.,Department of Anaesthesiology and Intensive Therapy, University of Szeged, 6 Semmelweis Street, Szeged, H 6725, Hungary
| | - Gergely H Fodor
- Department of Medical Physics and Informatics, University of Szeged, 9 Koranyi fasor, Szeged, H-6720, Hungary
| | - József Tolnai
- Department of Medical Physics and Informatics, University of Szeged, 9 Koranyi fasor, Szeged, H-6720, Hungary
| | - Barna Babik
- Department of Anaesthesiology and Intensive Therapy, University of Szeged, 6 Semmelweis Street, Szeged, H 6725, Hungary
| | - Ferenc Peták
- Department of Medical Physics and Informatics, University of Szeged, 9 Koranyi fasor, Szeged, H-6720, Hungary.
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Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med 2020; 14:583-600. [PMID: 32248333 DOI: 10.1007/s11684-019-0729-1] [Citation(s) in RCA: 271] [Impact Index Per Article: 54.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 10/29/2019] [Indexed: 12/20/2022]
Abstract
Diabetes mellitus is one of the major public health problems worldwide. Considerable recent evidence suggests that the cellular reduction-oxidation (redox) imbalance leads to oxidative stress and subsequent occurrence and development of diabetes and related complications by regulating certain signaling pathways involved in β-cell dysfunction and insulin resistance. Reactive oxide species (ROS) can also directly oxidize certain proteins (defined as redox modification) involved in the diabetes process. There are a number of potential problems in the clinical application of antioxidant therapies including poor solubility, storage instability and nonselectivity of antioxidants. Novel antioxidant delivery systems may overcome pharmacokinetic and stability problem and improve the selectivity of scavenging ROS. We have therefore focused on the role of oxidative stress and antioxidative therapies in the pathogenesis of diabetes mellitus. Precise therapeutic interventions against ROS and downstream targets are now possible and provide important new insights into the treatment of diabetes.
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Affiliation(s)
- Pengju Zhang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Tao Li
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Xingyun Wu
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Canhua Huang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
| | - Yuanyuan Zhang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
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Insulin Resistance Modifies the Effects of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction (from the OMEGA-REMODEL Randomized Clinical Trial). Am J Cardiol 2020; 125:678-684. [PMID: 31948661 DOI: 10.1016/j.amjcard.2019.11.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 11/15/2019] [Accepted: 11/19/2019] [Indexed: 12/31/2022]
Abstract
Insulin resistance early after acute myocardial infarction is associated with increased heart failure and mortality. OMEGA-REMODEL was a prospective double-blind 1:1 randomized control trial of patients with AMI. We reported that 6-month treatment with omega-3 fatty acid (O-3FA) 4 g/day attenuated cardiac remodeling accompanied by reduction in inflammation. We hypothesized that insulin resistance modifies the therapeutic effect of O-3FA on post-MI cardiac remodeling. The OMEGA-REMODEL study group was dichotomized according to cohort- and gender-specific median cutoff value of leptin-to-adiponectin ratio (LAR) at baseline (LAR-Hi vs LAR-Lo). Mixed model regression analyses were used to evaluate effect modification of O-3FA on reduction of left ventricular end-systolic volume index (LVESVI) by LAR status. Baseline LAR was evaluated on 325 patients (59 ± 11 years, 81% male). A total of 168 patients were categorized in LAR-Lo, and 157 in LAR-Hi. O-3FA treatment resulted in significant LVESVI reduction in patients with LAR-Lo but not with LAR-Hi (p = 0.0002 vs 0.66, respectively). Mixed model regression analysis showed significant modification of LAR on O-3FA's treatment effect in attenuating LVESVI (p = 0.021). In conclusion, this post-hoc efficacy analysis suggests that LAR status significantly modified O-3FA's treatment effect in attenuating cardiac remodeling. During the convalescent phase of acute infarct healing, patients with lower insulin resistance estimated by LAR appear to derive more therapeutic response from O-3FA toward improvement of LVESVI.
