|
1
|
Pitt B, Agarwal R, Anker SD, Rossing P, Ruilope L, Herzog CA, Greenberg B, Pecoits-Filho R, Lambelet M, Lawatscheck R, Scalise A, Filippatos G. Hypokalaemia in patients with type 2 diabetes and chronic kidney disease: the effect of finerenone-a FIDELITY analysis. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2025; 11:10-19. [PMID: 39380152 PMCID: PMC11805688 DOI: 10.1093/ehjcvp/pvae074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/11/2024] [Accepted: 10/07/2024] [Indexed: 10/10/2024]
Abstract
AIMS Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo. METHODS AND RESULTS Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium <4.0 or <3.5 mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups. In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium <4.0 and <3.5 mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium <4.0 vs. 4.0-4.5 mmol/L [hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.02-1.32, P = 0.022 and HR 1.20; 95% CI 1.00-1.44, P = 0.055, respectively]. Finerenone reduced the incidence of hypokalaemia with serum potassium <4.0 mmol/L (HR 0.63; 95% CI 0.60-0.66) and <3.5 mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium. CONCLUSION A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups. Clinical trials registration: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).
Collapse
Affiliation(s)
- Bertram Pitt
- Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Rajiv Agarwal
- Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN 46202, USA
| | - Stefan D Anker
- Department of Cardiology (CVK) of German Heart Center Charité; German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Charitépl. 1, 10117 Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev 2730, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen DK-2200 , Denmark
| | - Luis Ruilope
- Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research imas12, Madrid 28041, Spain
- CIBER-CV, Hospital Universitario 12 de Octubre, Madrid 28041, Spain
- Faculty of Sport Sciences, European University of Madrid, Madrid 28670, Spain
| | - Charles A Herzog
- Cardiology Division, Department of Internal Medicine, Hennepin Healthcare/University of Minnesota, Minneapolis, MN 55404, USA
| | | | | | - Marc Lambelet
- Chrestos Concept GmbH & Co. KG, Essen 45131, Germany
| | - Robert Lawatscheck
- Research and Development, Cardiology and Nephrology Clinical Development, Bayer AG, Berlin 13353, Germany
| | - Andrea Scalise
- Pharmaceutical Development, Bayer Hispania S.L., Division Pharmaceuticals, Barcelona 08970, Spain
| | - Gerasimos Filippatos
- Department of Cardiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens 12462, Greece
| |
Collapse
|
|
2
|
Yang H, Narayan S, Schmidt MV. From Ligands to Behavioral Outcomes: Understanding the Role of Mineralocorticoid Receptors in Brain Function. Stress 2023; 26:2204366. [PMID: 37067948 DOI: 10.1080/10253890.2023.2204366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/18/2023] Open
Abstract
Stress is a normal response to situational pressures or demands. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to the release of corticosteroids, which act in the brain via two distinct receptors: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Persistent HPA axis overactivation or dysregulation can disrupt an individual's homeostasis, thereby contributing to an increased risk for mental illness. On the other hand, successful coping with stressful events involves adaptive and cognitive processes in the brain that render individuals more resilient to similar stressors in the future. Here we review the role of the MR in these processes, starting with an overview of the physiological structure, ligand binding, and expression of MR, and further summarizing its role in the brain, its relevance to psychiatric disorders, and related rodent studies. Given the central role of MR in cognitive and emotional functioning, and its importance as a target for promoting resilience, future research should investigate how MR modulation can be used to alleviate disturbances in emotion and behavior, as well as cognitive impairment, in patients with stress-related psychiatric disorders.
Collapse
Affiliation(s)
- Huanqing Yang
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Sowmya Narayan
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- Department Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), 80804 Munich, Germany
| | - Mathias V Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| |
Collapse
|
|
3
|
Pan S, Guo Y, Yu W, Zhang J, Qiao X, Li L, Xu P, Zhai Y. Constitutive Androstane Receptor Agonist, TCPOBOP: Maternal Exposure Impairs the Growth and Development of Female Offspring in Mice. Int J Mol Sci 2023; 24:2602. [PMID: 36768963 PMCID: PMC9917268 DOI: 10.3390/ijms24032602] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Environmental chemicals, which are known to impact offspring health, have become a public concern. Constitutive activated receptor (CAR) is activated by various environmental chemicals and participates in xenobiotic metabolism. Here, we described the effects of maternal exposure to the CAR-specific ligand 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP, TC) on offspring health outcomes. Maternal TC exposure exhibited a stronger inhibition of body weight in 3-week-old and 8-week-old first-generation (F1) offspring female mice compared to controls. Further, maternal TC exposure obtained a strong increase in hepatic drug-metabolizing enzyme expression in 3-week-old female mice that persisted into 8-week-old adulthood. Interestingly, we observed distorted intestinal morphological features in 8-week-old F1 female mice in the TC-exposed group. Moreover, maternal TC exposure triggered a loss of intestinal barrier integrity by reducing the expression of intestinal tight junction proteins. Accordingly, maternal exposure to TC down-regulated serum triglyceride levels as well as decreased the expression of intestinal lipid uptake and transport marker genes. Mechanistically, maternal TC exposure activated the intestinal inflammatory response and disrupted the antioxidant system in the offspring female mice, thereby impeding the intestinal absorption of nutrients and seriously threatening offspring health. Altogether, these findings highlight that the effects of maternal TC exposure on offspring toxicity could not be ignored.
