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Thakur S, Mohanty P, Jadhav MS, Gaikwad AB, Jadhav HR. A perspective on the development of small molecular neprilysin inhibitors (NEPi) with emphasis on cardiorenal disease. Eur J Med Chem 2024; 280:116932. [PMID: 39378824 DOI: 10.1016/j.ejmech.2024.116932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/14/2024] [Accepted: 09/30/2024] [Indexed: 10/10/2024]
Abstract
Neprilysin is a cell surface metallo-endopeptidase, commonly identified as neutral endopeptidase (NEP), that plays a crucial role in the cleavage of peptides, for example, natriuretic peptides, angiotensin II, enkephalins, endothelin, bradykinin, substance P, glucagon-like peptide and amyloid beta. In the case of heart failure, a significant upsurge in NEP activity and expression enhances the degradation of natriuretic peptides. Therefore, NEP inhibitors have gained attention in the field of cardiology. NEP has been studied for over 40 years; however, it has recently gained attention with the US FDA approval of a fixed dose combination of sacubitril (NEP inhibitor) and valsartan (AT-1 inhibitor) for chronic heart failure treatment. The present review elucidates the role of neprilysin in cardiorenal disease, its pathophysiology, and how NEP inhibition benefits. It also summarizes the research advances in NEP inhibitors (NEPi) and their structure-activity relationships. Moreover, the review provides insight into NEPi effectiveness - alone or combined with other cardiorenal protective agents. It is expected to help medicinal chemists synthesize and develop novel NEPi.
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Affiliation(s)
- Shikha Thakur
- Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, (RJ), India
| | - Priyanka Mohanty
- Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, (RJ), India
| | - Madhav S Jadhav
- Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, (RJ), India
| | - Anil Bhanudas Gaikwad
- Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, (RJ), India
| | - Hemant R Jadhav
- Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, (RJ), India.
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Gallego M, Mora L, Toldrá F. Effect of ultrasound and enzymatic pre-treatments on the profile of bioactive peptides of beef liver hydrolysates. Food Res Int 2024; 197:115240. [PMID: 39593322 DOI: 10.1016/j.foodres.2024.115240] [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: 07/17/2024] [Revised: 09/26/2024] [Accepted: 10/18/2024] [Indexed: 11/28/2024]
Abstract
The use of meat by-products as a potential source of protein hydrolysates rich in bioactive peptides is of growing interest to valorise these products and improve their sustainable use. This study aimed to evaluate the effect of different pre-treatments (hydrolysis with pepsin, ultrasounds, and ultrasounds-assisted pepsin hydrolysis) on the peptide profile and bioactivity of beef liver hydrolysed with flavourzyme. The pre-treatments with pepsin increased the degree of hydrolysis and generation of free amino acids in the liver hydrolysates, whereas the subsequent hydrolysis with flavourzyme influenced the molecular weight distribution of the peptides. Samples pre-treated with pepsin and ultrasounds-assisted pepsin hydrolysates showed the highest values of antioxidant and inhibitory activity of ACE-I, ECE-I, DPP-IV, and neprilysin enzymes, and therefore these hydrolysates were characterised to obtain the bioactive peptide profiles. A total of 995 peptides were identified by tandem mass spectrometry in the most active fractions separated by reversed-phase liquid chromatography, and 20 of them were predicted as potentially responsible for the observed bioactivities and subsequently characterised by in silico tools. These results evidenced the potential of hydrolysis pre-treatments with pepsin and ultrasounds-assisted pepsin to obtain beef liver hydrolysates rich in bioactive peptides that could exert multifunctional bioactivities such as antioxidant, antihypertensive, and antidiabetic, while giving added value to this meat by-product.
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Affiliation(s)
- Marta Gallego
- Instituto de Agroquímica y Tecnología de Alimentos (CSIC), Avenue Agustín Escardino 7, 46980 Paterna, Valencia, Spain.
| | - Leticia Mora
- Instituto de Agroquímica y Tecnología de Alimentos (CSIC), Avenue Agustín Escardino 7, 46980 Paterna, Valencia, Spain
| | - Fidel Toldrá
- Instituto de Agroquímica y Tecnología de Alimentos (CSIC), Avenue Agustín Escardino 7, 46980 Paterna, Valencia, Spain.
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Erdogan BR, Yesilyurt-Dirican ZE, Karaomerlioglu I, Muderrisoglu AE, Sevim K, Michel MC, Arioglu-Inan E. Sacubitril/Valsartan Combination Partially Improves Cardiac Systolic, but Not Diastolic, Function through β-AR Responsiveness in a Rat Model of Type 2 Diabetes. Int J Mol Sci 2024; 25:10617. [PMID: 39408945 PMCID: PMC11476658 DOI: 10.3390/ijms251910617] [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: 07/11/2024] [Revised: 09/22/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
Cardiovascular complications are the major cause of diabetes mellitus-related morbidity and mortality. Increased renin-angiotensin-aldosterone system activity and decreased β-adrenergic receptor (β-AR) responsiveness contribute to diabetic cardiac dysfunction. We evaluated the effect of sacubitril/valsartan (neprilysin inhibitor plus angiotensin receptor antagonist combination) and valsartan treatments on the diabetic cardiac function through β-AR responsiveness and on protein expression of diastolic components. Six-week-old male Sprague Dawley rats were divided into control, diabetic, sacubitril/valsartan (68 mg/kg)-, and valsartan-treated (31 mg/kg) diabetic groups. Diabetes was induced by a high-fat diet plus low-dose streptozotocin (30 mg/kg, intraperitoneal). After 10 weeks of diabetes, rats were treated for 4 weeks. Systolic/diastolic function was assessed by in vivo echocardiography and pressure-volume loop analysis. β-AR-mediated responsiveness was assessed by in vitro papillary muscle and Langendorff heart experiments. Protein expression of sarcoplasmic reticulum calcium ATPase2a, phospholamban, and phosphorylated phospholamban was determined by Western blot. Sacubitril/valsartan improved ejection fraction and fractional shortening to a similar extent as valsartan alone. None of the treatments affected in vivo diastolic parameters or the expression of related proteins. β1-/β2-AR-mediated responsiveness was partially restored in treated animals. β3-AR-mediated cardiac relaxation (an indicator of diastolic function) responses were comparable among groups. The beneficial effect of sacubitril/valsartan on systolic function may be attributed to improved β1-/β2-AR responsiveness.
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Affiliation(s)
- Betul R. Erdogan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
| | - Zeynep E. Yesilyurt-Dirican
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
- Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara 06330, Türkiye
| | - Irem Karaomerlioglu
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
| | - Ayhanim Elif Muderrisoglu
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
- Department of Medical Pharmacology, Istanbul Medipol University, Istanbul 34815, Türkiye
| | - Kadir Sevim
- Department of Internal Medicine, Faculty of Veterinary Medicine, Ankara University, Ankara 06110, Türkiye;
| | - Martin C. Michel
- Department of Pharmacology, Johannes Gutenberg University, 55131 Mainz, Germany
| | - Ebru Arioglu-Inan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye; (B.R.E.); (Z.E.Y.-D.); (I.K.); (A.E.M.)
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Wang B, Pan Y, Xie Y, Wang C, Yang Y, Sun H, Yan Z, Cui Y, Li L, Zhou Y, Liu W, Pan Z. Metabolic and Immunological Implications of MME +CAF-Mediated Hypoxia Signaling in Pancreatic Cancer Progression: Therapeutic Insights and Translational Opportunities. Biol Proced Online 2024; 26:29. [PMID: 39342097 PMCID: PMC11438378 DOI: 10.1186/s12575-024-00254-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/04/2024] [Indexed: 10/01/2024] Open
Abstract
Pancreatic cancer is a devastating malignancy with a high mortality rate, poor prognosis, and limited treatment options. The tumor microenvironment (TME) plays a crucial role in tumor progression and therapy resistance. Multiple subpopulations of cancer-associated fibroblasts (CAFs) within the TME can switch between different states, exhibiting both antitumorigenic and protumorigenic functions in pancreatic cancer. It seems that targeting fibroblast-related proteins and other stromal components is an appealing approach to combat pancreatic cancer. This study employed single-cell transcriptome sequencing to identify MME (Membrane Metalloendopeptidase)-expressing CAFs in pancreatic cancer. Systematic screening was conducted based on tumor differentiation, lymph node metastasis, and T-stage parameters to identify and confirm the existence of a subpopulation of fibroblasts termed MME+CAFs. Subsequent analyses included temporal studies, exploration of intercellular communication patterns focusing on the hypoxia signaling pathway, and investigation of MME+CAF functions in the pancreatic cancer microenvironment. The pathway enrichment analysis and clinical relevance revealed a strong association between high MME expression and glycolysis, hypoxia markers, and pro-cancer inflammatory pathways. The role of MME+CAFs was validated through in vivo and in vitro experiments, including high-throughput drug screening to evaluate potential targeted therapeutic strategies. Single-cell transcriptome sequencing revealed tumor-associated fibroblasts with high MME expression, termed MME+CAF, exhibiting a unique end-stage differentiation function in the TME. MME+CAF involvement in the hypoxia signaling pathway suggested the potential effects on pancreatic cancer progression through intercellular communication. High MME expression was associated with increased glycolysis, hypoxia markers (VEGF), and pro-cancer inflammatory pathways in pancreatic cancer patients, correlating with lower survival rates, advanced disease stage, and higher oncogene mutation rates. Animal experiments confirmed that elevated MME expression in CAFs increases tumor burden, promotes an immunosuppressive microenvironment, and enhances resistance to chemotherapy and immunotherapy. The developed MME+CAF inhibitor IOX2 (a specific prolyl hydroxylase-2 (PHD2) inhibitor), combined with AG (Paclitaxel + Gemcitabine) and anti-PD1 therapy, demonstrated promising antitumor effects, offering a translational strategy for targeting MME in CAFs of pancreatic cancer. The study findings highlighted the significant role of MME+CAF in pancreatic cancer progression by shaping the TME and influencing key pathways. Targeting MME presented a promising strategy to combat the disease, with potential implications for therapeutic interventions aimed at disrupting MME+CAF functions and enhancing the efficacy of pancreatic cancer treatments.
