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Lee HJ, Chiang CH, Hsieh JH, Lin SC, Chen JW, Chang TT. Febuxostat facilitates neovasculogenesis in chronic kidney disease through xanthine oxidase/NADPH oxidase/c-Jun signaling pathways. Biomed Pharmacother 2025; 185:117952. [PMID: 40068488 DOI: 10.1016/j.biopha.2025.117952] [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: 01/14/2025] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/23/2025] Open
Abstract
The accumulation of uremic toxins in circulation contributes to the cardiovascular diseases that result from chronic kidney disease (CKD). Indoxyl sulfate (IS), which is a protein-bound uremic toxin, promotes cardiovascular diseases with impaired neovascularization by increasing the reactive oxygen species (ROS). This study aimed to investigate febuxostat, a potent xanthine oxidase (XO) inhibitor, for its potential effects on the mechanisms of neovasculogenesis in CKD. CKD mice were generated by 5/6 subtotal nephrectomy and orally administered with febuxostat. Human aortic endothelial cells (HAECs) were used and treated with IS to simulate the CKD conditions in vitro. In the CKD mice, febuxostat reduced systemic ROS and preserved kidney function, as evidenced by the reduced levels of serum blood urea nitrogen, creatinine, urinary albumin-to-creatinine ratios, and renal inflammatory proteins. Furthermore, febuxostat improved neovasculogenesis in an aortic ring assay, a Matrigel plug assay, and a wound healing assay, as evidenced by increased microvascular sprouting in the aortic rings, hemoglobin contents, and capillary density in the CKD mice. In IS-stimulated HAECs, the antioxidative, pro-angiogenic, and anti-inflammatory effects of febuxostat enhanced the tube formation and migration abilities via the XO/p47/c-Jun signaling pathways. In summary, febuxostat might provide renal protection and facilitate neovasculogenesis in CKD. Further clinical study may need to be conducted to verify the effects of febuxostat in CKD patients with vascular complications.
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Affiliation(s)
- Hsin-Jou Lee
- Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Hung Chiang
- Division of Urology, Department of Surgery and Department of Research and Development, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jung-Hung Hsieh
- Department of Surgery, Taipei Veterans General Hospital, Yuan-Shan Branch, Yilan, Taiwan
| | - Su-Chu Lin
- Department of Medical Research and Education, Taipei Veterans General Hospital, Yuan-Shan Branch, Yilan, Taiwan
| | - Jaw-Wen Chen
- Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Division of Cardiology, Taipei Medical University Hospital, Taipei, Taiwan; Faucalty of Medicine, Colleague of Medicine, Taipei Medical University, Taipei, Taiwan; Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ting-Ting Chang
- Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Ph.D. Program of Interdisciplinary Medicine and Biomedical Industry, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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Kawachi Y, Fujishima Y, Nishizawa H, Tanaka A, Yoshida H, Niwano S, Suzuki M, Shimomura I, Node K. Effect of the Xanthine Oxidase Inhibitor Febuxostat on the Cardio-Ankle Vascular Index in Asymptomatic Patients with Hyperuricemia and Liver Dysfunction: A Sub-Analysis of the PRIZE Study. J Atheroscler Thromb 2025; 32:474-490. [PMID: 39358230 PMCID: PMC11973522 DOI: 10.5551/jat.65087] [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: 04/30/2024] [Accepted: 08/25/2024] [Indexed: 10/04/2024] Open
Abstract
AIMS The effect of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular disease requires further investigation. This study aimed to evaluate the long-term effects of febuxostat on arterial stiffness, focusing on liver function. METHODS The PRIZE study involved random assignment of patients with asymptomatic hyperuricemia to receive either add-on febuxostat treatment (febuxostat group) or non-pharmacological treatment (control group). Of the 514 participants, 23 and 14 patients in the febuxostat and control groups, respectively, underwent assessment of arterial stiffness using the cardio-ankle vascular index (CAVI). The participants in each group were further grouped on the basis of their baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels (above or below the media value or 30 U/L). The primary endpoint was the change in the CAVI from baseline to 12 and 24 months. RESULTS Overall, no significant differences were found between the control and febuxostat groups in the least-squares mean estimates of changes in CAVI at 24 months (mean between-group difference, -0.41 [95% CI, -1.05 to 0.23]; p=0.204). However, there were significant differences in participants with higher baseline ALT or AST levels above 30 U/L at 24 months (mean between-group difference, -1.12 [95% CI, -2.23 to -0.01]; p=0.048 for ALT ≥ 30 U/L and -1.08 [95% CI, -2.13 to -0.03]; p=0.044 for AST ≥ 30 U/L). CONCLUSIONS Two-year treatment with febuxostat demonstrated a beneficial effect on CAVI in patients with hyperuricemia and liver dysfunction.
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Affiliation(s)
- Yusuke Kawachi
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuya Fujishima
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hitoshi Nishizawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, Saga, Japan
| | - Hisako Yoshida
- Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shinichi Niwano
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| | - Makoto Suzuki
- Department of Cardiology, Yokohama Minami Kyosai Hospital, Yokohama, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, Saga, Japan
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Yagi H, Akazawa H, Liu Q, Yamamoto K, Nawata K, Saga-Kamo A, Umei M, Kadowaki H, Matsuoka R, Shindo A, Okamura S, Toko H, Takeda N, Ando M, Yamauchi H, Takeda N, Fini MA, Ono M, Komuro I. XOR-Derived ROS in Tie2-Lineage Cells Including Endothelial Cells Promotes Aortic Aneurysm Progression in Marfan Syndrome. Arterioscler Thromb Vasc Biol 2025; 45:e63-e77. [PMID: 39882602 DOI: 10.1161/atvbaha.124.321527] [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: 07/15/2024] [Revised: 12/24/2024] [Accepted: 01/09/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND Marfan syndrome (MFS) is an inherited disorder caused by mutations in the FBN1 gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined. METHODS To elucidate the role of endothelial XOR (xanthine oxidoreductase)-derived reactive oxygen species in aortic aneurysm progression, we inhibited in vivo function of XOR either by endothelial cell (EC)-specific disruption of the Xdh gene or by systemic administration of an XOR inhibitor febuxostat in MFS mice harboring the Fbn1 missense mutation p.(Cys1041Gly). We assessed the aberrant activation of mechanosensitive signaling in the ascending aorta of Fbn1C1041G/+ mice. Further analysis of human aortic ECs investigated the mechanisms by which mechanical stress upregulates XOR expression. RESULTS We found a significant increase in reactive oxygen species generation in the ascending aorta of patients with MFS and Fbn1C1041G/+ mice, which was associated with a significant increase in protein expression and enzymatic activity of XOR protein in aortic ECs. Genetic disruption of Xdh in ECs or treatment with febuxostat significantly suppressed aortic aneurysm progression and improved perivascular infiltration of macrophages. Mechanistically, mechanosensitive signaling involving FAK (focal adhesion kinase)-p38 MAPK (p38 mitogen-activated protein kinase) and Egr-1 (early growth response-1) was aberrantly activated in the ascending aorta of Fbn1C1041G/+ mice, and mechanical stress on human aortic ECs upregulated XOR expression through Egr-1 upregulation. Consistently, EC-specific knockout of XOR or systemic administration of febuxostat in Fbn1C1041G/+ mice suppressed reactive oxygen species generation, FAK-p38 MAPK activation, and Egr-1 upregulation. CONCLUSIONS Aberrant activation of mechanosensitive signaling in vascular ECs triggered endothelial XOR activation and reactive oxygen species generation, which contributes to the progression of aortic aneurysms in MFS. These findings highlight a drug repositioning approach using a uric acid-lowering drug febuxostat as a potential therapy for MFS.
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Affiliation(s)
- Hiroki Yagi
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
- Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. Yamauchi)
| | - Hiroshi Akazawa
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Qing Liu
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Kimiko Yamamoto
- Laboratory of System Physiology, Department of Biomedical Engineering, Graduate School of Medicine (K.Y.)
| | - Kan Nawata
- Department of Cardiovascular Surgery, St. Marianna University School of Medicine, Kawasaki, Japan (K.N.)
| | - Akiko Saga-Kamo
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Masahiko Umei
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Hiroshi Kadowaki
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Ryo Matsuoka
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Akito Shindo
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Shun Okamura
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Haruhiro Toko
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
| | - Norifumi Takeda
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
- Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. Yamauchi)
| | - Masahiko Ando
- Department of Cardiac Surgery, Graduate School of Medicine (M.A., H. Yamauchi, M.O.), The University of Tokyo, Bunkyo-ku, Japan
- Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. Yamauchi)
| | - Haruo Yamauchi
- Department of Cardiac Surgery, Graduate School of Medicine (M.A., H. Yamauchi, M.O.), The University of Tokyo, Bunkyo-ku, Japan
- Marfan Syndrome Center, The University of Tokyo Hospital, Bunkyo-ku, Japan (H. Yagi, Norifumi Takeda, M.A., H. Yamauchi)
| | - Norihiko Takeda
- Division of Cardiology and Metabolism, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan (Norihiko Takeda)
| | - Mehdi A Fini
- Division of Pulmonary and Critical Care, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora (M.A.F.)
| | - Minoru Ono
- Department of Cardiac Surgery, Graduate School of Medicine (M.A., H. Yamauchi, M.O.), The University of Tokyo, Bunkyo-ku, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan
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Myszko M, Bychowski J, Skrzydlewska E, Łuczaj W. The Dual Role of Oxidative Stress in Atherosclerosis and Coronary Artery Disease: Pathological Mechanisms and Diagnostic Potential. Antioxidants (Basel) 2025; 14:275. [PMID: 40227238 PMCID: PMC11939617 DOI: 10.3390/antiox14030275] [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: 01/20/2025] [Revised: 02/18/2025] [Accepted: 02/24/2025] [Indexed: 04/15/2025] Open
Abstract
Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and coronary artery disease (CAD), with both beneficial and detrimental effects on cardiovascular health. On one hand, the excessive production of reactive oxygen species (ROS) contributes to endothelial dysfunction, inflammation, and vascular remodeling, which are central to the development and progression of CAD. These pathological effects drive key processes such as atherosclerosis, plaque formation, and thrombosis. On the other hand, moderate levels of oxidative stress can have beneficial effects on cardiovascular health. These include regulating vascular tone by promoting blood vessel dilation, supporting endothelial function through nitric oxide production, and enhancing the immune response to prevent infections. Additionally, oxidative stress can stimulate cellular adaptation to stress, promote cell survival, and encourage angiogenesis, which helps form new blood vessels to improve blood flow. Oxidative stress also holds promise as a source of biomarkers that could aid in the diagnosis, prognosis, and monitoring of CAD. Specific oxidative markers, such as malondialdehyde (MDA), isoprostanes (isoP), ischemia-modified albumin, and antioxidant enzyme activity, have been identified as potential indicators of disease severity and therapeutic response. This review explores the dual nature of oxidative stress in atherosclerosis and CAD, examining its mechanisms in disease pathogenesis as well as its emerging role in clinical diagnostics and targeted therapies. The future directions for research aimed at harnessing the diagnostic and therapeutic potential of oxidative stress biomarkers are also discussed. Understanding the balance between the detrimental and beneficial effects of oxidative stress could lead to innovative approaches in the prevention and management of CAD.