Collapse
Affiliation(s)
- Shijia Pan
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yuan Guo
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Wen Yu
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Jia Zhang
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Xiaoxiao Qiao
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Letong Li
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Pengfei Xu
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yonggong Zhai
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| |
Collapse
|
|
4
|
Mahaling B, Low SWY, Beck M, Kumar D, Ahmed S, Connor TB, Ahmad B, Chaurasia SS. Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders. Int J Mol Sci 2022; 23:ijms23052591. [PMID: 35269741 PMCID: PMC8910759 DOI: 10.3390/ijms23052591] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 12/13/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders.
Collapse
Affiliation(s)
- Binapani Mahaling
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Shermaine W. Y. Low
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Molly Beck
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Devesh Kumar
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Simrah Ahmed
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Thomas B. Connor
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
- Vitreoretinal Surgery, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Baseer Ahmad
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
- Vitreoretinal Surgery, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shyam S. Chaurasia
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: ; Tel.: +1-414-955-2050
| |
Collapse
|
|
5
|
Liu Q, Gao K, Zheng C, Guo C. The Risk Factors for Perioperative Serum Albumin Variation in Pediatric Patients Undergoing Major Gastroenterology Surgery. Front Surg 2021; 7:627174. [PMID: 33585551 PMCID: PMC7873733 DOI: 10.3389/fsurg.2020.627174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022] Open
Abstract
Background: The albumin, a negative acute-phase protein, is important for perioperative morbidity, even in patients with normal preoperative levels. This study intend to determine the perioperative factors related with the postoperative reduction in serum albumin (ΔALB) and its influence on perioperative outcome in a pediatric general surgical cohort. Methods: This single-center retrospective review included 939 pediatric patients who underwent major gastroenterology surgery from August 2010 to August 2019. The patients were dichotomized into a high ΔALB group (≥14.6%) and a low ΔALB group (<14.6%) based on the mean value of ΔALB (14.6%). the independent risk factors for ΔALB, were explored using the propensity score matching to minimize potential selection bias and subjected to method multivariable logistic regression model. Furthermore, in 366 matched patients, the influences of operating time on perioperative outcomes were analyzed. Results: Among the 996 patients reviewed, 939 patient records were enrolled in the final analysis. Controlling for other factors, multivariable analysis showed that a high CRP on POD 3 or 4 [odds ratio (OR) = 2.36 (95% CI, 1.51–3.86); p = 0.007], a longer operating time [OR = 1.18 (95% CI, 1.00–1.53); p = 0.014), and the presence of Charcot's triad [OR = 1.73 (95% CI, 1.05–2.83); p = 0.031] were factors that predicted a high ΔALB level. A high ΔALB level was also related with gastrointestinal functional recovery delay, reflected by the postoperative defecation (p = 0.013) and bowel movement (p = 0.019) delay and the high occurrence of postoperative complications (16.1 vs. 10.9%, OR, 1.57; 95% CI, 1.02–2.41, P = 0.0026). Conclusions: The high ΔALB level was correlated with postoperative outcome. To obtain a safe recovery and discharge after a major abdominal operation, the above risk factors for ΔALB could be addressed in the perioperative period.
Collapse
Affiliation(s)
- Qingshuang Liu
- Department of Pediatric General and Neonatal Surgery, Children's Hospital, Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Gao
- Department of Pediatric General and Neonatal Surgery, Children's Hospital, Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Chao Zheng
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Children's Hospital of Chongqing Medical University, Chongqing, China.,Department of Orthopedics, Children's Hospital, Chongqing Medical University, Chongqing, China
| | - Chunbao Guo
- Department of Pediatric General and Neonatal Surgery, Children's Hospital, Chongqing Medical University, Chongqing, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Children's Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
6
|
Cadegiani FA, Goren A, Wambier CG. Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS). Med Hypotheses 2020; 143:110112. [PMID: 32721806 PMCID: PMC7363620 DOI: 10.1016/j.mehy.2020.110112] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 12/15/2022]
Abstract
In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.
