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Ramani N, Patwardhan RS, Checker R, Singh B, Morjaria S, Kumar BK, Gurjar M, Gota V, Sharma D. Preclinical evaluation of sodium copper chlorophyllin: safety, pharmacokinetics, and therapeutic potential in breast cancer chemotherapy and cyclophosphamide-induced bladder toxicity. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04112-z. [PMID: 40274623 DOI: 10.1007/s00210-025-04112-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 03/26/2025] [Indexed: 04/26/2025]
Abstract
Sodium copper chlorophyllin (chlorophyllin, CHL), a semi-synthetic water-soluble derivative of green plant pigment chlorophyll, is associated with potential health benefits; however, systematic preclinical evaluation of its pharmacological and therapeutic potential remains limited. This study investigates safety, toxicology, pharmacokinetics, and efficacy of CHL as an adjunct to breast cancer chemotherapy. Acute and sub-acute oral toxicity of CHL was assessed in mice and rats under Good Laboratory Practice (GLP) conditions following OECD guidelines. Anti-cancer effects and mechanisms were evaluated in 4 T1mouse breast cancer cells using viability assays, colony formation analysis, and proteomics. Cyclophosphamide (CYP)-induced painful bladder syndrome (PBS) was studied in C57BL/6 female mice. In acute toxicity study, up to 5000 mg/kg bw of CHL was well tolerated without any signs of toxicity and death. In the sub-acute toxicity study, no features suggestive of drug-induced toxicity indicated No-Observed Adverse Effect Level (NOAEL) to be beyond 1000 mg/kg bw. CHL showed wide biodistribution, achieving sustained therapeutic concentrations in target tissues. CHL enhanced the anti-proliferative and cytotoxic effects of CYP in 4 T1 breast cancer cells, and proteomics studies revealed disruption in DNA damage repair, microtubule dynamics, and mitochondrial biogenesis, leading to apoptosis. CHL (100 mg/kg bw, oral) showed significant therapeutic benefit for treatment of CYP induced PBS. CHL alleviated PBS symptoms by restoring IL- 22 levels, reducing oxidative stress, and improving bladder functionality. Chlorophyllin appears to be relatively safe even at high doses, demonstrates potentially favorable pharmacology, and may hold promise for mitigating CYP-induced bladder toxicity and enhancing chemotherapy efficacy.
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Affiliation(s)
- Neha Ramani
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, 400094, India
| | - Raghavendra S Patwardhan
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, 400094, India.
| | - Rahul Checker
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, 400094, India
| | - Babita Singh
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Shruti Morjaria
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Binita K Kumar
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India
| | - Murari Gurjar
- Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre (ACTREC-TMC), Kharghar, Navi Mumbai, 410210, India
| | - Vikram Gota
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, 400094, India
- Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre (ACTREC-TMC), Kharghar, Navi Mumbai, 410210, India
| | - Deepak Sharma
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, 400094, India.
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Yi Y, Luo Q, Chen J, Chen Z, Aydemir HA, Chen P, Tang J, Luo F, Fang Z. Association between the uric acid-to-HDL-cholesterol ratio (UHR) and the risk of cardiovascular disease and dyslipidemia: a population-based study. Lipids Health Dis 2025; 24:143. [PMID: 40241174 PMCID: PMC12001538 DOI: 10.1186/s12944-025-02551-4] [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: 01/13/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND AND AIMS The uric acid-to-HDL-cholesterol ratio (UHR), a novel marker of metabolism and inflammation, has been investigated in various diseases. However, its potential associations with the incidence of cardiovascular disease (CVD) and dyslipidemia remain unclear. This study aimed to examine the relationships between the UHR and the incidence of CVD and dyslipidemia. The primary objective was to evaluate the role of the UHR in predicting CVD and dyslipidemia, whereas the secondary objective was to analyze the predictive effects of the UHR in different subgroups. METHODS We conducted a cross-sectional analysis using data from the 2001-2018 National Health and Nutrition Examination Survey (NHANES), which included 6,370 adults aged 18-80 years. Weighted binary logistic regression and subgroup analyses were performed to evaluate the independent associations between the UHR and the risk of various cardiovascular conditions, including overall CVD, congestive heart failure, myocardial infarction, angina, coronary heart disease, and dyslipidemia. To investigate potential nonlinear relationships between the UHR and these outcomes, restricted cubic spline modeling was applied to further elucidate the associations. RESULTS Among the 6,370 participants included in the study, 559 were diagnosed with CVD. Elevated UHR values were strongly associated with a greater incidence of CVD and its subtypes, including congestive heart failure, myocardial infarction, angina, and coronary heart disease (all P < 0.001). After accounting for weighted factors, participants in the higher UHR quartiles presented progressively higher rates of CVD: Quartile 1 (4.7%), Quartile 2 (6.3%), Quartile 3 (7.4%), and Quartile 4 (11%). A nonlinear relationship between the UHR and the risk of developing CVD was identified through restricted cubic spline (RCS) analysis. Among the subgroup of 4,117 participants with dyslipidemia, multivariable linear regression analysis demonstrated a significant positive association between the UHR and dyslipidemia (OR 17.38, 95% CI 16.24-18.60). This association remained robust even after adjusting for covariates (OR 11.65, 95% CI 8.995-15.17). RCS analysis further confirmed the nonlinear nature of this relationship. Subgroup analysis revealed no significant interaction between the UHR and overall CVD or CVD-related variables, such as congestive heart failure, myocardial infarction, angina, or coronary heart disease. However, for dyslipidemia, BMI showed a significant interaction, indicating that the positive association between the UHR and dyslipidemia risk is influenced by participants' BMI. CONCLUSION A high UHR is associated with an increased risk of various cardiovascular conditions and dyslipidemia. The incorporation of routine UHR monitoring into clinical practice can support the early identification of high-risk individuals, facilitate timely interventions, and reduce the burden of cardiovascular and metabolic diseases.
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Affiliation(s)
- Yanfeng Yi
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Qin Luo
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Jingfei Chen
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Zewei Chen
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Hacı Ahmet Aydemir
- Department of Family Medicine, Erzurum Regional Training and Research Hospital, Erzurum, 25000, Turkey
- Dr. Filiz Dolunay Family Health Center Unit Number 59, Yakutiye, Erzurum, Turkey
| | - Pengfei Chen
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Jianjun Tang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China.
| | - Fei Luo
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China.
| | - Zhenfei Fang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan, 410011, People's Republic of China.
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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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Liu Y, Li Z, Xu Y, Mao H, Huang N. Uric Acid and Atherosclerosis in Patients with Chronic Kidney Disease: Recent Progress, Mechanisms, and Prospect. KIDNEY DISEASES (BASEL, SWITZERLAND) 2025; 11:112-127. [PMID: 40124130 PMCID: PMC11928073 DOI: 10.1159/000543781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 01/16/2025] [Indexed: 03/25/2025]
Abstract
Background Chronic kidney disease (CKD) is a prevalent global health concern, significantly linked to increased cardiovascular morbidity and mortality. Among various risk factors, uric acid (UA) has emerged as a potentially modifiable contributor to cardiovascular complications in CKD patients. Summary Elevated serum uric acid levels frequently occur in individuals with CKD and are associated with the development of atherosclerosis (AS). Uric acid has been demonstrated to exacerbate inflammatory processes, promote oxidative stress, and cause endothelial dysfunction, which are critical factors that drive the formation of atherosclerotic plaques. Furthermore, high uric acid levels can worsen renal function, establishing a detrimental cycle that amplifies cardiovascular risk. Key Messages This review investigates the complex interconnection between UA and AS in patients with CKD, highlighting the underlying mechanisms and therapeutic considerations. A more profound comprehension of this relationship is essential for enhancing cardiovascular health and outcomes in this vulnerable population.
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Affiliation(s)
- Yuchu Liu
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Zeyu Li
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Yuanwen Xu
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Haiping Mao
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Naya Huang
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Nephrology, Ministry of Health of China, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
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Chen C, Liu K, Wang Y, Song X, Gao W, Wang Y, Chen Y, An Z, Yin C, Wang H, Wang S. In vitro colonic fermentation of fermented Radix Astragali by Poria cocos and anti-hyperuricemia mechanism based on network pharmacology and experiment verification. Front Nutr 2024; 11:1466702. [PMID: 39717393 PMCID: PMC11663651 DOI: 10.3389/fnut.2024.1466702] [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: 07/18/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Aim This research aimed to probe the effects of fecal microbiota and Lactobacillus acidophilus on the metabolism of Radix Astragali (RA) and Poria cocos solid fermenting Radix Astragali (FRA). It further explores pharmacological effects of RA, Poria cocos, and FRA on HUA mouse model and the mechanisms in HUA treatment. Methods Fecal microbiota and Lactobacillus acidophilus were used to ferment FRA and RA in vitro to probe the impacts of microbiota on the metabolism of active compound. A HUA mouse model was used to carry out pharmacodynamic experiment of anti-hyperuricemia. Network pharmacology and molecular docking was utilized to elucidate the underlying mechanisms of RA and Poria cocos in the treatment of HUA. Results The results indicated that astragaloside IV (AG IV), total saponins, and flavonoids continuously decreased in FRA and RA during 48 h fecal microbiota colonic fermentation. During Lactobacillus acidophilus fermentation, in FRA, the content of AG IV peaked at 12 h with a value of 1.14 ± 0.20 mg/g; total saponins and flavonoids reached the highest values of 136.34 ± 6.15 mg/g at 12 h and 6.35 ± 0.06 mg/g at 6 h; AG IV and total saponins reached the highest values 0.63 ± 0.05 mg/g and 115.12 ± 4.12 mg/g at 12 h and 24 h in RA, respectively; and total flavonoids consecutively decreased. The counts of Lactobacillus acidophilus increased significantly in FRA compared with RA. Pharmacodynamic outcomes revealed that FRA effectively reduced blood levels of uric acid (UA), triglycerides (TG), xanthine oxidase (XOD), alanine aminotransferase (ALT), and aspartate transaminase (AST) in HUA mice, exerting protective effects on the liver and kidney. Network pharmacology showed that there were 93 common targets for RA, Poria cocos, and HUA with the top five core targets tumor necrosis factor (TNF), signal transducer and activator of transcription 3 (STAT3), cysteinyl aspartate specific proteinase 3 (CASP3), jun proto-oncogene (JUN), and estrogen receptor 1 (ESR1). Molecular docking analysis revealed that AG IV, calycosin and formononetin bond well to the core targets. Conclusion This research revealed the interaction of RA and FRA with fecal microbiota and Lactobacillus acidophilus, RA and Poria cocos were featured with multiple components, target points, and signaling pathways in HUA treatment, which provided fresh insights for further HUA therapeutics.
