|
1
|
Lulic I, Lulic D, Pavicic Saric J, Bacak Kocman I, Rogic D. Personalized translational medicine: Investigating YKL-40 as early biomarker for clinical risk stratification in hepatocellular carcinoma recurrence post-liver transplantation. World J Transplant 2025; 15:103036. [DOI: 10.5500/wjt.v15.i2.103036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/05/2025] [Accepted: 01/14/2025] [Indexed: 02/21/2025] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) presents a significant challenge, with recurrence rates ranging from 8% to 20% globally. Current biomarkers, such as alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), lack specificity, limiting their utility in risk stratification. YKL-40, a glycoprotein involved in extracellular matrix remodeling, hepatic stellate cell activation, and immune modulation, has emerged as a promising biomarker for post-LT surveillance. Elevated serum levels of YKL-40 are associated with advanced liver disease, tumor progression, and poorer post-LT outcomes, highlighting its potential to address gaps in early detection and personalized management of HCC recurrence. This manuscript synthesizes clinical and mechanistic evidence to evaluate YKL-40’s predictive utility in post-LT care. While preliminary findings demonstrate its specificity for liver-related pathologies, challenges remain, including assay standardization, lack of prospective validation, and the need to distinguish between malignant and non-malignant causes of elevated levels. Integrating YKL-40 into multi-biomarker panels with AFP and DCP could enhance predictive accuracy and enable tailored therapeutic strategies. Future research should focus on multicenter studies to validate YKL-40’s clinical utility, address confounding factors like graft rejection and systemic inflammation, and explore its role in predictive models driven by emerging technologies such as artificial intelligence. YKL-40 holds transformative potential in reshaping post-LT care through precision medicine, providing a pathway for better outcomes and improved management of high-risk LT recipients.
Collapse
Affiliation(s)
- Ileana Lulic
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
| | - Dinka Lulic
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
- Immediate Medical Care Unit, Saint James Hospital, Sliema SLM-1030, Malta
| | - Jadranka Pavicic Saric
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
| | - Iva Bacak Kocman
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Merkur, Zagreb 10000, Croatia
| | - Dunja Rogic
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, Zagreb 10000, Croatia
| |
Collapse
|
|
2
|
Kjaergaard AD, Vaag AA, Jensen VH, Olsen MH, Højlund K, Vestergaard P, Hansen T, Thomsen RW, Jessen N. YKL-40 and risk of incident cancer in early type 2 diabetes: a Danish cohort study. Br J Cancer 2025; 132:1019-1026. [PMID: 40188292 PMCID: PMC12119867 DOI: 10.1038/s41416-025-02996-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/06/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND We examined the association of serum YKL-40, an inflammatory biomarker, with incident cancer risk in early type 2 diabetes. METHODS A cohort of 11,346 individuals newly diagnosed with type 2 diabetes was followed for up to 14 years. YKL-40 levels (n = 9010) were categorised into five percentiles (0-33%, 34-66%, 67-90%, 91-95%, and 96-100%), and baseline YKL-40 and CRP (n = 9644) were analyzed continuously (per 1 SD log increment) for comparison. Cox regression models assessed associations with obesity-related, gastrointestinal, liver, pancreatic, colorectal, bladder and lung cancers, as well as cancers of reproductive organs. RESULTS Adjusted HRs (95% CIs) for the highest versus lowest YKL-40 category were 2.4 (1.6-3.7) for obesity-related, 2.6 (1.7-4.1) for gastrointestinal, 44.2 (12.8-153.4) for liver, and 4.2 (1.3-14.1) for bladder cancers. No associations were found for other cancers. YKL-40 and CRP had similar prognostic abilities for obesity-related and gastrointestinal cancers, but YKL-40 outperformed CRP for liver and bladder cancers. Conversely, CRP was a stronger predictor for lung, colorectal, and ovarian cancers. DISCUSSION YKL-40 was associated with the risks of liver and bladder cancers, clearly outperforming CRP for these cancers. This suggests distinct prognostic roles for YKL-40 and CRP, and highlights YKL-40 as a promising biomarker for liver cancer.
Collapse
Affiliation(s)
- Alisa D Kjaergaard
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
| | - Allan A Vaag
- Steno Diabetes Center Copenhagen, Copenhagen University Hospital, Herlev, Denmark
- Lund University Diabetes Center, Lund University, Lund, Sweden and Department of Endocrinology, Skåne University Hospital, Malmö, Sweden
| | - Verena H Jensen
- Steno Diabetes Center Copenhagen, Copenhagen University Hospital, Herlev, Denmark
| | - Michael H Olsen
- Department of Internal Medicine and Steno Diabetes Center Zealand, Holbæk Hospital, Holbæk, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Reimar W Thomsen
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
| | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
3
|
Liu Y, Sun S, Yu B, Wang Q, Liu H, Shao X, Zhao H. Changes in serum levels of Chitinase protein-40 in children with Kawasaki disease and its clinical significance. BMC Pediatr 2025; 25:392. [PMID: 40380159 PMCID: PMC12085031 DOI: 10.1186/s12887-025-05721-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/29/2025] [Indexed: 05/19/2025] Open
Abstract
OBJECTIVES Kawasaki disease (KD) is an acute immune-mediated vasculitis primarily affecting coronary arteries, with limited specific diagnostic biomarkers available. Chitinase protein-40 (YKL-40), a glycoprotein secreted by neutrophils and macrophages, has been associated with vascular inflammation in cardiovascular diseases. This study aimed to investigate the role of YKL-40 in KD by analyzing its serum levels, correlations with inflammatory markers, and potential as a diagnostic and prognostic biomarker. METHODS Serum YKL-40 and interleukin-6 (IL-6) levels were measured using enzyme-linked immunosorbent assay (ELISA) in 46 children with KD (16 with coronary artery lesions [CAL], 30 without CAL) and 30 healthy controls. Correlations between YKL-40, IL-6, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell (WBC) count, and platelet (PLT) levels were analyzed. RESULTS YKL-40, IL-6, CRP, ESR, WBC, and PLT levels were significantly elevated in KD patients compared to controls. YKL-40 levels correlated positively with IL-6, CRP, and ESR. A serum YKL-40 threshold of ≥ 71.930 ng/mL predicted CAL with sensitivity and specificity of 0.875 and 0.800, respectively. Combining YKL-40 with IL-6 improved sensitivity and specificity to 0.938 and 0.833. CONCLUSIONS YKL-40 is significantly elevated in KD and correlates with inflammatory markers, suggesting its involvement in disease pathogenesis. It is a promising inflammatory biomarker and independent risk factor for predicting CAL in KD, offering potential for improved diagnosis and prognosis. CLINICAL TRIAL NUMBER Not applicable.
Collapse
Affiliation(s)
- Yalin Liu
- Pediatric Internal Medicine Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China
- Emergency Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China
| | - Shan Sun
- Emergency Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China
| | - Baolong Yu
- Pediatric Internal Medicine Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China
| | - Qianyun Wang
- Pediatric Internal Medicine Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China
| | - Hui Liu
- Pediatric Internal Medicine Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China
| | - Xianli Shao
- Pediatric Internal Medicine Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China
| | - Huafeng Zhao
- Pediatric Internal Medicine Department, WeiFang People's Hospital, Shandong Second Medical University, Weifang, 261000, China.
| |
Collapse
|
|
4
|
Liu S, Peng C, Xia S, Li C, Dai X, Liu X, Zhang M, Li X, Tang L. Chitinase 3-like protein 1: a diagnostic biomarker for early liver fibrosis in autoimmune liver diseases. Front Immunol 2025; 16:1504066. [PMID: 40352927 PMCID: PMC12061858 DOI: 10.3389/fimmu.2025.1504066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 04/07/2025] [Indexed: 05/14/2025] Open
Abstract
Background and Aims Chitinase 3-like protein 1 (CHI3L1) is a marker of liver fibrosis produced mainly by hepatic macrophages. However, few studies have assessed the relationship between CHI3L1 and liver fibrosis in autoimmune liver diseases (AILDs). We aimed to explore the diagnostic value of CHI3L1 for liver fibrosis in AILDs and to compare its application differences between AILDs and chronic hepatitis B (CHB) patients. Methods The fibrotic group was defined as liver stiffness measurement (LSM) > 9.70kPa. Serum CHI3L1 levels were measured by ELISA in 78 AILDs patients, 65 chronic hepatitis B patients. The diagnostic accuracy was evaluated by the area under the receiver operating characteristic curve (AUROC). Results Serum CHI3L1 levels in AILDs patients were positively correlated with LSM (r=0.750, p <0.001). The AUROC for serum CHI3L1 in identifying significant liver fibrosis was 0.939 (95% CI: 0.891 - 0.988), which was higher than that of other non - invasive fibrosis scores (APRI, FIB - 4, GPR, AAR, NLP, and PLR). At the optimal cutoff value of 86.84 ng/mL, the sensitivity and specificity were 92.9% and 83.3%, respectively. Furthermore, in patients with no significant difference in LSM, serum CHI3L1 levels were higher in the autoimmune liver disease group than in the CHB group. Conclusion Serum CHI3L1 is an effective non-invasive indicator for assessing liver fibrosis in AILDs patients and may vary in different etiologies.
Collapse
Affiliation(s)
- Shafei Liu
- School of Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Conggao Peng
- Department of Infectious Diseases, Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan(Hangzhou)Hospital, Hangzhou, China
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Shijia Xia
- School of Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chaonan Li
- School of Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiahong Dai
- Department of Infectious Diseases, Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan(Hangzhou)Hospital, Hangzhou, China
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xingyu Liu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Zhang
- School of Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Xiaoping Li
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Lingling Tang
- Department of Infectious Diseases, Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan(Hangzhou)Hospital, Hangzhou, China
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| |
Collapse
|
|
5
|
Kjaergaard AD, Vaag A, Jensen VH, Olsen MH, Højlund K, Vestergaard P, Hansen T, Thomsen RW, Jessen N. YKL-40, cardiovascular events, and mortality in individuals recently diagnosed with type 2 diabetes: A Danish cohort study. Diabetes Res Clin Pract 2025; 219:111970. [PMID: 39719182 DOI: 10.1016/j.diabres.2024.111970] [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: 11/22/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 12/26/2024]
Abstract
AIMS We investigated the association of the inflammatory biomarker YKL-40 with cardiovascular events (CVEs) and mortality in individuals with type 2 diabetes. METHODS We followed 11,346 individuals recently diagnosed with type 2 diabetes for up to 14 years. Baseline YKL-40 levels (measured in 9,010 individuals) were grouped into percentiles (0-33 %, 34-66 %, 67-90 %, and 91-100 %) and analyzed continuously (per 1 SD log increment), with comparisons to CRP (measured in 9,644 individuals). Cox regression assessed associations with atrial fibrillation (AF), ischemic stroke (IS), venous thromboembolism (VTE), myocardial infarction (MI), heart failure (HF), peripheral artery disease (PAD), and all-cause, cardiovascular, and cancer mortality. RESULTS Adjusted HRs (95% CIs) for the highest (91-100%) versus the lowest (0-33%) YKL-40 percentile category were 1.31 (1.04-1.66) for AF, 1.43 (0.98-2.07) for IS, 1.07 (0.65-1.76) VTE, 0.88 (0.52-1.48) for MI, 1.66 (1.19-2.31) for HF, 1.66 (1.12-2.48) for PAD, and 2.18 (1.85-2.56) for all-cause, 1.64 (1.07-2.50) for cardiovascular, and 2.73 (2.05-3.63) for cancer mortality. Each 1 SD log increase in YKL-40 and CRP levels similarly increased CVE risks, with CRP being superior for MI and cardiovascular mortality. CONCLUSIONS YKL-40 is a prognostic biomarker for most CVEs, and even more so for all-cause mortality, primarily driven by cancer-related causes.