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Affiliation(s)
- Bin Wang
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yue Pan
- Department of Acupuncture and Moxibustion, First Teaching Hospital of Tianjin, University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Yongjie Xie
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Cong Wang
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yinli Yang
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Haiyan Sun
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zhuchen Yan
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yameng Cui
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Ling Li
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yaoyao Zhou
- Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Weishuai Liu
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Pain Management, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Zhanyu Pan
- Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Integrative Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
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Esser N, Mongovin SM, Barrow BM, Zraika S. Gut-specific Neprilysin Deletion Protects Against Fat-induced Insulin Secretory Dysfunction in Male Mice. Endocrinology 2024; 165:bqae080. [PMID: 38953181 PMCID: PMC11242446 DOI: 10.1210/endocr/bqae080] [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: 03/27/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/03/2024]
Abstract
Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high-fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed a HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut-/-) were generated by crossing Vil-Cre and floxed neprilysin mice. Neprilysin activity was almost abolished throughout the gut in NEPGut-/- mice, and was similar in plasma, pancreas, and kidney in NEPGut-/- vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut-/- displayed lower fasting plasma glucose levels, improved glucose tolerance, and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in HFD-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction.
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Affiliation(s)
- Nathalie Esser
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Laboratory of Immunometabolism and Nutrition, GIGA-R, CHU Liège, University of Liège, Liège 4000, Belgium
| | - Stephen M Mongovin
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Breanne M Barrow
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Sakeneh Zraika
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195, USA
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Itoh Y, Suzuki S, Mineo R, Sasaki S, Tamba S, Sugiyama T, Yamamoto K. Pseudo-nephropathy and hyper-excretion of urinary C-peptide: an overlooked adverse effect of an angiotensin receptor-neprilysin inhibitor (ARNI). Diabetol Int 2024; 15:616-620. [PMID: 39101167 PMCID: PMC11291816 DOI: 10.1007/s13340-024-00730-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 05/05/2024] [Indexed: 08/06/2024]
Abstract
Sacubitril/valsartan, which is a combined angiotensin receptor-neprilysin inhibitor (ARNI), is used for the treatment of chronic heart failure and hypertension. Substrates of neprilysin are numerous, and the systemic effects of an ARNI remain to be determined. Increased urinary C-peptide (UCPR) and urinary albumin (UAlb) excretion has been reported with the use of an ARNI, but the mechanism is still unknown. We report an 84-year-old man with type 2 diabetes and hypertension. His UAlb and UCPR excretion and (to a lesser degree) the estimated glomerular filtration rate were increased after ARNI administration. They returned to basal levels after discontinuing ARNI administration. There was little or no change in glycemic control. Therefore, increased glomerular permeability and filtration could partially explain how neprilysin inhibition led to an elevation in UCPR excretion, in addition to other mechanisms, such as impairment of the renal ability to degrade C-peptide. Physicians must be cautious when interpreting the insulin secretion capability by UCPR and nephropathy by UAlb in ARNI-treated patients with diabetes.
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Affiliation(s)
- Yoshito Itoh
- Department of Endocrinology and Metabolism, Sumitomo Hospital, Osaka, 530-0005 Japan
| | - Shigehito Suzuki
- Department of Endocrinology and Metabolism, Sumitomo Hospital, Osaka, 530-0005 Japan
| | - Ryohei Mineo
- Department of Endocrinology and Metabolism, Sumitomo Hospital, Osaka, 530-0005 Japan
| | - Sho Sasaki
- Department of Endocrinology and Metabolism, Sumitomo Hospital, Osaka, 530-0005 Japan
| | - Sachiko Tamba
- Department of Endocrinology and Metabolism, Sumitomo Hospital, Osaka, 530-0005 Japan
| | - Takuya Sugiyama
- Department of Endocrinology and Metabolism, Sumitomo Hospital, Osaka, 530-0005 Japan
| | - Koji Yamamoto
- Department of Endocrinology and Metabolism, Sumitomo Hospital, Osaka, 530-0005 Japan
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Lemche E, Killick R, Mitchell J, Caton PW, Choudhary P, Howard JK. Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer's disease: A systematic review and qualitative meta-analysis. Neurobiol Dis 2024; 196:106485. [PMID: 38643861 DOI: 10.1016/j.nbd.2024.106485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 03/18/2024] [Accepted: 03/23/2024] [Indexed: 04/23/2024] Open
Abstract
Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.
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Affiliation(s)
- Erwin Lemche
- Section of Cognitive Neuropsychiatry and Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom.
| | - Richard Killick
- Section of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom
| | - Jackie Mitchell
- Department of Basic and Clinical Neurosciences, Maurice Wohl CIinical Neurosciences Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom
| | - Paul W Caton
- Diabetes Research Group, School of Life Course Sciences, King's College London, Hodgkin Building, Guy's Campus, London SE1 1UL, United Kingdom
| | - Pratik Choudhary
- Diabetes Research Group, Weston Education Centre, King's College London, 10 Cutcombe Road, London SE5 9RJ, United Kingdom
| | - Jane K Howard
- School of Cardiovascular and Metabolic Medicine & Sciences, Hodgkin Building, Guy's Campus, King's College London, Great Maze Pond, London SE1 1UL, United Kingdom
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Tudurachi BS, Anghel L, Tudurachi A, Sascău RA, Zanfirescu RL, Stătescu C. Unraveling the Cardiac Matrix: From Diabetes to Heart Failure, Exploring Pathways and Potential Medications. Biomedicines 2024; 12:1314. [PMID: 38927520 PMCID: PMC11201699 DOI: 10.3390/biomedicines12061314] [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: 04/09/2024] [Revised: 05/08/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Myocardial infarction (MI) often leads to heart failure (HF) through acute or chronic maladaptive remodeling processes. This establishes coronary artery disease (CAD) and HF as significant contributors to cardiovascular illness and death. Therefore, treatment strategies for patients with CAD primarily focus on preventing MI and lessening the impact of HF after an MI event. Myocardial fibrosis, characterized by abnormal extracellular matrix (ECM) deposition, is central to cardiac remodeling. Understanding these processes is key to identifying new treatment targets. Recent studies highlight SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RAs) as favorable options in managing type 2 diabetes due to their low hypoglycemic risk and cardiovascular benefits. This review explores inflammation's role in cardiac fibrosis and evaluates emerging anti-diabetic medications' effectiveness, such as SGLT2i, GLP1-RAs, and dipeptidyl peptidase-4 inhibitors (DPP4i), in preventing fibrosis in patients with diabetes post-acute MI. Recent studies were analyzed to identify effective medications in reducing fibrosis risk in these patients. By addressing these areas, we can advance our understanding of the potential benefits of anti-diabetic medications in reducing cardiac fibrosis post-MI and improve patient outcomes in individuals with diabetes at risk of HF.
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Affiliation(s)
- Bogdan-Sorin Tudurachi
- Internal Medicine Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700503 Iasi, Romania; (B.-S.T.); (R.A.S.); (C.S.)
- Cardiology Department, Cardiovascular Diseases Institute “Prof. Dr. George I. M. Georgescu”, 700503 Iasi, Romania; (A.T.); (R.-L.Z.)
| | - Larisa Anghel
- Internal Medicine Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700503 Iasi, Romania; (B.-S.T.); (R.A.S.); (C.S.)
- Cardiology Department, Cardiovascular Diseases Institute “Prof. Dr. George I. M. Georgescu”, 700503 Iasi, Romania; (A.T.); (R.-L.Z.)
| | - Andreea Tudurachi
- Cardiology Department, Cardiovascular Diseases Institute “Prof. Dr. George I. M. Georgescu”, 700503 Iasi, Romania; (A.T.); (R.-L.Z.)
| | - Radu Andy Sascău
- Internal Medicine Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700503 Iasi, Romania; (B.-S.T.); (R.A.S.); (C.S.)
- Cardiology Department, Cardiovascular Diseases Institute “Prof. Dr. George I. M. Georgescu”, 700503 Iasi, Romania; (A.T.); (R.-L.Z.)
| | - Răzvan-Liviu Zanfirescu
- Cardiology Department, Cardiovascular Diseases Institute “Prof. Dr. George I. M. Georgescu”, 700503 Iasi, Romania; (A.T.); (R.-L.Z.)
- Physiology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700503 Iasi, Romania
| | - Cristian Stătescu
- Internal Medicine Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700503 Iasi, Romania; (B.-S.T.); (R.A.S.); (C.S.)
- Cardiology Department, Cardiovascular Diseases Institute “Prof. Dr. George I. M. Georgescu”, 700503 Iasi, Romania; (A.T.); (R.-L.Z.)