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Affiliation(s)
- Caiyun Chen
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Keyu Liu
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Yishu Wang
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Xinru Song
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Wenjing Gao
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Yanlin Wang
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Yuxin Chen
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Ziqi An
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Changting Yin
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Haiyan Wang
- Office of Academic Affairs, Binzhou Medical University, Yantai, China
| | - Shaoping Wang
- School of Pharmaceutical Science, Binzhou Medical University, Yantai, China
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Cesar BN, Braga WMT, Hamerschlak N, Junior MDSD. Kidney function in newly diagnosed myeloma patients: factors associated with kidney impairment and recovery. BMC Nephrol 2024; 25:344. [PMID: 39390432 PMCID: PMC11468068 DOI: 10.1186/s12882-024-03717-5] [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: 04/11/2024] [Accepted: 08/16/2024] [Indexed: 10/12/2024] Open
Abstract
Kidney disease is a common complication of multiple myeloma (MM) and a risk factor for increased morbimortality. In this retrospective cohort study based on medical records, we analyzed the kidney function of patients with renal disease related to MM during the first year of treatment. All patients included were consecutively admitted to the outpatient services of two hospitals between January 2009 and January 2019 and met the diagnostic criteria for MM regardless of the reason for seeking medical help. We excluded patients who had kidney disease or who were on dialysis before MM diagnosis. We investigated the factors associated with renal function recovery using multivariate analysis. We evaluated 167 patients (median age of 66 ± 11.49 years). Almost half of the patients had arterial hypertension (76; 45.5%). The majority had International Staging System (ISS) grades 3 (73; 43.7%) or 2 (60; 35.9%). Seventy-four (44%) patients had an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m² at the time of MM diagnosis. Fifty-two patients (31%) underwent hematopoietic stem cell transplantation (HSCT). After 12 months, 4 (2.3%) patients needed dialysis, and 18 (10.7%) died. The factors associated with an eGFR < 60 ml/min/1.73 m² were anemia, hyperuricemia, 24-hour proteinuria > 1.0 g, and extramedullary plasmacytoma. However, only baseline renal function (eGFR > 60 ml/min/1.73 m2) and HSCT were associated with greater recovery of renal function at 12 months of follow-up.
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Affiliation(s)
- Bruno Nogueira Cesar
- Nephrology Division, Federal University of Sao Paulo, Universidade Federal de São Paulo (UNIFESP), Botucatu street - cj. 153, n° 591, 15th floor - Vila Clementino, Sao Paulo, 04023-062, SP, Brazil.
| | | | - Nelson Hamerschlak
- Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Marcelino de Souza Durão Junior
- Nephrology Division, Federal University of Sao Paulo and Kidney Transplant Unit, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
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Du L, Zong Y, Li H, Wang Q, Xie L, Yang B, Pang Y, Zhang C, Zhong Z, Gao J. Hyperuricemia and its related diseases: mechanisms and advances in therapy. Signal Transduct Target Ther 2024; 9:212. [PMID: 39191722 DOI: 10.1038/s41392-024-01916-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 06/08/2024] [Accepted: 06/27/2024] [Indexed: 08/29/2024] Open
Abstract
Hyperuricemia, characterized by elevated levels of serum uric acid (SUA), is linked to a spectrum of commodities such as gout, cardiovascular diseases, renal disorders, metabolic syndrome, and diabetes, etc. Significantly impairing the quality of life for those affected, the prevalence of hyperuricemia is an upward trend globally, especially in most developed countries. UA possesses a multifaceted role, such as antioxidant, pro-oxidative, pro-inflammatory, nitric oxide modulating, anti-aging, and immune effects, which are significant in both physiological and pathological contexts. The equilibrium of circulating urate levels hinges on the interplay between production and excretion, a delicate balance orchestrated by urate transporter functions across various epithelial tissues and cell types. While existing research has identified hyperuricemia involvement in numerous biological processes and signaling pathways, the precise mechanisms connecting elevated UA levels to disease etiology remain to be fully elucidated. In addition, the influence of genetic susceptibilities and environmental determinants on hyperuricemia calls for a detailed and nuanced examination. This review compiles data from global epidemiological studies and clinical practices, exploring the physiological processes and the genetic foundations of urate transporters in depth. Furthermore, we uncover the complex mechanisms by which the UA induced inflammation influences metabolic processes in individuals with hyperuricemia and the association with its relative disease, offering a foundation for innovative therapeutic approaches and advanced pharmacological strategies.
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Grants
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
- 82002339, 81820108020 National Natural Science Foundation of China (National Science Foundation of China)
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Affiliation(s)
- Lin Du
- Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
- Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Haorui Li
- Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
- Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041, China
| | - Qiyue Wang
- Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
- Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041, China
| | - Lei Xie
- Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
- Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041, China
| | - Bo Yang
- Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
- Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041, China
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Zhigang Zhong
- Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
- Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041, China.
| | - Junjie Gao
- Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
- Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041, China.
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Gan TM, Ye YY, Mo GL, Li JY. Progress of uric acid in cardiovascular disease. Cardiovasc Endocrinol Metab 2024; 13:e0300. [PMID: 38633361 PMCID: PMC11019825 DOI: 10.1097/xce.0000000000000300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 03/10/2024] [Indexed: 04/19/2024]
Abstract
Due to the global prevalence of hyperuricemia (HUA), there is growing interest in research on uric acid (UA). HUA is a common condition that has various adverse consequences, including gout and kidney disease. However, recent studies have also implicated UA in the development of cardiovascular diseases (CVD) such as atrial fibrillation (AF) and coronary heart disease (CHD). Experimental and clinical research has extensively demonstrated the detrimental effects of elevated serum UA levels on cardiovascular health. Furthermore, serum UA levels have been identified as predictors of CVD outcomes following percutaneous coronary intervention (PCI) and catheter ablation. Additionally, the use of UA-lowering therapy holds important implications for the management of CVD. This review aims to consolidate the current evidence on the relationship between serum UA and CVD.
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Affiliation(s)
- Tian-ming Gan
- Department of Cardiology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Yu-yu Ye
- Department of Cardiology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Guan-lian Mo
- Department of Cardiology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jin-yi Li
- Department of Cardiology, Affiliated Hospital of Guilin Medical University, Guilin, China
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Yuan J, Zhao J, Qin Y, Xing Y, Yu Z, Zhang Y, Wu H, Zheng Q, Hui Y, Guo S, Wang A, Han M, Ning X, Sun S. Association of serum uric acid with all-cause and cardiovascular mortality in chronic kidney disease stages 3-5. Nutr Metab Cardiovasc Dis 2024; 34:1518-1527. [PMID: 38508991 DOI: 10.1016/j.numecd.2024.01.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/19/2024] [Accepted: 01/28/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND AND AIMS The role of serum uric acid (SUA) in the prognosis of chronic kidney disease (CKD) is inconclusive. To explore the association of SUA level with all-cause and cardiovascular disease (CVD) mortality in patients with CKD. METHODS AND RESULTS Leveraging data from the National Health and Nutritional Examination Survey (NHANES) and linked national death records up to December 31 2019, we explored the association of SUA with all-cause and CVD mortality using weighted cox proportional hazards regression models and restricted cubic spline (RCS) models in patients with CKD stages 3-5. The study finally included 2644 patients with CKD stages 3-5, with a median SUA level of 6.5 mg/dL. After a median follow-up of 55 months, a total of 763 deaths were recorded, with 279 of them attributed to CVD. In the fully adjusted model, per 1 mg/dL increment in SUA concentration was found to be associated with increased HRs (95% CIs) of 1.07 (1.00, 1.14) for all-cause mortality and 1.11 (1.00, 1.24) for CVD mortality. Compared to Q2 (reference), those in Q4 had adjusted HRs of 1.72 (1.36, 2.17) for all-cause mortality and 2.17 (1.38, 3.41) for CVD mortality, while those in Q1 had adjusted HRs of 1.49 (1.19, 1.85) for all-cause mortality and 1.93 (1.26, 2.98) for CVD mortality. CONCLUSIONS Both higher and lower SUA levels were associated with increased risks of all-cause and CVD mortality in patients with CKD stages 3-5.
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Affiliation(s)
- Jinguo Yuan
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jin Zhao
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yunlong Qin
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yan Xing
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zixian Yu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yumeng Zhang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Hao Wu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Qiao Zheng
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yueqing Hui
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Shuxian Guo
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Anjing Wang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Mei Han
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaoxuan Ning
- Department of Geriatric, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
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Chen IC, Chou LJ, Huang SC, Chu TW, Lee SS. Machine learning-based comparison of factors influencing estimated glomerular filtration rate in Chinese women with or without non-alcoholic fatty liver. World J Clin Cases 2024; 12:2506-2521. [PMID: 38817230 PMCID: PMC11135451 DOI: 10.12998/wjcc.v12.i15.2506] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/13/2024] [Accepted: 04/09/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver (NAFLD) has increased recently. Subjects with NAFLD are known to have higher chance for renal function impairment. Many past studies used traditional multiple linear regression (MLR) to identify risk factors for decreased estimated glomerular filtration rate (eGFR). However, medical research is increasingly relying on emerging machine learning (Mach-L) methods. The present study enrolled healthy women to identify factors affecting eGFR in subjects with and without NAFLD (NAFLD+, NAFLD-) and to rank their importance. AIM To uses three different Mach-L methods to identify key impact factors for eGFR in healthy women with and without NAFLD. METHODS A total of 65535 healthy female study participants were enrolled from the Taiwan MJ cohort, accounting for 32 independent variables including demographic, biochemistry and lifestyle parameters (independent variables), while eGFR was used as the dependent variable. Aside from MLR, three Mach-L methods were applied, including stochastic gradient boosting, eXtreme gradient boosting and elastic net. Errors of estimation were used to define method accuracy, where smaller degree of error indicated better model performance. RESULTS Income, albumin, eGFR, High density lipoprotein-Cholesterol, phosphorus, forced expiratory volume in one second (FEV1), and sleep time were all lower in the NAFLD+ group, while other factors were all significantly higher except for smoking area. Mach-L had lower estimation errors, thus outperforming MLR. In Model 1, age, uric acid (UA), FEV1, plasma calcium level (Ca), plasma albumin level (Alb) and T-bilirubin were the most important factors in the NAFLD+ group, as opposed to age, UA, FEV1, Alb, lactic dehydrogenase (LDH) and Ca for the NAFLD- group. Given the importance percentage was much higher than the 2nd important factor, we built Model 2 by removing age. CONCLUSION The eGFR were lower in the NAFLD+ group compared to the NAFLD- group, with age being was the most important impact factor in both groups of healthy Chinese women, followed by LDH, UA, FEV1 and Alb. However, for the NAFLD- group, TSH and SBP were the 5th and 6th most important factors, as opposed to Ca and BF in the NAFLD+ group.