Collapse
Affiliation(s)
- Flavio A Cadegiani
- Department of Endocrinology, Federal University of São Paulo, SP, Brazil.
| | - Andy Goren
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Carlos G Wambier
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| |
Collapse
|
|
7
|
Cadegiani FA. Repurposing existing drugs for COVID-19: an endocrinology perspective. BMC Endocr Disord 2020; 20:149. [PMID: 32993622 PMCID: PMC7523486 DOI: 10.1186/s12902-020-00626-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. MAIN TEXT While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. CONCLUSION While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
Collapse
Affiliation(s)
- Flavio A Cadegiani
- Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), Rua Pedro de Toledo 781 - 13th floor, São Paulo, SP, 04039-032, Brazil.
| |
Collapse
|
|
8
|
Cadegiani FA, Wambier CG, Goren A. Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19. Front Med (Lausanne) 2020; 7:453. [PMID: 32850920 PMCID: PMC7399048 DOI: 10.3389/fmed.2020.00453] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/08/2020] [Indexed: 01/08/2023] Open
Affiliation(s)
- Flavio A Cadegiani
- Department of Endocrinology, Federal University of São Paulo, São Paulo, Brazil.,Corpometria Institute, Brasília, Brazil
| | - Carlos G Wambier
- Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Andy Goren
- Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, RI, United States.,Applied Biology Inc., Irvine, CA, United States
| |
Collapse
|
|
9
|
Spencer S, Wheeler‐Jones C, Elliott J. Aldosterone and the mineralocorticoid receptor in renal injury: A potential therapeutic target in feline chronic kidney disease. J Vet Pharmacol Ther 2020; 43:243-267. [PMID: 32128854 PMCID: PMC8614124 DOI: 10.1111/jvp.12848] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 01/20/2020] [Accepted: 02/09/2020] [Indexed: 12/24/2022]
Abstract
There is a growing body of experimental and clinical evidence supporting mineralocorticoid receptor (MR) activation as a powerful mediator of renal damage in laboratory animals and humans. Multiple pathophysiological mechanisms are proposed, with the strongest evidence supporting aldosterone-induced vasculopathy, exacerbation of oxidative stress and inflammation, and increased growth factor signalling promoting fibroblast proliferation and deranged extracellular matrix homeostasis. Further involvement of the MR is supported by extensive animal model experiments where MR antagonists (such as spironolactone and eplerenone) abrogate renal injury, including ischaemia-induced damage. Additionally, clinical trials have shown MR antagonists to be beneficial in human chronic kidney disease (CKD) in terms of reducing proteinuria and cardiovascular events, though current studies have not evaluated primary end points which allow conclusions to made about whether MR antagonists reduce mortality or slow CKD progression. Although differences between human and feline CKD exist, feline CKD shares many characteristics with human disease including tubulointerstitial fibrosis. This review evaluates the evidence for the role of the MR in renal injury and summarizes the literature concerning aldosterone in feline CKD. MR antagonists may represent a promising therapeutic strategy in feline CKD.
Collapse
Affiliation(s)
- Sarah Spencer
- Comparative Biomedical SciencesThe Royal Veterinary CollegeLondonUK
| | | | - Jonathan Elliott
- Comparative Biomedical SciencesThe Royal Veterinary CollegeLondonUK
| |
Collapse
|
|
10
|
Barrera‐Chimal J, Jaisser F. Vascular and inflammatory mineralocorticoid receptors in kidney disease. Acta Physiol (Oxf) 2020; 228:e13390. [PMID: 31529757 DOI: 10.1111/apha.13390] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/28/2019] [Accepted: 09/12/2019] [Indexed: 12/25/2022]
Abstract
Mineralocorticoid receptor (MR) activation in the kidney can occur outside the aldosterone-sensitive distal nephron in sites including the endothelium, smooth muscle and inflammatory cells. MR activation in these cells has deleterious effects on kidney structure and function by promoting oxidative injury, endothelial dysfunction and stiffness, vascular remodelling and calcification, decreased relaxation and activation of T cells and pro-inflammatory macrophages. Here, we review the data showing the cellular consequences of MR activation in endothelial, smooth muscle and inflammatory cells and how this affects the kidney in pathological situations. The evidence demonstrating a benefit of pharmacological or genetic MR inhibition in various models of kidney disease is also discussed.