Collapse
Affiliation(s)
- Alisa D Kjaergaard
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
| | - Allan Vaag
- Steno Diabetes Center Copenhagen, Copenhagen University Hospital, Herlev, Denmark
| | - Verena H Jensen
- Steno Diabetes Center Copenhagen, Copenhagen University Hospital, Herlev, Denmark
| | - Michael H Olsen
- Department of Internal Medicine and Steno Diabetes Center Zealand, Holbæk Hospital, Holbæk, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Reimar W Thomsen
- Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
6
|
Wang Z, Zhang K, Zhong C, Zhu Z, Zheng X, Yang P, Che B, Lu Y, Zhang Y, Xu T. Alcohol drinking modified the effect of plasma YKL-40 levels on stroke-specific mortality of acute ischemic stroke. Neuroscience 2024; 552:152-158. [PMID: 38944147 DOI: 10.1016/j.neuroscience.2024.06.028] [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: 04/09/2024] [Revised: 06/17/2024] [Accepted: 06/24/2024] [Indexed: 07/01/2024]
Abstract
OBJECTIVES Our study aimed to evaluate the association between plasma human cartilage glycoprotein-39 (YKL-40) and stroke-specific mortality at two years in acute ischemic stroke patients according to the drinking status and amount of alcohol consumption. We further investigated the effect of the interaction between these conditions and YKL-40 levels on the outcome. METHODS We measured plasma YKL-40 levels in 3267 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. Outcome data on stroke-specific mortality were collected at two years after stroke onset. RESULTS During the two years of follow-up, 208 (6.4 %) patients, including 44 drinkers and 164 nondrinkers, died of stroke-specific causes. The patients in the highest quartile of YKL-40 had a 3.52-fold (95 % CI: 1.15-10.76, P for trend = 0.006) risk of stroke-specific mortality compared with those in the lowest quartile among drinkers. However, no significant association between YKL-40 and the outcome was observed among nondrinkers (HR: 1.18, 95 % CI: 0.75-1.86, P for trend = 0.08). Alcohol drinking modified the effect of YKL-40 on the outcome (P for interaction = 0.04). Subgroup analyses revealed that each 1-unit increase in log-transformed YKL-40 was associated with a 72 % greater risk of stroke-specific mortality for light drinkers. This association was amplified with a 226 % increased risk of the outcome among heavy drinkers. CONCLUSIONS Elevated YKL-40 levels were associated with an increased risk of stroke-specific mortality at two years among drinkers with ischemic stroke. Drinking status substantially modified the effect of plasma YKL-40 levels on the outcome. This effect was amplified with the increased amount of alcohol consumption. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT01840072.
Collapse
Affiliation(s)
- Ziyi Wang
- Department of Neurology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Kaixin Zhang
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Chongke Zhong
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Zhengbao Zhu
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Xiaowei Zheng
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Pinni Yang
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Bizhong Che
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Yaling Lu
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Yonghong Zhang
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Tian Xu
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226001, China.
| |
Collapse
|
|
7
|
Jia WL, Jiang YY, Jiang Y, Meng X, Li H, Zhao XQ, Wang YL, Wang YJ, Gu HQ, Li ZX. Associations between admission levels of multiple biomarkers and subsequent worse outcomes in acute ischemic stroke patients. J Cereb Blood Flow Metab 2024; 44:742-756. [PMID: 37975323 PMCID: PMC11197142 DOI: 10.1177/0271678x231214831] [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: 05/07/2023] [Revised: 09/18/2023] [Accepted: 10/11/2023] [Indexed: 11/19/2023]
Abstract
The modified Rankin Scale change score (ΔmRS) is useful for evaluating acute poststroke functional improvement or deterioration. We investigated the relationship between multiple biomarkers and ΔmRS by analyzing data on 6931 patients with acute ischemic stroke (average age 62.3 ± 11.3 years, 2174 (31.4%) female) enrolled from the Third China National Stroke Registry (CNSR-III) and 15 available biomarkers. Worse outcomes at 3 months were defined as ΔmRS3m-discharge ≥1 (ΔmRS3m-discharge = mRS3m-mRSdischarge). Adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) were calculated from logistic regression models. At 3-months poststroke, 1026 (14.8%) patients experienced worse outcomes. The highest quartiles of white blood cells (WBCs) (aOR [95%CI],1.37 [1.12-1.66]), high-sensitivity C-reactive protein (hs-CRP) (1.37 [1.12-1.67]), interleukin-6 (IL-6) (1.43 [1.16-1.76]), interleukin-1 receptor antagonist (IL-1Ra) (1.46 [1.20-1.78]) and YKL-40 (1.31 [1.06-1.63]) were associated with an increased risk of worse outcomes at 3 months. Results remained stable except for YKL-40 when simultaneously adding multiple biomarkers to the basic traditional-risk-factor model. Similar results were observed at 6 and 12 months after stroke. This study indicated that WBCs, hs-CRP, IL-6, IL-1Ra, and YKL-40 were significantly associated with worse outcomes in acute ischemic stroke patients, and all inflammatory biomarkers except YKL-40 were independent predictors of worse outcomes at 3 months.
Collapse
Affiliation(s)
- Wei-Li Jia
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ying-Yu Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yong Jiang
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xia Meng
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Hao Li
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xing-Quan Zhao
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, China
| | - Yi-Long Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
| | - Yong-Jun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, China
| | - Hong-Qiu Gu
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zi-Xiao Li
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
| |
Collapse
|
|
8
|
Sæther LS, Szabo A, Akkouh IA, Haatveit B, Mohn C, Vaskinn A, Aukrust P, Ormerod MBEG, Eiel Steen N, Melle I, Djurovic S, Andreassen OA, Ueland T, Ueland T. Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain. Brain Behav Immun 2024; 118:287-299. [PMID: 38461955 DOI: 10.1016/j.bbi.2024.03.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/25/2024] [Accepted: 03/07/2024] [Indexed: 03/12/2024] Open
Abstract
Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.
Collapse
Affiliation(s)
- Linn Sofie Sæther
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway.
| | - Attila Szabo
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway
| | - Ibrahim A Akkouh
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital/University of Oslo, Oslo, Norway
| | - Beathe Haatveit
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Christine Mohn
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; National Centre for Suicide Research and Prevention, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Anja Vaskinn
- Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Centre for Research and Education in Forensic Psychiatry, Oslo University Hospital, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Norway
| | - Monica B E G Ormerod
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo Norway
| | - Nils Eiel Steen
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Ingrid Melle
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Srdjan Djurovic
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital/University of Oslo, Oslo, Norway
| | - Ole A Andreassen
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Torill Ueland
- Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Centre, University of Tromsø, Tromsø, Norway
| |
Collapse
|
|
9
|
Latifi Z, Oghbaei F, Salemi Z, Kamalipoya S, Fattahi A. Vitamin D and its binding protein in patients with leiomyomas. J Obstet Gynaecol Res 2024; 50:691-698. [PMID: 38192105 DOI: 10.1111/jog.15883] [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: 09/06/2023] [Accepted: 12/28/2023] [Indexed: 01/10/2024]
Abstract
AIM This study examined the levels of VitD, VitD binding protein (DBP), and free VitD in leiomyomas patients and their association with the quantity, dimensions, and site of fibroid growths. Additionally, we evaluated the potentiality of employing these factors as a biomarker tool for the diagnosis and assessment of uterine fibroid progression. METHODS This study involved the participation of 55 women with leiomyomas and 50 healthy women. We utilized commercial ELISA kits to measure the levels of total VitD and DBP in their serum. Additionally, we calculated the levels of free VitD and the ratio of VitD to DBP. Moreover, we determined the number, size, and location of the leiomyomas in the patients. RESULTS There were no significant differences in the levels of total VitD between the groups. However, patients had significantly lower levels of free VitD and higher levels of DBP compared to the control group. The size of the largest leiomyomas showed a negative relationship with free VitD and a positive relationship with DBP. Receiver operating characteristic analyses, showed that the cut-off value for free VitD was 4.47 pg/mL, with a sensitivity of 75.6% and a specificity of 74.4%. The cut-off value for DBP was 256.2 μg/mL, with a sensitivity of 86% and a specificity of 70.3%. CONCLUSIONS Free VitD and DBP potentially contribute to the development of leiomyomas and are linked to the size of these tumors. The measurement of serum levels of these factors could serve as additional biomarkers for the diagnosis of leiomyomas.
Collapse
Affiliation(s)
- Zeinab Latifi
- Nervous system stem cell research center, Semnan University of Medical Sciences, Semnan, Iran
| | - Farnaz Oghbaei
- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Zahra Salemi
- Department of Biochemistry, Arak University of Medical Sciences, Arak, Iran
| | - Samaneh Kamalipoya
- Students Research Committee, Arak University of Medical Sciences, Arak, Iran
| | - Amir Fattahi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
10
|
Blazevic N, Rogic D, Pelajic S, Miler M, Glavcic G, Ratkajec V, Vrkljan N, Bakula D, Hrabar D, Pavic T. YKL-40 as a biomarker in various inflammatory diseases: A review. Biochem Med (Zagreb) 2024; 34:010502. [PMID: 38125621 PMCID: PMC10731731 DOI: 10.11613/bm.2024.010502] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 09/04/2023] [Indexed: 12/23/2023] Open
Abstract
YKL-40 or Chitinase-3-Like Protein 1 (CHI3L1) is a highly conserved glycoprotein that binds heparin and chitin in a non-enzymatic manner. It is a member of the chitinase protein family 18, subfamily A, and unlike true chitinases, YKL-40 is a chitinase-like protein without enzymatic activity for chitin. Although its accurate function is yet unknown, the pattern of its expression in the normal and disease states suggests its possible engagement in apoptosis, inflammation and remodeling or degradation of the extracellular matrix. During an inflammatory response, YKL-40 is involved in a complicated interaction between host and bacteria, both promoting and attenuating immune response and potentially being served as an autoantigen in a vicious circle of autoimmunity. Based on its pathophysiology and mechanism of action, the aim of this review was to summarize research on the growing role of YKL-40 as a persuasive biomarker for inflammatory diseases' early diagnosis, prediction and follow-up (e.g., cardiovascular, gastrointestinal, endocrinological, immunological, musculoskeletal, neurological, respiratory, urinary, infectious) with detailed structural and functional background of YKL-40.
Collapse
Affiliation(s)
- Nina Blazevic
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Dunja Rogic
- Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb, Croatia
| | - Stipe Pelajic
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Marijana Miler
- Department of Clinical Chemistry, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Goran Glavcic
- Department of Surgery, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Valentina Ratkajec
- Department of Gastroenterology, General Hospital Virovitica, Virovitica, Croatia
| | - Nikolina Vrkljan
- Department of Internal Medicine, Intensive Care Unit, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Dejan Bakula
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Davor Hrabar
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Tajana Pavic
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| |
Collapse
|
|
11
|
Guha D, Misra V, Yin J, Horiguchi M, Uno H, Gabuzda D. Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy. AIDS 2023; 37:2137-2147. [PMID: 37503603 PMCID: PMC10615701 DOI: 10.1097/qad.0000000000003675] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
OBJECTIVE Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear. DESIGN Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND. METHODS Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls). RESULTS Median age was 53 years, median CD4 + cell count, and duration of HIV infection were 505 cells/μl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals ( P < 0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 ( P < 0.01) and vascular disease ( P = 0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models ( P < 0.01). Furthermore, plasma VCAM-1 correlated with NFL ( r = 0.29, P = 0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations. CONCLUSIONS Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.
Collapse
Affiliation(s)
- Debjani Guha
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Vikas Misra
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jun Yin
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Miki Horiguchi
- Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Hajime Uno
- Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Dana Gabuzda
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Neurology, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
12
|
Sipeki N, Kovats PJ, Deutschmann C, Schierack P, Roggenbuck D, Papp M. Location-based prediction model for Crohn's disease regarding a novel serological marker, anti-chitinase 3-like 1 autoantibodies. World J Gastroenterol 2023; 29:5728-5750. [PMID: 38075846 PMCID: PMC10701337 DOI: 10.3748/wjg.v29.i42.5728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 10/03/2023] [Accepted: 11/02/2023] [Indexed: 11/13/2023] Open
Abstract
BACKGROUND Defective neutrophil regulation in inflammatory bowel disease (IBD) is thought to play an important role in the onset or manifestation of IBD, as it could lead to damage of the intestinal mucosal barrier by the infiltration of neutrophils in the inflamed mucosa and the accumulation of pathogens. Like neutrophils in the context of innate immune responses, immunoglobulin A (IgA) as an acquired immune response partakes in the defense of the intestinal epithelium. Under normal conditions, IgA contributes to the elimination of microbes, but in connection with the loss of tolerance to chitinase 3-like 1 (CHI3L1) in IBD, IgA could participate in CHI3L1-mediated improved adhesion and invasion of potentially pathogenic microorganisms. The tolerance brake to CHI3L1 and the occurrence of IgA autoantibodies to this particular target, the exact role and underlying mechanisms of CHI3L1 in the pathogenesis of IBD are still unclear. AIM To determine the predictive potential of Ig subtypes of a novel serological marker, anti-CHI3L1 autoantibodies (aCHI3L1) in determining the disease phenotype, therapeutic strategy and long-term disease course in a prospective referral cohort of adult IBD patients. METHODS Sera of 257 Crohn's disease (CD) and 180 ulcerative colitis (UC) patients from a tertiary IBD referral center of Hungary (Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen) were assayed for IgG, IgA, and secretory IgA (sIgA) type aCHI3L1 by enzyme-linked immunosorbent assay using recombinant CHI3L1, along with 86 healthy controls (HCONT). RESULTS The IgA type was more prevalent in CD than in UC (29.2% vs 11.1%) or HCONT (2.83%; P < 0.0001 for both). However, sIgA subtype aCHI3L1 positivity was higher in both CD and UC patients than in HCONT (39.3% and 32.8% vs 4.65%, respectively; P < 0.0001). The presence of both IgA and sIgA aCHI3L1 antibodies was associated with colonic involvement (P < 0.0001 and P = 0.038, respectively) in patients with CD. Complicated disease behavior at sample procurement was associated with aCHI3L1 sIgA positivity (57.1% vs 36.0%, P = 0.009). IgA type aCH3L1 was more prevalent in patients with frequent relapse during the disease course in the CD group (46.9% vs 25.7%, P = 0.005). In a group of patients with concomitant presence of pure inflammatory luminal disease and colon involvement at the time of diagnosis, positivity for IgA or sIgA type aCH3L1 predicted faster progression towards a complicated disease course in time-dependent models. This association disappeared after merging subgroups of different disease locations. CONCLUSION CHI3L1 is a novel neutrophil autoantigenic target in IBD. The consideration of antibody classes along with location-based prediction may transform the future of serology in IBD.