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Affiliation(s)
- I-Chien Chen
- Department of Nursing, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
| | - Lin-Ju Chou
- Department of Nursing, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
| | - Shih-Chen Huang
- Department of Nursing, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
| | - Ta-Wei Chu
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Chief Executive Officer's Office, MJ Health Research Foundation, Taipei 114, Taiwan
| | - Shang-Sen Lee
- Department of Urology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan
- School of Medicine, Tzu Chi University, Hualian 970, Taiwan
- Department of Urology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
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Yan W, Wen S, Zhou L. Effect of Intestinal Flora on Hyperuricemia-Induced Chronic Kidney Injury in Type 2 Diabetic Patients and the Therapeutic Mechanism of New Anti-Diabetic Prescription Medications. Diabetes Metab Syndr Obes 2023; 16:3029-3044. [PMID: 37794899 PMCID: PMC10547008 DOI: 10.2147/dmso.s429068] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/22/2023] [Indexed: 10/06/2023] Open
Abstract
This article examined the current research on hyperuricemia (HUA) exacerbating diabetic kidney damage and novel anti-diabetic medications for treating these people. Hyperuricemia and type 2 diabetes (T2D), both of which are frequent metabolic disorders, are closely connected. Recent studies have shown that hyperuricemia can increase kidney injury in T2D patients by aggravating insulin resistance, by activating the renin-angiotensin-aldosterone system (RAAS), and by stimulating inflammatory factors, and the diversity, distribution, and metabolites of intestinal flora. Considering this, there are just a few of the research examining the effect of hyperuricemia on diabetic kidney injury via intestinal flora. Through the gut-kidney axis, intestinal flora primarily influences renal function. The primary mechanism is that variations in diversity, distribution, and metabolites of intestinal flora led to alterations in metabolites (such as short-chain fatty acids, Indoxyl sulfate and p-cresol sulfate, Trimethylamine N-oxide TMAO). This article reviewed the research and investigates the association between hyperuricemia and T2D, as well as the influence of hyperuricemia on diabetic kidney injury via intestinal flora. In addition, the current novel antidiabetic drugs are discussed, and their characteristics and mechanisms of action are reviewed. These novel antidiabetic drugs include SGLT2 inhibitors, GLP-1 receptor agonists, DDP-4 inhibitors, glucokinase (GK) enzyme activators (GK agonists), and mineralocorticoid receptor antagonists (MRA). Recent studies suggest that these new anti-diabetic medications may have a therapeutic effect on hyperuricemia-induced kidney impairment in diabetes patients via various mechanisms. Some of these medications may reduce blood uric acid levels, while others may improve kidney function by attenuating the overstimulation of RAAS or by decreasing insulin resistance and inflammation in the kidneys. These novel antidiabetic medicines may have a multifaceted approach to treating hyperuricemia-induced kidney impairment in diabetic patients; nevertheless, additional study is required to establish their efficacy and comprehend their specific mechanisms.
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Affiliation(s)
- Wei Yan
- Department of Endocrinology, Shanghai Pudong Hospital, n University, Shanghai, 201399, People’s Republic of China
- Department of General Practice, Jinshan Hospital, Fudan University, Shanghai, 201508, People’s Republic of China
| | - Song Wen
- Department of Endocrinology, Shanghai Pudong Hospital, n University, Shanghai, 201399, People’s Republic of China
| | - Ligang Zhou
- Department of Endocrinology, Shanghai Pudong Hospital, n University, Shanghai, 201399, People’s Republic of China
- Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
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12
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Luo L, Wang S, Chen B, Zhong M, Du R, Wei C, Huang F, Kou X, Xing Y, Tong G. Inhibition of inflammatory liver injury by the HMGB1-A box through HMGB1/TLR-4/NF-κB signaling in an acute liver failure mouse model. Front Pharmacol 2022; 13:990087. [PMID: 36313316 PMCID: PMC9614247 DOI: 10.3389/fphar.2022.990087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/29/2022] [Indexed: 11/17/2022] Open
Abstract
We aimed to investigate the preventive effect of high mobility group box 1 (HMGB1)-A box and the mechanism by which it alleviates inflammatory injury in acute liver failure (ALF) by inhibiting the extracellular release of HMGB1. BALB/c mice were intraperitoneally (i.p.) administered LPS/D-GalN to establish an ALF mouse model. HMGB1-A box was administered (i.p.) 1 h before establishing the ALF mouse model. The levels of extracellularly released HMGB1, TLR-4/NF-κB signaling molecules, the proinflammatory cytokines TNF-α, IL-1β, and IL-6 and COX-2 were measured in the liver tissue and/or serum by Immunohistochemistry, Western blotting and Enzyme-linked immunosorbent assay (ELISA). The levels of extracellularly released HMGB1, TLR-4/NF-κB signaling molecules and proinflammatory cytokines were measured in Huh7 cells as well as LPS- and/or HMGB1-A box treatment by confocal microscopy, Western blotting and ELISA. In the ALF mouse model, the levels of HMGB1 were significantly increased both in the liver and serum, TLR-4/NF-κB signaling molecules and proinflammatory cytokines also was upregulated. Notably, HMGB1-A box could reverse these changes. HMGB1-A box could also cause these changes in LPS-induced Huh7 cells. HMGB1-A box played a protective role by inhibiting inflammatory liver injury via the regulation of HMGB1/TLR-4/NF-κB signaling in the LPS/D-GaIN-induced ALF mouse model, which may be related to inhibiting the extracellular release of HMGB1.
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Affiliation(s)
- Lidan Luo
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Shuai Wang
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Bohao Chen
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, China
| | - Mei Zhong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, China
| | - Ruili Du
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, China
| | - ChunShan Wei
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Furong Huang
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Xinhui Kou
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Yufeng Xing
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Guangdong Tong
- Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
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Ma Q, Luan J, Bai Y, Xu C, Liu F, Chen B, Ju D, Xu H. Interleukin-22 in Renal Protection and Its Pathological Role in Kidney Diseases. Front Immunol 2022; 13:851818. [PMID: 35432360 PMCID: PMC9008451 DOI: 10.3389/fimmu.2022.851818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic kidney injury has gradually become a worldwide public health problem currently affecting approximately 10% of the population and can eventually progress to chronic end-stage renal disease characteristic by the result of epithelial atrophy. Interleukin-22 (IL-22) is a cytokine produced by activated immune cells, while acting mainly on epithelial cells ranging from innate immune response to tissue regeneration to maintain barrier integrity and promote wound healing. Accumulating data suggests that IL-22 has emerged as a fundamental mediator of epithelial homeostasis in the kidney through promoting tissue repair and regeneration, inhibiting oxidative stress, and producing antimicrobial peptides. Binding of IL-22 to its transmembrane receptor complex triggers janus kinase/tyrosine kinase 2 phosphorylation, which further activates a number of downstream cascades, including signal transducer and activator of transcription 3, MAP kinase, and protein kinase B, and initiates a wide array of downstream effects. However, the activation of the IL-22 signaling pathways promotes the activation of complement systems and enhances the infiltration of chemokines, which does harm to the kidney and may finally result in chronic renal failure of different autoimmune kidney diseases, including lupus nephritis, and IgA nephropathy. This review describes current knowledge of the basic features of IL-22, including structure, cellular origin and associated signaling pathways. Also, we summarize the latest progress in understanding the physiological and pathological effects of IL-22 in the kidney, suggesting the potential strategies for the specific application of this cytokine in the treatment of kidney disease.
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Affiliation(s)
- Qianqian Ma
- Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Jingyun Luan
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Yu Bai
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Caili Xu
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Fangyu Liu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bufeng Chen
- Department of Urology, Binzhou Medical University, Binzhou, China
| | - Dianwen Ju
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Hong Xu
- Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
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Wu H, Xie X, Sun M, Chen M, Tao X, Fang X, Meng X, Wei W, Yu M. Modification of mesenchymal stem cells by HMGB1 promotes the activity of Cav3.2 T-type calcium channel via PKA/β-catenin/γ-cystathionase pathway. Stem Cell Res Ther 2022; 13:4. [PMID: 35012644 PMCID: PMC8744322 DOI: 10.1186/s13287-021-02677-z] [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: 10/10/2021] [Accepted: 12/10/2021] [Indexed: 11/10/2022] Open
Abstract
Background Mesenchymal stem cells (MSC) hold great promise for treating cardiovascular disease. Recently, we genetically modified MSCs with high mobility group box 1 (HMGB1), and these cells demonstrated high mobility by efficient migrating and homing to target neointima. The possible mechanism was investigated in the current study. Methods Rat MSCs were transfected with lentivirus containing HMGB1 cDNA to yield MSC-H cell line stably overexpressing HMGB1. The MSC-C cells which were transfected with empty lentivirus served as negative control, and the differentially expressed genes were analyzed by microarray. The cell mobility was determined by transwell migration assay. Intracellular free calcium and the expression of Cav3.2 T-type calcium channel (CACNA1H) were assayed to analyze activity of CACNA1H-mediated calcium influx. H2S production and γ-cystathionase expression were examined to assess the activity of γ-cystathionase/H2S signaling. The interaction of HMGB1 with γ-cystathionase in MSC-H cells was analyzed by co-immunoprecipitation. Luciferase reporter assay was performed to determine whether the promoter activity of γ-cystathionase was regulated by interaction of β-catenin and TCF/LEF binding site. Intercellular cAMP, PKA activity, phosphorylation of β-catenin, and GSK3β were investigated to reveal cAMP/PKA mediated β-catenin activation. Result Microarray analysis revealed that differentially expressed genes were enriched in cAMP signaling and calcium signaling. CACNA1H was upregulated to increase intracellular free calcium and MSC-H cell migration. Blockage of CACNA1H by ABT-639 significantly reduced intracellular free calcium and cell migration. The γ-cystathionase/H2S signaling was responsible for CACNA1H activation. H2S production was increased with high expression of γ-cystathionase in MSC-H cells, which was blocked by γ-cystathionase inhibitor DL-propargylglycine. Upregulation of γ-cystathionase was not attributed to interaction with HMGB1 overexpressed in MSC-H cells although γ-cystathionase was suggested to co-immunoprecipitate with oxidized HMGB1. Bioinformatics analysis identified a conserved TCF/LEF binding site in the promoter of γ-cystathionase gene. Luciferase reporter assay confirmed that the promoter had positive response to β-catenin which was activated in MSC-H cells. Finally, cAMP/PKA was activated to phosphorylate β-catenin at Ser657 and GSK3β, enabling persisting activation of Wnt/β-catenin signaling in MSC-H cells. Conclusion Our study revealed that modification of MSCs with HMGB1 promoted CACNA1H-mediated calcium influx via PKA/β-catenin/γ-cystathionase pathway. This was a plausible mechanism for high mobility of MSC-H cell line. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02677-z.