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Wang S, Xiao Y, An X, Luo L, Gong K, Yu D. A comprehensive review of the literature on CD10: its function, clinical application, and prospects. Front Pharmacol 2024; 15:1336310. [PMID: 38389922 PMCID: PMC10881666 DOI: 10.3389/fphar.2024.1336310] [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: 11/14/2023] [Accepted: 01/29/2024] [Indexed: 02/24/2024] Open
Abstract
CD10, a zinc-dependent metalloprotease found on the cell surface, plays a pivotal role in an array of physiological and pathological processes including cardiovascular regulation, immune function, fetal development, pain response, oncogenesis, and aging. Recognized as a biomarker for hematopoietic and tissue stem cells, CD10 has garnered attention for its prognostic potential in the progression of leukemia and various solid tumors. Recent studies underscore its regulatory significance and therapeutic promise in combating Alzheimer's disease (AD), and it is noted for its protective role in preventing heart failure (HF), obesity, and type-2 diabetes. Furthermore, CD10/substance P interaction has also been shown to contribute to the pain signaling regulation and immunomodulation in diseases such as complex regional pain syndrome (CRPS) and osteoarthritis (OA). The emergence of COVID-19 has sparked interest in CD10's involvement in the disease's pathogenesis. Given its association with multiple disease states, CD10 is a prime therapeutic target; inhibitors targeting CD10 are now being advanced as therapeutic agents. This review compiles recent and earlier literature on CD10, elucidating its physicochemical attributes, tissue-specific expression, and molecular functions. Furthermore, it details the association of CD10 with various diseases and the clinical advancements of its inhibitors, providing a comprehensive overview of its growing significance in medical research.
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Affiliation(s)
- Shudong Wang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yinghui Xiao
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xingna An
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ling Luo
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Kejian Gong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Dehai Yu
- Public Research Platform, The First Hospital of Jilin University, Changchun, Jilin, China
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10
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Ali NH, Al‐Kuraishy HM, Al‐Gareeb AI, Alnaaim SA, Alexiou A, Papadakis M, Khalifa AA, Saad HM, Batiha GE. Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective. J Cell Mol Med 2024; 28:e17993. [PMID: 37847125 PMCID: PMC10826440 DOI: 10.1111/jcmm.17993] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 09/15/2023] [Accepted: 10/05/2023] [Indexed: 10/18/2023] Open
Abstract
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.
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Affiliation(s)
- Naif H. Ali
- Department of Internal Medicine, Medical CollegeNajran UniversityNajranSaudi Arabia
| | - Hayder M. Al‐Kuraishy
- Department of Clinical Pharmacology and Medicine, College of MedicineMustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and Medicine, College of MedicineMustansiriyah UniversityBaghdadIraq
| | - Saud A. Alnaaim
- Clinical Neurosciences Department, College of MedicineKing Faisal UniversityHofufSaudi Arabia
| | - Athanasios Alexiou
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
- AFNP MedWienAustria
| | - Marios Papadakis
- Department of Surgery IIUniversity Hospital Witten‐Herdecke, University of Witten‐HerdeckeWuppertalGermany
| | - Asmaa A. Khalifa
- Department of Pharmacology and Therapeutics, Faculty of PharmacyPharos University in AlexandriaAlexandriaEgypt
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary MedicineMatrouh UniversityMatrouhEgypt
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourAlBeheiraEgypt
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11
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Kjeldsen SA, Gluud LL, Werge MP, Pedersen JS, Bendtsen F, Alexiadou K, Tan T, Torekov SS, Iepsen EW, Jensen NJ, Richter MM, Goetze JP, Rungby J, Hartmann B, Holst JJ, Holst B, Holt J, Gustafsson F, Madsbad S, Svane MS, Bojsen-Møller KN, Wewer Albrechtsen NJ. Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy. iScience 2023; 26:108190. [PMID: 37953952 PMCID: PMC10638073 DOI: 10.1016/j.isci.2023.108190] [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: 05/09/2023] [Revised: 09/25/2023] [Accepted: 10/10/2023] [Indexed: 11/14/2023] Open
Abstract
Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.
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Affiliation(s)
- Sasha A.S. Kjeldsen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lise L. Gluud
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Mikkel P. Werge
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | - Julie S. Pedersen
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Kleopatra Alexiadou
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2BX, UK
| | - Tricia Tan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2BX, UK
| | - Signe S. Torekov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Eva W. Iepsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Nicole J. Jensen
- Department of Endocrinology, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Michael M. Richter
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark
| | - Jens P. Goetze
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Jørgen Rungby
- Department of Endocrinology, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jens J. Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Birgitte Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Joachim Holt
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Cardiology, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Sten Madsbad
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Endocrinology, Copenhagen University Hospital - Hvidovre, 2650 Hvidovre, Denmark
| | - Maria S. Svane
- Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
- Department of Endocrinology, Copenhagen University Hospital - Hvidovre, 2650 Hvidovre, Denmark
| | - Kirstine N. Bojsen-Møller
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Endocrinology, Copenhagen University Hospital - Hvidovre, 2650 Hvidovre, Denmark
| | - Nicolai J. Wewer Albrechtsen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
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12
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Esser N, Mongovin SM, Mundinger TO, Barrow BM, Zraika S. Neprilysin deficiency reduces hepatic gluconeogenesis in high fat-fed mice. Peptides 2023; 168:171076. [PMID: 37572792 PMCID: PMC10529503 DOI: 10.1016/j.peptides.2023.171076] [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: 04/28/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/14/2023]
Abstract
Neprilysin is a peptidase that cleaves glucoregulatory peptides, including glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK). Some studies suggest that its inhibition in diabetes and/or obesity improves glycemia, and that this is associated with enhanced insulin secretion, glucose tolerance and insulin sensitivity. Whether reduced neprilysin activity also improves hepatic glucose metabolism has not been explored. We sought to determine whether genetic deletion of neprilysin suppresses hepatic glucose production (HGP) in high fat-fed mice. Nep+/+ and Nep-/- mice were fed high fat diet for 16 weeks, and then underwent a pyruvate tolerance test (PTT) to assess hepatic gluconeogenesis. Since glycogen breakdown in liver can also yield glucose, we assessed liver glycogen content in fasted and fed mice. In Nep-/- mice, glucose excursion during the PTT was reduced when compared to Nep+/+ mice. Further, liver glycogen levels were significantly greater in fasted but not fed Nep-/- versus Nep+/+ mice. Since gut-derived factors modulate HGP, we tested whether gut-selective inhibition of neprilysin could recapitulate the suppression of hepatic gluconeogenesis observed with whole-body inhibition, and this was indeed the case. Finally, the gut-derived neprilysin substrates, GLP-1 and CCK, are well-known to suppress HGP. Having previously demonstrated elevated plasma GLP-1 levels in Nep-/- mice, we now measured plasma CCK bioactivity and reveal an increase in Nep-/- versus Nep+/+ mice, suggesting GLP-1 and/or CCK may play a role in reducing HGP under conditions of neprilysin deficiency. In sum, neprilysin modulates hepatic gluconeogenesis and strategies to inhibit its activity may reduce HGP in type 2 diabetes and obesity.
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Affiliation(s)
- Nathalie Esser
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States; Laboratory of Immunometabolism and Nutrition, GIGA-I3, CHU Liège, University of Liège, Liège, Belgium
| | - Stephen M Mongovin
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Thomas O Mundinger
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Breanne M Barrow
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Sakeneh Zraika
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States.
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13
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Kato T, Murakami T, Yabe D, Harada N. Impact of the angiotensin receptor-neprilysin inhibitor in clinical diabetes management: Potential benefits and pitfalls. J Diabetes Investig 2023; 14:1038-1040. [PMID: 37357546 PMCID: PMC10445196 DOI: 10.1111/jdi.14044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 06/27/2023] Open
Abstract
The possible mechanism of increased urinary C-peptide due to neprilysin inhibitors is investigated. Neprilysin inhibition blocks degradation of natriuretic peptides, and elicits a natriuretic and antihypertensive effect. Neprilysin inhibition might similarly block degradation of C-peptides in the kidney and thus increase the urinary C-peptide level.
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Affiliation(s)
- Tomoko Kato
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| | - Takaaki Murakami
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and MetabolismGifu University Graduate School of MedicineGifuJapan
- Department of Rheumatology and Clinical ImmunologyGifu University Graduate School of MedicineGifuJapan
- Center for One Medicine Innovative Translational ResearchGifu UniversityGifuJapan
| | - Norio Harada
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
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14
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Neves JS, Buysschaert M, Bergman M. Editorial: Prediabetes: new insights on the diagnosis, risk stratification, comorbidites, cardiovascular disease, microvascular complications, and treatment. Front Endocrinol (Lausanne) 2023; 14:1214479. [PMID: 37251678 PMCID: PMC10210134 DOI: 10.3389/fendo.2023.1214479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 05/04/2023] [Indexed: 05/31/2023] Open
Affiliation(s)
- João Sérgio Neves
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Martin Buysschaert
- Department of Endocrinology and Diabetology, Université Catholique de Louvain, University Clinic Saint-Luc, Brussels, Belgium
| | - Michael Bergman
- Division of Endocrinology, Diabetes and Metabolism, New York University Grossman School of Medicine, New York, NY, United States
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15
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Ghosh N, Chacko L, Bhattacharya H, Vallamkondu J, Nag S, Dey A, Karmakar T, Reddy PH, Kandimalla R, Dewanjee S. Exploring the Complex Relationship between Diabetes and Cardiovascular Complications: Understanding Diabetic Cardiomyopathy and Promising Therapies. Biomedicines 2023; 11:biomedicines11041126. [PMID: 37189744 DOI: 10.3390/biomedicines11041126] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023] Open
Abstract
Diabetes mellitus (DM) and cardiovascular complications are two unmet medical emergencies that can occur together. The rising incidence of heart failure in diabetic populations, in addition to apparent coronary heart disease, ischemia, and hypertension-related complications, has created a more challenging situation. Diabetes, as a predominant cardio-renal metabolic syndrome, is related to severe vascular risk factors, and it underlies various complex pathophysiological pathways at the metabolic and molecular level that progress and converge toward the development of diabetic cardiomyopathy (DCM). DCM involves several downstream cascades that cause structural and functional alterations of the diabetic heart, such as diastolic dysfunction progressing into systolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis, and subsequent heart failure over time. The effects of glucagon-like peptide-1 (GLP-1) analogues and sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular (CV) outcomes in diabetes have shown promising results, including improved contractile bioenergetics and significant cardiovascular benefits. The purpose of this article is to highlight the various pathophysiological, metabolic, and molecular pathways that contribute to the development of DCM and its significant effects on cardiac morphology and functioning. Additionally, this article will discuss the potential therapies that may be available in the future.