Collapse
Affiliation(s)
- Jonatan Barrera‐Chimal
- Laboratorio de Fisiología Cardiovascular y Trasplante Renal Unidad de Investigación en Medicina Traslacional Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez Instituto de Investigaciones Biomédicas Mexico City Mexico
| | - Frederic Jaisser
- INSERM U1116 Clinical Investigation Centre Lorraine University Vandoeuvre‐lès‐Nancy France
- INI‐CRCT (Cardiovascular and Renal Clinical Trialists) F‐CRIN Network Nancy France
- INSERM UMRS 1138 Centre de Recherche des Cordeliers Sorbonne University Paris Descartes University Paris France
| |
Collapse
|
|
11
|
Wooff Y, Man SM, Aggio-Bruce R, Natoli R, Fernando N. IL-1 Family Members Mediate Cell Death, Inflammation and Angiogenesis in Retinal Degenerative Diseases. Front Immunol 2019; 10:1618. [PMID: 31379825 PMCID: PMC6646526 DOI: 10.3389/fimmu.2019.01618] [Citation(s) in RCA: 160] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/28/2019] [Indexed: 12/22/2022] Open
Abstract
Inflammation underpins and contributes to the pathogenesis of many retinal degenerative diseases. The recruitment and activation of both resident microglia and recruited macrophages, as well as the production of cytokines, are key contributing factors for progressive cell death in these diseases. In particular, the interleukin 1 (IL-1) family consisting of both pro- and anti-inflammatory cytokines has been shown to be pivotal in the mediation of innate immunity and contribute directly to a number of retinal degenerations, including Age-Related Macular Degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, glaucoma, and retinopathy of prematurity (ROP). In this review, we will discuss the role of IL-1 family members and inflammasome signaling in retinal degenerative diseases, piecing together their contribution to retinal disease pathology, and identifying areas of research expansion required to further elucidate their function in the retina.
Collapse
Affiliation(s)
- Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Si Ming Man
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| |
Collapse
|
|
12
|
Abstract
OBJECTIVE The aim of this study was to investigate the clinical effects of prostaglandin E1 (PGE1) in patients who underwent surgery for gastrointestinal (GI) trauma, perforation, or obstruction. BACKGROUND PGE1 is thought to enhance intestinal blood supply and reduce GI complications during the postoperative period. METHODS The medical records of 889 patients undergoing major GI surgery were reviewed retrospectively. Propensity score matching was performed to adjust for any baseline differences. Clinical outcomes, including early GI function recovery, postoperative complications, and length of hospital stay, were evaluated in all patients. In 278 paired patients, selected nutritional, immunologic, and inflammatory variables were compared based on PGE1 administration. RESULTS After propensity score 1:1 matching, the baseline characteristics were similar for both groups. PGE1 was associated with prompt postoperative GI function recovery, including first bowel movement [2.6 ± 0.9 vs 3.1 ± 1.0 days after surgery in patients with and without PGE1 treatment, risk ratio 0.51, 95% confidence interval (CI) 0.41-0.65, P < 0.001] and first feeding within postoperative day 3 [179 (64.39%) vs 152 (54.68%); risk ratio 0.61, 95% CI 0.42-0.90, P = 0.012]. A lower overall postoperative complication rate, including infectious complications [45 (16.2%) vs 68 (24.5%); odds ratio 0.60, 95% CI 0.39-0.91, P = 0.010] and major complications [23 (8.3%) vs 48 (17.3%); odds ratio 0.43, 95% CI 0.26-0.73, P = 0.001], was noted in patients with PGE1 treatment than in patients without PGE1 treatment. Furthermore, the immunologic and inflammatory variable C-reactive protein on postoperative day 3 was reduced by PGE1 treatment (52.5 ± 36.4 vs 89.6 ± 42.4 mg/L; P = 0.037, t test). CONCLUSIONS PGE1 is associated with beneficial clinical effects, such as prompt postoperative GI function recovery and reduced overall postoperative complications after emergency GI surgery, which may be attributed to a reduced inflammatory response.
Collapse
|
|
13
|
Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. Kidney Int 2019; 96:302-319. [PMID: 31133455 DOI: 10.1016/j.kint.2019.02.030] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 02/04/2019] [Accepted: 02/20/2019] [Indexed: 12/13/2022]
Abstract
Chronic kidney disease (CKD) represents a global health concern, and its prevalence is increasing. The ultimate therapeutic option for CKD is kidney transplantation. However, the use of drugs that target specific pathways to delay or halt CKD progression, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors is limited in clinical practice. Mineralocorticoid receptor activation in nonclassical tissues, such as the endothelium, smooth muscle cells, inflammatory cells, podocytes, and fibroblasts may have deleterious effects on kidney structure and function. Several preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) ameliorate or cure kidney injury and dysfunction in different models of kidney disease. In this review, we present the preclinical evidence showing a benefit of MRAs in acute kidney injury, the transition from acute kidney injury to CKD, hypertensive and diabetic nephropathy, glomerulonephritis, and kidney toxicity induced by calcineurin inhibitors. We also discuss the molecular mechanisms responsible for renoprotection related to MRAs that lead to reduced oxidative stress, inflammation, fibrosis, and hemodynamic alterations. The available clinical data support a benefit of MRA in reducing proteinuria in diabetic kidney disease and improving cardiovascular outcomes in CKD patients. Moreover, a benefit of MRAs in kidney transplantation has also been observed. The past and present clinical trials describing the effect of MRAs on kidney injury are presented, and the risk of hyperkalemia and use of other options, such as potassium binding agents or nonsteroidal MRAs, are also addressed. Altogether, the available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.