Collapse
Affiliation(s)
- Nora Sipeki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
| | - Patricia Julianna Kovats
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
- Kálmán Laki Doctoral School, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
| | - Claudia Deutschmann
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
- Medipan GmbH & GA Generic Assays GmbH, Dahlewitz-Berlin 15827, Germany
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
| |
Collapse
|
|
13
|
Guha D, Misra V, Yin J, Horiguchi M, Uno H, Gabuzda D. Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.07.23.23293053. [PMID: 37546734 PMCID: PMC10402231 DOI: 10.1101/2023.07.23.23293053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Objective Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear. Design Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND. Methods Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls). Results Median age was 53 years, median CD4 count, and duration of HIV infection were 505 cells/μl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals (p<0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 (p<0.01) and vascular disease (p=0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models (p<0.01). Furthermore, plasma VCAM-1 correlated with NFL (r=0.29, p=0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations. Conclusions Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.
Collapse
Affiliation(s)
- Debjani Guha
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Vikas Misra
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jun Yin
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Miki Horiguchi
- Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Hajime Uno
- Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Dana Gabuzda
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Neurology, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
14
|
Fang C, Li J, Wang W, Wang Y, Chen Z, Zhang J. Establishment and validation of a clinical nomogram model based on serum YKL-40 to predict major adverse cardiovascular events during hospitalization in patients with acute ST-segment elevation myocardial infarction. Front Med (Lausanne) 2023; 10:1158005. [PMID: 37283624 PMCID: PMC10239942 DOI: 10.3389/fmed.2023.1158005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/02/2023] [Indexed: 06/08/2023] Open
Abstract
Objective This study aimed to investigate the predictive value of a clinical nomogram model based on serum YKL-40 for major adverse cardiovascular events (MACE) during hospitalization in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods In this study, 295 STEMI patients from October 2020 to March 2023 in the Second People's Hospital of Hefei were randomly divided into a training group (n = 206) and a validation group (n = 89). Machine learning random forest model was used to select important variables and multivariate logistic regression was included to analyze the influencing factors of in-hospital MACE in STEMI patients; a nomogram model was constructed and the discrimination, calibration, and clinical effectiveness of the model were verified. Results According to the results of random forest and multivariate analysis, we identified serum YKL-40, albumin, blood glucose, hemoglobin, LVEF, and uric acid as independent predictors of in-hospital MACE in STEMI patients. Using the above parameters to establish a nomogram, the model C-index was 0.843 (95% CI: 0.79-0.897) in the training group; the model C-index was 0.863 (95% CI: 0.789-0.936) in the validation group, with good predictive power; the AUC (0.843) in the training group was greater than the TIMI risk score (0.648), p < 0.05; and the AUC (0.863) in the validation group was greater than the TIMI risk score (0.795). The calibration curve showed good predictive values and observed values of the nomogram; the DCA results showed that the graph had a high clinical application value. Conclusion In conclusion, we constructed and validated a nomogram based on serum YKL-40 to predict the risk of in-hospital MACE in STEMI patients. This model can provide a scientific reference for predicting the occurrence of in-hospital MACE and improving the prognosis of STEMI patients.
Collapse
Affiliation(s)
- Caoyang Fang
- Department of Cardiology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
- Graduate School, Bengbu Medical College, Bengbu, Anhui, China
| | - Jun Li
- Department of Cardiology, The Lu’an Hospital Affiliated to Anhui Medical University, Lu’an, Anhui, China
- Department of Cardiology, The Lu’an People's Hospital, Lu’an, Anhui, China
| | - Wei Wang
- Department of Cardiology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Yuqi Wang
- Department of Cardiology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
- Graduate School, Bengbu Medical College, Bengbu, Anhui, China
| | - Zhenfei Chen
- Department of Cardiology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Jing Zhang
- Department of Cardiology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| |
Collapse
|
|
15
|
Kocabas R. Effect of Vitamin D on YKL-40: Rat Hypercholesterolemia Model. Korean Circ J 2023; 53:92-102. [PMID: 36792559 PMCID: PMC9932220 DOI: 10.4070/kcj.2022.0282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/03/2022] [Accepted: 12/27/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND OBJECTIVES YKL-40 is considered to be associated with cardiovascular disease (CVD). In this study, the effect of serum 25(OH) vitamin D [25(OH)VitD] differences between groups on YKL-40 was evaluated on a hypercholesterolemia rat model. METHODS Thirty-two male rats (wistar albino) were equally divided into 4 groups. The first group was the control group; the second group was high-cholesterol (H-CH) adequate vitamin D (VitD) group (H-AdeVD). The third group was the H-CH deficient VitD group (H-DefVD), and the last group was designed with the H-CH supplement VitD (H-SupVD). The feeding process consisted of 2 stages. At the first stage (5 months), the H-DefVD group was fed on VitD deficient chow, while the other groups (control, H-AdeVD, H-SupVD) were fed on standard chow. At the second stage (3 months), the H-AdeVD and the H-SupVD groups were fed on the H-CH chow, whereas the H-DefVD group was fed on the H-CH-VitD deficient chow. Moreover, the H-SupVD group was given 100 IU/kg/day VitD along with the H-CH chow. RESULTS Compared with the control group, interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and YKL-40 values in the H-DefVD groups increased significantly (p<0.001, p<0.001, p=0.009, p=0.005; sequentially). CONCLUSION It can be concluded that VitD can suppress the YKL-40, thus, it will prevent CVD development in rat. Therefore, further clinical studies related with human will reveal the effect of VitD and YKL-40 on CVD development.
Collapse
Affiliation(s)
- Rahim Kocabas
- Department of Biochemistry, Karamano\xc4\x9flu Mehmetbey University School of Medicine, Karaman, Turkey.
| |
Collapse
|
|
16
|
Tang Y, Du M, Qian W, Lu F, Dai J, Qi X, Liu W, Feng C, Sun X, Zhu Y, Wang Q, Zhou L. The diagnostic value of serum YKL-40 for myocardial involvement in idiopathic inflammatory myopathy. Clin Chim Acta 2022; 537:167-172. [DOI: 10.1016/j.cca.2022.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/20/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]
|
|
17
|
Laudanski K, Liu D, Okeke T, Restrepo M, Szeto WY. Persistent Depletion of Neuroprotective Factors Accompanies Neuroinflammatory, Neurodegenerative, and Vascular Remodeling Spectra in Serum Three Months after Non-Emergent Cardiac Surgery. Biomedicines 2022; 10:2364. [PMID: 36289630 PMCID: PMC9598177 DOI: 10.3390/biomedicines10102364] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/24/2022] Open
Abstract
We hypothesized that the persistent depletion of neuroprotective markers accompanies neuroinflammation and neurodegeneration in patients after cardiac surgery. A total of 158 patients underwent elective heart surgery with their blood collected before surgery (tbaseline) and 24 h (t24hr), seven days (t7d), and three months (t3m) post-surgery. The patients' serum was measured for markers of neurodegeneration (τau, τaup181-183, amyloid β1-40/β2-42, and S100), atypical neurodegeneration (KLK6 and NRGN), neuro-injury (neurofilament light/heavy, UC-HL, and GFAP), neuroinflammation (YKL-40 and TDP-43), peripheral nerve damage (NCAM-1), neuroprotection (apoE4, BDNF, fetuin, and clusterin), and vascular smoldering inflammation (C-reactive protein, CCL-28 IL-6, and IL-8). The mortality at 28 days, incidence of cerebrovascular accidents (CVA), and functional status were followed for three months. The levels of amyloid β1-40/β1-42 and NF-L were significantly elevated at all time points. The levels of τau, S100, KLK6, NRGN, and NCAM-1 were significantly elevated at 24 h. A cluster analysis demonstrated groupings around amyloids, KLK6, and NCAM-1. YKL-40, but not TDP-43, was significantly elevated across all time points. BDNF, apoE4, fetuin, and clusterin levels were significantly diminished long-term. IL-6 and IL-8 levles returned to baseline at t3m. The levels of CRP, CCL-28, and Hsp-70 remained elevated. At 3 months, 8.2% of the patients experienced a stroke, with transfusion volume being a significant variable. Cardiac-surgery patients exhibited persistent peripheral and neuronal inflammation, blood vessel remodeling, and the depletion of neuroprotective factors 3 months post-procedure.
Collapse
Affiliation(s)
- Krzysztof Laudanski
- Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Leonard Davis Institute for Health Economics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Da Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110055, China
| | - Tony Okeke
- Department of Bioengineering, Drexel University, Philadelphia, PA 19104, USA
| | - Mariana Restrepo
- College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Wilson Y. Szeto
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA
| |
Collapse
|
|
18
|
The Value of Serum YKL-40 and TNF-α in the Diagnosis of Acute ST-Segment Elevation Myocardial Infarction. Cardiol Res Pract 2022; 2022:4905954. [PMID: 36051575 PMCID: PMC9427287 DOI: 10.1155/2022/4905954] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/21/2022] [Accepted: 08/08/2022] [Indexed: 12/02/2022] Open
Abstract
Background Acute ST-segment elevation myocardial infarction (STEMI) is a serious cardiovascular disease that poses a great threat to the life and health of patients. Therefore, early diagnosis is important for STEMI patient treatment and prognosis. The purpose of this study was to investigate the value of serum YKL-40 and TNF-α in the diagnosis of STEMI. Methods From October 2020 to February 2022, 120 patients with STEMI were admitted to the Chest Pain Center of the Second People's Hospital of Hefei, and 81 patients with negative coronary angiography were selected as the control group. Serum YKL-40 and TNF-α concentrations were measured by sandwich ELISA. Pearson correlation was used to analyze the correlation between serum YKL-40, TNF-α, and serum troponin I (cTnI) in STEMI patients; multivariate logistic regression analysis was used to screen independent risk factors for STEMI. Three diagnostic models were constructed: cTnI univariate model (model A), combined serum YKL-40 and TNF-α model other than cTnI (model B), and combined cTnI and serum YKL-40 and TNF-α model (model C). We assessed the clinical usefulness of the diagnostic model by comparing AUC with decision curve analysis (DCA). Results Serum YKL-40 and TNF-α in the STEMI group were significantly higher than those in the control group (P < 0.001). On Pearson correlation analysis, there was a significant positive correlation between serum YKL-40, TNF-α, and cTnI levels in STEMI patients. Multivariate logistic regression analysis showed that serum YKL-40 and TNF-α were independent risk factors for the development of STEMI. The results of ROC analysis showed that the area under the curve (AUC) of serum YKL-40 for predicting the occurrence of STEMI was 0.704. The AUC of serum TNF-α for predicting the occurrence of STEMI was 0.852. The AUC of cTnI as a traditional model, model A, for predicting the occurrence of STEMI was 0.875. Model B predicted STEMI with an AUC of 0.851. The addition of serum YKL-40 and serum TNF-α to the traditional diagnostic model composed of cTnI constituted a new diagnostic model; that is, the AUC of model C for predicting the occurrence of STEMI was 0.930. Model C had a better net benefit between a threshold probability of 70–95% for DCA. Conclusion In this study, we demonstrate the utility of serum YKL-40 and TNF-α as diagnostic markers for STEMI and the clinical utility of diagnostic models by combining serum YKL-40 and TNF-α with cTnI.