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Affiliation(s)
- Marcin Myszko
- Department of Cardiology, Bialystok Regional Hospital, M. Skłodowskiej-Curie 25, 15-950 Bialystok, Poland; (M.M.); (J.B.)
| | - Jerzy Bychowski
- Department of Cardiology, Bialystok Regional Hospital, M. Skłodowskiej-Curie 25, 15-950 Bialystok, Poland; (M.M.); (J.B.)
| | - Elżbieta Skrzydlewska
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2d, 15-222 Bialystok, Poland;
| | - Wojciech Łuczaj
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2d, 15-222 Bialystok, Poland;
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Waheed YA, Liu J, Almayahe S, Sun D. The role of hyperuricemia in the progression of end-stage kidney disease and its molecular prospective in inflammation and cardiovascular diseases: A general review. Ther Apher Dial 2025. [PMID: 39966090 DOI: 10.1111/1744-9987.70000] [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: 11/04/2024] [Revised: 01/15/2025] [Accepted: 02/06/2025] [Indexed: 02/20/2025]
Abstract
With the ongoing development of the Chinese economy, the occurrence of chronic kidney disease (CKD) has experienced a remarkable upsurge recently, and due to uremia caused by CKD, the number of patients undergoing dialysis has shown a dramatic increase. China has been ranked first in the world for patients undergoing hemodialysis (HD) and peritoneal dialysis (PD) with approximately one million patients across the country. Due to the loss of kidney function caused by CKD, the kidneys tend to lose their ability to excrete uric acid (UA) out of the body; therefore, most patients undergoing dialysis are complicated with hyperuricemia (HUA). HUA is an abnormal disease of purine metabolism, and it's considered a chronic disease. More than 90% of patients suffering from HUA will not show any symptoms on physical examination. According to statistics, if high serum UA is left untreated, 55% of patients will develop severe problems due to the purine crystallization in the body, and the kidneys are the most affected organs by HUA causing renal insufficiency that can promote end-stage kidney disease (ESKD) by activating the renin-angiotensin system (RAS), which will lead to inflammation, arteriosclerosis, cardiovascular diseases (CVD), and other diseases. Lifestyle modifications and pharmacological interventions are the first primary choice for lowering UA, although dialysis will tend to reduce the high UA levels in the blood, drugs are also necessary. This review will summarize the mechanisms and metabolism of UA, the relationship between HUA and ESKD progression, HUA and inflammation, HUA and CVD, and pharmacological treatment of HUA.
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Affiliation(s)
- Yousuf Abdulkarim Waheed
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Clinical Research Center for Kidney Disease Xuzhou Medical University, Xuzhou, China
| | - Jie Liu
- Department of Nephrology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | | | - Dong Sun
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Clinical Research Center for Kidney Disease Xuzhou Medical University, Xuzhou, China
- Department of Internal Medicine and Diagnostics, Xuzhou Medical University, Xuzhou, China
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Elsaid KA, Zhang LX, Zhao T, Marks A, Jenkins D, Schmidt TA, Jay GD. Proteoglycan 4 (Lubricin) and regulation of xanthine oxidase in synovial macrophage as a mechanism of controlling synovitis. Arthritis Res Ther 2024; 26:214. [PMID: 39696446 DOI: 10.1186/s13075-024-03455-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 12/08/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Synovial macrophages (SMs) are important effectors of joint health and disease. A novel Cx3CR1 + TREM2 + SM population expressing the tight junction protein claudin-5, was recently discovered in synovial lining. Ablation of these SMs was associated with onset of arthritis. Proteoglycan 4 (PRG4) is a mucinous glycoprotein that fulfills lubricating and homeostatic roles in the joint. The aim of this work is to study the role of PRG4 in modulating synovitis in the context of SM homeostasis and assess the contribution of xanthine oxidase (XO)-hypoxia inducible factor alpha (HIF-1a) axis to this regulation. METHODS We used Prg4FrtloxP/FrtloxP;R26FlpoER/+, a novel transgenic mouse, where the Prg4Frt allele normally expresses the PRG4 protein and was designed to flank the first two exons of Prg4 with a flippase recognition target and "LOXP" sites. Inducing flippase activity with tamoxifen (TAM) inactivates the Frt allele and thus creates a conditional knockout state. We studied anti-inflammatory SMs and XO by quantitative immunohistochemistry, isolated RNA and studied immune pathway activations by multiplexed assays and isolated SMs and studied PRG4 signaling dysfunction in relation to glycolytic switching due to pro-inflammatory activation. Prg4 inactivated mice were treated with oral febuxostat, a specific XO inhibitor, and quantification of Cx3CR1 + TREM2 + SMs, XO immunostaining and synovitis assessment were conducted. RESULTS Prg4 inactivation induced Cx3CR1 + TREM2 + SM loss (p < 0.001) and upregulated glycolysis and innate immune pathways in the synovium. In isolated SMs, Xdh (p < 0.01) and Hif1a (p < 0.05) were upregulated. Pro-inflammatory activation of SMs was evident by enhanced glycolytic flux and XO-generated reactive oxygen species (ROS). Febuxostat reduced glycolytic flux (p < 0.001) and HIF-1a levels (p < 0.0001) in SMs. Febuxostat also reduced systemic inflammation (p < 0.001), synovial hyperplasia (p < 0.001) and preserved Cx3CR1 + TREM2 + SMs (p < 0.0001) in synovia of Prg4 inactivated mice. CONCLUSIONS PRG4 is a biologically significant modulator of synovial homeostasis via inhibition of XO expression and downstream HIF-1a activation. PRG4 signaling is anti-inflammatory and promotes synovial homeostasis in chronic synovitis, where direct XO inhibition is potentially therapeutic in chronic synovitis.
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Affiliation(s)
- Khaled A Elsaid
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, 92618, USA.
| | - Ling X Zhang
- Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, USA
| | | | - Ava Marks
- Brown University, Providence, RI, USA
| | - Derek Jenkins
- Department of Orthopaedics, Rhode Island Hospital, Providence, RI, USA
| | - Tannin A Schmidt
- Biomedical Engineering Department, School of Dental Medicine, University of Connecticut, Farmington, CT, USA
| | - Gregory D Jay
- Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, USA
- Department of Orthopaedics, Rhode Island Hospital, Providence, RI, USA
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7
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Baratta F, Moscucci F, Ettorre E, Bocale R, Cicero AFG, Cirillo P, Fogacci F, Lospinuso I, Savoia C, Mengozzi A, Virdis A, Borghi C, Desideri G. Influence of Uric Acid on Vascular and Cognitive Functions: Evidence for an Ambivalent Relationship. Metabolites 2024; 14:642. [PMID: 39590878 PMCID: PMC11596799 DOI: 10.3390/metabo14110642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/13/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
The growing recognition of the public health impact of cognitive impairment and dementia has sparked a global initiative to identify risk factors and develop strategies to prevent or slow the progression of these cognitive disorders. Uric acid, the end product of the metabolism of purine nucleotides, has been reported as a key factor of many conditions potentially involved in cognitive dysfunction/dementia. In addition, some studies support the hypothesis that elevated uric acid levels could reduce the risk of Alzheimer's disease, slow down the decline of cognition, and delay the progression of Alzheimer's disease, while other evidence achieves opposite positions. These discrepancies might reflect a biological ambivalence for uric acid depending on a very complex interplay of factors that include its concentrations achieved in biological fluids, the nature, and concentration of free radicals, the presence and concentration of other antioxidant molecules, potentially responsible for bi-directional effects of uric acid on brain health/functioning. In this narrative review, we attempt to elucidate the influential role of uric acid metabolism in cognitive functioning by discussing pathophysiological mechanisms putatively involved, being well aware that none of them can be considered one-sided due to the complexity of the human organism.
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Affiliation(s)
- Francesco Baratta
- Geriatric Unit, Department of Internal Medicine and Medical Specialties, AOU Policlinico Umberto I, 00161 Rome, Italy; (F.B.); (F.M.); (E.E.)
| | - Federica Moscucci
- Geriatric Unit, Department of Internal Medicine and Medical Specialties, AOU Policlinico Umberto I, 00161 Rome, Italy; (F.B.); (F.M.); (E.E.)
| | - Evaristo Ettorre
- Geriatric Unit, Department of Internal Medicine and Medical Specialties, AOU Policlinico Umberto I, 00161 Rome, Italy; (F.B.); (F.M.); (E.E.)
- Department of Clinical, Internal Medicine, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Raffaella Bocale
- Unit of Endocrinology, Agostino Gemelli University Hospital Foundation, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Catholic University of the Sacred Heart, 00168 Rome, Italy;
| | - Arrigo F. G. Cicero
- Cardiovascular Medicine Unit, IRCCS AOU BO, 40138 Bologna, Italy; (A.F.G.C.); (C.B.)
- Hypertension and Cardiovascular Risk Factor Research Center, Medical and Surgical Sciences Department, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy;
| | - Pietro Cirillo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, “Aldo Moro” University of Bari, 70122 Bari, Italy;
| | - Federica Fogacci
- Hypertension and Cardiovascular Risk Factor Research Center, Medical and Surgical Sciences Department, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy;
| | - Ilaria Lospinuso
- Geriatric Unit, Department of Internal Medicine and Medical Specialties, AOU Policlinico Umberto I, 00161 Rome, Italy; (F.B.); (F.M.); (E.E.)
| | - Carmine Savoia
- Clinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sant’Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy;
| | - Alessandro Mengozzi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (A.M.); (A.V.)
| | - Agostino Virdis
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (A.M.); (A.V.)
| | - Claudio Borghi
- Cardiovascular Medicine Unit, IRCCS AOU BO, 40138 Bologna, Italy; (A.F.G.C.); (C.B.)
- Hypertension and Cardiovascular Risk Factor Research Center, Medical and Surgical Sciences Department, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy;
| | - Giovambattista Desideri
- Geriatric Unit, Department of Internal Medicine and Medical Specialties, AOU Policlinico Umberto I, 00161 Rome, Italy; (F.B.); (F.M.); (E.E.)
- Department of Clinical, Internal Medicine, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy
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Zhu L, Liao Y, Jiang B. Role of ROS and autophagy in the pathological process of atherosclerosis. J Physiol Biochem 2024; 80:743-756. [PMID: 39110405 DOI: 10.1007/s13105-024-01039-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/25/2024] [Indexed: 12/29/2024]
Abstract
Activation of autophagy and production of reactive oxygen species occur at various stages of atherosclerosis. To clarify the role and mechanism of autophagy and reactive oxygen species in atherosclerosis is of great significance to the prevention and treatment of atherosclerosis. Recent studies have shown that basal autophagy plays an important role in protecting cells from oxidative stress, reducing apoptosis and enhancing atherosclerotic plaque stability. Autophagy deficiency and excessive accumulation of reactive oxygen species can impair the function of endothelial cells, macrophages and smooth muscle cells, trigger autophagic cell death, and lead to instability and even rupture of plaques. However, the main signaling pathways regulating autophagy, the molecular mechanisms of autophagy and reactive oxygen species interaction, how they are initiated and distributed in plaques, and how they affect atherosclerosis progression, remain to be clarified. At present, there is no autophagy inducer used to treat atherosclerosis clinically. Therefore, it is urgent to clarify the mechanism of autophagy and find new targets for autophagy. Antioxidant agents generally have defects such as low reactive oxygen species scavenging efficiency and high cytotoxicity. Highly potent autophagy inducers and reactive oxygen species scavengers still need to be further developed and validated to provide more possibilities for innovative treatments for atherosclerosis.
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Affiliation(s)
- Liyuan Zhu
- Center of Clinical Pharmacology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yingnan Liao
- Department of Laboratory Medicine, Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Bo Jiang
- Center of Clinical Pharmacology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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Ishii T, Seya N, Taguri M, Wakui H, Yoshimura A, Tamura K. Allopurinol, Febuxostat, and Nonuse of Xanthine Oxidoreductase Inhibitor Treatment in Patients Receiving Hemodialysis: A Longitudinal Analysis. Kidney Med 2024; 6:100896. [PMID: 39347518 PMCID: PMC11437761 DOI: 10.1016/j.xkme.2024.100896] [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] [Indexed: 10/01/2024] Open
Abstract
Rationale & Objective Allopurinol and febuxostat, which are xanthine oxidoreductase inhibitors, have been widely used as uric acid-lowering medications. However, evidence regarding their cardiovascular effects in hemodialysis is insufficient. This study compared the effects of allopurinol and febuxostat on mortality and cardiovascular outcomes in patients receiving hemodialysis. Study Design A retrospective observational cohort study. Setting & Participants Data of 6,791 patients who had no history of topiroxostat usage and underwent maintenance hemodialysis between March 2016 and March 2019 at Yokohama Daiichi Hospital, Zenjinkai, and its affiliated dialysis clinics in Japan's Kanagawa and Tokyo metropolitan areas were collected. Exposure Allopurinol, febuxostat, and nontreatment. Outcomes All-cause mortality, cardiovascular disease (CVD) events, heart failure (HF), acute myocardial infarction (AMI), and stroke. Analytical Approach For the main analyses, marginal structural Cox proportional hazards models were used to estimate HRs adjusted for time-varying confounding and selection bias because of censoring. Results Allopurinol and febuxostat showed significantly better survival than nontreatment for all-cause mortality (HR, 0.40; 95% CI, 0.30-0.54 and HR, 0.49; 95% CI, 0.38-0.63, respectively), without significant difference between allopurinol and febuxostat. Allopurinol showed significantly better survival than nontreatment, whereas febuxostat did not for CVD events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 1.01; 95% CI, 0.96-1.07, respectively), HF (HR, 0.71; 95% CI, 0.56-0.90 and HR, 1.03; 95% CI, 0.87-1.21, respectively), and AMI (HR, 0.48; 95% CI, 0.25-0.91 and HR, 0.76; 95% CI, 0.49-1.19, respectively). No comparisons showed significant results for stroke. Limitations The ratio of renal or intestinal excretion of uric acid and uremic toxins could not be elucidated, and we could not investigate gene polymorphism because of the large number of cases. Conclusions Allopurinol and febuxostat improved survival for all-cause mortality. Allopurinol and not febuxostat reduced the risk of CVD events, HF, and AMI.