Collapse
Affiliation(s)
- Jonatan Barrera-Chimal
- Laboratorio de Fisiología Cardiovascular y Trasplante Renal, Unidad de Medicina Traslacional, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Sophie Girerd
- Transplant Unit, Nephrology Department, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France; Institut national de la santé et de la recherche médicale U1116, Clinical Investigation Centre, Lorraine University, Vandoeuvre-lès-Nancy, France; Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, French-Clinical Research Infrastructure Network, Nancy, France
| | - Frederic Jaisser
- Institut national de la santé et de la recherche médicale U1116, Clinical Investigation Centre, Lorraine University, Vandoeuvre-lès-Nancy, France; Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, French-Clinical Research Infrastructure Network, Nancy, France; Institut national de la santé et de la recherche médicale, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France.
| |
Collapse
|
|
14
|
Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation. Clin Sci (Lond) 2019; 133:449-464. [PMID: 30705108 DOI: 10.1042/cs20180919] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/14/2019] [Accepted: 01/30/2019] [Indexed: 12/13/2022]
Abstract
The intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein-coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-α and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.
Collapse
|
|
15
|
Khedr RM, Ahmed AAE, Kamel R, Raafat EM. Sitagliptin attenuates intestinal ischemia/reperfusion injury via cAMP/PKA, PI3K/Akt pathway in a glucagon-like peptide 1 receptor-dependent manner. Life Sci 2018; 211:31-39. [PMID: 30195035 DOI: 10.1016/j.lfs.2018.09.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/07/2018] [Accepted: 09/03/2018] [Indexed: 12/21/2022]
Abstract
AIMS This study investigated the effect of sitagliptin prophylactic treatment on intestinal I/R rat model and explored the possible underlying mechanism. MAIN METHODS Forty-five male Sprague-Dawley rats were randomly assigned to 3 groups: Sham group (operation without clamping), I/R group (operation with clamping) and sitagliptin pretreated group (300 mg/kg/day; p.o.) for 2 weeks before I/R insult. Intestinal I/R was performed by clamping the superior mesenteric artery for 30 min, followed by 60 min reperfusion after removal of clamping. At the end of the experimental period, all rats were sacrificed for histopathological, biochemical, PCR and western blot assessment. KEY FINDINGS Pretreatment with sitagliptin remarkably alleviated the pathological changes induced by I/R in the jejunum, suppressed upregulated NF-κB, TNF-α, IL-1βand MPO caused by I/R. Moreover, sitagliptin decreased the Bax/Bcl-2 ratio and accordingly suppressed apoptotic tissue damage as reflected by a caspase-3 level reduction in rat intestine subjected to I/R injury. Interestingly, sitagliptin could obviously increase the active GLP-1 level and GLP-1 receptor mRNA expression in the jejunum of I/R rats. This was associated with the augmentation of the cAMP level and enhancement of PKA activity. Simultaneously, sitagliptin treatment was able to increase the protein expression levels of phosphorylated PI3K and Akt. SIGNIFICANCE Sitagliptin has shown protective effects against intestinal I/R injury in rats through reduction of intestinal inflammation and apoptosis. The molecular mechanisms may be partially correlated with activation of cAMP/PKA and PI3K/Akt signaling pathway by the GLP-1/GLP-1 receptor.
