Lectin YKL-40 Level and Telomere Length are Indicators of Insomnia Disorder.

OBJECTIVE: To explore the relationship between YKL-40 level, telomere length, and different subtypes of insomnia disorder. METHODS: A total of 145 individuals suffering from insomnia were enrolled and divided into four groups according to the insomniac subtypes: difficulty initiating sleep, early morning awakening, difficulty maintaining sleep, and mixed symptoms. Eighty healthy controls were also collected at the same time. Peripheral leukocyte genomic DNA was extracted, relative telomere lengths were measured using the real-time quantitative polymerase chain reaction method, and YKL-40 levels were determined using enzyme-linked immunoassay. Logistic regression modeling was used to analyze the correlation between different insomnia subtypes, YKL-40 level, and telomere length. RESULTS: People with telomere lengths in the lowest tertile were more likely to have trouble falling asleep (odds ratio (OR) 2.13, 95% confidence interval (CI) 1.22-3.63; p = 0.03) and had a higher frequency of mixed symptoms (OR 1.49, 95% CI 1.30-2.81; p = 0.04). People in the highest tertile of YKL-40 level had an increased chance of waking up early (OR 2.98, 95% CI 1.54-5.33; p = 0.01) and more mixed symptoms (OR 1.47, 95% CI 1.22-2.79; p = 0.02). Furthermore, using receiver operating characteristic curve analysis, the area under the curve of YKL-40 level and telomere length was 0.806 and 0.746, respectively. CONCLUSIONS: Telomere length in patients with difficulty initiating sleep and mixed symptoms was significantly shortened and the level of YKL-40 in people who have early morning awakening and mixed symptoms was significantly increased. Our findings provide the first evidence that leukocyte telomere length and YKL-40 level are individually linked to mixed symptoms.

Corrigendum: YKL-40 promotes chemokine expression following drug-induced liver injury via TF-PAR1 pathway in mice.

[This corrects the article DOI: 10.3389/fphar.2023.1205062.].

Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study.

INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. DISCUSSION: We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain. HIGHLIGHTS: Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.

Evaluation of the relationship between YKL-40 level and clinical severity in patients with Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a widespread tick-borne viral disease. YKL-40 (also known as chitinase-3-like-1 protein) is an acute phase protein released by various immune cells. The purpose of this study was to investigate the relationship between YKL-40 level and the clinical course and prognosis of CCHF. The study included 78 patients who were admitted to our hospital between April 15 and 30 August 2022 and had a positive polymerase chain reaction test result for CCHF. The patients were divided into two groups, severe and non-severe. In addition, a control group consisting of 22 healthy people was established. Mean serum YKL-40 levels were significantly higher in patients than controls (106.8 ng/mL ± 91.2 and 47.1 ng/mL ± 35.3, respectively; p < 0.001). However, mean YKL-40 levels were also significantly higher in patients with severe CCHF compared to non-severe cases (173.3 ± 112.3 and 67.5 ± 41.7, respectively; p < 0.001). A comparison of the 10 exitus patients and the 68 survivors revealed significantly higher YKL-40 levels in the exitus group (mean: 214.0 ± 139.0 and 92.8 ± 73.6, respectively; p = 0.001). A receiver operating characteristic analysis for YKL-40 levels to distinguish between severe and non-severe patients found an area under the curve of 0.925. YKL-40 levels were measured with a sensitivity of 97% and a specificity of 84% with a cutoff value of 90.7 ng/mL. YKL-40 levels measured at the time of hospital presentation in patients with CCHF can be used as a biomarker for clinical course and prognosis.