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Affiliation(s)
- Takeo Ishii
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Nephrology, Yokohama Daiichi Hospital Zenjinkai, Yokohama, Japan
| | - Nodoka Seya
- Department of Health Data Science, Tokyo Medical University, Tokyo, Japan
| | - Masataka Taguri
- Department of Health Data Science, Tokyo Medical University, Tokyo, Japan
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ashio Yoshimura
- Department of Health Data Science, Tokyo Medical University, Tokyo, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Nephrology and Hypertension, Yokohama City University Medical Center, Yokohama, Japan
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Sanchez C, Campeau A, Liu-Bryan R, Mikuls TR, O'Dell JR, Gonzalez DJ, Terkeltaub R. Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement and inflammation modulators. Sci Rep 2024; 14:24598. [PMID: 39426967 PMCID: PMC11490615 DOI: 10.1038/s41598-024-74154-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/24/2024] [Indexed: 10/21/2024] Open
Abstract
Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined in association with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Sera demonstrated altered complement activation and regulatory gene ontology biologic processes. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat treatment decreased complement activation biologic process proteins in cultured BMDMs. Reduced gout flares are linked with a XOI treatment-emergent serum protein interactome that includes inflammation regulators, associated with altered complement activation and regulatory biologic processes. Serum and leukocyte proteomics could help identify when gouty inflammatory processes begin to subside in response to ULT.Trial Registration: ClinicalTrials.gov Identifier NCT02579096, posted October 19, 2015.
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Affiliation(s)
- Concepcion Sanchez
- Department of Pharmacology, University of California, San Diego, CA, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, and Collaborative Center for Multiplexed Proteomics, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Anaamika Campeau
- Department of Pharmacology, University of California, San Diego, CA, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, and Collaborative Center for Multiplexed Proteomics, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Ru Liu-Bryan
- Division of Rheumatology, Autoimmunity and Inflammation, Department of Medicine, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA, 92093, USA
| | - Ted R Mikuls
- Department of Internal Medicine, University of Nebraska Medical Center, MSB 5544, 983331, Omaha, NE, 68198-3331, USA
- Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - James R O'Dell
- Department of Internal Medicine, University of Nebraska Medical Center, MSB 5544, 983331, Omaha, NE, 68198-3331, USA
- Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - David J Gonzalez
- Department of Pharmacology, University of California, San Diego, CA, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, and Collaborative Center for Multiplexed Proteomics, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Robert Terkeltaub
- Division of Rheumatology, Autoimmunity and Inflammation, Department of Medicine, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA, 92093, USA.
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11
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Laketa D, Lavrnja I. Extracellular Purine Metabolism-Potential Target in Multiple Sclerosis. Mol Neurobiol 2024; 61:8361-8386. [PMID: 38499905 DOI: 10.1007/s12035-024-04104-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 03/07/2024] [Indexed: 03/20/2024]
Abstract
The purinergic signaling system comprises a complex network of extracellular purines and purine-metabolizing ectoenzymes, nucleotide and nucleoside receptors, ATP release channels, and nucleoside transporters. Because of its immunomodulatory function, this system is critically involved in the pathogenesis of multiple sclerosis (MS) and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). MS is a chronic neuroinflammatory demyelinating and neurodegenerative disease with autoimmune etiology and great heterogeneity, mostly affecting young adults and leading to permanent disability. In MS/EAE, alterations were detected in almost all components of the purinergic signaling system in both peripheral immune cells and central nervous system (CNS) glial cells, which play an important role in the pathogenesis of the disease. A decrease in extracellular ATP levels and an increase in its downstream metabolites, particularly adenosine and inosine, were frequently observed at MS, indicating a shift in metabolism toward an anti-inflammatory environment. Accordingly, upregulation of the major ectonucleotidase tandem CD39/CD73 was detected in the blood cells and CNS of relapsing-remitting MS patients. Based on the postulated role of A2A receptors in the transition from acute to chronic neuroinflammation, the association of variants of the adenosine deaminase gene with the severity of MS, and the beneficial effects of inosine treatment in EAE, the adenosinergic system emerged as a promising target in neuroinflammation. More recently, several publications have identified ADP-dependent P2Y12 receptors and the major extracellular ADP producing enzyme nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) as novel potential targets in MS.
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Affiliation(s)
- Danijela Laketa
- Department of General Physiology and Biophysics, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Studentski Trg 3, Belgrade, Republic of Serbia.
| | - Irena Lavrnja
- Institute for Biological Research, Sinisa Stankovic" - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, Republic of Serbia
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12
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Mayers J, Hofman B, Sobiech I, Kwesiga MP. Insights into the biocompatibility of biodegradable metallic molybdenum for cardiovascular applications-a critical review. Front Bioeng Biotechnol 2024; 12:1457553. [PMID: 39376544 PMCID: PMC11456422 DOI: 10.3389/fbioe.2024.1457553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/02/2024] [Indexed: 10/09/2024] Open
Abstract
Atherosclerotic cardiovascular disease (ACD) is the leading cause of death worldwide. The gold standard of treatment is the implantation of a permanent stent implant that is often associated with complications such as thrombus formation, vascular neointimal response, and stent fracture, which altogether decrease the long-term safety and efficacy of the stent. Biodegradable metallic materials have become an attractive alternative because of the ability to facilitate a more physiological healing response while the metal degrades. Recently, Molybdenum (Mo) has been considered as a potential candidate due to its excellent mechanical and medical imaging properties. Moreover, the biomedical research studies performed to date have shown minimal adverse effects in vitro and in vivo. However, there are still concerns of toxicity at high doses, and the impact of the biochemical mechanisms of Mo on material performance especially in pathophysiological environments are yet to be explored. Mo is an essential co factor for enzymes such as xanthine oxidoreductase (XOR) that plays a critical role in vascular homeostasis and ACD progression. Herein, this review will focus on the biochemistry of Mo, its physiological and pathological effects with an emphasis on cardiovascular disease as well as the recent studies on Mo for cardiovascular applications and its advantages over other biodegradable metals. The limitations of Mo research studies will also be discussed and concluded with an outlook to move this revolutionary metallic biomaterial from the bench to the bedside.
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Affiliation(s)
- Janina Mayers
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI, United States
| | - Brianna Hofman
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, United States
| | - Indie Sobiech
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI, United States
| | - Maria P. Kwesiga
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI, United States
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13
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Elsaid KA, Zhang LX, Zhao T, Marks A, Jenkins D, Schmidt TA, Jay GD. Proteoglycan 4 (Lubricin) and Regulation of Xanthine Oxidase in Synovial Macrophage as A Mechanism of Controlling Synovitis. RESEARCH SQUARE 2024:rs.3.rs-4934175. [PMID: 39372933 PMCID: PMC11451733 DOI: 10.21203/rs.3.rs-4934175/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Background Synovial macrophages (SMs) are important effectors of joint health and disease. A novel Cx3CR1 + TREM2 + SM population expressing the tight junction protein claudin-5, was recently discovered in synovial lining. Ablation of these SMs was associated with onset of arthritis. Proteoglycan 4 (PRG4) is a mucinous glycoprotein that fulfills lubricating and homeostatic roles in the joint. The aim of this work is to study the role of PRG4 in modulating synovitis in the context of SM homeostasis and assess the contribution of xanthine oxidase (XO)-hypoxia inducible factor alpha (HIF-1α) axis to this regulation. Methods We used Prg4 FrlioxP/FrtloxP ;R26 FlPoER/+ , a novel transgenic mouse, where the Prg4 Frt allele normally expresses the PRG4 protein and was designed to flank the first two exons of Prg4 with a flippase recognition target and "LOXP" sites. Inducing flippase activity with tamoxifen (TAM) inactivates the Frt allele and thus creates a conditional knockout state. We studied anti-inflammatory SMs and XO by quantitative immunohistochemistry, isolated RNA and studied immune pathway activations by multiplexed assays and isolated SMs and studied PRG4 signaling dysfunction in relation to glycolytic switching due to pro-inflammatory activation. Prg4 inactivated mice were treated with oral febuxostat, a specific XO inhibitor, and quantification of Cx3CR1 + TREM2 + SMs, XO immunostaining and synovitis assessment were conducted. Results Prg4 inactivation induced Cx3CR1 + TREM2 + SM loss (p < 0.001) and upregulated glycolysis and innate immune pathways in the synovium. In isolated SMs, Xdh (p < 0.01) and Hif1a (p < 0.05) were upregulated. Pro-inflammatory activation of SMs was evident by enhanced glycolytic flux and XO-generated reactive oxygen species (ROS). Febuxostat reduced glycolytic flux (p < 0.001) and HIF-1α levels (p < 0.0001) in SMs. Febuxostat also reduced systemic inflammation (p < 0.001), synovial hyperplasia (p < 0.001) and preserved Cx3CR1 + TREM2 + SMs (p < 0.0001) in synovia of Prg4 inactivated mice. Conclusions PRG4 is a biologically significant modulator of synovial homeostasis via inhibition of XO expression and downstream HIF-1a activation. PRG4 signaling is anti-inflammatory and promotes synovial homeostasis in chronic synovitis, where direct XO inhibition is potentially therapeutic in chronic synovitis.
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14
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Sekine M, Fujiwara M, Okamoto K, Ichida K, Nagata K, Hille R, Nishino T. Significance and amplification methods of the purine salvage pathway in human brain cells. J Biol Chem 2024; 300:107524. [PMID: 38960035 PMCID: PMC11342100 DOI: 10.1016/j.jbc.2024.107524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 07/05/2024] Open
Abstract
Previous studies suggest that uric acid or reactive oxygen species, products of xanthine oxidoreductase (XOR), may associate with neurodegenerative diseases. However, neither relationship has ever been firmly established. Here, we analyzed human brain samples, obtained under protocols approved by research ethics committees, and found no expression of XOR and only low levels of uric acid in various regions of the brain. In the absence of XOR, hypoxanthine will be preserved and available for incorporation into the purine salvage pathway. To clarify the importance of salvage in the brain, we tested using human-induced pluripotent stem cell-derived neuronal cells. Stable isotope analyses showed that the purine salvage pathway was more effective for ATP synthesis than purine de novo synthesis. Blood uric acid levels were related to the intracellular adenylate pool (ATP + ADP + AMP), and reduced levels of this pool result in lower uric acid levels. XOR inhibitors are related to extracellular hypoxanthine levels available for uptake into the purine salvage pathway by inhibiting the oxidation of hypoxanthine to xanthine and uric acid in various organs where XOR is present and can prevent further decreases in the intracellular adenylate pool under stress. Furthermore, adding precursors of the pentose phosphate pathway enhanced hypoxanthine uptake, indicating that purine salvage is activated by phosphoribosyl pyrophosphate replenishment. These findings resolve previous contradictions regarding XOR products and provide new insights into clinical studies. It is suggested that therapeutic strategies maximizing maintenance of intracellular adenylate levels may effectively treat pathological conditions associated with ischemia and energy depletion.
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Affiliation(s)
- Mai Sekine
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo, Tokyo, Japan; Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
| | - Megumi Fujiwara
- Department of Laboratory of Morphological Analysis, Nippon Medical School, Bunkyo, Tokyo, Japan
| | - Ken Okamoto
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo, Tokyo, Japan
| | - Kimiyoshi Ichida
- Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Koji Nagata
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo, Tokyo, Japan
| | - Russ Hille
- Department of Biochemistry, University of California, Riverside, California, USA
| | - Takeshi Nishino
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo, Tokyo, Japan; Professor Emeritus, Nippon Medical School, Bunkyo, Tokyo, Japan; University of Tokyo Health Sciences, Tama, Tokyo, Japan.