Collapse
Affiliation(s)
- Rehab M Khedr
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
| | - Amany A E Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Rehab Kamel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt; Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
| | - Eman M Raafat
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| |
Collapse
|
|
16
|
Darwish MA, Abo-Youssef AM, Khalaf MM, Abo-Saif AA, Saleh IG, Abdelghany TM. Resveratrol influences platinum pharmacokinetics: A novel mechanism in protection against cisplatin-induced nephrotoxicity. Toxicol Lett 2018; 290:73-82. [PMID: 29574132 DOI: 10.1016/j.toxlet.2018.03.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 02/21/2018] [Accepted: 03/19/2018] [Indexed: 12/25/2022]
|
|
17
|
Turan I, Sayan Ozacmak H, Ozacmak VH, Barut F, Ozacmak ID. The effects of S-nitrosoglutathione on intestinal ischemia reperfusion injury and acute lung injury in rats: Roles of oxidative stress and NF-κB. Tissue Cell 2018; 52:35-41. [PMID: 29857826 DOI: 10.1016/j.tice.2018.03.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 03/16/2018] [Accepted: 03/24/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Intestinal ischemia and reperfusion (I/R) induces oxidative stress, inflammatory response, and acute lung injury. S-nitrosoglutathione (GSNO), a nitric oxide donor, has been documented to have protective effects on experimental ischemia models. AIM The aim of this study was to examine the effect of GSNO on I/R-induced intestine and lung damage and detect the potential mechanisms emphasizing the protective role of GSNO. METHODS Intestinal I/R was induced by occluding the superior mesenteric artery for 30 min followed by reperfusion for 180 min. GSNO was administered intravenously before reperfusion period (0.25 mg/kg). The levels of lipid peroxidation, reduced glutathione, and myeloperoxidase (MPO), histopathological evaluation and immunohistochemical expressions of both nuclear factor KappaB (NF-κB) and inducible nitric oxide (iNOS) in intestine and lung tissues were assessed. RESULTS Histolopathologic evaluation demonstrated that intestinal I/R induced severe damages in the intestine and the lung tissues. Histopathological scores decreased with GSNO treatment. GSNO treatment reduced lipid peroxidation and MPO levels and inhibited expression of NF-κB and iNOS in the intestine. CONCLUSION Our results suggest that GSNO treatment may ameliorate the intestinal and lung injury in rats, at least in part, by inhibiting inflammatory response and oxidative stress.
Collapse
Affiliation(s)
- Inci Turan
- Department of Physiology, Bulent Ecevit University Faculty of Medicine, Turkey.
| | - Hale Sayan Ozacmak
- Department of Physiology, Bulent Ecevit University Faculty of Medicine, Turkey
| | - V Haktan Ozacmak
- Department of Physiology, Bulent Ecevit University Faculty of Medicine, Turkey
| | - Figen Barut
- Department of Pathology, Bulent Ecevit University Faculty of Medicine, Turkey
| | - I Diler Ozacmak
- Or-Ahayim Private Balat Hospital, Department of General surgery, Bulent Ecevit University Faculty of Medicine, Turkey
| |
Collapse
|
|
18
|
Yamamoto K, Yamamoto T, Takamura M, Usui S, Murai H, Kaneko S, Taniguchi T. Effects of mineralocorticoid receptor antagonists on responses to hemorrhagic shock in rats. World J Crit Care Med 2018; 7:1-8. [PMID: 29430402 PMCID: PMC5797971 DOI: 10.5492/wjccm.v7.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/03/2017] [Accepted: 12/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effects of mineralocorticoid receptor (MR) antagonists on mortality and inflammatory responses after hemorrhagic shock (HS) in rats.
METHODS One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone (EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha (TNF-α) concentrations, and arterial blood gas at 8 h after HS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery.
RESULTS The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups (P = 0.888).
CONCLUSION Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.
Collapse
Affiliation(s)
- Kanako Yamamoto
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Takashi Yamamoto
- Department of Anesthesiology and Intensive Care Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Masayuki Takamura
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Soichiro Usui
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Hisayoshi Murai
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Shuichi Kaneko
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Takumi Taniguchi
- Department of Anesthesiology and Intensive Care Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| |
Collapse
|
|
19
|
Turan I, Ozacmak HS, Ozacmak VH, Barut F, Araslı M. Agmatine attenuates intestinal ischemia and reperfusion injury by reducing oxidative stress and inflammatory reaction in rats. Life Sci 2017; 189:23-28. [PMID: 28893640 DOI: 10.1016/j.lfs.2017.08.032] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 08/25/2017] [Accepted: 08/29/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Inci Turan
- Department of Physiology, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey.
| | - Hale Sayan Ozacmak
- Department of Physiology, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - V Haktan Ozacmak
- Department of Physiology, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Figen Barut
- Department of Pathology, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Mehmet Araslı
- Department of Immunology, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| |
Collapse
|
|
20
|
The Protective Effects of αB-Crystallin on Ischemia-Reperfusion Injury in the Rat Retina. J Ophthalmol 2017; 2017:7205408. [PMID: 29098085 PMCID: PMC5643040 DOI: 10.1155/2017/7205408] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 07/28/2017] [Accepted: 08/06/2017] [Indexed: 12/13/2022] Open
Abstract
To investigate whether αB-crystallin protects against acute retinal ischemic reperfusion injury (I/R) and elucidate the potential antioxidant mechanisms. Retinal I/R injury was made by elevating the intraocular pressure (IOP) 110 mmHg for 60 min, and αB-crystallin (1 × 10−5 g/L) or vehicle solution was administered intravitreously immediately after I/R injury. The animal was sacrificed 24 h, 1 w, and 1 m after the I/R injury. The retina damage was detected by hematoxylin and eosin (HE) staining and electroretinography (ERG). The level of malondialdehyde (MDA), nitric oxide (NO), and the total superoxide dismutase (T-SOD) was determined. An immunohistochemical study was performed to detect the activation of inducible nitric oxide synthase (iNOS) and NF- (nuclear factor-) kappaB (NF-κB) p65. The decrease of retinal thickness and the number of retinal ganglion cells (RGCs) can be suppressed by αB-crystallin. And the amplitudes of a- and b-wave were remarkably greater without αB-crystallin. Similarly, αB-crystallin also significantly decreased the level of MDA and NO and enhanced the activities of T-SOD. The positive expression of iNOS and NF-kappaB p65 was obviously reduced while treated with αB-crystallin. αB-crystallin can inhibit the expression of NF-κB and its antioxidative effect to protect the retina from I/R injury.