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Affiliation(s)
- Hao Wu
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaodong Xie
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mingyang Sun
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Chen
- Department of Gastroenterology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
| | - Xuan Tao
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Fang
- Department of Vascular Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohu Meng
- Department of Vascular Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Wei
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Min Yu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Kimura Y, Tsukui D, Kono H. Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis. Int J Mol Sci 2021; 22:ijms222212394. [PMID: 34830282 PMCID: PMC8624633 DOI: 10.3390/ijms222212394] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/06/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hyperuricemia is a common metabolic syndrome. Elevated uric acid levels are risk factors for gout, hypertension, and chronic kidney diseases. Furthermore, various epidemiological studies have also demonstrated an association between cardiovascular risks and hyperuricemia. In hyperuricemia, reactive oxygen species (ROS) are produced simultaneously with the formation of uric acid by xanthine oxidases. Intracellular uric acid has also been reported to promote the production of ROS. The ROS and the intracellular uric acid itself regulate several intracellular signaling pathways, and alterations in these pathways may result in the development of atherosclerotic lesions. In this review, we describe the effect of uric acid on various molecular signals and the potential mechanisms of atherosclerosis development in hyperuricemia. Furthermore, we discuss the efficacy of treatments for hyperuricemia to protect against the development of atherosclerosis.
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Affiliation(s)
- Yoshitaka Kimura
- Department of Internal Medicine, Faculty of Medicine, Teikyo University of Medicine, Tokyo 173-8605, Japan; (Y.K.); (D.T.)
- Department of Microbiology and Immunology, Faculty of Medicine, Teikyo University of Medicine, Tokyo 173-8605, Japan
| | - Daisuke Tsukui
- Department of Internal Medicine, Faculty of Medicine, Teikyo University of Medicine, Tokyo 173-8605, Japan; (Y.K.); (D.T.)
| | - Hajime Kono
- Department of Internal Medicine, Faculty of Medicine, Teikyo University of Medicine, Tokyo 173-8605, Japan; (Y.K.); (D.T.)
- Correspondence: ; Tel.: +81-3-3964-1211
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Namba T, Tsuge M, Yashiro M, Saito Y, Liu K, Nishibori M, Morishima T, Tsukahara H. Anti-high mobility group box 1 monoclonal antibody suppressed hyper-permeability and cytokine production in human pulmonary endothelial cells infected with influenza A virus. Inflamm Res 2021; 70:1101-1111. [PMID: 34455489 PMCID: PMC8403468 DOI: 10.1007/s00011-021-01496-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 07/18/2021] [Accepted: 08/20/2021] [Indexed: 11/24/2022] Open
Abstract
Objective High mobility group box-1 (HMGB1) has been reported to be involved in influenza A virus-induced acute respiratory distress syndrome (ARDS). We studied the efficacy of an anti-HMGB1 mAb using an in vitro model of TNF-α stimulation or influenza A virus infection in human pulmonary microvascular endothelial cells (HMVECs). Methods Vascular permeability of HMVECs was quantified using the Boyden chamber assay under tumor necrosis factor-α (TNF-α) stimulation or influenza A virus infection in the presence of anti-HMGB1 mAb or control mAb. The intracellular localization of HMGB1 was assessed by immunostaining. Extracellular cytokine concentrations and intracellular viral mRNA expression were quantified by the enzyme-linked immunosorbent assay and quantitative reverse transcription PCR, respectively. Results Vascular permeability was increased by TNF-α stimulation or influenza A infection; HMVECs became elongated and the intercellular gaps were extended. Anti-HMGB1 mAb suppressed both the increase in permeability and the cell morphology changes. Translocation of HMGB1 to the cytoplasm was observed in the non-infected cells. Although anti-HMGB1 mAb did not suppress viral replication, it did suppress cytokine production in HMVECs. Conclusion Anti-HMGB1 mAb might be an effective therapy for severe influenza ARDS.
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Affiliation(s)
- Takahiro Namba
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Mitsuru Tsuge
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
| | - Masato Yashiro
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yukie Saito
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Keyue Liu
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masahiro Nishibori
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tsuneo Morishima
- Department of Pediatrics, Aichi Medical University, Nagakute, Japan
| | - Hirokazu Tsukahara
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1497449. [PMID: 34307650 PMCID: PMC8285185 DOI: 10.1155/2021/1497449] [Citation(s) in RCA: 465] [Impact Index Per Article: 116.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022]
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are the main risk factors for the development of DN. In general, screening for microalbuminuria should be performed annually, starting 5 years after diagnosis in type 1 diabetes and at diagnosis and annually thereafter in type 2 diabetes. Standard therapy is blood glucose and blood pressure control using the renin-angiotensin system blockade, targeting A1c < 7%, and <130/80 mmHg. Regression of albuminuria remains an important therapeutic goal. However, there are problems in diagnosis and treatment of nonproteinuric DN (NP-DN), which does not follow the classic pattern of DN. In fact, the prevalence of DN continues to increase, and additional therapy is needed to prevent or ameliorate the condition. In addition to conventional therapies, vitamin D receptor activators, incretin-related drugs, and therapies that target inflammation may also be promising for the prevention of DN progression. This review focuses on the role of inflammation and oxidative stress in the pathogenesis of DN, approaches to diagnosis in classic and NP-DN, and current and emerging therapeutic interventions.
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Deng Y, Liu F, Yang X, Xia Y. The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation. Front Cardiovasc Med 2021; 8:641136. [PMID: 33718459 PMCID: PMC7952317 DOI: 10.3389/fcvm.2021.641136] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/03/2021] [Indexed: 12/26/2022] Open
Abstract
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia that leads to numerous adverse outcomes including stroke, heart failure, and death. Hyperuricemia is an important risk factor that contributes to atrium injury and AF, but the underlying molecular mechanism remains to be elucidated. In this review, we discussed the scientific evidence for clarifying the role of hyperuricemia in the pathogenesis of AF. Experimental and Clinical evidence endorse hyperuricemia as an independent risk factor for the incidence of AF. Various in vivo and in vitro investigations showed that hyperuricemia might play a critical role in the pathogenesis of AF at different UA concentrations through the activation of oxidative stress, inflammation, fibrosis, apoptosis, and immunity.
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Affiliation(s)
- Yawen Deng
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fei Liu
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaolei Yang
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yunlong Xia
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
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Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib. Toxicol Lett 2020; 338:1-9. [PMID: 33248157 DOI: 10.1016/j.toxlet.2020.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 11/10/2020] [Accepted: 11/13/2020] [Indexed: 01/02/2023]
Abstract
Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity.
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Morris G, Puri BK, Olive L, Carvalho A, Berk M, Walder K, Gustad LT, Maes M. Endothelial dysfunction in neuroprogressive disorders-causes and suggested treatments. BMC Med 2020; 18:305. [PMID: 33070778 PMCID: PMC7570030 DOI: 10.1186/s12916-020-01749-w] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. MAIN TEXT Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction. CONCLUSIONS Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.
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Affiliation(s)
- Gerwyn Morris
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
| | | | - Lisa Olive
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
- School of Psychology, Faculty of Health, Deakin University, Geelong, Australia
| | - Andre Carvalho
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - Michael Berk
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia.
- Orygen, The National Centre of Excellence in Youth Mental Health, the Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
| | - Ken Walder
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
| | - Lise Tuset Gustad
- Department of Circulation and medical imaging, Norwegian University of Technology and Science (NTNU), Trondheim, Norway
- Nord-Trøndelag Hospital Trust, Levanger Hospital, Levanger, Norway
| | - Michael Maes
- IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
- Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
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Zhao Z, Hu Z, Zeng R, Yao Y. HMGB1 in kidney diseases. Life Sci 2020; 259:118203. [PMID: 32781069 DOI: 10.1016/j.lfs.2020.118203] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/31/2020] [Accepted: 08/01/2020] [Indexed: 12/20/2022]
Abstract
High mobility group box 1 (HMGB1) is a highly conserved nucleoprotein involving in numerous biological processes, and well known to trigger immune responses as the damage-associated molecular pattern (DAMP) in the extracellular environment. The role of HMGB1 is distinct due to its multiple functions in different subcellular location. In the nucleus, HMGB1 acts as a chaperone to regulate DNA events including DNA replication, repair and nucleosome stability. While in the cytoplasm, it is engaged in regulating autophagy and apoptosis. A great deal of research has explored its function in the pathogenesis of renal diseases. This review mainly focuses on the role of HMGB1 and summarizes the pathway and treatment targeting HMGB1 in the various renal diseases which may open the windows of opportunities for the development of desirable therapeutic ends in these pathological conditions.
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Affiliation(s)
- Zhi Zhao
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China
| | - Zhizhi Hu
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China
| | - Rui Zeng
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China.
| | - Ying Yao
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China.
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Zawada AM, Carrero JJ, Wolf M, Feuersenger A, Stuard S, Gauly A, Winter AC, Ramos R, Fouque D, Canaud B. Serum Uric Acid and Mortality Risk Among Hemodialysis Patients. Kidney Int Rep 2020; 5:1196-1206. [PMID: 32775819 PMCID: PMC7403560 DOI: 10.1016/j.ekir.2020.05.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/29/2020] [Accepted: 05/18/2020] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION Although high serum uric acid (SUA) has been consistently associated with an increased risk of death in the general population and in persons with nondialysis chronic kidney disease (CKD), studies in patients undergoing dialysis are conflicting. It has been postulated that low SUA simply reflects poor nutritional status in dialysis patients. We here characterize the association between SUA and the risk of death in a large dialysis cohort and explore effect modification by underlying nutritional status as reflected by body composition. METHODS In this retrospective cohort study, we included 16,057 hemodialysis (HD) patients treated during 2007 to 2016 in NephroCare centers as recorded in the European Clinical Database (EuCliD). The association between SUA, all-cause, and cardiovascular (CV)-related mortality was evaluated with competing risk models and characterized with splines. Effect modification was explored by lean tissue index (LTI) and fat tissue index (FTI). RESULTS During a mean of 1.8 years of follow-up, 2791 patients (17.4%) died. We found a multivariable-adjusted U-shaped pattern between SUA and all-cause mortality. Patients with SUA levels of 6.5 mg/dl (387 μmol/l) were at the lowest risk of death (subdistribution hazard ratio = 0.94 [confidence interval {CI} 0.91; 0.96]). The form of association was not meaningfully affected by underlying LTI and FTI. CONCLUSION We found a U-shaped pattern between SUA levels and all-cause mortality among HD patients, which was independent of the patients' body composition.