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15
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El-Shoura EAM, Sharkawi SMZ, Abdelzaher LA, Abdel-Wahab BA, Ahmed YH, Abdel-Sattar AR. Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways. Immunopharmacol Immunotoxicol 2024; 46:509-520. [PMID: 38918173 DOI: 10.1080/08923973.2024.2373216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 06/22/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1β, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.
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Affiliation(s)
- Ehab A M El-Shoura
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
- Department of Pharmacy Practice, Faculty of Pharmacy, Horus University in Egypt, New Damietta, Egypt
| | - Souty M Z Sharkawi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Lobna A Abdelzaher
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Basel A Abdel-Wahab
- Department of Pharmacology, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Yasmine H Ahmed
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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Sanchez C, Campeau A, Liu-Bryan R, Mikuls TR, O'Dell JR, Gonzalez DJ, Terkeltaub R. Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators. RESEARCH SQUARE 2024:rs.3.rs-4278877. [PMID: 38766125 PMCID: PMC11100878 DOI: 10.21203/rs.3.rs-4278877/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Background Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Methods Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). Results At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined, with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains and chemokine PPBP/CXCL7, and increased urate crystal phagocytosis inhibitor sCD44. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat inhibited complement activation pathway proteins in cultured BMDMs. Conclusions Reduced gout flares are kinked with a XOI-treatment emergent complement- and inflammation-regulatory serum protein interactome. Serum and leukocyte proteomes could help identify onset of anti-inflammatory responsiveness to ULT in gout. Trial registration ClinicalTrials.gov Identifier: NCT02579096, posted October 19, 2015.
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Samimi F, Namiranian N, Sharifi-Rigi A, Siri M, Abazari O, Dastghaib S. Coenzyme Q10: A Key Antioxidant in the Management of Diabetes-Induced Cardiovascular Complications-An Overview of Mechanisms and Clinical Evidence. Int J Endocrinol 2024; 2024:2247748. [PMID: 38524871 PMCID: PMC10959587 DOI: 10.1155/2024/2247748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 03/26/2024] Open
Abstract
Background Diabetes mellitus (DM) presents a significant global health challenge with considerable cardiovascular implications. Coenzyme Q10 (CoQ10) has gained recognition for its potential as a natural antioxidant supplement in the management of diabetes and its associated cardiovascular complications. Aim This comprehensive review systematically examines the scientific rationale underlying the therapeutic properties of CoQ10 in mitigating the impact of diabetes and its cardiovascular consequences. The analysis encompasses preclinical trials (in vitro and in vivo) and clinical studies evaluating the efficacy and mechanisms of action of CoQ10. Result & Discussion. Findings reveal that CoQ10, through its potent antioxidant and anti-inflammatory attributes, demonstrates significant potential in reducing oxidative stress, ameliorating lipid profiles, and regulating blood pressure, which are crucial aspects in managing diabetes-induced cardiovascular complications. CoQ10, chemically represented as C59H90O4, was administered in capsule form for human studies at doses of 50, 100, 150, 200, and 300 mg per day and at concentrations of 10 and 20 μM in sterile powder for experimental investigations and 10 mg/kg in powder for mouse studies, according to the published research. Clinical trials corroborate these preclinical findings, demonstrating improved glycemic control, lipid profiles, and blood pressure in patients supplemented with CoQ10. Conclusion In conclusion, CoQ10 emerges as a promising natural therapeutic intervention for the comprehensive management of diabetes and its associated cardiovascular complications. Its multifaceted impacts on the Nrf2/Keap1/ARE pathway, oxidative stress, and metabolic regulation highlight its potential as an adjunct in the treatment of diabetes and related cardiovascular disorders. However, further extensive clinical investigations are necessary to fully establish its therapeutic potential and assess potential synergistic effects with other compounds.
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Affiliation(s)
- Fatemeh Samimi
- Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasim Namiranian
- Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ali Sharifi-Rigi
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morvarid Siri
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Abazari
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Zheng H, Xu Y, Liehn EA, Rusu M. Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction. Int J Mol Sci 2024; 25:3114. [PMID: 38542087 PMCID: PMC10970003 DOI: 10.3390/ijms25063114] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/31/2024] [Accepted: 02/10/2024] [Indexed: 06/26/2024] Open
Abstract
Currently, coronary artery bypass and reperfusion therapies are considered the gold standard in long-term treatments to restore heart function after acute myocardial infarction. As a drawback of these restoring strategies, reperfusion after an ischemic insult and sudden oxygen exposure lead to the exacerbated synthesis of additional reactive oxidative species and the persistence of increased oxidation levels. Attempts based on antioxidant treatment have failed to achieve an effective therapy for cardiovascular disease patients. The controversial use of vitamin C as an antioxidant in clinical practice is comprehensively systematized and discussed in this review. The dose-dependent adsorption and release kinetics mechanism of vitamin C is complex; however, this review may provide a holistic perspective on its potential as a preventive supplement and/or for combined precise and targeted therapeutics in cardiovascular management therapy.
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Affiliation(s)
- Huabo Zheng
- Department of Cardiology, Angiology and Intensive Care, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
- Institute of Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark;
| | - Yichen Xu
- Institute of Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark;
- Department of Histology and Embryology, Medicine and Life Sciences, Hainan Medical University, Haikou 571199, China
| | - Elisa A. Liehn
- Institute of Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark;
- National Institute of Pathology “Victor Babes”, Splaiul Independentei Nr. 99-101, 050096 Bucharest, Romania
| | - Mihaela Rusu
- Institute of Applied Medical Engineering, Helmholtz Institute, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
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19
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Sanchez C, Campeau A, Liu-Bryan R, Mikuls T, O'Dell J, Gonzalez D, Terkeltaub R. Sustained xanthine oxidase inhibitor treat to target urate lowering therapy rewires a tight inflammation serum protein interactome. RESEARCH SQUARE 2024:rs.3.rs-3770277. [PMID: 38260556 PMCID: PMC10802734 DOI: 10.21203/rs.3.rs-3770277/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background Effective xanthine oxidoreductase inhibition (XOI) urate-lowering treatment (ULT) to target significantly reduces gout flare burden and synovitis between 1-2 years therapy, without clearing all monosodium urate crystal deposits. Paradoxically, treat to target ULT is associated with increased flare activity for at least 1 year in duration on average, before gout flare burden decreases. Since XOI has anti-inflammatory effects, we tested for biomarkers of sustained, effective ULT that alters gouty inflammation. Methods We characterized the proteome of febuxostat-treated murine bone marrow macrophages. Blood samples (baseline and 48 weeks ULT) were analyzed by unbiased proteomics in febuxostat and allopurinol ULT responders from two, independent, racially and ethnically distinct comparative effectiveness trial cohorts (n=19, n=30). STRING-db and multivariate analyses supplemented determinations of significantly altered proteins via Wilcoxon matched pairs signed rank testing. Results The proteome of cultured IL-1b-stimulated macrophages revealed febuxostat-induced anti-inflammatory changes, including for classical and alternative pathway complement activation pathways. At 48 weeks ULT, with altered purine metabolism confirmed by serum metabolomics, serum urate dropped >30%, to normal (<6.8 mg/dL) in all the studied patients. Overall, flares declined from baseline. Treated gout patient sera and peripheral blood mononuclear cells (PBMCs) showed significantly altered proteins (p<0.05) in clustering and proteome networks. CRP was not a useful therapy response biomarker. By comparison, significant serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains essential for C5b-9 membrane attack complex assembly and function; increase in the NLRP3 inflammasome activation promoter vimentin; increased urate crystal phagocytosis inhibitor sCD44; increased gouty inflammation pro-resolving mediator TGFB1; decreased phagocyte-recruiting chemokine PPBP/CXCL7, and increased monocyte/macrophage-expressed keratin-related proteins (KRT9,14,16) further validated by PBMC proteomics. STRING-db analyses of significantly altered serum proteins from both cohorts revealed a tight interactome network including central mediators of gouty inflammation (eg, IL-1B, CXCL8, IL6, C5). Conclusions Rewiring of inflammation mediators in a tight serum protein interactome was a biomarker of sustained XOI-based ULT that effectively reduced serum urate and gout flares. Monitoring of the serum and PBMC proteome, including for changes in the complement pathway could help determine onset and targets of anti-inflammatory changes in response to effective, sustained XOI-based ULT.Trial Registration: ClinicalTrials.gov Identifier: NCT02579096.
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20
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Mudgal R, Singh S. Xanthine Oxidoreductase in the Pathogenesis of Endothelial Dysfunction: An Update. Curr Hypertens Rev 2024; 20:10-22. [PMID: 38318826 DOI: 10.2174/0115734021277772240124075120] [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: 08/17/2023] [Revised: 12/04/2023] [Accepted: 12/19/2023] [Indexed: 02/07/2024]
Abstract
Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in the formation of uric acid (UA) and is involved in the generation of reactive oxygen species (ROS). Overproduction of ROS has been linked to the pathogenesis of hypertension, atherosclerosis, and cardiovascular disease, with multiple studies over the last 30 years demonstrating that XOR inhibition is beneficial. The involvement of XOR and its constituents in the advancement of chronic inflammation and ROS, which are responsible for endothelial dysfunction, is the focus of this evidence-based review. An overabundance of XOR products and ROS appears to drive the inflammatory response, resulting in significant endothelium damage. It has also been demonstrated that XOR activity and ED are connected. Diabetes, hypertension, and cardiovascular disease are all associated with endothelial dysfunction. ROS mainly modifies the activity of vascular cells and can be important in normal vascular physiology as well as the development of vascular disease. Suppressing XOR activity appears to decrease endothelial dysfunction, probably because it lessens the generation of reactive oxygen species and the oxidative stress brought on by XOR. Although there has long been a link between higher vascular XOR activity and worse clinical outcomes, new research suggests a different picture in which positive results are mediated by XOR enzymatic activity. Here in this study, we aimed to review the association between XOR and vascular endothelial dysfunction. The prevention and treatment approaches against vascular endothelial dysfunction in atherosclerotic disease.
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Affiliation(s)
- Rajat Mudgal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Bihar, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Bihar, India
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21
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Buonfiglio F, Xia N, Yüksel C, Manicam C, Jiang S, Zadeh JK, Musayeva A, Elksne E, Pfeiffer N, Patzak A, Li H, Gericke A. Studies on the Effects of Hypercholesterolemia on Mouse Ophthalmic Artery Reactivity. Diseases 2023; 11:124. [PMID: 37873768 PMCID: PMC10594501 DOI: 10.3390/diseases11040124] [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: 08/17/2023] [Revised: 09/10/2023] [Accepted: 09/18/2023] [Indexed: 10/25/2023] Open
Abstract
Atherogenic lipoproteins may impair vascular reactivity, leading to tissue damage in various organs, including the eye. This study aimed to investigate whether ophthalmic artery reactivity is affected in mice lacking the apolipoprotein E gene (ApoE-/-), a model for hypercholesterolemia and atherosclerosis. Twelve-month-old male ApoE-/- mice and age-matched wild-type controls were used to assess vascular reactivity using videomicroscopy. Moreover, the vascular mechanics, lipid content, levels of reactive oxygen species (ROS), and expression of pro-oxidant redox enzymes and the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were determined in vascular tissue. Unlike the aorta, the ophthalmic artery of ApoE-/- mice developed no signs of endothelial dysfunction and no signs of excessive lipid deposition. Remarkably, the levels of ROS, nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NOX2, NOX4, and LOX-1 were increased in the aorta but not in the ophthalmic artery of ApoE-/- mice. Our findings suggest that ApoE-/- mice develop endothelial dysfunction in the aorta by increased oxidative stress via the involvement of LOX-1, NOX1, and NOX2, whereas NOX4 may participate in media remodeling. In contrast, the ophthalmic artery appears to be resistant to chronic apolipoprotein E deficiency. A lack of LOX-1 expression/overexpression in response to increased oxidized low-density lipoprotein levels may be a possible mechanism of action.