Collapse
|
|
21
|
Liu ZM, Zhang XY, Chen J, Shen JT, Jiang ZY, Guan XD. Terlipressin protects intestinal epithelial cells against oxygen-glucose deprivation/re-oxygenation injury via the phosphatidylinositol 3-kinase pathway. Exp Ther Med 2017; 14:260-266. [PMID: 28672923 PMCID: PMC5488628 DOI: 10.3892/etm.2017.4502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 02/01/2017] [Indexed: 12/29/2022] Open
Abstract
Intestinal ischemia/reperfusion (I/R) injury is associated with a high morbidity and mortality. Vasopressin is administered to critically ill patients with potential intestinal I/R. However, the impacts of vasopressin on intestinal epithelia under ischemic/anoxic conditions remain unclear. The aim of the present study was to evaluate the effects of terlipressin, a highly selective vasopressin V1 receptor agonist, on oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damage in intestinal epithelial cells (IEC-6). IEC-6 cells were subjected to OGD for 4 h, followed by 4 h re-oxygenation. Terlipressin was incubated with cells for 4 h following OGD. Following OGD/R, IEC-6 cell viability, proliferation and apoptosis, as well as cell cycle dynamics, were assessed and the levels of tumor necrosis factor (TNF)-α and 15-F2t-isoprostane in the culture medium were measured. In addition, wortmannin, a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, was administrated to investigate the mechanism of terlipressin action. The results demonstrated that IEC-6 cell viability and proliferation decreased, and cell apoptosis increased, following OGD/R. However, IEC-6 cell cycle dynamics did not significantly change 4 h after OGD. Incubation with 25 nM terlipressin significantly improved cell viability, proliferation and apoptosis. Furthermore, terlipressin inhibited the secretion of TNF-α and 15-F2t-isoprostane from IEC-6 cells following OGD/R. The aforementioned effects of terlipressin were completely abolished following the application of 2 µM wortmannin. Therefore, the current study demonstrated that terlipressin administration following OGD attenuates OGD/R-induced cell damage via the PI3K signaling pathway. These results may help physicians to better understand and more effectively use terlipressin in a clinical setting.
Collapse
Affiliation(s)
- Zi-Meng Liu
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xu-Yu Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Juan Chen
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jian-Tong Shen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhi-Yi Jiang
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiang-Dong Guan
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| |
Collapse
|
|
22
|
Cui HJ, Liu S, Yang R, Fu GH, Lu Y. N-stearoyltyrosine protects primary cortical neurons against oxygen-glucose deprivation-induced apoptosis through inhibiting anandamide inactivation system. Neurosci Res 2017; 123:8-18. [PMID: 28499834 DOI: 10.1016/j.neures.2017.04.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 04/13/2017] [Accepted: 04/17/2017] [Indexed: 12/22/2022]
Abstract
N-stearoylthrosine (NST), a synthesized anandamide (AEA) analogue, plays a neuroprotective role in neurodegenerative diseases and cerebrovascular diseases. Several studies have demonstrated that the endocannabinoids systems (ECS) are involved in the neuroprotective effects against cerebral ischemic injury. Oxygen-glucose deprivation (OGD)-induced neuronal injury elevated the levels of endocannabinoids and activated ECS. This research was conducted to investigate the neuroprotective effect of NST against OGD-induced neuronal injury in cultured primary cortical neurons and the potential mechanism involved. Cortical neurons were treated with NST at indicate concentrations for 30min prior to injury and OGD injured neurons were incubated with normal conditions for 0-24h. The best neuroprotective effect of NST against OGD-induced injury occurred at 10μM. All data indicated that the neuroprotective effect of NST against OGD-induced injury resulted from blocking anandamide membrane transporter (AMT) (IC50=11.74nM) and inhibiting fatty acid amide hydrolase activity (FAAH) (IC50=16.54nM). Our findings demonstrated that NST has an important role in cerebral ischemic injury pathological progression through activating cannabinoid receptors by inhibiting AEA inactivation system. These data suggested a potential role for NST in the therapeutic consideration of cerebral ischemic injury. However, inhibition of AEA inactivation system may provide a neuroprotective effect during cerebral ischemic injury.