Collapse
|
|
19
|
Kerget B, Özkan HB, Afşin DE, Koçak AO, Laloglu E, Uçar EY, Sağlam L. Evaluation of serum YKL-40 level among clinical risk scores for early mortality in acute pulmonary thromboembolism. Clin Biochem 2022; 108:20-26. [PMID: 35853494 DOI: 10.1016/j.clinbiochem.2022.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/08/2022] [Accepted: 07/13/2022] [Indexed: 11/03/2022]
Abstract
INTRODUCTION Pulmonary embolism (PE) often occurs secondary to deep vein thrombosis and is an important cause of mortality and morbidity. This study aimed to evaluate the relationship between YKL-40 level and clinical risk score in patients with PE. METHODS The study included a total of 100 patients, 80 patients diagnosed with PE in the emergency department and 20 healthy controls. Patients with PE were divided into four groups: high-risk patients (n = 20), high-intermediate-risk patients (n = 20), low-intermediate-risk patients (n = 20), and low-risk patients (n = 20). Serum YKL-40 levels were measured by enzyme-linked immunosorbent assay. Pulmonary artery obstruction index (PAOI) was calculated from computed tomography angiography images. RESULTS PAOI increased in correlation with PE risk and differed significantly between all patient groups (p < 0.001). Troponin-I levels were significantly higher in the high-risk and high-intermediate-risk groups compared to the other groups (p < 0.001), but did not differ significantly between high-risk and high-intermediate-risk patients (p = 0.09). YKL-40 level was significantly higher in the high-risk PE group than the high-intermediate-risk group (p < 0.001). In receiving operator characteristic curve analysis assessing the discriminatory value of YKL-40 for high-risk PE patients, a cut-off value of 227.2 ng/mL had sensitivity of 85 % and specificity of 70 %. DISCUSSION YKL-40 may be an important biomarker in decisions regarding early thrombolytic treatment in patients with high-intermediate-risk PE. In addition, medical treatments targeting YKL-40 may also reduce thrombotic tendency in high-risk patient groups.
Collapse
Affiliation(s)
- Buğra Kerget
- Department of Pulmonary Diseases, Ataturk University School of Medicine, 25240, Yakutiye, Erzurum, Turkey.
| | - Hatice Beyza Özkan
- Department of Pulmonary Diseases, Ataturk University School of Medicine, 25240, Yakutiye, Erzurum, Turkey
| | - Dursun Erol Afşin
- Depertmant of Pulmonary Diseases, Health Sciences University Erzurum Regional Education and Research Hospital, Erzurum, Turkey
| | - Abdullah Osman Koçak
- Department of Emergency Medicine, Ataturk University School of Medicine, 25240, Yakutiye, Erzurum, Turkey
| | - Esra Laloglu
- Department of Biochemistry, Ataturk University School of Medicine, 25240, Yakutiye, Erzurum, Turkey
| | - Elif Yılmazel Uçar
- Department of Pulmonary Diseases, Ataturk University School of Medicine, 25240, Yakutiye, Erzurum, Turkey
| | - Leyla Sağlam
- Department of Pulmonary Diseases, Ataturk University School of Medicine, 25240, Yakutiye, Erzurum, Turkey
| |
Collapse
|
|
20
|
Krarup HB, Rex KF, Andersen S. Mortality in Greenlanders with chronic hepatitis B virus infection. J Viral Hepat 2022; 29:432-437. [PMID: 35357746 PMCID: PMC9321676 DOI: 10.1111/jvh.13673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/02/2022] [Accepted: 03/07/2022] [Indexed: 12/09/2022]
Abstract
In-depth reviewing of all medical records and clinical databases concluded a 7-year shorter lifespan among Greenlanders infected with hepatitis B virus (HBV) compared with non-infected. Mortality did not associate with liver disease or any other specific disease entity. A possible mechanism for the reduced lifespan is subclinical inflammation that may be augmented by chronic viral infection. We hypothesized that chronic HBV infection contributes to this process causing a reduced life span. We added measurement of two markers of inflammation to the 10-year follow-up on our study of HBV among 50- through 69-years-old subjects in Greenland. The markers were YKL40 related to liver disease and hsCRP as a global marker of inflammation. Survival was evaluated using Cox regression with time until death entered as dependent variable and age, sex, smoking, alcohol intake, BMI, the presence of HBsAg and one marker of inflammation as explanatory variables. Forty-eight percent of participants with chronic HBV infection were alive after 10 years compared with 65% of participants without infection (p = 0.003). Survival associated with age (p < 0.001), BMI (p = 0.003) and both YKL40 and hsCRP (both, p < 0.001). Harbouring HBV influenced 10-year survival in the Cox regression after adjusting for age, sex, BMI, smoking, alcohol intake and inflammation. In conclusion, chronic low-grade inflammation and being infected with HBV were independent markers of mortality in otherwise healthy subjects. Thus, the 7-year shorter lifespan among Greenlanders with chronic HBV infection seems related to the long-lasting infection. Our findings call for caution in perceiving a chronic infection as benign.
Collapse
Affiliation(s)
- Henrik B. Krarup
- Department of Molecular DiagnosticsAalborg University HospitalAalborgDenmark,Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Karsten F. Rex
- Department of Internal MedicineQueen Ingrid’s HospitalNuukGreenland,Arctic Health Research CentreAalborg University HospitalAalborgDenmark
| | - Stig Andersen
- Department of Clinical MedicineAalborg UniversityAalborgDenmark,Department of Internal MedicineQueen Ingrid’s HospitalNuukGreenland,Arctic Health Research CentreAalborg University HospitalAalborgDenmark,Greenland Institute for Health ResearchIlisimatusarfikGreenland UniversityNuukGreenland,Department of Geriatric MedicineAalborg University HospitalAalborgDenmark
| |
Collapse
|
|
21
|
Lu Y, Chang N, Zhao X, Xue R, Liu J, Yang L, Li L. Activated Neutrophils Secrete Chitinase-Like 1 and Attenuate Liver Inflammation by Inhibiting Pro-Inflammatory Macrophage Responses. Front Immunol 2022; 13:824385. [PMID: 35529851 PMCID: PMC9069964 DOI: 10.3389/fimmu.2022.824385] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 03/21/2022] [Indexed: 11/26/2022] Open
Abstract
Excessive activation and recruitment of neutrophils are generally considered to be associated with pathological aggravation of multiple diseases. However, as the role of neutrophils in tissue injury repair is receiving increasing attention, it is necessary to further explore the beneficial role of activated neutrophils in promoting the resolution of inflammation after injury. In this study, we found that activated neutrophils have a crucial function in suppressing liver inflammation. In methionine-choline-deficient and high-fat (MCDHF) diet induced liver inflammation in mice, tail vein injection of activated neutrophils (A-Neu, stimulated by sphingosine 1-phosphate) inhibited the expressions of pro-inflammatory cytokines in the liver, including C-C chemokine motif ligand 4, tumor necrosis factor and nitric oxide synthase 2, and attenuated liver injury. However, non-activated neutrophils (N-Neu) did not have these effects. In vitro, pro-inflammatory macrophages were co-cultured with N-Neu or A-Neu by transwell, respectively. A-Neu was found to suppress the pro-inflammatory phenotype of macrophages by using RT-qPCR, western blot and cytometric bead array. Microarray analysis showed that there were systematic variations in transcript expression levels between N-Neu and A-Neu. GeneVenn software was used to show the gene expression overlap between GO terms including Regulation of Cell Communication, Cytokine Secretion, Inflammatory Response and Extracellular Space clusters. We identified that Chitinase-like 1 (CHIL1) secreted by S1P activated neutrophils may be an important mediators affecting the pro-inflammatory macrophage responses. In the injured liver of mice induced by MCDHF diet, the expression of Chil1 mRNA increased and was positively correlated with the neutrophil marker Ly6g. Moreover, the secretion of CHIL1 in A-Neu increased significantly. Strikingly, the effect of A-Neu on macrophage response was reproduced by incubating pro-inflammatory macrophages with recombinant CHIL1. A-Neu conditioned medium were incubated with CHIL1 antibody-conjugated protein G beads, magnetically separated to immunodepletion CHIL1 from the A-Neu supernatant, which can partially weaken its inhibitory effect of A-Neu on the production of macrophage pro-inflammatory cytokines. Together, the conclusions indicated that A-Neu could inhibit the pro-inflammatory macrophage responses by secreting CHIL1, thereby effectively inhibiting liver inflammation.
Collapse
|
|
22
|
Diagnostic Value of Serum Chitinase-3-Like Protein 1 for Liver Fibrosis: A Meta-analysis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3227957. [PMID: 35360517 PMCID: PMC8961437 DOI: 10.1155/2022/3227957] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/08/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
Abstract
Background Serum chitinase-3-like protein 1 (CHI3L1) is a promising marker for diagnosing liver fibrosis. This meta-analysis was carried out to assess the diagnostic performance of serum CHI3L1 for the estimation of liver fibrosis. Methods Systematic searches were performed on PubMed, Embase, Web of Science, Scopus, the Cochrane Library, Google Scholar, Sinomed, the China National Knowledge Infrastructure (CNKI), the Chinese Medical Journal Database, and the Wanfang databases for available studies. The primary studies were screened strictly according to inclusion and exclusion criteria, and sensitivity, specificity, and other measures of accuracy of serum CHI3L1 for evaluating liver fibrosis were pooled with 95% confidence intervals. I2 was calculated to assess heterogeneity, and sources of heterogeneity were explored by subgroup analysis. Deeks' test was used to assess for publication bias, and likelihood ratio was used to determine posttest probability. Results Our research integrated 11 articles, accounting for 1897 patients older than 18 years old. The pooled sensitivity and specificity for significant fibrosis, advanced fibrosis, and cirrhosis were 0.79 and 0.82 with an area under the receiver operating characteristic curve (AUC) of 0.85, 0.81 and 0.83 with an AUC of 0.91, and 0.72 and 0.74 with an AUC of 0.85, respectively. Random-effects models were used to assess for significant heterogeneity, and subgroup analysis showed that age and aetiology of included patients were likely sources of heterogeneity. No potential publication bias was found for serum CHI3L1 in the diagnosis of significant fibrosis, advanced fibrosis, or cirrhosis, and posttest probability was moderate. Conclusion Measurement of serum CHI3L1 is a feasible diagnostic tool for liver fibrosis.
Collapse
|
|
23
|
Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis. Proc Natl Acad Sci U S A 2021; 118:2019633118. [PMID: 33888584 DOI: 10.1073/pnas.2019633118] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Older age at the time of infection with hepatitis viruses is associated with an increased risk of liver fibrosis progression. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. We compared gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old. Chitinase 3-like 1 (CHI3L1), which encodes chitinase-like protein YKL-40/CHI3L1, was identified as the gene with the greatest age-dependent increase in expression in liver tissue. We investigated the cellular source of CHI3L1 in the liver and its function using liver tissue specimens and in vitro models. CHI3L1 expression was significantly higher in livers of patients with cirrhosis of diverse etiologies compared with controls represented by patients who underwent liver resection for hemangioma. The highest intrahepatic CHI3L1 expression was observed in cirrhosis due to hepatitis D virus, followed by hepatitis C virus, hepatitis B virus, and alcohol-induced cirrhosis. In situ hybridization of CHI3L1 messenger RNA (mRNA) identified hepatocytes as the major producers of CHI3L1 in normal liver and in cirrhotic tissue, wherein hepatocytes adjacent to fibrous septa showed higher CHI3L1 expression than did those in more distal areas. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression.
Collapse
|
|
24
|
Liu Q, Chen X, Liu C, Pan L, Kang X, Li Y, Du C, Dong S, Xiang AP, Xu Y, Zhang Q. Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression. Cell Death Dis 2021; 12:240. [PMID: 33664231 PMCID: PMC7933182 DOI: 10.1038/s41419-021-03524-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 01/19/2021] [Accepted: 02/10/2021] [Indexed: 12/31/2022]
Abstract
Liver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.
Collapse
Grants
- This work was supported by the National Key Research and Development Program of China (2017YFA0106100, 2018YFA0107203, 2017YFA010550), National Natural Science Foundation of China (81971526, 81670601, 81760112, 31601184, 81870449, 81970537, 81970109), Guangdong Basic and Applied Basic Research Foundation (2020A1515010272, 2020A1515011385), Key project fund of Guangdong Natural Science Foundation (2017A030311034), Special fund for frontier and key technology innovation of Guangdong (2015B020226004) and National Keypoint Research and Invention program of the thirteenth (2018ZX10723203), the Key Scientific and Technological Projects of Guangdong Province (2019B020236004, 2019B020234001, 2019B020235002, 2017B020230004), Key Scientific and Technological Program of Guangzhou City (201803040011, 201802020023), Pearl River S&T Nova Program of Guangzhou (201906010095), Fundamental Research Funds for the Central Universities (20ykpy149).