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Affiliation(s)
- Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Ning Xia
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Can Yüksel
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Caroline Manicam
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Subao Jiang
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Jenia Kouchek Zadeh
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Aytan Musayeva
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Eva Elksne
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Andreas Patzak
- Institute of Translational Physiology, Charité—Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Huige Li
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
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Sedik AA, Hassan SA, Shafey HI, Khalil WKB, Mowaad NA. Febuxostat attenuates aluminum chloride-induced hepatorenal injury in rats with the impact of Nrf2, Crat, Car3, and MNK-mediated apoptosis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:83356-83375. [PMID: 37340161 PMCID: PMC10359240 DOI: 10.1007/s11356-023-28182-9] [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: 02/01/2023] [Accepted: 06/05/2023] [Indexed: 06/22/2023]
Abstract
Aluminum (Al) is a ubiquitous xenobiotic with known toxicity for both humans and animals. Our study was conducted to investigate the protective role of febuxostat (Feb) against aluminum chloride (AlCl3)-induced hepatorenal injury in rats. Hepatorenal injury was induced by oral administration of AlCl3 (40 mg/kg b.w.), for 2 months. Twenty-four male Sprague-Dawley rats were randomly allocated into four groups (six rats/group). The first group received the vehicle thought the experiment. The second group was considered as a control positive group. The third and fourth groups received oral treatment of Feb (10 mg/kg.b.w.) and (15 mg/kg.b.w.), respectively with AlCl3, concurrently for 2 months. Twenty-four hours, after the last treatment, serum biochemical, molecular, histopathology, and immunohistochemical studies were evaluated. Our findings showed that rats intoxicated with Alcl3 had disturbed biochemical picture. In addition, intoxication with AlCl3 increased oxidative stress and apoptosis, as demonstrated by an increase in malodialdeyde (MDA), carnitine o-acetyltransferase (Crat), and carbonic anhydrase (Car3) with a decrease in glutathione (GSH), MAP kinase-interacting serine/threonine kinase (MNK) and nuclear factor-erythroid 2-related factor 2 (Nrf2) mRNA expression. Furthermore, the levels of tumor necrosis factor-alpha (TNF-α) and the levels of caspase-3 were elevated with sever hepatic and renal pathological changes. Conversely, Feb (15 mg/kg.b.w.) could improve the serum biochemical indices and repressed MDA, Crat, and Car3 levels, whereas it increased GSH, MNK, and Nrf2 levels. Feb inhibited the apoptotic effect of AlCl3 in the liver and kidney by decreasing caspase-3 and TNF-α expression. The protective effect of Feb against AlCl3 toxicity was confirmed by histopathological findings. Moreover, molecular docking studies supported the anti-inflammatory effect of Feb due to its significant binding interactions with cyclooxygenase-1 (COX-1), NF-kappa-B-inducing kinase (NIK), and mitogen-activated protein kinases-p38 (MAPK-p38). The findings suggest that Feb system Feb can avert Alcl3-induced hepatotoxicity and nephrotoxicity by enhancing the antioxidant defense system, and inhibiting the inflammatory cascade and apoptosis.
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Affiliation(s)
- Ahmed A Sedik
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Center, El-Buhouth St., Dokki, Cairo, 12622, Egypt.
| | - Soha A Hassan
- Basic Science Department, Faculty of Dentistry, October 6 University, Giza, Egypt
| | - Heba I Shafey
- Department of Cell Biology, National Research Centre, El-Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Wagdy K B Khalil
- Department of Cell Biology, National Research Centre, El-Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Noha A Mowaad
- Narcotics, Ergogenics and Poisons Department, Medical Research and Clinical Studies Institute, National Research Center, El-Buhouth St., Dokki, Cairo, 12622, Egypt
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23
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Liuzzo G, Patrono C. Allopurinol does not improve cardiovascular outcomes in ischaemic heart disease. Eur Heart J 2023; 44:1016-1017. [PMID: 36733214 DOI: 10.1093/eurheartj/ehad014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Giovanna Liuzzo
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Largo A. Gemelli 8, Rome 00168, Lazio, Italy
- Cardiovascular and Pulmonary Sciences, Catholic University, School of Medicine, Largo F. Vito, 1-00168 Rome, Lazio, Italy
| | - Carlo Patrono
- Pharmacology, Catholic University School of Medicine, Largo F. Vito, 1-00168 Rome, Lazio, Italy
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24
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Batty M, Bennett MR, Yu E. The Role of Oxidative Stress in Atherosclerosis. Cells 2022; 11:3843. [PMID: 36497101 PMCID: PMC9735601 DOI: 10.3390/cells11233843] [Citation(s) in RCA: 143] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 12/02/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.
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Affiliation(s)
| | | | - Emma Yu
- Section of Cardiorespiratory Medicine, University of Cambridge, Cambridge CB2 0BB, UK
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25
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Role of Oxidative Stress in the Pathogenesis of Atherothrombotic Diseases. Antioxidants (Basel) 2022; 11:antiox11071408. [PMID: 35883899 PMCID: PMC9312358 DOI: 10.3390/antiox11071408] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/12/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
Oxidative stress is generated by the imbalance between reactive oxygen species (ROS) formation and antioxidant scavenger system’s activity. Increased ROS, such as superoxide anion, hydrogen peroxide, hydroxyl radical and peroxynitrite, likely contribute to the development and complications of atherosclerotic cardiovascular diseases (ASCVD). In genetically modified mouse models of atherosclerosis, the overexpression of ROS-generating enzymes and uncontrolled ROS formation appear to be associated with accelerated atherosclerosis. Conversely, the overexpression of ROS scavenger systems reduces or stabilizes atherosclerotic lesions, depending on the genetic background of the mouse model. In humans, higher levels of circulating biomarkers derived from the oxidation of lipids (8-epi-prostaglandin F2α, and malondialdehyde), as well as proteins (oxidized low-density lipoprotein, nitrotyrosine, protein carbonyls, advanced glycation end-products), are increased in conditions of high cardiovascular risk or overt ASCVD, and some oxidation biomarkers have been reported as independent predictors of ASCVD in large observational cohorts. In animal models, antioxidant supplementation with melatonin, resveratrol, Vitamin E, stevioside, acacetin and n-polyunsaturated fatty acids reduced ROS and attenuated atherosclerotic lesions. However, in humans, evidence from large, placebo-controlled, randomized trials or prospective studies failed to show any athero-protective effect of antioxidant supplementation with different compounds in different CV settings. However, the chronic consumption of diets known to be rich in antioxidant compounds (e.g., Mediterranean and high-fish diet), has shown to reduce ASCVD over decades. Future studies are needed to fill the gap between the data and targets derived from studies in animals and their pathogenetic and therapeutic significance in human ASCVD.
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26
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Sun M, Hines N, Scerbo D, Buchanan J, Wu C, Ten Eyck P, Zepeda-Orozco D, Taylor EB, Jalal DI. Allopurinol Lowers Serum Urate but Does Not Reduce Oxidative Stress in CKD. Antioxidants (Basel) 2022; 11:1297. [PMID: 35883787 PMCID: PMC9312025 DOI: 10.3390/antiox11071297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/16/2022] [Accepted: 06/25/2022] [Indexed: 12/31/2022] Open
Abstract
Xanthine oxidase (XO) contributes to oxidative stress and vascular disease. Hyperuricemia and gout are common in patients with chronic kidney disease (CKD), a population at increased risk of vascular disease. We evaluated effects of allopurinol on serum XO activity and metabolome of CKD patients who had participated in a randomized double-blind clinical trial of allopurinol vs. placebo. XO activity was measured in participants' serum. XO expression in venous endothelial cells was evaluated via immunofluorescence. Gas chromatography mass spectrometry (GC/MS) was utilized for metabolomics analysis. We found that in patients with stage 3 CKD and hyperuricemia, allopurinol lowered serum urate while increasing serum xanthine levels. Allopurinol, however, did not significantly suppress measured serum XO activity. Of note, baseline serum XO activity was low. Additionally, neither baseline serum XO activity nor XO protein expression were associated with measures of vascular dysfunction or with systemic or endothelial biomarkers of oxidative stress. Allopurinol affected several pathways, including pentose phosphate, pyrimidine, and tyrosine metabolism. Our findings suggest that circulating XO does not contribute to vascular disease in CKD patients. In addition to inhibition of XO activity, allopurinol was observed to impact other pathways; the implications of which require further study.
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Affiliation(s)
- Mingyao Sun
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
| | - Nicole Hines
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
| | - Diego Scerbo
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Jane Buchanan
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Chaorong Wu
- Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242, USA; (C.W.); (P.T.E.)
| | - Patrick Ten Eyck
- Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242, USA; (C.W.); (P.T.E.)
| | - Diana Zepeda-Orozco
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, Division of Nephrology and Hypertension, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Eric B. Taylor
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Diana I. Jalal
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
- Iowa City VA Medical Center, Iowa City, IA 52242, USA
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27
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Tanaka A, Toyoda S, Kato T, Yoshida H, Hamasaki S, Watarai M, Ishizu T, Ueda S, Inoue T, Node K. Association between serum urate level and carotid atherosclerosis: an insight from a post hoc analysis of the PRIZE randomised clinical trial. RMD Open 2022; 8:rmdopen-2022-002226. [PMID: 35410947 PMCID: PMC9003608 DOI: 10.1136/rmdopen-2022-002226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Objectives Elevated serum urate (SU) levels are associated with arterial atherosclerosis and subsequent cardiovascular events. However, an optimal therapeutic target SU level for delaying atherosclerotic progression in patients with hyperuricaemia remains uncertain. The aim of this analysis was to assess an association between changes in SU level and carotid intima–media thickness (IMT) to examine whether an optimal SU concentration exists to delay atherosclerotic progression. Methods This was a post hoc analysis of the PRIZE (programme of vascular evaluation under uric acid control by xanthine oxidase inhibitor, febuxostat: multicentre, randomised controlled) study of Japanese adults with asymptomatic hyperuricaemia. The primary endpoint of this analysis was an association between changes in SU levels and mean common carotid artery IMT (CCA-IMT) after 24 months of febuxostat treatment. Results Among subjects treated with febuxostat (n=239), a total of 204 who had both data on SU and mean CCA-IMT at baseline and 24 months were included in this analysis. The mean baseline SU level was 7.7±1.0 mg/dL, and febuxostat treatment significantly reduced SU concentrations at 24 months (estimated mean change ‒3.051 mg/dL, 95% CI ‒3.221 to ‒2.882). A multivariable linear regression analysis revealed that a reduction in SU level was associated with changes in mean CCA-IMT values at 24 months (p=0.025). In contrast, the achieved SU concentrations were not associated with changes in mean CCA-IMT at 24 months. Conclusion A greater reduction in SU, but not its achieved concentrations, may be associated with delayed progression of carotid IMT in patients with asymptomatic hyperuricaemia treated with febuxostat. Trial registration number UMIN000012911
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Affiliation(s)
- Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, Saga, Japan
| | - Shigeru Toyoda
- Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan
| | - Toru Kato
- Department of Cardiovascular Medicine, National Hospital Organisation Tochigi Medical Center, Utsunomiya, Japan
| | - Hisako Yoshida
- Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shuichi Hamasaki
- Department of Cardiology, Imakiire General Hospital, Kagoshima, Japan
| | | | - Tomoko Ishizu
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Shinichiro Ueda
- Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Nishihara, Japan
| | - Teruo Inoue
- Center for Advanced Medical Science Research, Dokkyo Medical University, Mibu, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, Saga, Japan
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Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response. Int J Mol Sci 2022; 23:ijms23073561. [PMID: 35408922 PMCID: PMC8998340 DOI: 10.3390/ijms23073561] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/19/2022] [Accepted: 03/21/2022] [Indexed: 12/13/2022] Open
Abstract
Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O2- levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation.
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29
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Targeting Reactive Oxygen Species in Atherosclerosis via Chinese Herbal Medicines. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1852330. [PMID: 35047104 PMCID: PMC8763505 DOI: 10.1155/2022/1852330] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/14/2021] [Indexed: 12/14/2022]
Abstract
Cardio-cerebrovascular disease (CCVD) has become the leading cause of human mortality with the coming acceleration of global population aging. Atherosclerosis is among the most common pathological changes in CCVDs. It is also a multifactorial disorder; oxidative stress caused by excessive production of reactive oxygen species (ROS) has become an important mechanism of atherosclerosis. Chinese herbal medicine (CHM) is a major type of natural medicine that has made great contributions to human health. CHMs are increasingly used in the auxiliary clinical treatment of atherosclerosis. Although their mechanism of action is unclear, CHMs can exert a variety of antiatherosclerosis effects by regulating intracellular ROS. In this review, we discussed the mechanism of ROS regulation in atherosclerosis and analyzed the role of CHMs in the treatment of atherosclerosis via ROS.