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Affiliation(s)
- Nilanjan Ghosh
- Molecular Pharmacology Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Leena Chacko
- BioAnalytical Lab, Meso Scale Discovery, Rockville, MD 20850-3173, USA
| | - Hiranmoy Bhattacharya
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | | | - Sagnik Nag
- Department of Biotechnology, Vellore Institute of Technology (VIT), School of Biosciences & Technology, Tiruvalam Road, Vellore 632014, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata 700073, India
| | - Tanushree Karmakar
- Dr. B C Roy College of Pharmacy and Allied Health Sciences, Durgapur 713206, India
| | | | - Ramesh Kandimalla
- Department of Biochemistry, Kakatiya Medical College, Warangal 506007, India
| | - Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
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16
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Mohany M, Ahmed MM, Al-Rejaie SS. The Role of NF-κB and Bax/Bcl-2/Caspase-3 Signaling Pathways in the Protective Effects of Sacubitril/Valsartan (Entresto) against HFD/STZ-Induced Diabetic Kidney Disease. Biomedicines 2022; 10:2863. [PMID: 36359384 PMCID: PMC9717728 DOI: 10.3390/biomedicines10112863] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 10/31/2022] [Accepted: 11/04/2022] [Indexed: 08/30/2023] Open
Abstract
LCZ696 (valsartan/sacubitril) has the potential to slow the progression of diabetic kidney disease (DKD) according to previous reports. However, the renoprotective mechanism underlying LCZ696 remains unknown. This study aimed to investigate the therapeutic potential and underlying mechanism of LCZ696 in DKD in a type 2 diabetic (T2D) rat model. This model was established in this experiment by feeding a high-fat diet (HFD) for six weeks with a single dose of streptozotocin (STZ, 30 mg/kg body weight). Valsartan or LCZ696 was orally administered to T2D animals for eight weeks. HFD/STZ rats showed hyperglycemia, impaired insulin secretion, significant increases in urea, creatinine, cytokines, nuclear factor kappa B (NF-κB), oxidative stress, caspase-3 activity, glomerular and tubular damage, glomerulsclerosis, Bax and caspese-3 expressions along with a significant decline in IL-10, antioxidant markers, and Bcl-2 expression. The administration of LCZ696 to diabetic rats reduced the serum concentrations of glucose, urea, and creatinine. In addition, ELISA results demonstrated that diabetic rats treated with LCZ696 exhibited a reduction in inflammatory (IL-1β, TNF-α, IL-6) and an increase in anti-inflammatory (IL-10) cytokine levels. In addition, a notable decrease in NF-κB and caspase-3 activity was observed. At the level of renal tissue homogenate, diabetic animals treated with LCZ696 demonstrated clear restorations in GSH content and other antioxidant enzyme levels, in addition to a significant decrease in TBARS levels. In addition, LCZ696 inhibited the expression of the Bax and cleaved caspase-3 proteins and enhanced the expression of the Bcl-2 protein. Improvements in histopathological changes in kidney tissues confirmed and significantly supported these biochemical findings. In summary, LCZ696 alleviated DKD with possible mechanisms including inhibition of inflammation and apoptosis.
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Affiliation(s)
| | | | - Salim S. Al-Rejaie
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh 1145, Saudi Arabia; (M.M.); (M.M.A.)
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17
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Nishiya Y, Daimon M, Mizushiri S, Yanagimachi M, Tanabe J, Matsuki K, Sato E, Matsumura K. Neprilysin Inhibitor May Increase Urinary C-Peptide Excretion. Diabetes Care 2022; 45:e122-e123. [PMID: 35713575 DOI: 10.2337/dc22-0538] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/03/2022] [Indexed: 02/03/2023]
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18
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Real-world experience of angiotensin receptor neprilysin inhibitor on the glucose-lowering effect. Sci Rep 2022; 12:9703. [PMID: 35690600 PMCID: PMC9188559 DOI: 10.1038/s41598-022-13366-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 05/17/2022] [Indexed: 11/08/2022] Open
Abstract
We investigated the effect of angiotensin receptor neprilysin inhibitor (ARNI) on glycemic control in Korean patients. This retrospective cohort study was conducted at a single tertiary hospital. We compared the HbA1c level reduction between the ARNI and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in chronic heart failure patients with diabetes. We also examined whether the target HbA1c level was reached and the time to start insulin between the two groups. Over the study period, ARNI did not significantly lower the HbA1c level after adjusting confounding factors compared to ACEIs or ARBs. However, as a result of a simple comparison using Mann–Whitney U test, ARNI group showed significant decrease in HbA1c at 6, 12, and 24 months compared to ACEIs or ARBs group (p = 0.003, 0.009, and 0.026, respectively). The initiation of insulin was delayed in the ARNI group, but this difference was not significant based on the result of hazard ratio, but cumulative incidence was significantly lower in the ARNI group. In the real world, the blood glucose-control effects of ARNI were not superior to those of ACEIs or ARBs. However, long-term studies are needed as ARNI use increases to obtain more statistically significant results.
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19
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Esser N, Schmidt C, Barrow BM, Cronic L, Hackney DJ, Mongovin SM, Hogan MF, Templin AT, Castillo JJ, Hull RL, Zraika S. Insulinotropic Effects of Neprilysin and/or Angiotensin Receptor Inhibition in Mice. Front Endocrinol (Lausanne) 2022; 13:888867. [PMID: 35733766 PMCID: PMC9207331 DOI: 10.3389/fendo.2022.888867] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Treatment of heart failure with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improved glycemic control in individuals with type 2 diabetes. The relative contribution of neprilysin inhibition versus angiotensin II receptor antagonism to this glycemic benefit remains unknown. Thus, we sought to determine the relative effects of the neprilysin inhibitor sacubitril versus the angiotensin II receptor blocker valsartan on beta-cell function and glucose homeostasis in a mouse model of reduced first-phase insulin secretion, and whether any beneficial effects are additive/synergistic when combined in sacubitril/valsartan. High fat-fed C57BL/6J mice treated with low-dose streptozotocin (or vehicle) were followed for eight weeks on high fat diet alone or supplemented with sacubitril, valsartan or sacubitril/valsartan. Body weight and fed glucose levels were assessed weekly. At the end of the treatment period, insulin release in response to intravenous glucose, insulin sensitivity, and beta-cell mass were determined. Sacubitril and valsartan, but not sacubitril/valsartan, lowered fasting and fed glucose levels and increased insulin release in diabetic mice. None of the drugs altered insulin sensitivity or beta-cell mass, but all reduced body weight gain. Effects of the drugs on insulin release were reproduced in angiotensin II-treated islets from lean C57BL/6J mice, suggesting the insulin response to each of the drugs is due to a direct effect on islets and mechanisms therein. In summary, sacubitril and valsartan each exert beneficial insulinotropic, glycemic and weight-reducing effects in obese and/or diabetic mice when administered alone; however, when combined, mechanisms within the islet contribute to their inability to enhance insulin release.