Collapse
Affiliation(s)
- Heng-Jing Cui
- Department of Pharmacy, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Sha Liu
- Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Rui Yang
- Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Guo-Hui Fu
- Department of Pathology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Yang Lu
- Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
| |
Collapse
|
|
23
|
Huang L, Ma XY, Jiang ZY, Hu YJ, Zheng CT, Yang XF, Wang L, Gao KG. Effects of soybean isoflavone on intestinal antioxidant capacity and cytokines in young piglets fed oxidized fish oil. J Zhejiang Univ Sci B 2016; 17:965-974. [PMID: 27921401 PMCID: PMC5172600 DOI: 10.1631/jzus.b1600078] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 05/04/2016] [Indexed: 01/29/2023]
Abstract
To investigate the effect of glycitein, a synthetic soybean isoflavone (ISF), on the intestinal antioxidant capacity, morphology, and cytokine content in young piglets fed oxidized fish oil, 72 4-d-old male piglets were assigned to three treatments. The control group was fed a basal diet containing fresh fish oil, and the other two groups received the same diet except for the substitution with the same dosage of oxidized fish oil alone or with ISF (oxidized fish oil plus ISF). After 21 d of feeding, supplementation of oxidized fish oil increased the levels of malondialdehyde (MDA), oxidized glutathione (GSSG), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), nuclear factor κ B (NF-κB), inducible nitric oxide synthase (iNOS), NO, and Caspase-3 in jejunal mucosa, and decreased the villous height in duodenum and the levels of secretory immunoglobulin A (sIgA) and IL-4 in the jejunal mucosa compared with supplementation with fresh oil. The addition of oxidized fish oil plus ISF partially alleviated this negative effect. The addition of oxidized fish oil plus ISF increased the villous height and levels of sIgA and IL-4 in jejunal mucosa, but decreased the levels of IL-1β and IL-2 in jejunal mucosa (P<0.05) compared with oxidized fish oil. Collectively, these results show that dietary supplementation of ISF could partly alleviate the negative effect of oxidized fish oil by improving the intestinal morphology as well as the antioxidant capacity and immune function in young piglets.
Collapse
|
|
24
|
Chen J, Wang ZZ, Zhang S, Zuo W, Chen NH. Does mineralocorticoid receptor play a vital role in the development of depressive disorder? Life Sci 2016; 152:76-81. [DOI: 10.1016/j.lfs.2016.03.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Revised: 03/09/2016] [Accepted: 03/11/2016] [Indexed: 01/01/2023]
|
|
25
|
Spironolactone Effect in Hepatic Ischemia/Reperfusion Injury in Wistar Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:3196431. [PMID: 26798418 PMCID: PMC4700188 DOI: 10.1155/2016/3196431] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 10/07/2015] [Accepted: 10/11/2015] [Indexed: 02/08/2023]
Abstract
Introduction. Ischemia/reperfusion (IR) injury, often associated with liver surgery, is an unresolved problem in the clinical practice. Spironolactone is an antagonist of aldosterone that has shown benefits over IR injury in several tissues, but its effects in hepatic IR are unknown. Objective. To evaluate the effect of spironolactone on IR-induced damage in liver. Materials and Methods. Total hepatic ischemia was induced in rats for 20 min followed by 60 min of reperfusion. Spironolactone was administered and hepatic injury, cytokine production, and oxidative stress were assessed. Results. After IR, increased transaminases levels and widespread acute inflammatory infiltrate, disorganization of hepatic hemorrhage trabeculae, and presence of apoptotic bodies were observed. Administration of SPI reduced biochemical and histological parameters of liver injury. SPI treatment increased IL-6 levels when compared with IR group but did not modify either IL-1β or TNF-α with respect to IR group. Regarding oxidative stress, increased levels of catalase activity were recorded in IR + SPI group in comparison with group without treatment, whereas MDA levels were similar in IR + SPI and IR groups. Conclusions. Spironolactone reduced the liver damage induced by IR, and this was associated with an increase in IL-6 production and catalase activity.
Collapse
|
|
26
|
Organ-Protective Effects of Red Wine Extract, Resveratrol, in Oxidative Stress-Mediated Reperfusion Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:568634. [PMID: 26161238 PMCID: PMC4487914 DOI: 10.1155/2015/568634] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 10/09/2014] [Indexed: 12/25/2022]
Abstract
Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed.
Collapse
|