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Affiliation(s)
- Adam M. Zawada
- Fresenius Medical Care Deutschland GmbH, EMEA Medical Office, Bad Homburg, Germany
| | - Juan Jesus Carrero
- European Renal Nutrition (ERN) Working Group of the European Renal Association–European Dialysis Transplant Association (ERA-EDTA), London, United Kingdom
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Melanie Wolf
- Fresenius Medical Care Deutschland GmbH, EMEA Medical Office, Bad Homburg, Germany
| | - Astrid Feuersenger
- Fresenius Medical Care Deutschland GmbH, EMEA Medical Office, Bad Homburg, Germany
| | - Stefano Stuard
- Fresenius Medical Care Deutschland GmbH, Global Medical Office—Clinical & Therapeutic Governance EMEA, Bad Homburg, Germany
| | - Adelheid Gauly
- Fresenius Medical Care Deutschland GmbH, EMEA Medical Office, Bad Homburg, Germany
| | - Anke C. Winter
- Fresenius Medical Care Deutschland GmbH, EMEA Medical Office, Bad Homburg, Germany
| | - Rosa Ramos
- Fresenius Medical Care España, S.A., Departamento Dirección Médica, Tres Cantos, Spain
| | - Denis Fouque
- European Renal Nutrition (ERN) Working Group of the European Renal Association–European Dialysis Transplant Association (ERA-EDTA), London, United Kingdom
- Department of Nephrology, Université de Lyon, UCBL, Carmen, Centre Hospitalier Lyon-Sud, Pierre Bénite, France
| | - Bernard Canaud
- Fresenius Medical Care Deutschland GmbH, Global Medical Office, Bad Homburg, Germany
- University of Montpellier, School of Medicine, Montpellier, France
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Zou Z, Chen S, Li Y, Cai J, Fang Y, Xie J, Fang W, Kang D, Xu Y. Risk factors for renal failure and short-term prognosis in patients with spontaneous intracerebral haemorrhage complicated by acute kidney injury. BMC Nephrol 2020; 21:311. [PMID: 32727417 PMCID: PMC7391601 DOI: 10.1186/s12882-020-01949-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 07/13/2020] [Indexed: 11/21/2022] Open
Abstract
Background Although acute kidney injury (AKI) is a known risk factor for adverse clinical outcomes in patients with spontaneous intracerebral haemorrhage (SICH), little is known about the predisposing factors that contribute to renal failure and short-term prognosis in the setting of SICH already complicated by AKI. In this study, we aimed to identify the renal failure factors in SICH patents with AKI. Methods Five hundred forty-three patients with SICH complicated by differential severities of AKI who were admitted to the First Affiliated Hospital of Fujian Medical University from January 2016 to December 2018 were retrospectively studied. Logistic regression and receiver operator characteristic (ROC) curve analysis were performed to determine the best predictive and discriminative variables. Multivariate Cox regression analysis was performed to identify prognostic factors for renal recovery. Results In the multivariable adjusted model, we found that hypernatremia, metabolic acidosis, elevated serum creatine kinase, hyperuricaemia, proteinuria, and the use of colloids and diuretics were all independent risk factors for the occurrence of stage 3 AKI in SICH patients. The area under the curve analysis indicated that hypernatremia and hyperuricaemia were predictive factors for stage 3 AKI, and the combination of these two parameters increased their predictability for stage 3 AKI. Kaplan-Meier survival curves revealed that the renal recovery rate in SICH patients with stages 1 and 2 AKI was significantly higher than that in SICH patients with stage 3 AKI. Multivariate Cox regression analysis suggested that hypernatremia and the occurrence of stage 3 AKI are predictors for poor short-term renal recovery. Conclusions These findings illustrate that hypernatremia and hyperuricaemia represent potential risk factors for the occurrence of stage 3 AKI in SICH patients. Those patients with hypernatremia and stage 3 AKI were associated with a poor short-term prognosis in renal recovery.
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Affiliation(s)
- Zhenhuan Zou
- Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
| | - Siying Chen
- Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
| | - Yinshuang Li
- Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
| | - Jiawei Cai
- Department of Neurosurgery, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Yulu Fang
- Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
| | - Jingzhi Xie
- Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
| | - Wenhua Fang
- Department of Neurosurgery, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Dezhi Kang
- Department of Neurosurgery, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Yanfang Xu
- Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China.
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Research Advances in the Mechanisms of Hyperuricemia-Induced Renal Injury. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5817348. [PMID: 32685502 PMCID: PMC7336201 DOI: 10.1155/2020/5817348] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/03/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022]
Abstract
Uric acid is the end product of purine metabolism in humans, and its excessive accumulation leads to hyperuricemia and urate crystal deposition in tissues including joints and kidneys. Hyperuricemia is considered an independent risk factor for cardiovascular and renal diseases. Although the symptoms of hyperuricemia-induced renal injury have long been known, the pathophysiological molecular mechanisms are not completely understood. In this review, we focus on the research advances in the mechanisms of hyperuricemia-caused renal injury, primarily on oxidative stress, endothelial dysfunction, renal fibrosis, and inflammation. Furthermore, we discuss the progress in hyperuricemia management.
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25
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Jung SW, Kim SM, Kim YG, Lee SH, Moon JY. Uric acid and inflammation in kidney disease. Am J Physiol Renal Physiol 2020; 318:F1327-F1340. [PMID: 32223310 DOI: 10.1152/ajprenal.00272.2019] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Asymptomatic hyperuricemia is frequently observed in patients with kidney disease. Although a substantial number of epidemiologic studies have suggested that an elevated uric acid level plays a causative role in the development and progression of kidney disease, whether hyperuricemia is simply a result of decreased renal excretion of uric acid or is a contributor to kidney disease remains a matter of debate. Over the last two decades, multiple experimental studies have expanded the knowledge of the biological effects of uric acid beyond its role in gout. In particular, uric acid induces immune system activation and alters the characteristics of resident kidney cells, such as tubular epithelial cells, endothelial cells, and vascular smooth muscle cells, toward a proinflammatory and profibrotic state. These findings have led to an increased awareness of uric acid as a potential and modifiable risk factor in kidney disease. Here, we discuss the effects of uric acid on the immune system and subsequently review the effects of uric acid on the kidneys mainly in the context of inflammation.
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Affiliation(s)
- Su Woong Jung
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Republic of Korea
| | - Su-Mi Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Republic of Korea
| | - Yang Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Republic of Korea
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Republic of Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Republic of Korea
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26
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Synergistic effect of Aconiti Lateralis Radix Praeparata water-soluble alkaloids and Ginseng Radix et Rhizoma total ginsenosides compatibility on acute heart failure rats. J Chromatogr B Analyt Technol Biomed Life Sci 2020; 1137:121935. [DOI: 10.1016/j.jchromb.2019.121935] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 11/16/2019] [Accepted: 12/06/2019] [Indexed: 11/23/2022]
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Du J, Kong X, Liang L, Chen Q, Yin L, Xu D. Plasma D-Dimer Level and the Failure of Forearm Autologous Arteriovenous Fistula in Patients With End-Stage Renal Disease. Ther Apher Dial 2019; 24:400-407. [PMID: 31705787 DOI: 10.1111/1744-9987.13454] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 10/11/2019] [Accepted: 11/06/2019] [Indexed: 11/28/2022]
Abstract
Failed autologous arteriovenous fistula (AVF) is a major issue in the creation of functional hemodialysis vascular access. To date, the relationship between D-dimer and AVF failure is still uncertain. Hence, we conducted a retrospective cohort study to explore the patency rate of forearm AVFs and to clarify whether plasma D-dimer level can predict the failure of AVFs. In this study, 290 ESRD patients (the mean age 54.1 ± 14.6 years, 63.8% of them were males) receiving forearm AVFs surgery were consecutively enrolled with a median follow-up time of 34 months. Primary patency rates and risk factors associated with AVFs failure were explored by the Kaplan-Meier method or Cox proportional hazards model. Patients were divided into two groups based on the median level of D-dimer (group 1 <1.1 mg/L and group 2 ≥1.1 mg/L). The Kaplan-Meier survival analysis demonstrated that the patency of AVF in group 1 was similar in group 2, which were 92.4% versus 88.9%, 84.8% versus 84.0%, 80.0% versus 79.2%, 76.7% versus 78.5%, and 76.7% versus 78.5% at 12, 24, 36, 48, and 60 months (Log-rank test, P = 0.8), respectively. In the crude analysis, D-dimer (per 1 mg/L increase) was independently associated with AVFs failure, with OR of 1.08 (95% CI, 1.02-1.15). However, after adjusting for potential confounders, the D-dimer (per 1 mg/L increase) was not associated with the AVFs failure (OR = 1.06, 95% CI = 0.99-1.13). This study did not find that the plasma D-dimer level can predict the failure of forearm AVFs.
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Affiliation(s)
- Jing Du
- Department of Nephrology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.,Center of Blood Purification, Weifang People's Hospital, Weifang, China
| | - Xianglei Kong
- Department of Nephrology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Liming Liang
- Department of Nephrology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Qinlan Chen
- Department of Nephrology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Lili Yin
- Center of Blood Purification, Weifang People's Hospital, Weifang, China
| | - Dongmei Xu
- Department of Nephrology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, China.,Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.,Nephrology Research Institute of Shandong Province, Jinan, China
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Kopel J, Pena-Hernandez C, Nugent K. Evolving spectrum of diabetic nephropathy. World J Diabetes 2019; 10:269-279. [PMID: 31139314 PMCID: PMC6522757 DOI: 10.4239/wjd.v10.i5.269] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/13/2019] [Accepted: 05/13/2019] [Indexed: 02/05/2023] Open
Abstract
Diabetes remains an important health issue as more patients with chronic and uncontrolled diabetes develop diabetic nephropathy (DN), which classically presents with proteinuria followed by a progressive decrease in renal function. However, an increasing proportion of DN patients have a decline in kidney function and vascular complications without proteinuria, known as non-proteinuric DN (NP-DN). Despite the increased incidence of NP-DN, few clinical or experimental studies have thoroughly investigated the pathophysiological mechanisms and targeted treatment for this form of DN. In this review, we will examine the differences between conventional DN and NP-DN and consider potential pathophysiological mechanisms, diagnostic markers, and treatment for both DN and NP-DN. The investigation of the pathophysiology of NP-DN should provide additional insight into the cardiovascular factors influencing renal function and disease and provide novel treatments for the vascular complications seen in diabetic patients.
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Affiliation(s)
- Jonathan Kopel
- Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79416, United States
| | - Camilo Pena-Hernandez
- Department of Internal Medicine, Division of Nephrology, Lubbock, TX 79430, United States
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States
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Wang Y, Wang L, Gong Z. Regulation of Acetylation in High Mobility Group Protein B1 Cytosol Translocation. DNA Cell Biol 2019; 38:491-499. [PMID: 30874449 DOI: 10.1089/dna.2018.4592] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
High mobility group protein B1 (HMGB1) is a nonhistone that mainly binds to nucleus DNA. As an important late inflammatory transmitter, extracellular HMGB1 is involved in the inflammatory immune response, tumor growth, infiltration, and metastasis. HMGB1 is actively released by activated inflammatory cells or passively released by necrotic cells. Then the released extracellular HMGB1 further induces monocytes/macrophages, neutrophils, and dendritic cells to secrete inflammatory cytokines. Therefore, HMGB1 can not only act as a proinflammatory factor to directly involve in tissue damage, but also acts as an inflammatory medium to aggravate the inflammatory cascade reaction. Studies have shown that the post-translational modification (PTM) participated in the process of HMGB1 cytosol translocation and extracellular release. The acetylation modification is the most common PTM for localization sequence of HMGB1, and the affinity of HMGB1 to DNA depends on the degree of acetylation for HMGB1. The acetylation can weaken the binding of HMGB1 to DNA, which means less HMGB1 cytosol translocation and extracellular release. This article reviews the acetylation regulation mechanisms of cytosol translocation and extracellular release of HMGB1 and provides a therapeutic strategy for controlling HMGB1-induced inflammatory responses in the future.