Collapse
Affiliation(s)
- Qiuli Liu
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering, Center for Stem Cell Biology and Tissue Engineering, Ministry of Education, Sun Yat-sen University, 510080, Guangzhou, China
| | - Xiaoyong Chen
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering, Center for Stem Cell Biology and Tissue Engineering, Ministry of Education, Sun Yat-sen University, 510080, Guangzhou, China
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, China
| | - Chang Liu
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Lijie Pan
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Xinmei Kang
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Yanli Li
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Cong Du
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, 510630, Guangzhou, China
| | - Shuai Dong
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Andy Peng Xiang
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
- Key Laboratory for Stem Cells and Tissue Engineering, Center for Stem Cell Biology and Tissue Engineering, Ministry of Education, Sun Yat-sen University, 510080, Guangzhou, China.
| | - Yan Xu
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
| | - Qi Zhang
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, 510630, Guangzhou, China.
| |
Collapse
|
|
25
|
Wang Y, Li B, Jiang Y, Zhang R, Meng X, Zhao X, Wang Y, Zhao X, Liu G. YKL-40 Is Associated With Ultrasound-Determined Carotid Atherosclerotic Plaque Instability. Front Neurol 2021; 12:622869. [PMID: 33679587 PMCID: PMC7925412 DOI: 10.3389/fneur.2021.622869] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/15/2021] [Indexed: 12/24/2022] Open
Abstract
Background and Aims: YKL-40, an inflammatory biomarker, has been reported to be involved in the process and progression of atherosclerosis. Several studies have investigated the association between YKL-40 and plaque and suggested YKL-40 might be a potential biomarker for plaque instability. This study aimed to investigate the association between YKL-40 and carotid plaque instability. Methods: Based on a community-based study in Beijing from February 2014 to May 2016, 1,132 participants with carotid plaques were enrolled in this study. Data on demographics and medical history were collected through face-to-face interviews, and fasting blood samples were collected and stored. We used ultrasound to evaluate the presence of carotid plaque and its instability. The level of YKL-40 was measured by enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression analysis was performed to investigate the association between YKL-40 level and carotid atherosclerotic plaque instability. Results: The mean age of the 1,132 participants was 58.0 (52.0-64.0) years, and 560 (49.5%) were male. Unstable plaques were detected in 855 (75.53%) participants. YKL-40 level was classified into four groups according to its quartile: quartile 1: <25.47 ng/mL, quartile 2: 25.47-39.53 ng/mL, quartile 3: 39.53-70.55 ng/mL, quartile 4: ≥70.55 ng/mL. After adjusting for age, sex, smoking, alcohol drinking, medical history, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, homocysteine, high-sensitivity C-reactive protein, and plaque thickness, the top quartiles of YKL-40 level were significantly associated with unstable plaque (quartile 3: OR 2.10, 95% CI 1.29-3.40; quartile 4: OR 1.70, 95% CI 1.04-2.80). Conclusion: This study found that YKL-40 was associated with carotid plaque instability determined by ultrasound. Individuals with high YKL-40 may have a higher risk of unstable carotid plaque.
Collapse
Affiliation(s)
- Yu Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Bohong Li
- Department of Rehabilitation Medicine, The People's Hospital of Xiangzhou District, Zhuhai, China
| | - Yong Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Runhua Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Xia Meng
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Xingquan Zhao
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Xihai Zhao
- Department of Biomedical Engineering, Center for Biomedical Imaging Research, School for Medicine, Tsinghua University, Beijing, China
| | - Gaifen Liu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| |
Collapse
|
|
26
|
Zhang S, Sousa A, Lin M, Iwano A, Jain R, Ma B, Lee CM, Park JW, Kamle S, Carlson R, Lee GG, Elias JA, Wands JR. Role of Chitinase 3-Like 1 Protein in the Pathogenesis of Hepatic Insulin Resistance in Nonalcoholic Fatty Liver Disease. Cells 2021; 10:201. [PMID: 33498326 PMCID: PMC7909438 DOI: 10.3390/cells10020201] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/15/2021] [Accepted: 01/17/2021] [Indexed: 02/08/2023] Open
Abstract
A recently discovered human glycoprotein, chitinase 3-like 1 (Chi3L1), may play a role in inflammation, tissue remodeling, and visceral fat accumulation. We hypothesize that Chi3L1 gene expression is important in the development of hepatic insulin resistance characterized by the generation of pAKT, pGSK, and pERK in wild type and Chi3L1 knockout (KO) murine liver following insulin stimulation. The Chi3L1 gene and protein expression was evaluated by Real Time PCR and ELISA; lipid accumulation in hepatocytes was also assessed. To alter Chi3L1 function, three different anti-Chi3L1 monoclonal antibodies (mAbs) were administered in vivo and effects on the insulin signaling cascade and hepatic lipid deposition were determined. Transmission of the hepatic insulin signal was substantially improved following KO of the CHi3L1 gene and there was reduced lipid deposition produced by a HFD. The HFD-fed mice exhibited increased Chi3L1 expression in the liver and there was impaired insulin signal transduction. All three anti-Chi3L1 mAbs partially restored hepatic insulin sensitivity which was associated with reduced lipid accumulation in hepatocytes as well. A KO of the Chi3L1 gene reduced lipid accumulation and improved insulin signaling. Therefore, Chi3L1 gene upregulation may be an important factor in the generation of NAFLD/NASH phenotype.
Collapse
Affiliation(s)
- Songhua Zhang
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Aryanna Sousa
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Mengqui Lin
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Ayako Iwano
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Rishubh Jain
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Bing Ma
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Chang Min Lee
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Jin Wook Park
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Suchitra Kamle
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Rolf Carlson
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| | - Ghun Geun Lee
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
| | - Jack A. Elias
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA; (B.M.); (C.M.L.); (J.W.P.); (S.K.); (G.G.L.); (J.A.E.)
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02912, USA
| | - Jack R. Wands
- Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (S.Z.); (A.S.); (M.L.); (A.I.); (R.J.); (R.C.)
| |
Collapse
|
|
27
|
Pinteac R, Montalban X, Comabella M. Chitinases and chitinase-like proteins as biomarkers in neurologic disorders. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2021; 8:e921. [PMID: 33293459 PMCID: PMC7803328 DOI: 10.1212/nxi.0000000000000921] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022]
Abstract
Chitinases are hydrolytic enzymes widely distributed in nature. Despite their physiologic and pathophysiologic roles are not well understood, chitinases are emerging as biomarkers in a broad range of neurologic disorders, where in many cases, protein levels measured in the CSF have been shown to correlate with disease activity and progression. In this review, we will summarize the structural features of human chitinases and chitinase-like proteins and their potential physiologic and pathologic functions in the CNS. We will also review existing evidence for the role of chitinases and chitinase-like proteins as diagnostic and prognostic biomarkers in inflammatory, neurodegenerative diseases, and psychiatric disorders. Finally, we will comment on future perspectives of chitinase studies in neurologic conditions.
Collapse
Affiliation(s)
- Rucsanda Pinteac
- From the Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Xavier Montalban
- From the Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Manuel Comabella
- From the Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.
| |
Collapse
|
|
28
|
Serum transforming growth factor β and leucine-rich α-2-glycoprotein 1 as potential biomarkers for diagnosis of uterine leiomyomas. J Gynecol Obstet Hum Reprod 2020; 50:102037. [PMID: 33307240 DOI: 10.1016/j.jogoh.2020.102037] [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: 10/11/2020] [Revised: 11/26/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Transforming growth factor β (TGF-β) and leucine-rich α-2-glycoprotein 1 (LRG1) play significant roles in the pathogenicity of uterine leiomyomas (ULMs). The current study aimed to assess the diagnostic values of serum TGF-β and LRG1 in terms of the presence and severity of ULMs. METHODS Premenopausal women with ULMs (n=44) together with age-adjusted ULM-free individuals (n=41) were incorporated into the study. ULMs were detected and evaluated using transvaginal ultrasonography. Serum levels of TGF-β and LRG1 were quantified by enzyme-linked immunosorbent assay. RESULTS Mean concentrations of serum TGF-β and LRG1 were significantly higher in the group of patients with ULMs compared to the control group (p<0.05). The volume of the largest leiomyoma was positively correlated with the levels of TGF-β (r = 0.414, p= 0.005) and LRG1 (r = 0.341, p= 0.023). The receiver-operating characteristics analysis demonstrated moderate and robust values of area under the curve for TGF-β (0.755) and LRG1 (0.90), respectively. CONCLUSION Increases in serum levels of TGF-β and LRG1 is associated with the incidence and severity of ULMs. LRG1 in particular but also TGF-β may be able to serve as reliable biomarkers for the diagnosis and monitoring of ULMs.
Collapse
|
|
29
|
YKL-40 as a novel biomarker in cardio-metabolic disorders and inflammatory diseases. Clin Chim Acta 2020; 511:40-46. [PMID: 33002471 DOI: 10.1016/j.cca.2020.09.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 09/25/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023]
Abstract
Dyslipidaemia is associated with numerous health problems that include the combination of insulin resistance, hypertension and obesity, ie, metabolic syndrome. Although the use of statins to decrease serum low density lipoprotein cholesterol (LDL-C) has been an effective therapeutic in treating atherosclerosis, the persistence of high atherosclerotic risk, ie, residual risk, is notable and is not simply explained as a phenomenon of dyslipidaemia. As such, it is imperative that we identify new biomarkers to monitor treatment and more accurately predict future cardiovascular events. This athero-protective strategy includes the assessment of novel inflammatory biomarkers such as YKL-40. Recent evidence has implicated YKL-40 in patients with inflammatory diseases and cardio-metabolic disorders, making it potentially useful to evaluate disease severity, prognosis and survival. In this review, we summarize role of YKL-40 in the pathogenesis of cardio-metabolic disorders and explore its use as a novel biomarker for monitoring athero-protective therapy.
Collapse
|
|
30
|
Holst CB, Christensen IJ, Skjøth-Rasmussen J, Hamerlik P, Poulsen HS, Johansen JS. Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40. Front Oncol 2020; 10:478. [PMID: 32363159 PMCID: PMC7180208 DOI: 10.3389/fonc.2020.00478] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 03/17/2020] [Indexed: 01/10/2023] Open
Abstract
Background: Complex local and systemic immune dysfunction in glioblastoma (GBM) may affect survival. Interleukin (IL)-6 and YKL-40 are pleiotropic biomarkers present in the tumor microenvironment and involved in immune regulation. We therefore analyzed plasma IL-6, YKL-40, and genetic variation in YKL-40 and explored their ability to distinguish between glioma subtypes and predict survival in GBM. Methods: One hundred fifty-eight patients with glioma WHO grade II-IV were included in the study. Plasma collected at surgery was analyzed for IL-6 and YKL-40 (CHI3L1) by ELISA. CHI3L1 rs4950928 genotyping was analyzed on whole-blood DNA. Results: Neither plasma IL-6 nor YKL-40 corrected for age or rs4950928 genotype could differentiate GBM from lower grade gliomas. GC and GG rs4950928 genotype were associated with lower plasma YKL-40 levels (CC vs. GC, p = 0.0019; CC vs. GG, p = 0.01). Only 10 and 14 out of 94 patients with newly diagnosed GBM had elevated IL-6 or YKL-40, respectively. Most patients received corticosteroid treatment at time of blood-sampling. Higher pretreatment plasma IL-6 was associated with short overall survival (OS) [HR = 1.19 (per 2-fold change), p = 0.042] in univariate analysis. The effect disappeared in multivariate analysis. rs4950928 genotype did not associate with OS [HR = 1.30, p = 0.30]. In recurrent GBM, higher YKL-40 [HR = 2.12 (per 2-fold change), p = 0.0005] but not IL-6 [HR = 0.99 (per 2-fold change), p = 0.92] were associated with short OS in univariate analysis. Conclusion: In recurrent GBM high plasma YKL-40 may hold promise as a prognostic marker. In newly diagnosed GBM perioperative plasma IL-6, YKL-40, and genetic variation in YKL-40 did not associate with survival. Corticosteroid use may complicate interpretation of results.
Collapse
Affiliation(s)
- Camilla Bjørnbak Holst
- Department of Radiation Biology, Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.,Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Ib Jarle Christensen
- Department of Gastroenterology, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre, Denmark
| | - Jane Skjøth-Rasmussen
- Department of Neurosurgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Petra Hamerlik
- Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
| | - Hans Skovgaard Poulsen
- Department of Radiation Biology, Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Julia Sidenius Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
31
|
Hoste EA, Vaara ST, De Loor J, Haapio M, Nuytinck L, Demeyere K, Pettilä V, Meyer E. Urinary cell cycle arrest biomarkers and chitinase 3-like protein 1 (CHI3L1) to detect acute kidney injury in the critically ill: a post hoc laboratory analysis on the FINNAKI cohort. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2020; 24:144. [PMID: 32276601 PMCID: PMC7149885 DOI: 10.1186/s13054-020-02867-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 03/31/2020] [Indexed: 12/13/2022]
Abstract
Background Acute kidney injury (AKI) is a frequently occurring syndrome in critically ill patients and is associated with worse outcomes. Biomarkers allow early identification and therapy of AKI which may improve outcomes. Urine chitinase 3-like protein 1 (uCHI3L1) was recently identified as a promising urinary biomarker for AKI. In this multicenter study, we evaluated the diagnostic performance for AKI stage 2 or greater of uCHI3L1 in comparison with the urinary cell cycle arrest biomarkers urinary tissue inhibitor of metalloproteinases-2 (TIMP-2)•insulin-like growth factor-binding protein 7 (IGFBP7) measured by NephroCheck Risk®. Methods Post hoc laboratory study of the prospective observational FINNAKI study. Of this cohort, we included patients with stored admission urine samples and availability of serum creatinine at day 1 of admission. Patients who already had AKI stage 2 or 3 at ICU admission were excluded. AKI was defined and staged according to the KDIGO definition and staging system. The primary endpoint was AKI stage 2 or 3 at day 1. Biomarker performance was assessed by the area under the curve of the receiver operating characteristic curve (AUC). We assessed individual performance and different combinations of urine biomarkers. Results Of 660 included patients, 49 (7.4%) had AKI stages 2–3 at day 1. All urine biomarkers were increased at admission in AKI patients. All biomarkers and most combinations had AUCs < 0.700. The combination uCHI3L1•TIMP-2 was best with a fair AUC of 0.706 (0.670, 0.718). uCHI3L1 had a positive likelihood ratio (LR) of 2.25 which was comparable to that of the NephroCheck Risk® cutoff of 2.0, while the negative LR of 0.53 was comparable to that of the NephroCheck Risk® cutoff of 0.3. Conclusions We found that uCHI3L1 and NephroCheck Risk® had a comparable diagnostic performance for diagnosis of AKI stage 2 or greater within a 24-h period in this multicenter FINNAKI cohort. In contrast to initial discovery and validation studies, the diagnostic performance was poor. Possible explanations for this observation are differences in patient populations, proportion of emergency admissions, proportion of functional AKI, rate of developing AKI, and observation periods for diagnosis of AKI.