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Urate-lowering therapy for CKD patients with asymptomatic hyperuricemia without proteinuria elucidated by attribute-based research in the FEATHER Study. Sci Rep 2022; 12:3784. [PMID: 35260678 PMCID: PMC8904814 DOI: 10.1038/s41598-022-07737-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/21/2022] [Indexed: 11/08/2022] Open
Abstract
Attribute-based medicine is essential for patient-centered medicine. To date, the groups of patients with chronic kidney disease (CKD) requiring urate-lowering therapy are clinically unknown. Herein, we evaluated the efficacy of febuxostat using a cross-classification, attribute-based research approach. We performed post hoc analysis of multicenter, randomized, double-blind, placebo-controlled trial data for 395 patients with stage 3 CKD and asymptomatic hyperuricemia. Participants were divided into febuxostat or placebo groups and subcohorts stratified and cross-classified by proteinuria and serum creatinine concentrations. In patients stratified based on proteinuria, the mean eGFR slopes were significantly higher in the febuxostat group than in the placebo group (P = 0.007) in the subcohort without proteinuria. The interaction between febuxostat treatment and presence of proteinuria in terms of eGFR slope was significant (P for interaction = 0.019). When cross-classified by the presence of proteinuria and serum creatinine level, the mean eGFR slopes significantly differed between the febuxostat and placebo groups (P = 0.040) in cross-classified subcohorts without proteinuria and with serum creatinine level ≥ median, but not in the cross-classified subcohorts with proteinuria and serum creatinine level < median. Febuxostat mitigated the decline in kidney function among stage 3 CKD patients with asymptomatic hyperuricemia without proteinuria.
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Makridakis M, Vlahou A. Redox Proteomics Analysis of Atherosclerotic Aortas: Application of the "OxICAT" Method. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2419:629-644. [PMID: 35237993 DOI: 10.1007/978-1-0716-1924-7_39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Atherosclerosis development and progression have been linked to vascular reactive oxygen species (ROS). Plaque formation and especially instability, frequently resulting in acute coronary syndromes, have been linked to cell apoptosis and senescence, but also mainly to increased cellular oxidative stress. ROS are characterized by their high chemical reactivity and a resulting short half-life. This high reactivity usually involves reversible and/or irreversible protein modifications and specifically the covalent oxidative modification of cysteine residues. The latter can be used for the identification of protein-chemical footprints, leading to indirect monitoring of ROS. Proteomics and especially liquid chromatography tandem mass spectrometry (LC-MS/MS) approaches have emerged as a powerful tool to identify such protein modifications in biological samples (e.g., body fluids, tissues, cells). Application of a well-established quantitative thiol trapping technique termed OxICAT enables the detection and quantification of oxidative thiol modifications of thousands of proteins in a single experiment. In this chapter, a step-by-step guide for the redox proteomics analysis of atherosclerotic aortas, by utilizing the OxICAT method, as optimized by our group is provided.
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Affiliation(s)
- Manousos Makridakis
- Center of Systems Biology, Biomedical Research Foundation, Academy of Athens (BRFAA), Athens, Greece.
| | - Antonia Vlahou
- Center of Systems Biology, Biomedical Research Foundation, Academy of Athens (BRFAA), Athens, Greece
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Topiroxostat versus allopurinol in patients with chronic heart failure complicated by hyperuricemia: A prospective, randomized, open-label, blinded-end-point clinical trial. PLoS One 2022; 17:e0261445. [PMID: 35077456 PMCID: PMC8789120 DOI: 10.1371/journal.pone.0261445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/08/2021] [Indexed: 11/23/2022] Open
Abstract
Background The benefits of xanthine oxidase inhibitors to chronic heart failure (CHF) patients is controversial. We investigated the beneficial effects of a novel xanthine oxidoreductase inhibitor, topiroxostat, in patients with CHF and hyperuricemia (HU), in comparison to allopurinol. Methods and results The prospective, randomized open-label, blinded-end-point study was performed in 141 patients with CHF and HU at 4 centers. Patients were randomly assigned to either topiroxostat or allopurinol group to achieve target uric acid level ≤6.0 mg/dL. According to the protocol, 140 patients were followed up for 24 weeks. Percent change in ln (N-terminal-proB-type natriuretic peptide) at week 24 (primary endpoint) was comparable between topiroxostat and allopurinol groups (1.6±8.2 versus -0.4±8.0%; P = 0.17). In the limited number of patients with heart failure with reduced ejection fraction (HFrEF) (left ventricle ejection fraction <45%), ratio of peak early diastolic flow velocity at mitral valve leaflet to early diastolic mitral annular motion velocity (E/e’) decreased in topiroxostat group, but not in allopurinol group. Urinary 8-hydroxy-2’-deoxyguanosine and L-type fatty acid-binding protein levels increased and osmolality decreased significantly in allopurinol group, while these changes were less or absent in topiroxostat group. In allopurinol group HFrEF patients, additional to the increases in these urinary marker levels, urinary creatinine levels decreased, with no change in clearance, but not in topiroxostat group. Conclusions Compared with allopurinol, topiroxostat did not show great benefits in patients with CHF and HU. However, topiroxostat might have potential advantages of reducing left ventricular end-diastolic pressure, not worsening oxidative stress in proximal renal tubule, and renoprotection over allopurinol in HFrEF patients.
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Nishizawa H, Maeda N, Shimomura I. Impact of hyperuricemia on chronic kidney disease and atherosclerotic cardiovascular disease. Hypertens Res 2022; 45:635-640. [PMID: 35046512 DOI: 10.1038/s41440-021-00840-w] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 11/30/2021] [Indexed: 11/09/2022]
Abstract
Hyperuricemia is caused by reduced renal/extrarenal excretion and overproduction of uric acid. It is affected by genetic predisposition related to uric acid transporters and by visceral fat accumulation due to overnutrition. The typical symptomatic complication of hyperuricemia is gout caused by monosodium urate crystals. Accumulated evidence from epidemiological studies suggests that hyperuricemia is also a risk factor for hypertension, chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (CVD). However, it remains to be determined whether urate-lowering therapy for asymptomatic patients with hyperuricemia is effective in preventing CKD or CVD progression. This mini review focuses mainly on recent papers investigating the relationship between hyperuricemia and CKD or CVD and studies of urate-lowering therapy. Accumulated studies have proposed mechanisms of renal damage and atherosclerosis in hyperuricemia, including inflammasome activation, decreased nitric oxide bioavailability and oxidative stress induced by uric acid, urate crystals and xanthine oxidoreductase (XOR)-mediated reactive oxygen species. Since patients with hyperuricemia are a heterogeneous population with complex pathologies, it may be important to assess whether an outcome is the result of decreasing serum uric acid levels or an inhibitory effect on XOR. To clarify the impact of hyperuricemia on CKD and CVD progression, high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed.
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Affiliation(s)
- Hitoshi Nishizawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.
| | - Norikazu Maeda
- Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan
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Snigurska IO, Bozhko VV, Miloslavsky DK, Starchenko TG. GOUT AND HYPERURICEMIA AS ADDITIONAL FACTORS OF DETERIORATION OF CARDIAC AND RENAL PATHOLOGIES. BULLETIN OF PROBLEMS BIOLOGY AND MEDICINE 2022. [DOI: 10.29254/2077-4214-2022-3-166-87-99] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- I. O. Snigurska
- Government Institution “L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine”
| | - V. V. Bozhko
- Government Institution “L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine”
| | - D. K. Miloslavsky
- Government Institution “L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine”
| | - T. G. Starchenko
- Government Institution “L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine”
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Guma M, Dadpey B, Coras R, Mikuls TR, Hamilton B, Quehenberger O, Thorisdottir H, Bittleman D, Lauro K, Reilly SM, Liu-Bryan R, Terkeltaub R. Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes. Arthritis Res Ther 2022; 24:175. [PMID: 35879786 PMCID: PMC9310412 DOI: 10.1186/s13075-022-02852-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 06/26/2022] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVE Linked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial. METHODS Sera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes. RESULTS Serum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to β-adrenergic-agonism or TNF. CONCLUSION Metabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.
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Affiliation(s)
- Monica Guma
- grid.266100.30000 0001 2107 4242Department of Medicine, UC San Diego, San Diego VA Healthcare Service, 3350 La Jolla Village Drive, San Diego, CA 92161 USA ,grid.7080.f0000 0001 2296 0625Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona Spain
| | - Benyamin Dadpey
- grid.217200.60000 0004 0627 2787Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093 USA
| | - Roxana Coras
- grid.266100.30000 0001 2107 4242Department of Medicine, UC San Diego, San Diego VA Healthcare Service, 3350 La Jolla Village Drive, San Diego, CA 92161 USA ,grid.7080.f0000 0001 2296 0625Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona Spain
| | - Ted R. Mikuls
- grid.266813.80000 0001 0666 4105University of Nebraska Medical Center, Omaha, NE 68198 USA
| | - Bartlett Hamilton
- grid.266813.80000 0001 0666 4105University of Nebraska Medical Center, Omaha, NE 68198 USA
| | - Oswald Quehenberger
- grid.217200.60000 0004 0627 2787Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093 USA
| | - Hilda Thorisdottir
- grid.266100.30000 0001 2107 4242Department of Medicine, UC San Diego, San Diego VA Healthcare Service, 3350 La Jolla Village Drive, San Diego, CA 92161 USA
| | - David Bittleman
- grid.266100.30000 0001 2107 4242Department of Medicine, UC San Diego, San Diego VA Healthcare Service, 3350 La Jolla Village Drive, San Diego, CA 92161 USA
| | - Kimberly Lauro
- grid.266100.30000 0001 2107 4242Department of Medicine, UC San Diego, San Diego VA Healthcare Service, 3350 La Jolla Village Drive, San Diego, CA 92161 USA
| | - Shannon M. Reilly
- grid.217200.60000 0004 0627 2787Division of Metabolism and Endocrinology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093 USA ,grid.5386.8000000041936877XWeill Center for Metabolic Health, Department of Medicine, Weill Cornell Medicine, New York, NY 10021 USA
| | - Ru Liu-Bryan
- grid.266100.30000 0001 2107 4242Department of Medicine, UC San Diego, San Diego VA Healthcare Service, 3350 La Jolla Village Drive, San Diego, CA 92161 USA
| | - Robert Terkeltaub
- grid.266100.30000 0001 2107 4242Department of Medicine, UC San Diego, San Diego VA Healthcare Service, 3350 La Jolla Village Drive, San Diego, CA 92161 USA
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Odake K, Tsujii M, Iino T, Chiba K, Kataoka T, Sudo A. Febuxostat treatment attenuates oxidative stress and inflammation due to ischemia-reperfusion injury through the necrotic pathway in skin flap of animal model. Free Radic Biol Med 2021; 177:238-246. [PMID: 34737143 DOI: 10.1016/j.freeradbiomed.2021.10.033] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 10/23/2021] [Accepted: 10/26/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Ischemia-reperfusion (I/R) injury is a major contributor to skin flap necrosis, which is a serious complication of reconstructive surgery. The purpose of this study was to evaluate the protective effect of treatment with febuxostat, a selective xanthine oxidase inhibitor, on I/R injury in the skin flap of an animal (rat) model. METHODS Superficial epigastric flaps were raised in Sprague-Dawley rats and subjected to ischemia for 3 h. Febuxostat at a dose of 10 mg/kg/day was administered to rats in drinking water from 1 week before the surgery (Feb group). Control animals received no drugs (Con group). The mean ratio of flap survival and contraction was evaluated and compared between animals with and without administration of febuxostat on day 5 after the surgery. In addition, infiltration by polymorphonuclear leukocytes and muscles of the panniculus carnosus in the flap were histologically evaluated using hematoxylin-eosin staining. Furthermore, xanthine oxidase activity, ATP levels, superoxide dismutase activity, and expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor-α, and interleukin-1β were quantitatively assessed in the skin flap 24 h after the surgery. RESULTS In the Feb group, the survival and contraction rates at the 5 d timepoint post-surgery were significantly higher and lower than those in the Con group, respectively. Histological analysis showed significant reduction in polymorphonuclear leukocyte infiltration and muscle injury scores due to I/R injury in the Feb group. The expression of 8-OHdG was also significantly inhibited in animals administered febuxostat. Biochemical analysis showed a significant reduction in xanthine oxidase activity and significant increases in ATP levels and superoxide dismutase activity in the Feb group. Furthermore, the expression of interleukin-1β was significantly lower in the Feb group than in the Con group. CONCLUSION Febuxostat, which is clinically used for the treatment of hyperuricemia, was effective against necrosis of the skin flap via inhibition of oxidative stress and inflammation caused by I/R injury.