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Affiliation(s)
- Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Luwen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
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Tao X, Sun M, Chen M, Ying R, Su W, Zhang J, Xie X, Wei W, Meng X. HMGB1-modified mesenchymal stem cells attenuate radiation-induced vascular injury possibly via their high motility and facilitation of endothelial differentiation. Stem Cell Res Ther 2019; 10:92. [PMID: 30867070 PMCID: PMC6416980 DOI: 10.1186/s13287-019-1197-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/25/2019] [Accepted: 02/28/2019] [Indexed: 12/28/2022] Open
Abstract
Background Vascular injury is one of the most common detrimental effects of cancer radiotherapy on healthy tissues. Since the efficacy of current preventive and therapeutic strategies remains limited, the exploration of new approaches to treat radiation-induced vascular injury (RIV) is on high demands. The use of mesenchymal stem cells (MSCs) to treat RIV holds great promise thanks to their well-documented function of mediating tissue regeneration after injury. Recently, we genetically modified MSCs with high mobility group box 1 (HMGB1) and demonstrated the high efficacy of these cells in treating graft atherosclerosis. The current study was to investigate the protective effect of HMGB1-modified MSCs (MSC-H) on RIV by using a rat model. Methods Female F344 rats received an intravenous injection of male F344 MSC-H cells or vehicle control at four doses of 2 × 106 cells with a 15-day interval starting from 30 days after irradiation to the abdominal aorta. The aortas were procured for histological and biomedical analysis at 90 days after irradiation. Cell migration to irradiated aortas was traced by green fluorescent protein and sex determination region on the Y chromosome. In vitro cell migration and endothelial differentiation of MSC-H cells were analyzed by stromal-derived factor 1-induced transwell assay and RNA microarray, respectively. The contribution of extracellular HMGB1 to the bioactivity of MSC-H cells was investigated by inhibition experiments with HMGB1 antibody. Result MSC-H cell infusion alleviated neointimal formation, vascular inflammation, and fibrosis in irradiated aortas, which was associated with local migration and endothelial differentiation of MSC-H cells. The MSC-H cells showed high motility and potential of endothelial differentiation in vitro. Microarray analysis suggested multiple pathways like MAPK and p53 signaling were activated during endothelial differentiation. MSC-H cells highly expressed CXC chemokine receptor 4 and migrated progressively after stromal-derived factor 1 stimulation, which was blocked by the antagonist of CXC chemokine receptor 4. Finally, the migration and endothelial differentiation of MSC-H cells were inhibited by HMGB1 antibody. Conclusion MSC-H cell infusion significantly attenuated RIV, which was associated with their high motility and endothelial differentiation potential. Multiple pathways that possibly contributed to the efficacy of MSC-H cells were suggested and deserved further investigation. Electronic supplementary material The online version of this article (10.1186/s13287-019-1197-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xuan Tao
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mingyang Sun
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Chen
- Department of Gastroenterology, Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing, China
| | - Rongchao Ying
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenjie Su
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Zhang
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaodong Xie
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Wei
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China. .,Department of Gastroenterological Surgery, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.
| | - Xiaohu Meng
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Srivastava A, Palsson R, Leaf DE, Higuera A, Chen ME, Palacios P, Baron RM, Sabbisetti V, Hoofnagle AN, Vaingankar SM, Palevsky PM, Waikar SS. Uric Acid and Acute Kidney Injury in the Critically Ill. Kidney Med 2019; 1:21-30. [PMID: 32734180 PMCID: PMC7380422 DOI: 10.1016/j.xkme.2019.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Rationale & Objective Uric acid is excreted by the kidney and accumulates in acute kidney injury (AKI). Whether higher plasma uric acid level predisposes to AKI or its complications is not known. Study Design Prospective observational cohort study. Setting & Participants 2 independent cohorts of critically ill patients: (1) 208 patients without AKI admitted to the intensive care unit (ICU) at Brigham & Women's Hospital between October 2008 and December 2016; and (2) 250 participants with AKI requiring renal replacement therapy (RRT) who had not yet initiated RRT enrolled in the Acute Renal Failure Trial Network (ATN) Study. Exposure Plasma uric acid level upon ICU admission and before RRT initiation in the ICU and ATN Study cohorts, respectively. Outcomes Incident AKI and 60-day mortality in the ICU and ATN Study cohorts, respectively. Analytical Approach Logistic regression models were used to test the association of plasma uric acid level with incident AKI and 60-day mortality. Results In the ICU cohort, median plasma uric acid level was 4.7 (interquartile range [IQR], 3.6-6.4) mg/dL, and 40 patients (19.2%) developed AKI. Higher plasma uric acid levels associated with incident AKI, but this association was confounded by serum creatinine level and was not significant after multivariable adjustment (adjusted OR per doubling of uric acid, 1.50; 95% CI, 0.80-2.81). In the ATN Study cohort, median plasma uric acid level was 11.1 (IQR, 8.6-14.2) mg/dL, and 125 participants (50.0%) died within 60 days. There was no statistically significant association between plasma uric acid levels and 60-day mortality in either unadjusted models or after multivariable adjustment for demographic, severity-of-illness, and kidney-specific covariates (adjusted OR per doubling of uric acid, 1.15; 95% CI, 0.71-1.86). Limitations Heterogeneity of ICU patients. Conclusions Plasma uric acid levels upon ICU admission or before RRT initiation are not independently associated with adverse clinical outcomes in critically ill patients.
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Affiliation(s)
- Anand Srivastava
- Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.,Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
| | - Ragnar Palsson
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
| | - Angelica Higuera
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA
| | - Margaret E Chen
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA
| | - Polly Palacios
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
| | - Rebecca M Baron
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA
| | | | - Andrew N Hoofnagle
- Department of Laboratory Medicine, University of Washington, Seattle, WA
| | | | - Paul M Palevsky
- Renal Section, Veterans Affairs Pittsburgh Healthcare System and Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Sushrut S Waikar
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
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Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and Consequences of Necroinflammation. Physiol Rev 2018; 98:727-780. [PMID: 29465288 DOI: 10.1152/physrev.00041.2016] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium and thereby represent the strongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflammation can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each particular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions.
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Affiliation(s)
- Maysa Sarhan
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Walter G Land
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Wulf Tonnus
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Christian P Hugo
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Andreas Linkermann
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
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Luo P, Xu Z, Li G, Yan H, Zhu Y, Zhu H, Ma S, Yang B, He Q. HMGB1 represses the anti-cancer activity of sunitinib by governing TP53 autophagic degradation via its nucleus-to-cytoplasm transport. Autophagy 2018; 14:2155-2170. [PMID: 30205729 PMCID: PMC6984767 DOI: 10.1080/15548627.2018.1501134] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Sunitinib, a multikinase inhibitor approved for a number of cancer indications has a low response rate. Identifying mechanisms of resistance could lead to rational combination regimens that could improve clinical outcomes. Here we report that resistance to sunitinib therapy was driven by autophagic degradation of TP53/p53. Deletion of ATG7 or ATG5 suppressed TP53 degradation, as did knockdown of SQSTM1/p62. Mechanistically, the transport of TP53 from the nucleus to the cytoplasm was essential for the sunitinib-induced autophagic degradation of TP53 and did not require TP53 nuclear export signals (NESs). Moreover, TP53 degradation was achieved by the transport of its nuclear binding target, HMGB1, which shifted TP53 from the nucleus to the cytoplasm. The inhibition of HMGB1 sensitized cancer cells to sunitinib. Importantly, sunitinib induced the degradation of all TP53 proteins, except for TP53 proteins with mutations in the interaction domain of TP53 with HMGB1 (amino acids 313 to 352). In conclusion, our data identify an alternative HMGB1-mediated TP53 protein turnover mechanism that participates in the resistance of sunitinib and suggest HMGB1 as a potential therapeutic target for improving clinical outcomes of sunitinib.
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Affiliation(s)
- Peihua Luo
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
| | - Zhifei Xu
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
| | - Guanqun Li
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
| | - Hao Yan
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
| | - Yi Zhu
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
| | - Hong Zhu
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
| | - Shenglin Ma
- b Department of Oncology , Hangzhou First People's Hospital, Nanjing Medical University , Hangzhou , China
| | - Bo Yang
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
| | - Qiaojun He
- a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China
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High-mobility group box 1 is responsible for monosodium urate crystal-induced inflammation in human U937 macrophages. Biochem Biophys Res Commun 2018; 503:3248-3255. [DOI: 10.1016/j.bbrc.2018.08.139] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/23/2018] [Indexed: 01/21/2023]
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Rajaee A, Barnett R, Cheadle WG. Pathogen- and Danger-Associated Molecular Patterns and the Cytokine Response in Sepsis. Surg Infect (Larchmt) 2018; 19:107-116. [DOI: 10.1089/sur.2017.264] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
- Arezoo Rajaee
- Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Rebecca Barnett
- Department of Surgery, University of Louisville, Louisville, Kentucky
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Srivastava A, Kaze AD, McMullan CJ, Isakova T, Waikar SS. Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD. Am J Kidney Dis 2017; 71:362-370. [PMID: 29132945 DOI: 10.1053/j.ajkd.2017.08.017] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 08/10/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown. STUDY DESIGN Prospective observational cohort study. SETTINGS & PARTICIPANTS 3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013. PREDICTOR Baseline uric acid concentrations. OUTCOMES Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality. RESULTS During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ≥ 45mL/min/1.73m2 (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m2. There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007). LIMITATIONS Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time. CONCLUSIONS Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD.
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Affiliation(s)
- Anand Srivastava
- Renal Division, Brigham & Women's Hospital, Boston, MA; Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
| | - Arnaud D Kaze
- Renal Division, Brigham & Women's Hospital, Boston, MA
| | | | - Tamara Isakova
- Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
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Abstract
During sepsis, the alarmin HMGB1 is released from tissues and promotes systemic inflammation that results in multi-organ damage, with the kidney particularly susceptible to injury. The severity of inflammation and pro-damage signaling mediated by HMGB1 appears to be dependent on the alarmin's redox state. Therefore, we examined HMGB1 redox in kidney cells during sepsis. Using intravital microscopy, CellROX labeling of kidneys in live mice indicated increased ROS generation in the kidney perivascular endothelium and tubules during lipopolysaccharide (LPS)-induced sepsis. Subsequent CellROX and MitoSOX labeling of LPS-stressed endothelial and kidney proximal tubule cells demonstrated increased ROS generation in these cells as sepsis worsens. Consequently, HMGB1 oxidation increased in the cytoplasm of kidney cells during its translocation from the nucleus to the circulation, with the degree of oxidation dependent on the severity of sepsis, as measured in in vivo mouse samples using a thiol assay and mass spectrometry (LC-MS/MS). The greater the oxidation of HMGB1, the greater the ability of the alarmin to stimulate pro-inflammatory cyto-/chemokine release (measured by Luminex Multiplex) and alter mitochondrial ATP generation (Luminescent ATP Detection Assay). Administration of glutathione and thioredoxin inhibitors to cell cultures enhanced HMGB1 oxidation during sepsis in endothelial and proximal tubule cells, respectively. In conclusion, as sepsis worsens, ROS generation and HMGB1 oxidation increases in kidney cells, which enhances HMGB1's pro-inflammatory signaling. Conversely, the glutathione and thioredoxin systems work to maintain the protein in its reduced state.