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Affiliation(s)
- Nathalie Esser
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
- Laboratory of Immunometabolism and Nutrition, GIGA Infection, Immunity and Inflammation, University of Liège, Liège, Belgium
| | - Christine Schmidt
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Breanne M. Barrow
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Laura Cronic
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Daryl J. Hackney
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Stephen M. Mongovin
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Meghan F. Hogan
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Andrew T. Templin
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Joseph J. Castillo
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Rebecca L. Hull
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Sakeneh Zraika
- Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
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20
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Weiß E, Jantscher-Krenn E, Hiden U. Zirkulierendes Neprilysin in der Schwangerschaft. Geburtshilfe Frauenheilkd 2022. [DOI: 10.1055/s-0042-1750258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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21
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Xu X, Li Y, Shi S, Lv J, Wang Y, Zheng H, Mao X, Wu H, Zhang B, Song Q. The Application of Angiotensin Receptor Neprilysin Inhibitor in Cardiovascular Diseases: A Bibliometric Review From 2000 to 2022. Front Cardiovasc Med 2022; 9:899235. [PMID: 35600466 PMCID: PMC9114353 DOI: 10.3389/fcvm.2022.899235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/19/2022] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular disease (CVD) has become a huge challenge for the global public health system due to its high morbidity, mortality and severe economic burden. In recent years, angiotensin receptor neprilysin inhibitor (ARNI), a new class of drugs, has shown good therapeutic effects on CVD patients in several clinical studies, reducing the morbidity and mortality of CVD patients. In this study, we retrieved publications on ARNI research in the cardiovascular field from the Web of Science core collection and analyzed the annual output, spatial and temporal distribution, institutions and authors, core journals, keywords and co-cited literature based on CiteSpace. As a result, 604 publications were retrieved, and the number of annual publications generally increased year by year, with the largest number of articles. The analysis of the co-occurrence of output countries and authors showed that a few developed countries such as the United States, Canada, and United Kingdom are the most active in this field, forming academic groups represented by John Joseph Valentine McMurray and Scott D. Solomon, and New England Journal of Medicine, Cirulation, and Journal of the American College of Cardiology are the most popular journals in the field, with research hotspots focused on ARNI in the treatment of total ejection fraction heart failure, hypertension and its target organ damage, with the potential for future benefit throughout the cardiovascular event chain as research progresses. This study reveals the prospective application of ARNI in the cardiovascular field and the research hotspots, providing broader and deeper guidance for its use in the clinic, which is beneficial to improve the treatment and prognosis of CVD patients.
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Affiliation(s)
- Xia Xu
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yumeng Li
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shuqing Shi
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiayu Lv
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yajiao Wang
- College of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Haoran Zheng
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xinxin Mao
- College of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Huaqin Wu
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Huaqin Wu, ;
| | - Bingxuan Zhang
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Bingxuan Zhang, ;
| | - Qingqiao Song
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Qingqiao Song, ;
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22
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Heart Failure and Drug Therapies: A Metabolic Review. Int J Mol Sci 2022; 23:ijms23062960. [PMID: 35328390 PMCID: PMC8950643 DOI: 10.3390/ijms23062960] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/01/2022] [Accepted: 03/01/2022] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the leading cause of mortality globally with at least 26 million people worldwide living with heart failure (HF). Metabolism has been an active area of investigation in the setting of HF since the heart demands a high rate of ATP turnover to maintain homeostasis. With the advent of -omic technologies, specifically metabolomics and lipidomics, HF pathologies have been better characterized with unbiased and holistic approaches. These techniques have identified novel pathways in our understanding of progression of HF and potential points of intervention. Furthermore, sodium-glucose transport protein 2 inhibitors, a drug that has changed the dogma of HF treatment, has one of the strongest types of evidence for a potential metabolic mechanism of action. This review will highlight cardiac metabolism in both the healthy and failing heart and then discuss the metabolic effects of heart failure drugs.
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Esser N, Mongovin SM, Parilla J, Barrow BM, Mundinger TO, Fountaine BS, Larmore MJ, Castillo JJ, Akter R, Hull RL, Zraika S. Neprilysin inhibition improves intravenous but not oral glucose-mediated insulin secretion via GLP-1R signaling in mice with β-cell dysfunction. Am J Physiol Endocrinol Metab 2022; 322:E307-E318. [PMID: 35128957 PMCID: PMC8917916 DOI: 10.1152/ajpendo.00234.2021] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Type 2 diabetes is associated with the upregulation of neprilysin, a peptidase capable of cleaving glucoregulatory peptides such as glucagon-like peptide-1 (GLP-1). In humans, use of the neprilysin inhibitor sacubitril in combination with an angiotensin II receptor blocker was associated with increased plasma GLP-1 levels and improved glycemic control. Whether neprilysin inhibition per se is mediating these effects remains unknown. We sought to determine whether pharmacological neprilysin inhibition on its own confers beneficial effects on glycemic status and β-cell function in a mouse model of reduced insulin secretion, and whether any such effects are dependent on GLP-1 receptor (GLP-1R) signaling. High-fat-fed male wild-type (Glp1r+/+) and GLP-1R knockout (Glp1r-/-) mice were treated with low-dose streptozotocin (STZ) to recapitulate type 2 diabetes-associated β-cell dysfunction, or vehicle as control. Mice were continued on high-fat diet alone or supplemented with the neprilysin inhibitor sacubitril for 8 wk. At the end of the study period, β-cell function was assessed by oral or intravenous glucose-tolerance test. Fasting and fed glucose were significantly lower in wild-type mice treated with sacubitril, although active GLP-1 levels and insulin secretion during oral glucose challenge were unchanged. In contrast, insulin secretion in response to intravenous glucose was significantly enhanced in sacubitril-treated wild-type mice, and this effect was blunted in Glp1r-/- mice. Similarly, sacubitril enhanced insulin secretion in vitro in islets from STZ-treated Glp1r+/+ but not Glp1r-/- mice. Together, our data suggest the insulinotropic effects of pharmacological neprilysin inhibition in a mouse model of β-cell dysfunction are mediated via intra-islet GLP-1R signaling.NEW & NOTEWORTHY The neprilysin inhibitor, sacubitril, improves glycemic status in a mouse model of reduced insulin secretion. Sacubitril enhances intravenous but not oral glucose-mediated insulin secretion. The increased glucose-mediated insulin secretion is GLP-1 receptor-dependent. Neprilysin inhibition does not raise postprandial circulating active GLP-1 levels.
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Affiliation(s)
- Nathalie Esser
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
- Laboratory of Immunometabolism and Nutrition, GIGA-I3, University of Liège, Liège, Belgium
| | | | - Jacqueline Parilla
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
| | - Breanne M Barrow
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Thomas O Mundinger
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
| | | | - Megan J Larmore
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Joseph J Castillo
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
| | - Rehana Akter
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
| | - Rebecca L Hull
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
| | - Sakeneh Zraika
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
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24
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Zhang X, Zhou Y, Ma R. Potential effects and application prospect of angiotensin receptor-neprilysin inhibitor in diabetic kidney disease. J Diabetes Complications 2022; 36:108056. [PMID: 34893426 DOI: 10.1016/j.jdiacomp.2021.108056] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/21/2021] [Accepted: 09/25/2021] [Indexed: 12/18/2022]
Abstract
Diabetic kidney disease (DKD) is one of the main causes of end-stage renal disease (ESRD) and all-cause mortality in diabetic patients, despite the extensive use of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Angiotensin receptor-neprilysin inhibitor (ARNI), combining ARB and neutral endopeptidase inhibitor (NEPI), is likely to have potential favorable effects in DKD. This review summarizes existing preclinical and clinical studies on mechanism of ARNI and its potential effects on DKD. In preclinical studies, ARNI manifested its renoprotective effects by improving natriuresis, ameliorating inflammation, oxidative stress and renal dysfunction, and slowing down glomerulosclerosis and tubulointerstitial injury of kidney, but its effect on proteinuria is still controversial. Beneficial effects of ARNI on blood glucose regulation and glycometabolism have also been reported. There are no clinical studies of ARNI that specifically focus on DKD patients so far. ARNI has application potential in DKD, but there still need clinical studies that focus on DKD patients to determine its effectiveness, safety and underlying mechanism.
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Affiliation(s)
- Xingjian Zhang
- Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yan Zhou
- Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Ruixia Ma
- Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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25
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Pascual-Figal D, Bayés-Genis A, Beltrán-Troncoso P, Caravaca-Pérez P, Conde-Martel A, Crespo-Leiro MG, Delgado JF, Díez J, Formiga F, Manito N. Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review. Front Cardiovasc Med 2021; 8:754499. [PMID: 34859070 PMCID: PMC8631913 DOI: 10.3389/fcvm.2021.754499] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 10/06/2021] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) is a clinical syndrome characterized by the presence of dyspnea or limited exertion due to impaired cardiac ventricular filling and/or blood ejection. Because of its high prevalence, it is a major health and economic burden worldwide. Several mechanisms are involved in the pathophysiology of HF. First, the renin-angiotensin-aldosterone system (RAAS) is over-activated, causing vasoconstriction, hypertension, elevated aldosterone levels and sympathetic tone, and eventually cardiac remodeling. Second, an endogenous compensatory mechanism, the natriuretic peptide (NP) system is also activated, albeit insufficiently to counteract the RAAS effects. Since NPs are degraded by the enzyme neprilysin, it was hypothesized that its inhibition could be an important therapeutic target in HF. Sacubitril/valsartan is the first of the class of dual neprilysin and angiotensin receptor inhibitors (ARNI). In patients with HFrEF, treatment with sacubitril/valsartan has demonstrated to significantly reduce mortality and the rates of hospitalization and rehospitalization for HF when compared to enalapril. This communication reviews in detail the demonstrated benefits of sacubitril/valsartan in the treatment of patients with HFrEF, including reduction of mortality and disease progression as well as improvement in cardiac remodeling and quality of life. The hemodynamic and organic effects arising from its dual mechanism of action, including the impact of neprilysin inhibition at the renal level, especially relevant in patients with type 2 diabetes mellitus, are also reviewed. Finally, the evidence on the demonstrated safety and tolerability profile of sacubitril/valsartan in the different subpopulations studied has been compiled. The review of this evidence, together with the recommendations of the latest clinical guidelines, position sacubitril/valsartan as a fundamental pillar in the treatment of patients with HFrEF.