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Affiliation(s)
- Kazuya Odake
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Japan
| | - Masaya Tsujii
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Japan.
| | - Takahiro Iino
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Japan
| | - Katsura Chiba
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Japan
| | - Takeshi Kataoka
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Japan
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Polito L, Bortolotti M, Battelli MG, Bolognesi A. Xanthine oxidoreductase: A leading actor in cardiovascular disease drama. Redox Biol 2021; 48:102195. [PMID: 34844041 PMCID: PMC8636850 DOI: 10.1016/j.redox.2021.102195] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/19/2021] [Accepted: 11/19/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases (CVD) are the leading cause of global mortality and their pathogenesis lies mainly in the atherosclerotic process. There are close connections linking oxidative stress and inflammation to endothelial dysfunction, atherosclerosis and, consequently, to CVD. This review focuses on the role of xanthine oxidoreductase (XOR) and its products on the development of chronic inflammation and oxidative stress, responsible for atheromatous plaque formation. Evidence is reported that an excessive level of XOR products favors inflammatory response and plaque development, thereby promoting major cardiovascular risk factors. Also, the relationship between hyperuricemia and hypertension as well as between XOR activity and CVD is confirmed. In spite of the increasing number of clinical studies investigating the output of cardiovascular patients treated with urate-lowering therapies (including uricosuric drugs, XOR inhibitors and recombinant uricase) the results are still uncertain. The inhibition of XOR activity appears more promising than just the control of uricemia level in preventing cardiovascular events, possibly because it also reduces the intracellular accumulation of urate, as well as the production of reactive oxygen species. However, XOR inhibition also reduces the availability of the multifaced mediator nitric oxide and, at present, can be recommended only in hyperuricemic patients.
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Affiliation(s)
- Letizia Polito
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126, Bologna, Italy.
| | - Massimo Bortolotti
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126, Bologna, Italy.
| | - Maria Giulia Battelli
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126, Bologna, Italy.
| | - Andrea Bolognesi
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126, Bologna, Italy.
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Xu D, Murakoshi N, Tajiri K, Duo F, Okabe Y, Murakata Y, Yuan Z, Li S, Aonuma K, Song Z, Shimoda Y, Mori H, Sato A, Nogami A, Aonuma K, Ieda M. Xanthine oxidase inhibitor febuxostat reduces atrial fibrillation susceptibility by inhibition of oxidized CaMKII in Dahl salt-sensitive rats. Clin Sci (Lond) 2021; 135:2409-2422. [PMID: 34386810 DOI: 10.1042/cs20210405] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 08/06/2021] [Accepted: 08/13/2021] [Indexed: 11/17/2022]
Abstract
Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). However, the effects of the xanthine oxidase (XO) inhibition for AF remain to be fully elucidated. We investigated the effects of a novel XO inhibitor febuxostat on AF compared with allopurinol in hypertension rat model. Five-week-old Dahl salt-sensitive rats were fed either low-salt (LS) (0.3% NaCl) or high-salt (HS) (8% NaCl) diet. After 4 weeks of diet, HS diet rats were divided into three groups: orally administered to vehicle (HS-C), febuxostat (5 mg/kg/day) (HS-F), or allopurinol (50 mg/kg/day) (HS-A). After 4 weeks of treatment, systolic blood pressure (SBP) was significantly higher in HS-C than LS, and it was slightly but significantly decreased by treatment with each XO inhibitor. AF duration was significantly prolonged in HS-C compared with LS, and significantly suppressed in both HS-F and HS-A (LS; 5.8 ± 3.5 s, HS-C; 33.9 ± 23.7 s, HS-F; 15.0 ± 14.1 s, HS-A; 20.1 ± 11.9 s: P<0.05). Ca2+ spark frequency was obviously increased in HS-C rats and reduced in the XO inhibitor-treated rats, especially in HS-F group. Western blotting revealed that the atrial expression levels of Met281/282-oxidized Ca2+/Calmodulin-dependent kinase II (CaMKII) and Ser2814-phosphorylated ryanodine receptor 2 were significantly increased in HS-C, and those were suppressed in HS-F and HS-A. Decreased expression of gap junction protein connexin 40 in HS-C was partially restored by treatment with each XO inhibitor. In conclusion, XO inhibitor febuxostat, as well as allopurinol, could reduce hypertension-related increase in AF perpetuation by restoring Ca2+ handling and gap junction.
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Affiliation(s)
- DongZhu Xu
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Nobuyuki Murakoshi
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kazuko Tajiri
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Feng Duo
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yuta Okabe
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yoshiko Murakata
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Zixun Yuan
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Siqi Li
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kazuhiro Aonuma
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Zonghu Song
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yuzuno Shimoda
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Haruka Mori
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Akira Sato
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Akihiko Nogami
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kazutaka Aonuma
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Masaki Ieda
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Pai RZ, Fang Q, Tian G, Zhu B, Ge X. Expression and role of interleukin-1β and associated biomarkers in deep vein thrombosis. Exp Ther Med 2021; 22:1366. [PMID: 34659512 PMCID: PMC8515515 DOI: 10.3892/etm.2021.10800] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 05/05/2021] [Indexed: 01/04/2023] Open
Abstract
Lower extremity deep vein thrombosis (DVT) is a common peripheral vascular disease, in which inflammation plays an important role. The aim of the present study was to investigate the expression and role of inflammatory factors in DVT. A rat model of venous thrombosis of the lower extremities was established through venous ligation surgery. The rats were examined at 2, 8, 24, 48 and 72 h after the induction of inferior venous stenosis and compared with control and sham surgery groups. The serum levels of interleukin-1β (IL-1β), tissue factor (TF) and xanthine oxidase (XOD) were measured using ELISAs. The morphology of the DVT tissue was observed by hematoxylin and eosin staining. Circulating endothelial cells (CECs) in peripheral blood were counted by flow cytometry. Reverse transcription-quantitative PCR and western blotting were used to detect mRNA and protein expression, respectively. The serum levels of IL-1β, TF and XOD exhibited no significant differences between the control and sham surgery groups. However, those in the rat model of DVT presented an upward trend from 2 to 24 h and peaked at 24 h, with a significant difference from the respective levels in the control and sham surgery groups. The histopathological analysis revealed the presence of red and mixed thrombi in the rats 2-48 h following the induction of inferior venous stenosis group with inflammatory cell infiltration in the vascular wall. Thrombus formation was evident after 72 h. While significant difference was observed in the number of CECs in the peripheral blood between the control and sham surgery groups, the number of peripheral blood CECs in the rats with inferior venous stenosis group increased from 8 to 72 h, with significant differences among these groups. The mRNA levels of IL-1β, TF, XOD and NF-κB in the tissues peaked at 24 h, with significant differences compared with those in the control and sham surgery groups. In addition, the protein expression level of NF-κB increased from 2 to 72 h. In conclusion, these results suggest that the high expression of IL-1β, TF, XOD and NF-κB may promote thrombus formation.
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Affiliation(s)
- Rouzimaimaiti Zila Pai
- Department of General Practice, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Qingbo Fang
- Department of Vascular Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Guanglei Tian
- Department of Hepatobiliary Surgery, Graduate School, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Bing Zhu
- Department of Vascular Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
| | - Xiaohu Ge
- Department of Vascular Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830001, P.R. China
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Herb M, Gluschko A, Schramm M. Reactive Oxygen Species: Not Omnipresent but Important in Many Locations. Front Cell Dev Biol 2021; 9:716406. [PMID: 34557488 PMCID: PMC8452931 DOI: 10.3389/fcell.2021.716406] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 08/19/2021] [Indexed: 01/08/2023] Open
Abstract
Reactive oxygen species (ROS), such as the superoxide anion or hydrogen peroxide, have been established over decades of research as, on the one hand, important and versatile molecules involved in a plethora of homeostatic processes and, on the other hand, as inducers of damage, pathologies and diseases. Which effects ROS induce, strongly depends on the cell type and the source, amount, duration and location of ROS production. Similar to cellular pH and calcium levels, which are both strictly regulated and only altered by the cell when necessary, the redox balance of the cell is also tightly regulated, not only on the level of the whole cell but in every cellular compartment. However, a still widespread view present in the scientific community is that the location of ROS production is of no major importance and that ROS randomly diffuse from their cellular source of production throughout the whole cell and hit their redox-sensitive targets when passing by. Yet, evidence is growing that cells regulate ROS production and therefore their redox balance by strictly controlling ROS source activation as well as localization, amount and duration of ROS production. Hopefully, future studies in the field of redox biology will consider these factors and analyze cellular ROS more specifically in order to revise the view of ROS as freely flowing through the cell.
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Affiliation(s)
- Marc Herb
- Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany
| | - Alexander Gluschko
- Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany
| | - Michael Schramm
- Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany
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41
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Kawachi Y, Fujishima Y, Nishizawa H, Nakamura T, Akari S, Murase T, Saito T, Miyazaki Y, Nagao H, Fukuda S, Kita S, Katakami N, Doki Y, Maeda N, Shimomura I. Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation. JCI Insight 2021; 6:e144762. [PMID: 34494551 PMCID: PMC8492303 DOI: 10.1172/jci.insight.144762] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 07/21/2021] [Indexed: 12/20/2022] Open
Abstract
Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9–derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.
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Affiliation(s)
- Yusuke Kawachi
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuya Fujishima
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hitoshi Nishizawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | | | - Seigo Akari
- Sanwa Kagaku Kenkyusho Co., Ltd., Inabe, Mie, Japan
| | | | | | | | - Hirofumi Nagao
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shiro Fukuda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,Department of Adipose Management, and
| | - Naoto Katakami
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | | | - Norikazu Maeda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease. Int J Mol Sci 2021; 22:ijms22179221. [PMID: 34502127 PMCID: PMC8431537 DOI: 10.3390/ijms22179221] [Citation(s) in RCA: 245] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 02/07/2023] Open
Abstract
Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.
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Agnoletti D, Cicero AFG, Borghi C. The Impact of Uric Acid and Hyperuricemia on Cardiovascular and Renal Systems. Cardiol Clin 2021; 39:365-376. [PMID: 34247750 DOI: 10.1016/j.ccl.2021.04.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The description of gout dates back almost 5000 years, and scientific interest in uric acid increased when it was found to be involved in the pathogenesis of gout. Since then, many basic and clinical studies have assessed the implications of uric acid for the oxidative system, inflammation, and cardiovascular and renal outcomes. Uric acid-lowering therapy failed to improve clinical hard outcomes in asymptomatic hyperuricemia, and it is retained in symptomatic hyperuricemia. Dietary and lifestyle modifications are critical to manage hyperuricemia. More studies are warranted to investigate the role of uric acid-lowering drugs on cardiovascular outcomes.
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Affiliation(s)
- Davide Agnoletti
- Internal Medicine Department, IRCCS Sacro Cuore Hospital, Viale Luigi Rizzardi 4, Negrar di Valpolicella (VR) 37024, Italy
| | - Arrigo F G Cicero
- Medical and Surgical Sciences Department, University of Bologna, Via Albertoni 15, Bologna 40138, Italy
| | - Claudio Borghi
- Medical and Surgical Sciences Department, University of Bologna, Via Albertoni 15, Bologna 40138, Italy.
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Tsukamoto T, Tsujii M, Odake K, Iino T, Nakamura T, Matsumine A, Sudo A. Febuxostat reduces muscle wasting in tumor-bearing mice with LM8 osteosarcoma cells via inhibition of reactive oxygen species generation. Free Radic Res 2021; 55:810-820. [PMID: 34278932 DOI: 10.1080/10715762.2021.1947502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Cachexic condition due to malignant tumors has been a challenging problem. The aim of this study is to analyze effects of febuxostat on both in vitro and in vivo models of the wasting of skeletal muscles, due to LM8 osteosarcoma cells. C2C12 myotubes were incubated in the conditioned medium of LM8. Febuxostat was added at a concentration of 3 µM and 30 µM, and ROS, diameter of myotubes, and expression of atrogin-1 were analyzed. Furthermore, an in vivo study was performed by subcutaneous injection of LM8 on C3H mice. Febuxostat was administered in the drinking water at 5 µg/ml, and 25 µg/ml. In addition, tumor-bearing mice without febuxostat (group TB) and control mice (group C) were established. At 4 weeks, body weight, wet weights of the gastrocnemius muscles, XO activity, 8-OHdG, and expression of TNF-α and IL-6 were evaluated. ROS generation, atrophy of myotubes, and upregulation of atrogin-1 were clearly observed in C2C12 myotubes following incubation in the conditioned medium. These pathological conditions were significantly inhibited by febuxostat administration. Furthermore, mice in group TB showed significant loss of body weight and muscle weight in which XO activity, 8-OHdG, and expression of IL-6 were significantly increased compared to those in group C. Febuxostat administration not only significantly improved the body weight and muscleweight, but also reduced markers of oxidative stress and pro-inflammatory cytokines. Febuxostat did not show anti-tumor effects. Febuxostat, which is clinically used for treatment of hyperuricemia, is effective against the wasting of the skeletal muscles induced by LM8 osteosarcoma cells.