Bioenergetic and Inflammatory Alterations in Regressed and Non-Regressed Patients with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with multiple physiological abnormalities. Current laboratory and clinical evidence most commonly report mitochondrial dysfunction, oxidative stress, and immunological imbalance in almost every cell type of the body. The present work aims to evaluate oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and inflammation-related molecules such as Cyclooxygenase-2 (COX-2), chitinase 3-like protein 1 (YKL-40), Interleukin-1 beta (IL-1ß), Interleukin-9 (IL-9) in ASD children with and without regression compared to healthy controls. Children with ASD (n = 56) and typically developing children (TDC, n = 12) aged 1.11 to 11 years were studied. Mitochondrial activity was examined in peripheral blood mononuclear cells (PBMCs) isolated from children with ASD and from the control group, using a metabolic analyzer. Gene and protein levels of IL-1ß, IL-9, COX-2, and YKL-40 were investigated in parallel. Our results showed that PBMCs of the ASD subgroup of regressed patients (ASD R(+), n = 21) had a specific pattern of mitochondrial activity with significantly increased maximal respiration, respiratory spare capacity, and proton leak compared to the non-regressed group (ASD R(-), n = 35) and TDC. Furthermore, we found an imbalance in the studied proinflammatory molecules and increased levels in ASD R(-) proving the involvement of inflammatory changes. The results of this study provide new evidence for specific bioenergetic profiles of immune cells and elevated inflammation-related molecules in ASD. For the first time, data on a unique metabolic profile in ASD R(+) and its comparison with a random group of children of similar age and sex are provided. Our data show that mitochondrial dysfunction is more significant in ASD R(+), while in ASD R(-) inflammation is more pronounced. Probably, in the group without regression, immune mechanisms (immune dysregulation, leading to inflammation) begin initially, and at a later stage mitochondrial activity is also affected under exogenous factors. On the other hand, in the regressed group, the initial damage is in the mitochondria, and perhaps at a later stage immune dysfunction is involved.

Prognostic and predictive role of YKL-40 in anal squamous cell carcinoma: a serological and tissue-based analysis in a multicentric cohort.

Introduction: Anal squamous cell carcinoma (ASC) is a rare gastrointestinal malignancy showing an increased incidence over the past decades. YKL-40 is an immune modulator and pro-angiogenetic factor that showed a promising prognostic and predictive potential in several malignancies, but limited data are available for ASC. This study aims to provide an extensive evaluation of the prognostic and predictive role of YKL-40 in a multicenter cohort of ASC patients. Methods: We retrospectively retrieved 72 consecutive cases of ASC diagnosed between February 2011 and March 2021. Both serum and tissue protein expression of YKL-40 were assessed, the latter in ASC tumor cells and peritumor immune cells. Results: Increased YKL-40 serum levels at the time of diagnosis were associated with older age (p = 0.035), presence of cardiovascular/metabolic comorbidities (p = 0.007), and death for any cause (p = 0.011). In addition, high serum levels of YKL-40 were associated with a poor prognosis (HR: 2.82, 95% CI: 1.01-7.84; p = 0.047). Protein expression of YKL-40 in ASC tumor cells was significantly associated with low tumor grade (p = 0.031), while the increased expression in peritumor immune cells was associated with a worse response of patients to chemoradiotherapy (p = 0.007). However, YKL-40 protein expression in ASC tumor cells or peritumor immune cells did not significantly impact patient overall survival. Discussion: In conclusion, YKL-40 resulted a relevant prognostic (serum level) and predictive (tissue protein expression in peritumor immune cells) biomarker and can considerably improve ASC patient clinical management.

High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and ß, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPß and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.

Elevated Serum Levels of YKL-40, YKL-39, and SI-CLP in Patients with Treatment Failure to DMARDs in Patients with Rheumatoid Arthritis.

Around 30-60% of patients with rheumatoid arthritis (RA) present treatment failure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Chitinase-like proteins (CLPs) (YKL-40, YKL-39, SI-CLP) might play a role, as they are associated with the inflammatory process. This study aimed to evaluate CLP utility as a biomarker in the treatment failure of csDMARDs. A case-control study included 175 RA patients classified into two groups based on therapeutic response according to DAS28-ESR: responders (DAS28 < 3.2); non-responders (DAS28 ≥ 3.2). CLP serum levels were determined by ELISA. Multivariable logistic regression and receiver operating characteristic (ROC) curves were used to evaluate CLPs' utility as biomarkers of treatment failure. Non-responders presented higher levels of YKL-40, YKL-39, and SI-CLP compared with responders (all: p < 0.001). YKL-40 correlated positively with YKL-39 (rho = 0.39, p < 0.001) and SI-CLP (rho = 0.23, p = 0.011) and YKL-39 with SI-CLP (rho = 0.34, p < 0.001). The addition of CLPs to the regression models improves diagnostic accuracy (AUC 0.918) compared to models including only clinical classical variables (AUC 0.806) p < 0.001. Non-responders were positive for all CLPs in 35.86%. Conclusions: CLPs could be considered as a useful biomarker to assess treatment failure, due to their association with clinical variables and improvement to the performance of regression models.