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Affiliation(s)
- Domingo Pascual-Figal
- Cardiology Department, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Antoni Bayés-Genis
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Department of Medicine, Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Autonomous University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain
| | | | - Pedro Caravaca-Pérez
- Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain
- Cardiology Service, Hospital Universitario 12 de Octubre, Madrid, Spain
- Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | | | - Maria G. Crespo-Leiro
- Advanced Heart Failure and Heart Transplant Unit, Cardiology Department, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
- Institute of Biomedical Research (INIBIC), A Coruña, Spain
| | - Juan F. Delgado
- Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain
- Cardiology Service, Hospital Universitario 12 de Octubre, Madrid, Spain
- Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Javier Díez
- Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain
- Cardiovascular Diseases Programme, Centre of Applied Medical Research, University of Navarra, Pamplona, Spain
- Departments of Nephrology, Cardiology, and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain
- Navarra Institute for Health Research, Pamplona, Spain
| | - Francesc Formiga
- Internal Medicine Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
| | - Nicolás Manito
- Heart Failure and Heart Transplantation Unit, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
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26
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Sujana C, Salomaa V, Kee F, Costanzo S, Söderberg S, Jordan J, Jousilahti P, Neville C, Iacoviello L, Oskarsson V, Westermann D, Koenig W, Kuulasmaa K, Reinikainen J, Blankenberg S, Zeller T, Herder C, Mansmann U, Peters A, Thorand B. Natriuretic Peptides and Risk of Type 2 Diabetes: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium. Diabetes Care 2021; 44:2527-2535. [PMID: 34521639 DOI: 10.2337/dc21-0811] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/13/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD. RESEARCH DESIGN AND METHODS Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models. RESULTS Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236). CONCLUSIONS NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms.
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Affiliation(s)
- Chaterina Sujana
- Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.,Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Pettenkofer School of Public Health, Ludwig-Maximilians-Universität, Munich, Germany.,German Center for Diabetes Research (DZD), Partner Munich-Neuherberg, Munich-Neuherberg, Germany
| | - Veikko Salomaa
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Frank Kee
- Centre for Public Health, Queens University of Belfast, Belfast, Northern Ireland, U.K
| | - Simona Costanzo
- Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Isernia, Italy
| | - Stefan Söderberg
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Jens Jordan
- Institute of Aerospace Medicine, German Aerospace Center (DLR) and University of Cologne, Cologne, Germany
| | - Pekka Jousilahti
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Charlotte Neville
- Centre for Public Health, Queens University of Belfast, Belfast, Northern Ireland, U.K
| | - Licia Iacoviello
- Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Isernia, Italy.,Research Center in Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Viktor Oskarsson
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Dirk Westermann
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
| | - Wolfgang Koenig
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.,Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.,German Centre for Cardiovascular Research (DZHK e.V.), partner site Munich Heart Alliance, Munich, Germany
| | - Kari Kuulasmaa
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Jaakko Reinikainen
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Stefan Blankenberg
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.,German Centre for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Hamburg, Germany
| | - Tanja Zeller
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.,German Centre for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Hamburg, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.,Division of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), Partner Düsseldorf, Munich-Neuherberg, Germany
| | - Ulrich Mansmann
- Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Pettenkofer School of Public Health, Ludwig-Maximilians-Universität, Munich, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.,German Center for Diabetes Research (DZD), Partner Munich-Neuherberg, Munich-Neuherberg, Germany.,German Centre for Cardiovascular Research (DZHK e.V.), partner site Munich Heart Alliance, Munich, Germany
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27
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Renal Hemodynamics and Renin-Angiotensin-Aldosterone System Profiles in Patients With Heart Failure. J Card Fail 2021; 28:385-393. [PMID: 34487814 DOI: 10.1016/j.cardfail.2021.08.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/19/2021] [Accepted: 08/17/2021] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF. METHODS In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5). RESULTS The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only. CONCLUSIONS A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile.
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28
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Angiotensin receptor blocker neprilysin inhibitors. World J Cardiol 2021. [DOI: 10.4330/wjc.v13.i8.326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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29
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Usuda D, Higashikawa T, Hotchi Y, Usami K, Shimozawa S, Tokunaga S, Osugi I, Katou R, Ito S, Yoshizawa T, Asako S, Mishima K, Kondo A, Mizuno K, Takami H, Komatsu T, Oba J, Nomura T, Sugita M. Angiotensin receptor blocker neprilysin inhibitors. World J Cardiol 2021; 13:325-339. [PMID: 34589168 PMCID: PMC8436684 DOI: 10.4330/wjc.v13.i8.325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/09/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with, or eject, blood. It is a multifaceted clinical condition that affects up to 2% of the population in the developed world, and is linked to significant morbidity and mortality; it is therefore considered a major concern for public health. Regarding the mechanism of HF, three neurohumoral factors - the renin-angiotensin-aldosterone system, the sympathetic nervous system, and natriuretic peptides - are related to the pathology of chronic HF (CHF), and the targets of treatment. Angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor), namely sacubitril/valsartan (SAC/VAL), has been introduced as a treatment for CHF. SAC/VAL is an efficacious, safe, and cost-effective therapy that improves quality of life and longevity in patients with HF with reduced ejection fraction (HFrEF), and reduces hospital admissions. An in-hospital initiation strategy offers a potential new avenue to improve the clinical uptake of SAC/VAL. In the last five years, SAC/VAL has been established as a cornerstone component of comprehensive disease-modifying medical therapy in the management of chronic HFrEF. On the other hand, further work, with carefully designed and controlled preclinical studies, is necessary for understanding the molecular mechanisms, effects, and confirmation of issues such as long-term safety in both human and animal models.
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Affiliation(s)
- Daisuke Usuda
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan.
| | - Toshihiro Higashikawa
- Geriatric Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi-shi 935-8531, Toyama, Japan
| | - Yuta Hotchi
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Kenki Usami
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Shintaro Shimozawa
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Shungo Tokunaga
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Ippei Osugi
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Risa Katou
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Sakurako Ito
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Toshihiko Yoshizawa
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Suguru Asako
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Kentaro Mishima
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Akihiko Kondo
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Keiko Mizuno
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Hiroki Takami
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Takayuki Komatsu
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Jiro Oba
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Tomohisa Nomura
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
| | - Manabu Sugita
- Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-8521, Tokyo, Japan
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Kjeldsen SAS, Hansen LH, Esser N, Mongovin S, Winther-Sørensen M, Galsgaard KD, Hunt JE, Kissow H, Ceutz FR, Terzic D, Mark PD, Plomgaard P, Goetze JP, Goossens GH, Blaak EE, Deacon CF, Rosenkilde MM, Zraika S, Holst JJ, Wewer Albrechtsen NJ. Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism. J Endocr Soc 2021; 5:bvab084. [PMID: 34337276 PMCID: PMC8317634 DOI: 10.1210/jendso/bvab084] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Indexed: 01/12/2023] Open
Abstract
Context Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted. Objective This work aims to investigate whether NEP inhibition increases glucagon levels. Methods Plasma concentrations of glucagon and AAs were measured in eight healthy men during a mixed meal with and without a single dose of the NEP inhibitor/angiotensin II type 1 receptor antagonist, sacubitril/valsartan (194 mg/206 mg). Long-term effects of sacubitril/valsartan (8 weeks) were investigated in individuals with obesity (n = 7). Mass spectrometry was used to investigate NEP-induced glucagon degradation, and the derived glucagon fragments were tested pharmacologically in cells transfected with the glucagon receptor (GCGR). Genetic deletion or pharmacological inhibition of NEP with or without concomitant GCGR antagonism was tested in mice to evaluate effects on AA metabolism. Results In healthy men, a single dose of sacubitril/valsartan significantly increased postprandial concentrations of glucagon by 228%, concomitantly lowering concentrations of AAs including glucagonotropic AAs. Eight-week sacubitril/valsartan treatment increased fasting glucagon concentrations in individuals with obesity. NEP cleaved glucagon into 5 inactive fragments (in vitro). Pharmacological NEP inhibition protected both exogenous and endogenous glucagon in mice after an AA challenge, while NEP-deficient mice showed elevated fasting and AA-stimulated plasma concentrations of glucagon and urea compared to controls. Conclusion NEP cleaves glucagon, and inhibitors of NEP result in hyperglucagonemia and may increase postprandial AA catabolism without affecting glycemia.
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Affiliation(s)
- Sasha A S Kjeldsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark
| | - Lasse H Hansen
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.,Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Nathalie Esser
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, Washington 98195-6426, USA.,Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA
| | - Steve Mongovin
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA
| | - Marie Winther-Sørensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark
| | - Katrine D Galsgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jenna E Hunt
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Frederik R Ceutz
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark
| | - Dijana Terzic
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Peter D Mark
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Peter Plomgaard
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jens P Goetze
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Gijs H Goossens
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Ellen E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Carolyn F Deacon
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Sakeneh Zraika
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, Washington 98195-6426, USA.,Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.,Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark
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Ai J, Shuai Z, Tang K, Li Z, Zou L, Liu M. Sacubitril/valsartan alleviates myocardial fibrosis in diabetic cardiomyopathy rats. Hellenic J Cardiol 2021; 62:389-391. [PMID: 33957252 DOI: 10.1016/j.hjc.2021.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/13/2021] [Accepted: 04/20/2021] [Indexed: 01/08/2023] Open
Affiliation(s)
- Jiao Ai
- Department of Internal Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Zhuang Shuai
- Department of Internal Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Kai Tang
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China
| | - Zongyu Li
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China
| | - Luwei Zou
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China
| | - Mao Liu
- Department of Cardiology, Cardiovascular Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, China; Department of Internal Medicine, Quxian People's Hospital, Dazhou, China.