Collapse
Affiliation(s)
- Eric A Hoste
- Intensive Care Unit, Ghent University Hospital, 2K12, Route 1280a, C. Heymanslaan 10, 9000, Ghent, Belgium. .,Research Fund-Flanders (FWO), Egmontstraat 5, 1000, Brussel, Belgium.
| | - Suvi T Vaara
- Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Box 340, 00029, Helsinki, Finland
| | - Jorien De Loor
- Intensive Care Unit, Ghent University Hospital, 2K12, Route 1280a, C. Heymanslaan 10, 9000, Ghent, Belgium
| | - Mikko Haapio
- Division of Nephrology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Box 340, FI-00029 HUS, Helsinki, Finland
| | - Lieve Nuytinck
- Faculty of Medicine and Health Sciences, Health Innovation and Research Institute of the Ghent University Hospital (UZ Gent) (HIRUZ) Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium
| | - Kristel Demeyere
- Department of Pharmacology, Toxicology and Biochemistry, Laboratory of Biochemistry, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium
| | - Ville Pettilä
- Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Box 340, 00029, Helsinki, Finland
| | - Evelyne Meyer
- Department of Pharmacology, Toxicology and Biochemistry, Laboratory of Biochemistry, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium
| | | |
Collapse
|
|
32
|
Schroder J, Jakobsen JC, Winkel P, Hilden J, Jensen GB, Sajadieh A, Larsson A, Ärnlöv J, Harutyunyan M, Johansen JS, Kjøller E, Gluud C, Kastrup J. Prognosis and Reclassification by YKL-40 in Stable Coronary Artery Disease. J Am Heart Assoc 2020; 9:e014634. [PMID: 32114892 PMCID: PMC7335588 DOI: 10.1161/jaha.119.014634] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background The inflammatory biomarker YKL‐40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum YKL‐40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all‐cause mortality. We used Cox proportional hazards regression models adjusted for C‐reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL‐40 to the risk factors was calculated using the Cox‐Breslow method and c‐statistic. A total of 2200 patients were randomized to placebo, with a follow‐up duration of 10 years. YKL‐40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL‐40) 1.13, 95% CI 1.03–1.24, P=0.013) and all‐cause mortality (hazard ratio 1.32, 95% CI 1.17–1.49, P<0.0001). Considering whether a composite‐outcome event was more likely to have, or not have, occurred to date, we found 68.4% of such predictions to be correct when based on the standard predictors, and 68.5% when serum YKL‐40 was added as a predictor. Equivalent results were obtained with c‐statistics. Conclusions Higher serum YKL‐40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL‐40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00121550.
Collapse
Affiliation(s)
- Jakob Schroder
- Department of Cardiology Bispebjerg Hospital University of Copenhagen Copenhagen Denmark
| | - Janus Christian Jakobsen
- Copenhagen Trial Unit Centre for Clinical Intervention Research Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark.,Department of Cardiology Holbæk Hospital Holbæk Denmark.,Department of Regional Health Research The Faculty of Heath Sciences University of Southern Denmark Odense Denmark
| | - Per Winkel
- Copenhagen Trial Unit Centre for Clinical Intervention Research Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark
| | - Jørgen Hilden
- Section of Biostatistics Department of Public Health Research University of Copenhagen Copenhagen Denmark
| | - Gorm Boje Jensen
- Department of Cardiology Hvidovre Hospital Copenhagen University Hospital Copenhagen Denmark
| | - Ahmad Sajadieh
- Department of Cardiology Bispebjerg Hospital University of Copenhagen Copenhagen Denmark
| | - Anders Larsson
- Department of Medical Sciences Uppsala University Uppsala Sweden
| | - Johan Ärnlöv
- Department of Neurobiology, Care Sciences and Society/Division of Family Medicine Karolinska Institute Stockholm Sweden.,Department of Health and Social Sciences Dalarna University Falun Sweden
| | - Marina Harutyunyan
- Department of Cardiology Rigshospitalet University of Copenhagen København Denmark
| | - Julia S Johansen
- Department of Medicine Herlev and Gentofte Hospital Copenhagen Denmark
| | - Erik Kjøller
- Copenhagen Trial Unit Centre for Clinical Intervention Research Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark.,Department of Cardiology S Herlev Hospital University of Copenhagen Denmark
| | - Christian Gluud
- Copenhagen Trial Unit Centre for Clinical Intervention Research Rigshospitalet, Copenhagen University Hospital Copenhagen Denmark
| | - Jens Kastrup
- Department of Cardiology Rigshospitalet University of Copenhagen København Denmark
| |
Collapse
|
|
33
|
Prediction of Unresectability and Prognosis in Patients Undergoing Surgery on Suspicion of Pancreatic Cancer Using Carbohydrate Antigen 19-9, Interleukin 6, and YKL-40. Pancreas 2020; 49:53-61. [PMID: 31856080 DOI: 10.1097/mpa.0000000000001466] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVES The aim was to determine whether serum levels of carbohydrate antigen (CA) 19-9, interleukin 6 (IL-6), and YKL-40 could identify advanced disease and poor prognosis in pancreatic cancer (PC) patients intraoperatively diagnosed with locally advanced or metastatic disease. METHODS Two hundred ninety patients were included with preoperative blood samples. Plasma IL-6 and YKL-40 were determined by enzyme-linked immunosorbent assays. RESULTS Interleukin 6 was elevated in patients with unresectable PC compared with resectable PC (P = 0.03). Carbohydrate antigen 19-9 and YKL-40 were similar. Patients with resectable tumors and greater than median preoperative CA 19-9, IL-6, and YKL-40 had shorter overall survival than patients with low levels (CA 19-9: hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.13-2.83; P = 0.01; IL-6: HR, 1.83; 95% CI, 1.20-2.78; P = 0.01; YKL-40: HR, 1.60; 95% CI, 1.02-2.49; P = 0.04). Patients with resectable tumors and 2 or 3 high biomarker levels had significantly reduced overall survival compared with patients with low levels (2 high: HR, 2.97; 95% CI, 1.44-6.10; P = 0.00; 3 high: HR, 3.10; 95% CI, 1.45-6.65; P = 0.00). CONCLUSIONS Preoperative levels of CA 19-9, IL-6, and YKL-40 may be useful to identify a subgroup of PC patients with poor prognosis.
Collapse
|
|
34
|
Ismail H, Helby J, Hölmich LR, Chakera AH, Bastholt L, Klyver H, Sjøgren P, Schmidt H, Schöllhammer L, Johansen JS, Nordestgaard BG, Bojesen SE. Measured and genetically predicted plasma YKL-40 levels and melanoma mortality. Eur J Cancer 2019; 121:74-84. [PMID: 31563729 DOI: 10.1016/j.ejca.2019.08.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 07/15/2019] [Accepted: 08/01/2019] [Indexed: 01/22/2023]
Abstract
PURPOSE High plasma levels of YKL-40 might be associated with mortality in patients with melanoma, and it is unknown if YKL-40 is causally related to mortality. EXPERIMENTAL DESIGN We studied two cohorts: 2618 patients with melanoma from hospital clinics and 1413 general population patients with melanoma, totalling 4031 patients followed up for mortality end-points for up to 20 years. All were genotyped for CHI3L1 rs4950928, highly predictive of lifelong plasma YKL-40, and plasma YKL-40 levels were measured in 2165 patients. We tested the hypotheses that measured and genetically predicted high plasma YKL-40 are associated with increased mortality in patients with melanoma. RESULTS For the hospital melanoma cohort, age- and sex-adjusted hazard ratios for death in individuals with measured plasma YKL-40 in the 96-100th percentile versus 1-95th percentile and per 10-percentile increase were 1.52 (95% confidence interval, 1.07-2.16) and 1.07 (1.02-1.11), respectively, most pronounced for patients with localised melanomas. Each C-allele of the CHI3L1 rs4950928 genotype was associated with plasma YKL-40 level increases of 32% in the hospital melanoma cohort (p = 6 × 10-48) and 43% in the general population melanoma cohort (p = 7 × 10-13). Multifactorially adjusted ratios for these increases in the combined cohorts were 1.04 (1.00-1.09) observationally for measured plasma YKL-40 and 0.98 (0.86-1.12) for the genetically predicted plasma YKL-40. CONCLUSION Measured, but not genetically predicted, increasing plasma YKL-40 was associated with increased mortality in patients with melanoma. Plasma YKL-40 is a marker but less likely to be a cause of increased mortality in patients with melanoma.
Collapse
Affiliation(s)
- Hafsa Ismail
- Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Jens Helby
- Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Lisbet R Hölmich
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Plastic Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
| | - Annette H Chakera
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Plastic Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
| | - Lars Bastholt
- Department of Oncology, Odense University Hospital, Denmark
| | - Helle Klyver
- Department of Plastic Surgery, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Pia Sjøgren
- Department of Plastic Surgery, Aarhus University Hospital, Denmark
| | - Henrik Schmidt
- Department of Oncology, Aarhus University Hospital, Denmark
| | - Liv Schöllhammer
- Department of Plastic Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
| | - Julia S Johansen
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Oncology and Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark
| | - Stig E Bojesen
- Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark.
| |
Collapse
|
|
35
|
Temel Yüksel İ, Aslan Çetin B, Köroğlu N, Aydoğan Mathyk B, Erdem B. Inflammatory marker YKL-40 levels in intrahepatic cholestasis of pregnancy. Gynecol Endocrinol 2019; 35:635-637. [PMID: 30688121 DOI: 10.1080/09513590.2018.1563889] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy is a diagnosis of exclusion and presents with unexplained pruritus, abnormal liver function tests, and increased serum bile acid levels, particularly in the third trimester of pregnancy. Serum YKL-40 levels are increased in liver diseases and our aim was to investigate YKL-40 levels in pregnant women with ICP. 40 women with intrahepatic cholestasis of pregnancy and 40 healthy pregnant women were included in this cross-sectional study. Serum YKL-40 levels were measured in both groups and correlation analysis were performed between the YKL-40 and other liver function tests. Serum YKL-40 concentrations were higher in the intrahepatic cholestasis of pregnancy group than in the control group (103.46 ± 53.03 vs. 57.60 ± 30.30 ng/ml, p = .002). The cutoff YKL-40 serum concentration was 84.80 ng/ml for the diagnosis of intrahepatic cholestasis of pregnancy. There was no correlation between fasting bile acids and YKL-40 levels. However, there was a significant positive correlation between the YKL-40 levels and aspartate aminotransferase (r = 0.22, p = .04) and alanine aminotransferase (r = 0.24, p = .02). Raised YKL-40 levels might support the evidence on inflammatory processes in intrahepatic cholestasis of pregnancy.