Endotoxins (LPS) increase cellular oxidative stress during sepsis. During its translocation, HMGB1 gets oxidized in the cytoplasm. Thioredoxin and glutathione keep HMGB1 in a reduced redox state during sepsis. HMGB1 oxidation enhances its stimulation of inflammatory cyto-/chemokine release.
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Uric Acid Induces Endothelial Dysfunction by Activating the HMGB1/RAGE Signaling Pathway. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4391920. [PMID: 28116308 PMCID: PMC5237466 DOI: 10.1155/2017/4391920] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Revised: 10/25/2016] [Accepted: 11/06/2016] [Indexed: 02/07/2023]
Abstract
Uric acid (UA) is a risk factor for endothelial dysfunction, a process in which inflammation may play an important role. UA increases high mobility group box chromosomal protein 1 (HMGB1) expression and extracellular release in endothelial cells. HMGB1 is an inflammatory cytokine that interacts with the receptor for advanced glycation end products (RAGE), inducing an oxidative stress and inflammatory response, which leads to endothelial dysfunction. In this study, human umbilical vein endothelial cells (HUVECs) were incubated with a high concentration of UA (20 mg/dL) after which endothelial function and the expression of HMGB1, RAGE, nuclear factor kappa B (NF-κB), inflammatory cytokines, and adhesion molecules were evaluated. UA inhibited endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production in HUVECs, increased intracellular HMGB1 expression and extracellular HMGB1 secretion, and upregulated RAGE expression. UA also activated NF-κB and increased the level of inflammatory cytokines. Blocking RAGE significantly suppressed the upregulation of RAGE and HMGB1 and prevented the increase in DNA binding activity of NF-κB and the levels of inflammatory cytokines. It also blocked the decrease in eNOS expression and NO production induced by UA. Our results suggest that high concentrations of UA cause endothelial dysfunction via the HMGB1/RAGE signaling pathway.
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Zhou JQ, Qiu T, Zhang L, Chen ZB, Wang ZS, Ma XX, Li D. Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model. Acta Cir Bras 2016; 31:176-82. [PMID: 27050788 DOI: 10.1590/s0102-865020160030000005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 02/15/2016] [Indexed: 01/15/2023] Open
Abstract
PURPOSE To investigate the potential effects of pretreatment with allopurinol on renal ischemia/reperfusion injury (IRI) in a rat model. METHODS Twenty four rats were subjected to right kidney uninephrectomy were randomly distributed into the following three groups (n=8): Group A (sham-operated group); Group B (ischemic group) with 30 min of renal ischemia after surgery; and Group C (allopurinol + ischemia group) pretreated with allopurinol at 50 mg/kg for 14 days. At 72 h after renal reperfusion, the kidney was harvested to assess inflammation and apoptosis. RESULTS Pretreatment with allopurinol significantly improved renal functional and histological grade scores following I/R injury (p<0.05). Compared with Group B, the expression levels of caspase-3 and Bax were markedly reduced in Group C, meanwhile, whereas expression of bcl-2 was clearly increased (p<0.05). A newly described marker of inflammation, High Mobility Group Box 1(HMGB1), showed reduced expression in Group C (p<0.05). CONCLUSION Pretreatment with allopurinol had a protective effect on kidney ischemia/reperfusion injury, which might be related to the inhibition of HMGB1 expression.
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Affiliation(s)
- Jiang-qiao Zhou
- Department of Organ Transplantation, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
| | - Tao Qiu
- Department of Organ Transplantation, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
| | - Lu Zhang
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
| | - Zhong-bao Chen
- Department of Organ Transplantation, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
| | - Zhi-shun Wang
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
| | - Xiao-xiong Ma
- Department of Organ Transplantation, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
| | - Dongyu Li
- Intensive Care Unit, PuAi Hospital, Anlu, Hubei, China
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Land WG, Agostinis P, Gasser S, Garg AD, Linkermann A. Transplantation and Damage-Associated Molecular Patterns (DAMPs). Am J Transplant 2016; 16:3338-3361. [PMID: 27421829 DOI: 10.1111/ajt.13963] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/24/2016] [Accepted: 07/10/2016] [Indexed: 01/25/2023]
Abstract
Upon solid organ transplantation and during cancer immunotherapy, cellular stress responses result in the release of damage-associated molecular patterns (DAMPs). The various cellular stresses have been characterized in detail over the last decades, but a unifying classification based on clinically important aspects is lacking. Here, we provide an in-depth review of the most recent literature along with a unifying concept of the danger/injury model, suggest a classification of DAMPs, and review the recently elaborated mechanisms that result in the emission of such factors. We further point out the differences in DAMP responses including the release following a heat shock pattern, endoplasmic reticulum stress, DNA damage-mediated DAMP release, and discuss the diverse pathways of regulated necrosis in this respect. The understanding of various forms of DAMPs and the consequences of their different release patterns are prerequisite to associate serum markers of cellular stresses with clinical outcomes.
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Affiliation(s)
- W G Land
- German Academy of Transplantation Medicine, Munich, Germany.,Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,LabexTRANSPLANTEX, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - P Agostinis
- Cell Death Research and Therapy (CDRT) Lab, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, Leuven, Belgium
| | - S Gasser
- Immunology Programme and Department of Microbiology and Immunology, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - A D Garg
- Cell Death Research and Therapy (CDRT) Lab, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, Leuven, Belgium
| | - A Linkermann
- Cluster of Excellence EXC306, Inflammation at Interfaces, Schleswig-Holstein, Germany.,Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany
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NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy? J Immunol Res 2016; 2016:4684268. [PMID: 27294158 PMCID: PMC4880686 DOI: 10.1155/2016/4684268] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 04/10/2016] [Indexed: 12/31/2022] Open
Abstract
Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue.
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Chen H, Guan B, Shen J. Targeting ONOO -/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment. ACTA ACUST UNITED AC 2016. [DOI: 10.1159/000442468] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Chen Y, Pitzer AL, Li X, Li PL, Wang L, Zhang Y. Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1. J Cell Mol Med 2015; 19:2715-27. [PMID: 26293846 PMCID: PMC4687695 DOI: 10.1111/jcmm.12657] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 06/23/2015] [Indexed: 01/24/2023] Open
Abstract
Recent studies have indicated that the inflammasome plays a critical role in the pathogenesis of vascular diseases. However, the pathological relevance of this inflammasome activation, particularly in vascular cells, remains largely unknown. Here, we investigated the role of endothelial (Nucleotide‐binding Oligomerization Domain) NOD‐like receptor family pyrin domain containing three (Nlrp3) inflammasomes in modulating inter‐endothelial junction proteins, which are associated with endothelial barrier dysfunction, an early onset of obesity‐associated endothelial injury. Our findings demonstrate that the activation of Nlrp3 inflammasome by visfatin markedly decreased the expression of inter‐endothelial junction proteins including tight junction proteins ZO‐1, ZO‐2 and occludin, and adherens junction protein VE‐cadherin in cultured mouse vascular endothelial (VE) cell monolayers. Such visfatin‐induced down‐regulation of junction proteins in endothelial cells was attributed to high mobility group box protein 1 (HMGB1) release derived from endothelial inflammasome‐dependent caspase‐1 activity. Similarly, in the coronary arteries of wild‐type mice, high‐fat diet (HFD) treatment caused a down‐regulation of inter‐endothelial junction proteins ZO‐1, ZO‐2, occludin and VE‐cadherin, which was accompanied with enhanced inflammasome activation and HMGB1 expression in the endothelium as well as transmigration of CD43+ T cells into the coronary arterial wall. In contrast, all these HFD‐induced alterations in coronary arteries were prevented in mice with Nlrp3 gene deletion. Taken together, these data strongly suggest that the activation of endothelial Nlrp3 inflammasomes as a result of the increased actions of injurious adipokines such as visfatin produces HMGB1, which act in paracrine or autocrine fashion to disrupt inter‐endothelial junctions and increase paracellular permeability of the endothelium contributing to the early onset of endothelial injury during metabolic disorders such as obesity or high‐fat/cholesterol diet.
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Affiliation(s)
- Yang Chen
- Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Ashley L Pitzer
- Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Xiang Li
- Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.,Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA
| | - Pin-Lan Li
- Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Lei Wang
- Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yang Zhang
- Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.,Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA
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Zullo J, Matsumoto K, Xavier S, Ratliff B, Goligorsky MS. The cell secretome, a mediator of cell-to-cell communication. Prostaglandins Other Lipid Mediat 2015; 120:17-20. [PMID: 25936481 DOI: 10.1016/j.prostaglandins.2015.03.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/26/2015] [Accepted: 03/27/2015] [Indexed: 02/08/2023]
Abstract
We are witnessing the emergence of a novel type of biological regulation, namely, the communication between cells via their secreted substances, the secretome. This brief overview is based on the available published data and our own experience. We discuss three vignettes illustrating the importance of communication via the secretome: (1) the secretome of stem cells and its effects in sepsis and systemic inflammatory response; (2) the profibrotic secretomes partially responsible for development of fibrotic complications; and (3) the contribution of senescence-associated secretory products to the propagation of the senescence phenotype. Considering the richness of secretomes of different cells under diverse conditions, it becomes imperative to gain insights into their individual components in an attempt to harness cell secretomes for therapeutic purposes.
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Affiliation(s)
- Joseph Zullo
- Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College, Valhalla, NY 10595, USA
| | - Kei Matsumoto
- Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College, Valhalla, NY 10595, USA
| | - Sandhya Xavier
- Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College, Valhalla, NY 10595, USA
| | - Brian Ratliff
- Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College, Valhalla, NY 10595, USA
| | - Michael S Goligorsky
- Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College, Valhalla, NY 10595, USA.