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The Drosophila melanogaster Neprilysin Nepl15 is involved in lipid and carbohydrate storage. Sci Rep 2021; 11:2099. [PMID: 33483521 PMCID: PMC7822871 DOI: 10.1038/s41598-021-81165-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 01/04/2021] [Indexed: 11/09/2022] Open
Abstract
The prototypical M13 peptidase, human Neprilysin, functions as a transmembrane "ectoenzyme" that cleaves neuropeptides that regulate e.g. glucose metabolism, and has been linked to type 2 diabetes. The M13 family has undergone a remarkable, and conserved, expansion in the Drosophila genus. Here, we describe the function of Drosophila melanogaster Neprilysin-like 15 (Nepl15). Nepl15 is likely to be a secreted protein, rather than a transmembrane protein. Nepl15 has changes in critical catalytic residues that are conserved across the Drosophila genus and likely renders the Nepl15 protein catalytically inactive. Nevertheless, a knockout of the Nepl15 gene reveals a reduction in triglyceride and glycogen storage, with the effects likely occurring during the larval feeding period. Conversely, flies overexpressing Nepl15 store more triglycerides and glycogen. Protein modeling suggests that Nepl15 is able to bind and sequester peptide targets of catalytically active Drosophila M13 family members, peptides that are conserved in humans and Drosophila, potentially providing a novel mechanism for regulating the activity of neuropeptides in the context of lipid and carbohydrate homeostasis.
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33
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Randhawa VK, Dhanvantari S, Connelly KA. How Diabetes and Heart Failure Modulate Each Other and Condition Management. Can J Cardiol 2020; 37:595-608. [PMID: 33276047 DOI: 10.1016/j.cjca.2020.11.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 12/21/2022] Open
Abstract
Heart failure (HF) and diabetes mellitus (DM) confer considerable burden on the health care system. Although these often occur together, DM can increase risk of HF, whereas HF can accelerate complications of DM. HF is a clinical syndrome resulting from systolic or diastolic impairment caused by ischemic, nonischemic (eg, DM), or other etiologies. HF exists along a spectrum from stage A (ie, persons at risk of DM) to stage D (ie, refractory HF from end-stage DM cardiomyopathy [DMCM]). HF is further categorized by reduced, midrange, and preserved ejection fraction (EF). In type 2 DM, the most prevalent form of DM, several pathophysiological mechanisms (eg, insulin resistance and hyperglycemia) can contribute to myocardial damage, leading to DMCM. Management of HF and DM and patient outcomes are guided by EF and drug efficacy. In this review, we focus on the interplay between HF and DM on disease pathophysiology, management, and patient outcomes. Specifically, we highlight the role of novel antihyperglycemic (eg, sodium glucose cotransporter 2 inhibitors) and HF therapies (eg, renin-angiotensin-aldosterone system inhibitors) on HF outcomes in patients with DM and HF.
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Affiliation(s)
- Varinder Kaur Randhawa
- Cardiovascular Medicine, Kaufman Center for Heart Failure, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Savita Dhanvantari
- Metabolism and Diabetes, Imaging Program, Lawson Health Research Institute and Medical Biophysics, Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Kim A Connelly
- Division of Cardiology, Department of Medicine, St Michael's Hospital, Keenan Research Centre for Biomedical Research, Toronto, Ontario, Canada.
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34
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Nalivaeva NN, Zhuravin IA, Turner AJ. Neprilysin expression and functions in development, ageing and disease. Mech Ageing Dev 2020; 192:111363. [PMID: 32987038 PMCID: PMC7519013 DOI: 10.1016/j.mad.2020.111363] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 09/17/2020] [Accepted: 09/20/2020] [Indexed: 12/21/2022]
Abstract
Neprilysin (NEP) is an integral membrane-bound metallopeptidase with a wide spectrum of substrates and physiological functions. It plays an important role in proteolytic processes in the kidney, cardiovascular regulation, immune response, cell proliferation, foetal development etc. It is an important neuropeptidase and amyloid-degrading enzyme which makes NEP a therapeutic target in Alzheimer's disease (AD). Moreover, it plays a preventive role in development of cancer, obesity and type-2 diabetes. Recently a role of NEP in COVID-19 pathogenesis has also been suggested. Despite intensive research into NEP structure and functions in different organisms, changes in its expression and regulation during brain development and ageing, especially in age-related pathologies, is still not fully understood. This prevents development of pharmacological treatments from various diseases in which NEP is implicated although recently a dual-acting drug sacubitril-valsartan (LCZ696) combining a NEP inhibitor and angiotensin receptor blocker has been approved for treatment of heart failure. Also, various natural compounds capable of upregulating NEP expression, including green tea (EGCG), have been proposed as a preventive medicine in prostate cancer and AD. This review summarizes the existing literature and our own research on the expression and activity of NEP in normal brain development, ageing and under pathological conditions.
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Affiliation(s)
- N N Nalivaeva
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
| | - I A Zhuravin
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - A J Turner
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
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35
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Li B, Li N, Guo S, Zhang M, Li J, Zhai N, Wang H, Zhang Y. The changing features of serum adropin, copeptin, neprilysin and chitotriosidase which are associated with vascular endothelial function in type 2 diabetic retinopathy patients. J Diabetes Complications 2020; 34:107686. [PMID: 32768333 DOI: 10.1016/j.jdiacomp.2020.107686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 07/14/2020] [Accepted: 07/19/2020] [Indexed: 12/21/2022]
Abstract
AIMS Adropin (AD), copeptin (CP), neprilysin (NEP) and chitotriosidase (CHIT1) have been associated with the regulation of vascular endothelial function. In this work, we analyzed the plasma concentrations of cytokines (AD, CP, NEP and CHIT1) in type 2 diabetic patients with or without retinopathy (DR) to predict the risk of DR for diabetic patients. METHOD A total of 392 patients diagnosed as type 2 diabetes mellitus (T2DM) and 120 healthy volunteers as a control group were enrolled in this study. T2DM patients were divided into three groups: diabetes without retinopathy (NDR, n = 174) group, non-proliferative diabetic retinopathy (NPDR, n = 118) group and proliferative diabetic retinopathy (PDR, n = 100) group. The serum AD, CP, NEP and CHIT1 levels of subjects were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS We reported a significant decrease in AD and a significant increase in CP, NEP and CHIT1 in NDR as well as DR patients when compared with controls (p < 0.05), the lower level of AD and significantly higher levels of CP, NEP and CHIT1 were seen in DR patients compared to NDR group (p < 0.05), at the same time, we observed the lowest level of AD and the highest levels of CP, NEP and CHIT1 in the PDR group. Logistic regression analysis showed that AD was a protective factor for DR, conversely, CP, NEP and CHIT1 were the independent risk factors (p < 0.05). Moreover, receiver operating characteristic curve analyses indicated that CP had greater diagnosis capacity with an AUC (the areas under the ROC curve) of 0.901 than AD, NEP, CHIT1 for DR patients. CONCLUSION The decreased AD level and the elevated CP, NEP and CHIT1 levels involved in vascular endothelial function may be evidence facilitating the presence of DR. Thereby they can be explored to use as promising non-invasive biomarkers for prediction of DR severity, distinguishing DR from diabetic patients.
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Affiliation(s)
- Baoxin Li
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China
| | - Na Li
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China
| | - Shuqin Guo
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China
| | - Mali Zhang
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China
| | - Jie Li
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China
| | - Na Zhai
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China
| | - He Wang
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China
| | - Yunliang Zhang
- Department of Endocrinology, Baoding NO.1 Central Hospital, Baoding 071000, Hebei, China; Hebei Provincial Center for Optical Sensing Innovations, Baoding 071000, Hebei, China.
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36
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Sankhe R, Rathi E, Manandhar S, Kumar A, Pai SRK, Kini SG, Kishore A. Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study. J Mol Struct 2020; 1224:129073. [PMID: 32834116 PMCID: PMC7422802 DOI: 10.1016/j.molstruc.2020.129073] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/11/2020] [Accepted: 08/11/2020] [Indexed: 12/17/2022]
Abstract
Drug repurposing of FDA approved drugs from ZINC 12 database was done using the crystal structure of extracellular domain of human NEP (PDB ID: 5JMY) The interactions with catalytic triad of HIS583, HIS587 and GLU646 are important for NEP inhibition. Based on XP molecular docking, binding energy, IFD-SP and MD simulation top 4 NEP inhibitors were identified. ZINC000000601283 and ZINC000003831594 were found to be stable during MD simulation and may act as NEP inhibitors. Neprilysin (NEP) is a neutral endopeptidase with diverse physiological roles in the body. NEP's role in degradation of diverse classes of peptides such as amyloid beta, natriuretic peptide, substance P, angiotensin, endothelins, etc., is associated with pathologies of alzheimer's, kidney and heart diseases, obesity, diabetes and certain malignancies. Hence, the functional inhibition of NEP in the above systems can be a good therapeutic target. In the present study, in-silico drug repurposing approach was used to identify NEP inhibitors. Molecular docking was carried out using GLIDE tool. 2934 drugs from the ZINC12 database were screened using high throughput virtual screening (HTVS) followed by standard precision (SP) and extra precision (XP) docking. Based on the XP docking score and ligand interaction, the top 8 hits were subjected to free ligand binding energy calculation, to filter out 4 hits (ZINC000000001427, ZINC000001533877, ZINC000000601283, and ZINC000003831594). Further, induced fit docking-standard precision (IFD-SP) and molecular dynamics (MD) studies were performed. The results obtained from MD studies suggest that ZINC000000601283-NEP and ZINC000003831594-NEP complexes were most stable for 20ns simulation period as compared to ZINC000001533877-NEP and ZINC000000001427-NEP complexes. Interestingly, ZINC000000601283 and ZINC000003831594 showed similarity in binding with the reported NEP inhibitor sacubitrilat. Findings from this study suggest that ZINC000000601283 and ZINC000003831594 may act as NEP inhibitors. In future studies, the role of ZINC000000601283 and ZINC000003831594 in NEP inhibition should be tested in biological systems to evaluate therapeutic effect in NEP associated pathological conditions.