Collapse
Affiliation(s)
- İlkbal Temel Yüksel
- a Obstetrics and Gynecology Department , Kanuni Sultan Süleyman Training and Research Hospital , İstanbul , Turkey
| | - Berna Aslan Çetin
- a Obstetrics and Gynecology Department , Kanuni Sultan Süleyman Training and Research Hospital , İstanbul , Turkey
| | - Nadiye Köroğlu
- a Obstetrics and Gynecology Department , Kanuni Sultan Süleyman Training and Research Hospital , İstanbul , Turkey
| | | | - Baki Erdem
- a Obstetrics and Gynecology Department , Kanuni Sultan Süleyman Training and Research Hospital , İstanbul , Turkey
| |
Collapse
|
|
36
|
Nada D, Julien C, Rompré PH, Akoume MY, Gorman KF, Samuels ME, Levy E, Kost J, Li D, Moreau A. Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis. Sci Rep 2019; 9:5712. [PMID: 30952886 PMCID: PMC6450973 DOI: 10.1038/s41598-019-41191-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 03/01/2019] [Indexed: 12/03/2022] Open
Abstract
The cellular and molecular mechanisms underlying spinal deformity progression in adolescent idiopathic scoliosis (AIS) remain poorly understood. In this study, 804 French-Canadian patients and 278 age- and sex-matched controls were enrolled and genotyped for 12 single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene or its promoter. The plasma YKL-40 levels were determined by ELISA. We showed that elevation of circulating YKL-40 levels was correlated with a reduction of spinal deformity progression risk. We further identified significant associations of multiple CHI3L1 SNPs and their haplotypes with plasma YKL-40 levels and scoliosis severity as a function of their classification in a specific endophenotype. In the endophenotype FG3 group, we found that patients harboring the haplotype G-G-A-G-G-A (rs880633|rs1538372|rs4950881|rs10399805|rs6691378|rs946261), which presented in 48% of the cases, showed a positive correlation with the plasma YKL-40 levels (P = 7.6 × 10-6 and coefficient = 36). Conversely, the haplotype A-A-G-G-G-G, which presented in 15% of the analyzed subjects, showed a strong negative association with the plasma YKL-40 levels (P = 2 × 10-9 and coefficient = -9.56). We found that this haplotype showed the strongest association with AIS patients in endophenotype FG2 (P = 9.9 × 10-6 and coefficient = -13.53), who more often develop severe scoliosis compared to those classified in the other two endophenotypes. Of note, it showed stronger association in females (P = 1.6 × 10-7 and coefficient = -10.08) than males (P = 0.0021 and coefficient = -9.01). At the functional level, we showed that YKL-40 treatments rescued Gi-coupled receptor signalling dysfunction occurring in primary AIS osteoblasts. Collectively, our findings reveal a novel role for YKL-40 in AIS pathogenesis and a new molecular mechanism interfering with spinal deformity progression.
Collapse
Affiliation(s)
- Dina Nada
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital, Research Center, Montreal, QC, Canada
- Program of Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Cédric Julien
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital, Research Center, Montreal, QC, Canada
| | - Pierre H Rompré
- Faculty of Dentistry, Université de Montréal, Montreal, QC, Canada
| | - Marie-Yvonne Akoume
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital, Research Center, Montreal, QC, Canada
| | - Kristen F Gorman
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital, Research Center, Montreal, QC, Canada
- Department of Biological Sciences, California State University, Chico, CA, USA
| | - Mark E Samuels
- Sainte-Justine University Hospital Research Center, Montreal, QC, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Emile Levy
- Sainte-Justine University Hospital Research Center, Montreal, QC, Canada
- Department of Nutrition, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Jason Kost
- Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA
| | - Dawei Li
- Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA
- Neuroscience, Behavior, and Health Initiative, University of Vermont, Burlington, Vermont, USA
| | - Alain Moreau
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital, Research Center, Montreal, QC, Canada.
- Program of Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
- Department of Stomatology, Faculty of Dentistry, Université de Montréal, Montreal, QC, Canada.
| |
Collapse
|
|
37
|
Yang L, Dong H, Lu H, Liao Y, Zhang H, Xu L, Tan Y, Cao S, Tan J, Fu S. Serum YKL-40 predicts long-term outcome in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Medicine (Baltimore) 2019; 98:e14920. [PMID: 30896649 PMCID: PMC6709285 DOI: 10.1097/md.0000000000014920] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 01/09/2019] [Accepted: 02/26/2019] [Indexed: 11/26/2022] Open
Abstract
Serum YKL-40, a potential inflammatory marker, is greatly increased at the early stage of ST-segment elevation myocardial infarction (STEMI). Here, we hypothesized that YKL-40 levels at admission could predict the long-term outcomes after STEMI.A total of 324 patients with acute STEMI undergoing primary percutaneous coronary intervention (PCI) were consecutively enrolled and followed for 24 months. The baseline clinical and procedural data were recorded, and serum YKL-40 levels at admission were measured using ELISA method. The endpoint of interest was major adverse cardiac event (MACE), including all-cause death, recurrent myocardial infarction, and hospitalization for heart failure.Patients with elevated serum YKL-40 levels (≥126.8 ng/mL) were more likely to be older and smoker and to present with type 2 diabetes, advanced Killip class, multivessel disease and intra-aortic balloon pump, with increased levels of admission glucose, triglyceride, and high-sensitivity C-reactive protein and decreased level of high-density lipoprotein cholesterol. During the follow-up period, the incidence of MACE was notably higher in the high than in the low YKL-40 groups (28.4% vs 11.1%, P < .001). Kaplan-Meier curve showed that elevated YKL-40 levels were associated with reduced MACE-free survivals (log-rank P < .001). In multivariate Cox regression analysis, we found that high serum YKL-40 level was an independent predictor of MACE after controlling for clinical and angiographic variables (hazard ratio: 1.65, 95% confidence interval: 1.14-2.39, P = .008).The results of our study indicate that serum YKL-40 may be used as a biomarker to predict the long-term outcome after PCI in patients with STEMI.
Collapse
Affiliation(s)
| | - Hui Dong
- Department of Intensive Care Unit
| | | | | | | | | | - Yun Tan
- Department of Intensive Care Unit
| | - Song Cao
- Department of Intensive Care Unit
| | - Jinhui Tan
- Department of Anesthesia, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, China
| | | |
Collapse
|
|
38
|
Zadi Heydarabad M, Baharaghdam S, Azimi A, Mohammadi H, Eivazi Ziaei J, Yazdanpanah B, Zak MS, Farahani ME, Dohrabpour A, Partash N, Talebi M. The role of tumor suppressor of resveratrol and prednisolone by downregulation of YKL-40 expression in CCRF-CEM cell line. J Cell Biochem 2018; 120:3773-3779. [PMID: 30426549 DOI: 10.1002/jcb.27659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 08/21/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Acute lymphoblastic leukemia (ALL) is characterized by excessive accumulation of lymphoblast and progenitors. Leukemia is the most common cancer in children and ALL is the most common subtype. Many studies have shown that the YKL-40 gene is one of the most widely expressed genes in tumors, including leukemia, but not in healthy blood cells. Clinical studies have shown that serum YKL-40 levels have a positive correlation with tumor expansion, in addition to being a prognostic agent independent of a short relapse-free interval, as well as a brief overall survival in patients with various cancers. The previous study shows that YKL-40 is closely related to the degree of pathology or degree of human leukemia pathology and plays an important role in cell proliferation. Hence, the YKL-40 can be an attractive target in designing anticancer therapies. METHODS CCRF-CEM cells were treated with resveratrol and prednisolone. For analysis of YKL-40 expression changes under medication, real-time polymerase chain reaction (PCR) and Western blot techniques were used at resonating intervals of 24 and 48 hours. RESULTS The effect of 15, 50, and 100 μM resveratrol and 700 μM of prednisolone on CCRF-CEM cells reduced YKL-40. The YKL-40 gene was quantitatively measured using RT-PCR. The Western blot method was used to evaluate changes in the expression of YKL-40 protein. CONCLUSION In this study, we first evaluated YKL-40 expression and resveratrol and prednisolone effect on YKL-40 in ALL. This finding supports the idea of targeting YKL-40 as a new drug treatment of ALL and extends the use of resveratrol in antileukemia research.
Collapse
Affiliation(s)
| | - Sina Baharaghdam
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ako Azimi
- Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Hamed Mohammadi
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jamal Eivazi Ziaei
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behruz Yazdanpanah
- Department of Laboratory Sciences, School Paramedics, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohsen Sharif Zak
- Clinical Biochemistry and Laboratory, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Aghdas Dohrabpour
- Department of Microbiology, Yasuj Branch, Islamic Azad University, Tehran, Iran
| | - Nasim Partash
- Department of Nursing, School of Nursing and Midwifery, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Mehdi Talebi
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.,Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
39
|
Bowler MA, Bersi MR, Ryzhova LM, Jerrell RJ, Parekh A, Merryman WD. Cadherin-11 as a regulator of valve myofibroblast mechanobiology. Am J Physiol Heart Circ Physiol 2018; 315:H1614-H1626. [PMID: 30359089 DOI: 10.1152/ajpheart.00277.2018] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Cadherin-11 (CDH11) is upregulated in a variety of fibrotic diseases, including arthritis and calcific aortic valve disease. Our recent work has identified CDH11 as a potential therapeutic target and shown that treatment with a CDH11 functional blocking antibody can prevent hallmarks of calcific aortic valve disease in mice. The present study investigated the role of CDH11 in regulating the mechanobiological behavior of valvular interstitial cells believed to cause calcification. Aortic valve interstitial cells were harvested from Cdh11+/+, Cdh11+/-, and Cdh11-/- immortomice. Cells were subjected to inflammatory cytokines transforming growth factor (TGF)-β1 and IL-6 to characterize the molecular mechanisms by which CDH11 regulates their mechanobiological changes. Histology was performed on aortic valves from Cdh11+/+, Cdh11+/-, and Cdh11-/- mice to identify key responses to CDH11 deletion in vivo. We showed that CDH11 influences cell behavior through its regulation of contractility and its ability to bind substrates via focal adhesions. We also show that transforming growth factor-β1 overrides the normal relationship between CDH11 and smooth muscle α-actin to exacerbate the myofibroblast disease phenotype. This phenotypic switch is potentiated through the IL-6 signaling axis and could act as a paracrine mechanism of myofibroblast activation in neighboring aortic valve interstitial cells in a positive feedback loop. These data suggest CDH11 is an important mediator of the myofibroblast phenotype and identify several mechanisms by which it modulates cell behavior. NEW & NOTEWORTHY Cadherin-11 influences valvular interstitial cell contractility by regulating focal adhesions and inflammatory cytokine secretion. Transforming growth factor-β1 overrides the normal balance between cadherin-11 and smooth muscle α-actin expression to promote a myofibroblast phenotype. Cadherin-11 is necessary for IL-6 and chitinase-3-like protein 1 secretion, and IL-6 promotes contractility. Targeting cadherin-11 could therapeutically influence valvular interstitial cell phenotypes in a multifaceted manner.
Collapse
Affiliation(s)
- Meghan A Bowler
- Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee
| | - Matthew R Bersi
- Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee
| | - Larisa M Ryzhova
- Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee
| | - Rachel J Jerrell
- Department of Otolaryngology, Vanderbilt University , Nashville, Tennessee
| | - Aron Parekh
- Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee.,Department of Otolaryngology, Vanderbilt University , Nashville, Tennessee.,Vanderbilt-Ingram Cancer Center , Nashville, Tennessee
| | - W David Merryman
- Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee
| |
Collapse
|
|
40
|
Obesity modulates the association between sleep apnea treatment and CHI3L1 levels but not CHIT1 activity in moderate to severe OSA: an observational study. Sleep Breath 2018; 22:1101-1109. [PMID: 30311184 PMCID: PMC6244533 DOI: 10.1007/s11325-018-1731-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/07/2018] [Accepted: 10/01/2018] [Indexed: 12/22/2022]
Abstract
Purpose The inflammatory markers chitinase-3-like protein 1 (CHI3L1) and chitotriosidase (CHIT1) have both been associated with cardiovascular complications. The aim of this preliminary observational study was to assess the roles and interaction of obstructive sleep apnea (OSA) severity and body mass index (BMI) with plasma CHI3L1 levels and CHIT1 activity in patients with moderate to severe OSA. The second aim was to assess the roles and interaction of positive airway pressure (PAP) treatment and BMI on the expression of the same proteins. Methods The study included 97 OSA patients with an apnea–hypopnea index (AHI) ≥ 15 and full usage of PAP treatment after 4 months. Plasma CHI3L1 levels and CHIT1 activity were measured before and after treatment. Results Multiple linear regression analysis demonstrated an independent association of BMI on CHI3L1 levels (p < 0.05) but not on CHIT1 activity. The OSA severity markers (AHI and oxygen desaturation index) did not independently or in interaction with BMI levels associate with CHI3L1 levels or with CHIT1 activity (p > 0.05). A two-way repeated measures ANOVA revealed a significant interaction between PAP treatment effect (before vs. after) and BMI groups (< 35 kg/m2 vs. ≥ 35 kg/m2) on CHI3L1 levels (p = 0.03) but not on CHIT1 activity (p = 0.98). Conclusions Obesity independently associated with CHI3L1 levels. Association between OSA severity and CHI3L1 levels or CHIT1 activity (independent of or dependent on obesity level) could not be confirmed. However, decrease was observed in CHI3L1 levels after PAP treatment in severely obese OSA patients but not in those less obese. Electronic supplementary material The online version of this article (10.1007/s11325-018-1731-6) contains supplementary material, which is available to authorized users.