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Affiliation(s)
- Tadashi Tsukamoto
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Masaya Tsujii
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Kazuya Odake
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Takahiro Iino
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Tomoki Nakamura
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Akihiko Matsumine
- Department of Orthopaedic Surgery, Fukui University Faculty of Medical Science, Eiheiji-Cho, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
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45
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Ganji M, Nardi V, Prasad M, Jordan KL, Bois MC, Franchi F, Zhu XY, Tang H, Young MD, Lerman LO, Lerman A. Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression. Stroke 2021; 52:2792-2801. [PMID: 34107737 DOI: 10.1161/strokeaha.120.032964] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Morsaleh Ganji
- Department of Cardiovascular Medicine (M.G., V.N., M.P., F.F., M.D.Y., A.L.), Mayo Clinic, Rochester, MN
| | - Valentina Nardi
- Department of Cardiovascular Medicine (M.G., V.N., M.P., F.F., M.D.Y., A.L.), Mayo Clinic, Rochester, MN
| | - Megha Prasad
- Department of Cardiovascular Medicine (M.G., V.N., M.P., F.F., M.D.Y., A.L.), Mayo Clinic, Rochester, MN
| | - Kyra L Jordan
- Department of Nephrology and Hypertension (K.L.J., X.Y.Z., H.T., L.O.L.), Mayo Clinic, Rochester, MN
| | - Melanie C Bois
- Department of Laboratory Medicine and Pathology (M.C.B.), Mayo Clinic, Rochester, MN
| | - Federico Franchi
- Department of Cardiovascular Medicine (M.G., V.N., M.P., F.F., M.D.Y., A.L.), Mayo Clinic, Rochester, MN
| | - Xiang Y Zhu
- Department of Nephrology and Hypertension (K.L.J., X.Y.Z., H.T., L.O.L.), Mayo Clinic, Rochester, MN
| | - Hui Tang
- Department of Nephrology and Hypertension (K.L.J., X.Y.Z., H.T., L.O.L.), Mayo Clinic, Rochester, MN
| | - Melissa D Young
- Department of Cardiovascular Medicine (M.G., V.N., M.P., F.F., M.D.Y., A.L.), Mayo Clinic, Rochester, MN
| | - Lilach O Lerman
- Department of Nephrology and Hypertension (K.L.J., X.Y.Z., H.T., L.O.L.), Mayo Clinic, Rochester, MN
| | - Amir Lerman
- Department of Cardiovascular Medicine (M.G., V.N., M.P., F.F., M.D.Y., A.L.), Mayo Clinic, Rochester, MN
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Chen Q, Qi X, Zhang W, Zhang Y, Bi Y, Meng Q, Bian H, Li Y. Catalpol Inhibits Macrophage Polarization and Prevents Postmenopausal Atherosclerosis Through Regulating Estrogen Receptor Alpha. Front Pharmacol 2021; 12:655081. [PMID: 33995075 PMCID: PMC8120111 DOI: 10.3389/fphar.2021.655081] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/21/2021] [Indexed: 12/19/2022] Open
Abstract
Lacking estrogen increases the risk of atherosclerosis (AS) in postmenopausal women. Inflammation plays a vital role in the pathological process of AS, and macrophages are closely related to inflammation. Catalpol is an iridoid glucoside extracted from the fresh roots of the traditional Chinese herb Rehmanniae radix preparata. In this study, we aimed to evaluate the effects of catalpol on macrophage polarization and postmenopausal AS. In addition, we investigated whether the mechanism of catalpol was dependent on regulating the expression of estrogen receptors (ERs). In vitro, lipopolysaccharides (LPS) and interferon-γ (IFN-γ) were applied to induce M1 macrophage polarization. In vivo, the ApoE-/- mice were fed with a high-fat diet to induce AS, and ovariectomy was operated to mimic the estrogen cessation. We demonstrated catalpol inhibited M1 macrophage polarization induced by LPS and INF-γ, and eliminated lipid accumulation in postmenopausal AS mice. Catalpol not only suppressed the inflammatory response but also reduced the level of oxidative stress. Then, ERs (ERα and ERβ) inhibitors and ERα siRNA were also applied in confirming that the protective effect of catalpol was mediated by ERα, rather than ERβ. In conclusion, catalpol significantly inhibited macrophage polarization and prevented postmenopausal AS by increasing ERα expression.
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Affiliation(s)
- Qi Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xu Qi
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weiwei Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuhan Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yunhui Bi
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qinghai Meng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Huimin Bian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu Li
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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47
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Role of macrophage autophagy in atherosclerosis: modulation by bioactive compounds. Biochem J 2021; 478:1359-1375. [PMID: 33861844 DOI: 10.1042/bcj20200894] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/28/2022]
Abstract
Atherosclerosis is a chronic inflammatory disease associated with lipid metabolism disorder. Autophagy is a catabolic process and contributes to maintaining cellular homeostasis. Substantial evidence suggests that defective autophagy is implicated in several diseases, including atherosclerosis, while increased autophagy mitigates atherosclerosis development. Thus, understanding the mechanisms of autophagy regulation and its association with atherosclerosis is vital to develop new therapies against atherosclerosis. Dietary bioactive compounds are non-nutrient natural compounds that include phenolics, flavonoids, and carotenoids. Importantly, these bioactive compounds possess anti-inflammatory, antioxidant, and antibacterial properties that may alleviate various chronic diseases. Recently, examining the effects of bioactive compounds on autophagy activity in atherogenesis has drawn considerable attention. The current review discusses the role of macrophage autophagy in the development and progression of atherosclerosis. We also summarize our current knowledge of the therapeutic potential of bioactive compounds on atherosclerosis and autophagy.
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48
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Andreadou I, Daiber A, Baxter GF, Brizzi MF, Di Lisa F, Kaludercic N, Lazou A, Varga ZV, Zuurbier CJ, Schulz R, Ferdinandy P. Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling. Free Radic Biol Med 2021; 166:33-52. [PMID: 33588049 DOI: 10.1016/j.freeradbiomed.2021.02.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/03/2021] [Accepted: 02/06/2021] [Indexed: 02/06/2023]
Abstract
The morbidity and mortality from cardiovascular diseases (CVD) remain high. Metabolic diseases such as obesity, hyperlipidemia, diabetes mellitus (DM), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as well as hypertension are the most common comorbidities in patients with CVD. These comorbidities result in increased myocardial oxidative stress, mainly from increased activity of nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, mitochondria as well as downregulation of antioxidant defense systems. Oxidative and nitrosative stress play an important role in ischemia/reperfusion injury and may account for increased susceptibility of the myocardium to infarction and myocardial dysfunction in the presence of the comorbidities. Thus, while early reperfusion represents the most favorable therapeutic strategy to prevent ischemia/reperfusion injury, redox therapeutic strategies may provide additive benefits, especially in patients with heart failure. While oxidative and nitrosative stress are harmful, controlled release of reactive oxygen species is however important for cardioprotective signaling. In this review we summarize the current data on the effect of hypertension and major cardiometabolic comorbidities such as obesity, hyperlipidemia, DM, NAFLD/NASH on cardiac redox homeostasis as well as on ischemia/reperfusion injury and cardioprotection. We also review and discuss the therapeutic interventions that may restore the redox imbalance in the diseased myocardium in the presence of these comorbidities.
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Affiliation(s)
- Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
| | - Andreas Daiber
- Department of Cardiology 1, Molecular Cardiology, University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr, Germany.
| | - Gary F Baxter
- Division of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, United Kingdom
| | | | - Fabio Di Lisa
- Department of Biomedical Sciences, University of Padova, Italy; Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Nina Kaludercic
- Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Antigone Lazou
- Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
| | - Coert J Zuurbier
- Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Rainer Schulz
- Institute of Physiology, Justus Liebig University Giessen, Giessen, Germany.
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary
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He B, Nie Q, Wang F, Han Y, Yang B, Sun M, Fan X, Ye Z, Liu P, Wen J. Role of pyroptosis in atherosclerosis and its therapeutic implications. J Cell Physiol 2021; 236:7159-7175. [PMID: 33755211 DOI: 10.1002/jcp.30366] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/20/2021] [Accepted: 03/08/2021] [Indexed: 12/11/2022]
Abstract
Atherosclerosis is a significant cardiovascular burden and a leading cause of death worldwide, recognized as a chronic sterile inflammatory disease. Pyroptosis is a novel proinflammatory regulated cell death, characterized by cell swelling, plasma membrane bubbling, and robust release of proinflammatory cytokines (such as interleukin IL-1β and IL-18). Mounting studies have addressed the crucial contribution of pyroptosis to atherosclerosis and clarified the candidate therapeutic agents targeting pyroptosis for atherosclerosis. Herein, we review the initial characterization of pyroptosis, the detailed mechanisms of pyroptosis, current evidence about pyroptosis and atherosclerosis, and potential therapeutic strategies that target pyroptosis in the development of atherosclerosis.
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Affiliation(s)
- Bin He
- Department of Cardiovascular Surgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Qiangqiang Nie
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Feng Wang
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Yongxin Han
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Bo Yang
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Mingsheng Sun
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Xueqiang Fan
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Zhidong Ye
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Peng Liu
- Department of Cardiovascular Surgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Jianyan Wen
- Department of Cardiovascular Surgery, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
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50
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Nessa N, Kobara M, Toba H, Adachi T, Yamamoto T, Kanamura N, Pezzotti G, Nakata T. Febuxostat Attenuates the Progression of Periodontitis in Rats. Pharmacology 2021; 106:294-304. [PMID: 33735887 DOI: 10.1159/000513034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 11/11/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Periodontitis is a lifestyle-related disease that is characterized by chronic inflammation in gingival tissue. Febuxostat, a xanthine oxidase inhibitor, exerts anti-inflammatory and antioxidant effects. OBJECTIVE The present study investigated the effects of febuxostat on periodontitis in a rat model. METHODS Male Wistar rats were divided into 3 groups: control, periodontitis, and febuxostat-treated periodontitis groups. Periodontitis was induced by placing a ligature wire around the 2nd maxillary molar and the administration of febuxostat (5 mg/kg/day) was then initiated. After 4 weeks, alveolar bone loss was assessed by micro-computed tomography and methylene blue staining. The expression of osteoprotegerin (OPG), a bone resorption inhibitor, was detected by quantitative RT-PCR and immunological staining, and the number of osteoclasts in gingival tissue was assessed by tartrate-resistant acid phosphatase staining. The mRNA and protein expression levels of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β), in gingival tissue were measured using quantitative RT-PCR and immunological staining. Oxidative stress in gingival tissue was evaluated by the expression of 4-hydroxy-2-nonenal (4-HNE), and 8-hydroxy-2-deoxyguanosine (8-OHdG). To clarify the systemic effects of periodontitis, blood pressure and glucose tolerance were examined. RESULTS In rats with periodontitis, alveolar bone resorption was associated with reductions in OPG and increases in osteoclast numbers. The gingival expression of TNF-α, IL-1β, 4-HNE, and 8-OHdG was up-regulated in rats with periodontitis. Febuxostat significantly reduced alveolar bone loss, proinflammatory cytokine levels, and oxidative stress. It also attenuated periodontitis-induced glucose intolerance and blood pressure elevations. CONCLUSION Febuxostat prevented the progression of periodontitis and associated systemic effects by inhibiting proinflammatory mediators and oxidative stress.
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Affiliation(s)
- Naseratun Nessa
- Division of Pathological Science, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Miyuki Kobara
- Division of Pathological Science, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan,
| | - Hiroe Toba
- Division of Pathological Science, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tetsuya Adachi
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiro Yamamoto
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Narisato Kanamura
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Giuseppe Pezzotti
- Department of Material Science and Engineering, Kyoto Institute of Technology, Kyoto, Japan
| | - Tetsuo Nakata
- Division of Pathological Science, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
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