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Affiliation(s)
- Runali Sankhe
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India
| | - Ekta Rathi
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India
| | - Suman Manandhar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India
| | - Avinash Kumar
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India
| | - Sreedhara Ranganath K Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India
| | - Suvarna G Kini
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India
| | - Anoop Kishore
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India
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Mohammed El Tabaa M, Mohammed El Tabaa M. Targeting Neprilysin (NEP) pathways: A potential new hope to defeat COVID-19 ghost. Biochem Pharmacol 2020; 178:114057. [PMID: 32470547 PMCID: PMC7250789 DOI: 10.1016/j.bcp.2020.114057] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023]
Abstract
COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.
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Affiliation(s)
- Manar Mohammed El Tabaa
- Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute, University of Sadat City, Egypt.
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Martignoni M, Benedetti M, Davey GP, Tipton KF, McDonald AG. Degradation of thymic humoral factor γ2 in human, rat and mouse blood: An experimental and theoretical study. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140467. [PMID: 32512181 PMCID: PMC7274130 DOI: 10.1016/j.bbapap.2020.140467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/12/2020] [Accepted: 06/03/2020] [Indexed: 11/28/2022]
Abstract
The degradation of the immunomodulatory octapeptide, thymic humoral factor γ2 (THF-γ2, thymoctonan) has been studied in whole blood samples from human, rat and mouse. The peptide, Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu, was shown to be rapidly degraded by peptidases. The half-life of the intact peptide was less than 6 min at 37 °C in blood from the three species tested. The main fragments formed from THF-γ2 were found to be Glu-Asp-Gly-Pro-Lys-Phe-Leu (2–8), Asp-Gly-Pro-Lys-Phe-Leu (3–8) and Glu-Asp-Gly-Pro-Lys (2–6) in human and in rat blood and 2–8 and 2–6 in mouse blood. Analysis of the time course of degradation revealed a sequential removal of single amino acids from the N-terminus (aminopeptidase activities) in a process that was apparently unable to cleave the Gly-Pro bond (positions 4–5 in the peptide) together with an independent cleavage of the Lys-Phe bond (positions 6–7 in the peptide) to release the dipeptide Phe-Leu. This behaviour and the effects of inhibitors showed the involvement of metallo-exopeptidases in the N-terminal digestion and a phosphoramidon-sensitive metallo-endopeptidase in the cleavage of the Lys-Phe bond. The degradation patterns in human blood were modelled in terms of the competing pathways involved approximating to first-order kinetics, and an analytical solution obtained via the method of Laplace Transforms. The half-life of THF degradation in whole rat blood sample was found to be significantly lower than in human or mouse.
The immunomodulatory octapeptide THF-γ2 is rapidly degraded in human and rodent blood.
The half-life of the intact peptide was <6 min in all species.
The nature of the peptidases involved was determined by the use of specific inhibitors.
Laplace transforms were used to model the degradation patterns in human blood.
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Affiliation(s)
| | | | - Gavin P Davey
- School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland
| | - Keith F Tipton
- School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland
| | - Andrew G McDonald
- School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
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Bakhle Y. The Second Gaddum Lecture: its origins and outcomes. Br J Pharmacol 2020; 177:969-977. [PMID: 31722438 PMCID: PMC7042101 DOI: 10.1111/bph.14928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/03/2019] [Accepted: 10/07/2019] [Indexed: 10/25/2022] Open
Abstract
Fifty years ago, the BJP published the Second Gaddum Lecture, given by John Vane to the British Pharmacological Society. This article assesses the origins of the experiments described in the Lecture, linking them directly to Gaddum's use of bioassay, a defining feature of pharmacology. The outcomes of those experiments are also assessed, tracking those results that have survived the past five decades. Two of the major advances in cardiovascular medicine, the ACE inhibitors, as anti-hypertensives, and low-dose aspirin, to prevent thrombosis were initiated by the work in this Lecture. Physiologically significant outcomes include a new non-respiratory function of the lung, based on the metabolism of endogenous vasoactive substrates in the pulmonary circulation and the recognition of the endothelium as a highly interactive component of blood vessels. The present state of the art in pharmacology, physiology and medicine owes much to the work described in the Second Gaddum Lecture.
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40
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Teyssier VR, Simard JM, Dornan MH, Tournoux F, DaSilva JN. Radiosynthesis of the 11 C-methyl derivative of LBQ657 for PET investigation of the neprilysin inhibitor sacubitril. J Labelled Comp Radiopharm 2020; 63:65-71. [PMID: 31912556 DOI: 10.1002/jlcr.3817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/19/2019] [Accepted: 11/21/2019] [Indexed: 11/08/2022]
Abstract
Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo-endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O-11 C-methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [11 C]methyl ester ([11 C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a 11 C-methyl instead of an ethyl. [11 C]MeOLBQ was produced in a one-pot two-step synthesis. The O-11 C-methylation of the pentanoic acid part was done with [11 C]methyl triflate followed by the deprotection of the tert-butyl ester precursor in acidic conditions. [11 C]MeOLBQ ([11 C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay-corrected from [11 C]CO2 , n = 3) high molar activity 348 ± 100 GBq/μmol (9425 ± 2720 mCi/μmol) at EOS, in high chemical (>95%) and radiochemical (>99%) purities. The total synthesis time including HPLC purification and reformulation was 29 minutes. To our knowledge, this is the first PET-labeled analog of the clinically used NEP inhibitor sacubitril.
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Affiliation(s)
- Valentin R Teyssier
- Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
- Institut de Génie Biomédical, Faculté de Médecine, Université de Montréal, Québec, Canada
| | - José-Mathieu Simard
- Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Mark H Dornan
- Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
- Département de Radiologie, radio-oncologie et médecine nucléaire, Faculté de médecine, Université de Montréal, Québec, Canada
| | - François Tournoux
- Département de Médecine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
- Centre cardiovasculaire, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Jean N DaSilva
- Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
- Institut de Génie Biomédical, Faculté de Médecine, Université de Montréal, Québec, Canada
- Département de Radiologie, radio-oncologie et médecine nucléaire, Faculté de médecine, Université de Montréal, Québec, Canada
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Potential of Renin-Angiotensin-Aldosterone System Modulations in Diabetic Kidney Disease: Old Players to New Hope! Rev Physiol Biochem Pharmacol 2020; 179:31-71. [PMID: 32979084 DOI: 10.1007/112_2020_50] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Due to a tragic increase in the incidences of diabetes globally, diabetic kidney disease (DKD) has emerged as one of the leading causes of end-stage renal diseases (ESRD). Hyperglycaemia-mediated overactivation of the renin-angiotensin-aldosterone system (RAAS) is key to the development and progression of DKD. Consequently, RAAS inhibition by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is the first-line therapy for the clinical management of DKD. However, numerous clinical and preclinical evidences suggested that RAAS inhibition can only halt the progression of the DKD to a certain extent, and they are inadequate to cure DKD completely. Recent studies have improved understanding of the complexity of the RAAS. It consists of two counter-regulatory arms, the deleterious pressor arm (ACE/angiotensin II/AT1 receptor axis) and the beneficial depressor arm (ACE2/angiotensin-(1-7)/Mas receptor axis). These advances have paved the way for the development of new therapies targeting the RAAS for better treatment of DKD. In this review, we aimed to summarise the involvement of the depressor arm of the RAAS in DKD. Moreover, in modern drug discovery and development, an advance approach is the bispecific therapeutics, targeting two independent signalling pathways. Here, we discuss available reports of these bispecific drugs involving the RAAS as well as propose potential treatments based on neurohormonal balance as credible therapeutic strategies for DKD.
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Antihypertensive Treatment in Diabetic Kidney Disease: The Need for a Patient-Centered Approach. ACTA ACUST UNITED AC 2019; 55:medicina55070382. [PMID: 31315312 PMCID: PMC6681235 DOI: 10.3390/medicina55070382] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/02/2019] [Accepted: 07/12/2019] [Indexed: 12/22/2022]
Abstract
Diabetic kidney disease affects up to forty percent of patients with diabetes during their lifespan. Prevention and treatment of diabetic kidney disease is currently based on optimal glucose and blood pressure control. Renin–angiotensin aldosterone inhibitors are considered the mainstay treatment for hypertension in diabetic patients, especially in the presence of albuminuria. Whether strict blood pressure reduction entails a favorable renal outcome also in non-albuminuric patients is at present unclear. Results of several clinical trials suggest that an overly aggressive blood pressure reduction, especially in the context of profound pharmacologic inhibition of the renin–angiotensin–aldosterone system may result in a paradoxical worsening of renal function. On the basis of this evidence, it is proposed that blood pressure reduction should be tailored in each individual patient according to renal phenotype.
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