Collapse
|
|
41
|
Sánchez-Jiménez BA, Brizuela-Alcántara D, Ramos-Ostos MH, Alva-López LF, Uribe-Esquivel M, Chávez-Tapia NC. Both alcoholic and non-alcoholic steatohepatitis association with cardiovascular risk and liver fibrosis. Alcohol 2018; 69:63-67. [PMID: 29660603 DOI: 10.1016/j.alcohol.2017.11.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 11/09/2017] [Accepted: 11/12/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. Mortality in NAFLD is mainly related to cardiovascular disease (CVD) and cancer. NAFLD and its association with both CVD and liver disease risk have been well evaluated, but the association of NAFLD with alcohol, known as "both alcoholic and non-alcoholic steatohepatitis" (BASH), remains uncertain. The objective of this study was to assess the influence of alcohol and obesity in the development of liver and cardiovascular disease risk. METHODS This was a case-control study that included patients from a regular check-up. Alcohol consumption was evaluated with MAST, AUDIT, and CAGE. Cardiovascular risk was evaluated using the Framingham score, and liver fibrosis was evaluated with APRI and NAFLD score. Patients were classified in five groups: healthy patients, steatosis with obesity, steatosis with alcoholism, BASH, and idiopathic steatosis. RESULTS A total of 414 patients were included. The BASH group represented 16% of patients, and showed a greater proportion of patients with high cardiovascular risk with 17% (p = 0.001), and liver fibrosis with 9%, according to the APRI score (p = 0.10). A multivariate logistic regression showed that alcohol consumption >140 g/week (OR 2.546, 95% CI 1.11-5.81, p = 0.003) and BMI >25 kg/m2 (OR 12.64, 95% CI 1.66 96.20, p = 0.001) were related to high cardiovascular risk. Liver fibrosis according to APRI was only related to alcohol consumption >140 g/week (OR 2.74, 95% CI 1-7.48, p = 0.03). CONCLUSIONS BASH remains an area not well explored, and of great implication given the increasing number of patients affected. We observed an additive effect of both etiologies in the development of high cardiovascular and liver disease risk.
Collapse
|
|
42
|
Höbaus C, Tscharre M, Herz CT, Pesau G, Wrba T, Koppensteiner R, Schernthaner GH. YKL-40 levels increase with declining ankle-brachial index and are associated with long-term cardiovascular mortality in peripheral arterial disease patients. Atherosclerosis 2018; 274:152-156. [PMID: 29783062 DOI: 10.1016/j.atherosclerosis.2018.05.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/26/2018] [Accepted: 05/02/2018] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND AIMS YKL-40 is an inflammatory marker secreted by macrophages and is expressed in atherosclerotic plaques. YKL-40 increases in coronary artery disease (CAD) with poor coronary collateral vessel development. Higher levels are linked to reduced survival in CAD patients. Studies evaluating YKL-40 in patients with peripheral arterial disease (PAD) are scarce. This study aims to elucidate a possible link between YKL-40 and PAD severity as well as cardiovascular long-term mortality. METHODS YKL-40 was measured at baseline in 365 elderly PAD patients (age 69 ± 10.4, 33.7% women, Fontaine stage I-II) by bead-based multiplex assay. Patients were followed for seven years to assess long-term cardiovascular and all-cause survival by Kaplan-Meier and Cox regression. RESULTS YKL-40 levels were associated with declining ankle-brachial index (ABI) in PAD patients without Moenckeberg's mediasclerosis (R = -0.189, p=0.002). PAD patients with mediasclerosis exhibited higher YKL-40 levels (p=0.002). Baseline YKL-40 levels were significantly associated with cardiovascular mortality (HR 1.52 (1.21-1.91), p < 0.001) and all-cause mortality (HR 1.45 (1.20-1.75), p < 0.001) over a seven-year observation period. After multivariable adjustment for gender, patient age, known carotid artery disease, known coronary artery disease, smoking status, systolic blood pressure, HbA1c, low density lipoprotein cholesterol, estimated glomerular filtration rate, aspartate aminotransferase, and C-reactive protein, YKL-40 remained significantly associated with cardiovascular (HR 1.34 (1.02-1.75), p=0.033) and all-cause mortality (HR 1.25 (1.01-1.55), p=0.039). CONCLUSIONS Increased YKL-40 levels are independently associated with poor long-term cardiovascular survival in peripheral arterial disease patients. Furthermore, YKL-40 correlates with patients' ABI in PAD in the absence of mediasclerosis.
Collapse
Affiliation(s)
- Clemens Höbaus
- Division of Angiology, Medicine II, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Maximilian Tscharre
- 3rd Medical Department with Cardiology and Intensive Care Medicine, Wilhelminenspital, Montleartstraße 37, 1160, Vienna, Austria
| | - Carsten Thilo Herz
- Division of Endocrinology and Metabolism, Medicine III, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Gerfried Pesau
- Division of Angiology, Medicine II, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Thomas Wrba
- IT4Science, IT-Systems & Communications, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Renate Koppensteiner
- Division of Angiology, Medicine II, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Gerit-Holger Schernthaner
- Division of Angiology, Medicine II, Medical University Vienna, Spitalgasse 23, 1090, Vienna, Austria.
| |
Collapse
|
|
43
|
YENER Y, YERLİKAYA FH. Western diet induces endogen oxidative deoxyribonucleic acid damage and infl ammation in Wistar rats. REV NUTR 2018. [DOI: 10.1590/1678-98652018000300001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
ABSTRACT Objective Nutritional diseases such as metabolic syndrome, cardiovascular disorder, chronic inflammation or even cancer are observed in people who sustain their lifestyle by Western diet due to high calorie intake. The origin of these diseases are the degraded deoxyribonucleic acid structure. In this study, we investigated whether Western diet produced endogenous oxidative deoxyribonucleic acid damage, apoptosis or inflammation. Methods Twenty-eight male Wistar rats, aged 10-12 weeks, were divided into four groups. The rats in control group received the standard diet and the remaining rats were given one of the following three diets for four weeks: a high-fat diet containing 35% fat, a high-sucrose diet containing 69% sucrose and Western diet comprising both two types of diets. After treatment the serum 8-hydroxy-2-deoxyguanosine, poly (adenosine diphosphate ribose) polymerase-1, chitinase-3-like protein 1, soluble urokinase-type plasminogen activator receptor, Fas ligand and cytochrome c levels were measured. Results It was observed no changes in the serum soluble urokinase-type plasminogen activator receptor, Fas ligand and cytochrome c levels whereas a statistically significant increase in the serum 8-hydroxy-2-deoxyguanosine, poly (adenosine diphosphate ribose) polymerase-1 and chitinase-3-like protein 1 levels were found only in rats that were given Western diet. Conclusion The findings show that Western diet produced endogenous oxidative deoxyribonucleic acid damage, which then increased serum poly (adenosine diphosphate ribose) polymerase-1 levels, eventually leading to inflammation.
Collapse
|
|
44
|
Persson F, Borg R. YKL-40 in dialysis patients: another candidate in the quest for useful biomarkers in nephrology. Kidney Int 2018; 93:21-22. [PMID: 29291818 DOI: 10.1016/j.kint.2017.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 08/10/2017] [Indexed: 11/26/2022]
Abstract
End-stage renal disease is characterized by widespread inflammation and an increased cardiovascular mortality rate. Biomarkers are frequently examined to diversify risk prediction in addition to the usual clinical variables and also to explore potential pathological mechanisms that may be targets for future intervention. YKL-40 is an inflammatory biomarker that has been examined in a range of diseases and clinical conditions, and now in a dialysis population. The question is whether this marker will provide clues for future interventions.
Collapse
Affiliation(s)
| | - Rikke Borg
- Department of Nephrology, Zeeland University Hospital, Roskilde, Denmark; Institute of Clinical Medicine, University of Copenhagen, Denmark
| |
Collapse
|
|
45
|
Jung YY, Kim KC, Park MH, Seo Y, Park H, Park MH, Chang J, Hwang DY, Han SB, Kim S, Son DJ, Hong JT. Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice. Am J Cancer Res 2018; 8:749-766. [PMID: 29344304 PMCID: PMC5771091 DOI: 10.7150/thno.20183] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 11/09/2017] [Indexed: 02/06/2023] Open
Abstract
Although the important role of amyloid precursor protein (APP) in vascular diseases associated with Alzheimer's disease (AD) has been demonstrated, the underlying molecular mechanisms and physiological consequences are unclear. We aimed to evaluate vascular inflammation and atherosclerosis in Swedish mutant of human APP transgenic (APPsw-Tg) and ApoE-/-/APPsw-Tg mice. We also aimed to explore the mechanisms underlying any changes observed in these mice compared with non-Tg controls. Methods: The transgenic and non-Tg mouse strains were subjected to partial ligation of the left carotid artery to induce atherosclerotic changes, which were measured using histological approaches, immunohistochemistry, quantitative polymerase chain reaction, and gene expression microarrays. Results: Our results showed increased vascular inflammation, arterial wall thickness, and atherosclerosis in APPsw-Tg and ApoE-/-/APPsw-Tg mice. We further found that the expression of chitinase-3-like-1 (Chi3l1) is increased in the APPsw-Tg mouse artery and Chi3l1 mediates endothelial cell (EC) inflammation and vascular smooth muscle cell (VSMC) activation, which in turn exacerbates atherosclerosis. In addition, using two publicly available microarray datasets from the dorsolateral prefrontal cortex of people with AD and unaffected controls as well as inflamed human umbilical vein endothelial cells, we found that Chi3l1 and associated inflammatory gene were significantly associated with AD, evaluated by co-expression network analysis and functional annotation. Knockdown of Chi3l1 in the arterial endothelium in vivo suppressed the development of atherosclerosis. We also show that microRNA 342-3p (miR-342-3p) inhibits EC inflammation and VSMC activation through directly targeting Chi3l1, and that APPsw increased Chi3l1 expression by reducing miR-342-3p expression in the arterial endothelium, promoting atherosclerosis. Conclusion: Our findings suggest that targeting Chi3l1 might provide new diagnostic and therapeutic strategies for vascular diseases in patients with AD.
Collapse
|
|
46
|
Chen XL, Li Q, Huang WS, Lin YS, Xue J, Wang B, Jin KL, Shao B. Serum YKL-40, a prognostic marker in patients with large-artery atherosclerotic stroke. Acta Neurol Scand 2017; 136:97-102. [PMID: 27650381 DOI: 10.1111/ane.12688] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND PURPOSE Inflammation comprises important aspects of large-artery atherosclerosis (LAA) stroke pathophysiology. YKL-40 is a new and emerging biomarker that is associated with both acute and chronic inflammations. Elevated serum concentrations of YKL-40 have been reported in patients with atherosclerosis and other cardiovascular diseases. This study investigates whether serum YKL-40 concentrations on admission can predict 3-month clinical outcomes after LAA stroke. METHODS We recruited control patients (n=85) and those with LAA stroke (n=141) according to the TOAST classification system. The modified Rankin scale at 3 months after stroke was used to evaluate the prognosis. The prognostic accuracy was assessed by the receiver operating characteristic curve. RESULTS Serum YKL-40 level was significantly higher for LAA patients than for controls (P<.001). Patients with poor outcomes (n=36) had significantly increased serum YKL-40 concentrations on admission (P=.01). High YKL-40 levels predicted poor functional outcome (OR=6.47, P=.02). Moreover, the combination of YKL-40 level and the NIHSS score could improve the prognostic accuracy of the NIHSS in predicting functional outcome (combined areas under the curve, 0.87; 95% CI, 0.80-0.94; P<.001). CONCLUSIONS The level of serum YKL-40 is a significant and independent biomarker to predict the clinical outcome of LAA stroke.
Collapse
Affiliation(s)
- X.-L. Chen
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research; First Affiliated Hospital, Wenzhou Medical University; Wenzhou China
- Department of Rehabilitation; Wenzhou people’s hospital; Wenzhou China
| | - Q. Li
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research; First Affiliated Hospital, Wenzhou Medical University; Wenzhou China
| | - W.-S. Huang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research; First Affiliated Hospital, Wenzhou Medical University; Wenzhou China
| | - Y.-S. Lin
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research; First Affiliated Hospital, Wenzhou Medical University; Wenzhou China
| | - J. Xue
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research; First Affiliated Hospital, Wenzhou Medical University; Wenzhou China
| | - B. Wang
- Department of Pharmacology and Neuroscience; University of North Texas Health Science Center; Fort Worth TX USA
| | - K.-L. Jin
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research; First Affiliated Hospital, Wenzhou Medical University; Wenzhou China
- Department of Pharmacology and Neuroscience; University of North Texas Health Science Center; Fort Worth TX USA
| | - B. Shao
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research; First Affiliated Hospital, Wenzhou Medical University; Wenzhou China
| |
Collapse
|