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Xiao J, Fu C, Zhang X, Zhu D, Chen W, Lu Y, Ye Z. Soluble monosodium urate, but not its crystal, induces toll like receptor 4-dependent immune activation in renal mesangial cells. Mol Immunol 2015; 66:310-8. [PMID: 25909495 DOI: 10.1016/j.molimm.2015.03.250] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Revised: 03/21/2015] [Accepted: 03/30/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Uric acid has emerged as a novel and potential modifiable risk factor for the incidence and progression of kidney diseases, however, the deteriorate effect of uric acid on renal mesangial cells remains unclear. The present study is to examine the immune activation of soluble and crystal forms of uric acid in human mesangial cells. METHODS We stimulated primary human mesangial cells (HMCs) with increasing concentrations (from 50 to 200 μg/ml) of soluble monosodium urate (MSU) or MSU crystals. We examined interleukin (IL)-1β protein expression levels in cell culture by ELISA. The stimulated HMCs were further stimulated with soluble MSU or MSU crystals at 200 μg/ml with or without the pre-incubation of toll like receptor (TLR) 4 inhibitor TAK242 (1μM). TLR4, nod-like receptor protein (NLRP3, also known as NALP3), IL-1β, human leukocyte antigen (HLA)-DR and CD40 were examined by Realtime-PCR, Western blot and ELISA, respectively. RESULTS We found that both soluble MSU and MSU crystals increased IL-1β protein expression levels in dose-dependent fashion. Soluble MSU significantly enhanced the expression of TLR4, NLRP3, IL-1β, HLA-DR and CD40 while MSU crystals only upregulated the expression of TLR4 and IL-1β. TLR4 inhibitor TAK242 significantly blocked the up-regulation of NLRP3, IL-1β, HLA-DR and CD40 induced by soluble MSU while no TAK242 suppression effect on MSU crystals induced IL-1β up-regulation was found. CONCLUSIONS Our results suggested that soluble MSU, but not MSU crystals, induce NLRP3, IL-1β, HLA-DR and CD40 upregulation in a TLR4-dependent manner. These findings indicate that soluble MSU may play a pathological role in hyperuricemia induced renal mesangial injury.
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Affiliation(s)
- Jing Xiao
- Department of Nephrology, Huadong Hospital affiliated to Fudan University, Shanghai, PR China
| | - Chensheng Fu
- Department of Nephrology, Huadong Hospital affiliated to Fudan University, Shanghai, PR China
| | - Xiaoli Zhang
- Department of Nephrology, Huadong Hospital affiliated to Fudan University, Shanghai, PR China
| | - Dingyu Zhu
- Department of Nephrology, Huadong Hospital affiliated to Fudan University, Shanghai, PR China
| | - Weijun Chen
- Department of Nephrology, Huadong Hospital affiliated to Fudan University, Shanghai, PR China
| | - Yijun Lu
- Department of Nephrology, Huadong Hospital affiliated to Fudan University, Shanghai, PR China
| | - Zhibin Ye
- Department of Nephrology, Huadong Hospital affiliated to Fudan University, Shanghai, PR China.
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Kim SM, Lee SH, Kim YG, Kim SY, Seo JW, Choi YW, Kim DJ, Jeong KH, Lee TW, Ihm CG, Won KY, Moon JY. Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy. Am J Physiol Renal Physiol 2015; 308:F993-F1003. [PMID: 25651569 DOI: 10.1152/ajprenal.00637.2014] [Citation(s) in RCA: 141] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 01/21/2015] [Indexed: 11/22/2022] Open
Abstract
IL-1β-secreting nucleotide-binding oligomerization domain protein 3 (NLRP3) inflammasomes play a pivotal role in triggering innate immune responses in metabolic disease. We investigated the role of soluble uric acid in NLRP3 inflammasome activation in macrophages to demonstrate the effect of systemic hyperuricemia on progressive kidney damage in type 2 diabetes. THP-1 cells, human acute monocytic leukemia cells, were cultured to obtain macrophages, and HK-2 cells, human renal proximal tubule cells, were cultured and stimulated with uric acid. In vivo, we designed four rat groups as follows: 1) Long-Evans Tokushima Otsuka (LETO); 2) Otsuka Long-Evans Tokushima Fatty (OLETF); 3) OLETF+high-fructose diet (HFD) for 16 wk; and 4) OLETF+HFD+allopurinol (10 mg/dl administered in the drinking water). Soluble uric acid stimulated NLRP3 inflammasomes to produce IL-1β in macrophages. Uric acid-induced MitoSOX mediates NLRP3 activation and IL-1β secretion. IL-1β from macrophages activates NF-κB in cocultured proximal tubular cells. In vivo, intrarenal IL-1β expression and macrophage infiltration increased in HFD-fed OLETF rats. Lowering the serum uric acid level resulted in improving the albuminuria, tubular injury, macrophage infiltration, and renal IL-1β (60% of HFD-fed OLETF) independently of glycemic control. Direct activation of proximal tubular cells by uric acid resulted in (C-X-C motif) ligand 12 and high mobility group box-1 release and accelerated macrophage recruitment and the M1 phenotype. Taken together, these data support direct roles of hyperuricemia in activating NLRP3 inflammasomes in macrophages, promoting chemokine signaling in the proximal tubule and contributing to the progression of diabetic nephropathy through cross talk between macrophages and proximal tubular cells.
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Affiliation(s)
- Su-Mi Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Yang-Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Se-Yun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Jung-Woo Seo
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Young-Wook Choi
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Dong-Jin Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Kyung-Hwan Jeong
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Tae-Won Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Chun-Gyoo Ihm
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
| | - Kyu-Yeoun Won
- Department of Pathology, Kyung Hee University, College of Medicine, Seoul, Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea; and
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High-mobility group box 1 is a novel deacetylation target of Sirtuin1. Kidney Int 2014; 87:95-108. [PMID: 24940804 PMCID: PMC4270955 DOI: 10.1038/ki.2014.217] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 04/30/2014] [Accepted: 05/01/2014] [Indexed: 12/18/2022]
Abstract
High mobility group box 1 (HMGB1) undergoes acetylation, nuclear-to-cytoplasmic translocation and release from stressed kidneys, unleashing a signaling cascade of events leading to systemic inflammation. Here we tested whether the deacetylase activity of Sirtuin1 (SIRT1) participates in regulating nuclear retention of HMGB1 to ultimately modulate damage signaling initiated by HMGB1 secretion during stress. When immunoprecipitated acetylated HMGB1 was incubated with SIRT1, HMGB1 acetylation decreased by 57%. Proteomic analysis showed that SIRT1 deacetylates HMGB1 at four lysine residues (55, 88, 90 and 177) within the pro-inflammatory and nuclear localization signal domains of HMGB1. Genetic ablation or pharmacological inhibition of SIRT1 in endothelial cells increased HMGB1 acetylation and translocation. In vivo, deletion of SIRT1 reduced nuclear HMGB1 while increasing its acetylation and release into circulation during basal and ischemic conditions causing increased renal damage. Conversely, resveratrol pretreatment led to decreased HMGB1 acetylation, its nuclear retention, decreased systemic release and reduced tubular damage. Thus, a vicious cycle is set into motion in which the inflammation-induced repression of SIRT1 disables deacetylation of HMGB1, facilitates its nuclear-to-cytoplasmic translocation and systemic release, thereby maintaining inflammation.
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Eisenbacher JL, Schrezenmeier H, Jahrsdörfer B, Kaltenmeier C, Rojewski MT, Yildiz T, Beyer T, Erle A, Wiegmann DS, Grassl S, Hang R, Körper S, Wiesneth M, Lotze MT, Lotfi R. S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes. THE JOURNAL OF IMMUNOLOGY 2014; 192:6102-10. [DOI: 10.4049/jimmunol.1303144] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Kulkarni OP, Hartter I, Mulay SR, Hagemann J, Darisipudi MN, Kumar Vr S, Romoli S, Thomasova D, Ryu M, Kobold S, Anders HJ. Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. J Am Soc Nephrol 2014; 25:978-89. [PMID: 24459235 PMCID: PMC4005301 DOI: 10.1681/asn.2013050528] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 12/11/2013] [Indexed: 12/14/2022] Open
Abstract
AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired post-ischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.
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Affiliation(s)
- Onkar P Kulkarni
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Ingo Hartter
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Shrikant R Mulay
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Jan Hagemann
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Murthy N Darisipudi
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Santhosh Kumar Vr
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Simone Romoli
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Dana Thomasova
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Mi Ryu
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
| | - Sebastian Kobold
- Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Hans-Joachim Anders
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and
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50
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Thierry A, Giraud S, Robin A, Barra A, Bridoux F, Ameteau V, Hauet T, Girard JP, Touchard G, Gombert JM, Herbelin A. The alarmin concept applied to human renal transplantation: evidence for a differential implication of HMGB1 and IL-33. PLoS One 2014; 9:e88742. [PMID: 24586382 PMCID: PMC3930579 DOI: 10.1371/journal.pone.0088742] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 01/10/2014] [Indexed: 02/06/2023] Open
Abstract
The endogenous molecules high mobility group box 1 (HMGB1) and interleukin-33 (IL-33) have been identified as alarmins, capable of mediating danger signals during tissue damage. Here, we address their possible role as innate-immune mediators in ischemia-reperfusion injury (IRI) following human kidney transplantation. We analysed serum and urinary HMGB1 and IL-33 levels, all determined by enzyme-linked immunosorbent assay, in a cohort of 26 deceased renal transplant recipients. Urinary HMGB1 and IL-33 levels were significantly increased as soon as 30 min after reperfusion, as compared to those before treatment. Moreover, both serum and urinary IL-33 (but not HMGB1) increase was positively correlated with cold ischemia time, from 30 min to 3 days post-transplantation. In vitro, human umbilical vein endothelial cells subjected to hypoxia conditions released both HMGB-1 and IL-33, while only the latter was further increased upon subsequent re-oxygenation. Finally, we postulate that leukocytes from renal recipient patients are targeted by both HMGB1 and IL-33, as suggested by increased transcription of their respective receptors (TLR2/4 and ST2L) shortly after transplantation. Consistent with this view, we found that iNKT cells, an innate-like T cell subset involved in IRI and targeted by IL-33 but not by HMGB1 was activated 1 hour post-transplantation. Altogether, these results are in keeping with a potential role of IL-33 as an innate-immune mediator during kidney IRI in humans.
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Affiliation(s)
- Antoine Thierry
- Service de Néphrologie-Hémodialyse-Transplantation rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
| | - Sébastien Giraud
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
- Université de Poitiers, Poitiers, France
| | - Aurélie Robin
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
| | - Anne Barra
- Université de Poitiers, Poitiers, France
- Institut national de la santé et de la recherche médicale U935, Poitiers, France
- Laboratoire d’Immunologie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Franck Bridoux
- Service de Néphrologie-Hémodialyse-Transplantation rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
- Université de Poitiers, Poitiers, France
| | - Virginie Ameteau
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
- Université de Poitiers, Poitiers, France
| | - Thierry Hauet
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
- Université de Poitiers, Poitiers, France
- Laboratoire de Biochimie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Jean-Philippe Girard
- Institut de Pharmacologie et de Biologie Structurale, Toulouse, France
- Centre national de la recherche scientifique, Unité Mixte de recherche, Toulouse, France
- Université de Toulouse, Toulouse, France
| | - Guy Touchard
- Service de Néphrologie-Hémodialyse-Transplantation rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
- Université de Poitiers, Poitiers, France
| | - Jean-Marc Gombert
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
- Université de Poitiers, Poitiers, France
- Laboratoire d’Immunologie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - André Herbelin
- Institut national de la santé et de la recherche médicale U1082, Poitiers, France
- Université de Poitiers, Poitiers, France
- * E-mail:
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