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Tzoumas N, Farrah TE, Dhaun N, Webb DJ. Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease. Br J Pharmacol 2020; 177:5467-5488. [PMID: 31721165 PMCID: PMC7707100 DOI: 10.1111/bph.14920] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/15/2019] [Accepted: 10/21/2019] [Indexed: 12/21/2022] Open
Abstract
PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.
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Affiliation(s)
- Nikolaos Tzoumas
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.,Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK
| | - Tariq E Farrah
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neeraj Dhaun
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - David J Webb
- British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Urbaniak SK, Boguszewska K, Szewczuk M, Kaźmierczak-Barańska J, Karwowski BT. 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine (8-oxodG) and 8-Hydroxy-2'-Deoxyguanosine (8-OHdG) as a Potential Biomarker for Gestational Diabetes Mellitus (GDM) Development. Molecules 2020; 25:molecules25010202. [PMID: 31947819 PMCID: PMC6982778 DOI: 10.3390/molecules25010202] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 12/30/2019] [Accepted: 01/01/2020] [Indexed: 12/12/2022] Open
Abstract
The growing clinical and epidemiological significance of gestational diabetes mellitus results from its constantly increasing worldwide prevalence, obesity, and overall unhealthy lifestyle among women of childbearing age. Oxidative stress seems to be the most important predictor of gestational diabetes mellitus development. Disturbances in the cell caused by oxidative stress lead to different changes in biomolecules, including DNA. The nucleobase which is most susceptible to oxidative stress is guanine. Its damage results in two main modifications: 8-hydroxy-2′-deoxyguanosineor 8-oxo-7,8-dihydro-2′-deoxyguanosine. Their significant level can indicate pathological processes during pregnancy, like gestational diabetes mellitus and probably, type 2 diabetes mellitus after pregnancy. This review provides an overview of current knowledge on the use of 8-hydroxy-2′-deoxyguanosineand/or 8-oxo-7,8-dihydro-2′-deoxyguanosine as a biomarker in gestational diabetes mellitus and allows us to understand the mechanism of 8-hydroxy-2′-deoxyguanosineand/or 8-oxo-7,8-dihydro-2′-deoxyguanosine generation during this disease.
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Radman M, McGuire J, Zimmerman J. Childhood Obesity, Endothelial Cell Activation, and Critical Illness. Front Pediatr 2020; 8:441. [PMID: 32850554 PMCID: PMC7419464 DOI: 10.3389/fped.2020.00441] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 06/25/2020] [Indexed: 12/13/2022] Open
Abstract
Pediatric obesity is increasing in prevalence and is frequently an antecedent to adult obesity and adult obesity-associated morbidities such as atherosclerosis, type II diabetes, and chronic metabolic syndrome. Endothelial cell activation, one aspect of inflammation, is present in the early stages of atherosclerosis, often prior to the onset of symptoms. Endothelial activation is a pathological condition in which vasoconstricting, pro-thrombotic, and proliferative mediators predominate protective vasodilating, anti-thrombogenic, and anti-mitogenic mediators. Many studies report poor outcomes among obese children with systemic endothelial activation. Likewise, the link between childhood obesity and poor outcomes in critical illness is well-established. However, the link between obesity and severity of endothelial activation specifically in the setting of critical illness is largely unstudied. Although endothelial cell activation is believed to worsen disease in critically ill children, the nature and extent of this response is poorly understood due to the difficulty in measuring endothelial cell dysfunction and destruction. Based on the data available for the obese, asymptomatic population and the obese, critically ill population, the authors posit that obesity, and obesity-associated chronic inflammation, including oxidative stress and insulin resistance, may contribute to endothelial activation and associated worse outcomes among critically ill children. A research agenda to examine this hypothesis is suggested.
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Affiliation(s)
- Monique Radman
- Seattle Children's Hospital, Pediatric Critical Care, University of Washington, Seattle, WA, United States
| | - John McGuire
- Seattle Children's Hospital, Pediatric Critical Care, University of Washington, Seattle, WA, United States
| | - Jerry Zimmerman
- Seattle Children's Hospital, Pediatric Critical Care, University of Washington, Seattle, WA, United States
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50
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Tekin K, Tekin MI. Oxidative stress and diabetic retinopathy. Pathology 2020. [DOI: 10.1016/b978-0-12-815972-9.00003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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