Tracking neuroinflammatory biomarkers in Alzheimer's disease: a strategy for individualized therapeutic approaches?

BACKGROUND: Recent trials of anti-amyloid-ß (Aß) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD. MAIN BODY: Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aß reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aß deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aß ("A"), tau ("T"), and neurodegeneration ("N"), by incorporating a novel inflammatory component ("I"). CONCLUSIONS: The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients.

A humanized Anti-YKL-40 antibody inhibits tumor development.

Drugs specifically targeting YKL-40, an over-expressed gene (CHI3L1) in various diseases remain developed. The current study is to create a humanized anti-YKL-40 neutralizing antibody and characterize its potentially therapeutic signature. We utilized in silico CDR-grafting bioinformatics to replace the complementarity determining regions (CDRs) of human IgG1 with mouse CDRs of our previously established anti-YKL-40 antibody (mAY). In fifteen candidates (VL1-3/VH1-5) of heavy and light chain variable region combination, one antibody L3H4 named Rosazumab demonstrated strong binding affinity with YKL-40 (KD = 4.645 × 10-8 M) and high homology with human IgG (80 %). In addition, we established different overlapping amino acid peptides of YKL-40 and found that Rosazumab specifically bound to residues K337, K342, and R344, the KR-rich functional domain of YKL-40. Rosazumab inhibited migration and tube formation of YKL-40-expressing tumor cells and induced tumor cell apoptosis. Mechanistically, Rosazumab induced interaction of N-cadherin with ß-catenin and activation of downstream MST1/RASSF1/Histone H2B axis, leading to chromosomal DNA breakage and cell apoptosis. Treatment of xenografted tumor mice with Rosazumab twice a week for 4 weeks inhibited tumor growth and angiogenesis, but induced tumor apoptosis. Rosazumab injected in mice distributed to blood, tumor, and other multiple organs, but did not impact in function or structure of liver and kidney, indicating non-detectable toxicity in vivo. Collectively, the study is the first one to demonstrate that a humanized YKL-40 neutralizing antibody offers a valuable means to block tumor development.

Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies.

Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]). Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies. Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1. Outcome: Incident CKD or end-stage kidney disease. Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts. Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31). Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts. Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

Serum YKL-40 and Serum Krebs von den Lungen-6 as Potential Predictive Biomarkers for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

BACKGROUND: Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis (RA) and is associated with a poor prognosis. However, the role of blood biomarkers in RA-associated interstitial lung disease (RA-ILD) is ill-defined. We aim to evaluate the role of YKL-40 and Krebs von den Lungen-6 (KL-6) in the diagnosis and severity evaluation of RA-ILD. METHODS: 45 RA-non-ILD patients and 38 RA-ILD patients were included. The clinical data and the levels of YKL-40 and KL-6 were measured and collected for all patients. The risk factors for RA-ILD were analyzed and their correlation with relevant indicators and predictive value for RA-ILD was explored. RESULTS: The levels of YKL-40 and KL-6 in RA-ILD patients were higher than RA-non-ILD patients (p < .001). Both YKL-40 and KL-6 were correlated with the incidence of RA-ILD. The predictive power of combined KL-6 and YKL-40 for the presence of ILD was 0.789, with a sensitivity and specificity at 73.7% and 73.3%, respectively. In RA-ILD patients, both YKL-40 and KL-6 were positively correlated with the Scleroderma Lung Study (SLS) I score and negatively correlated with pulmonary function. CONCLUSIONS: KL-6 and YKL-40 might be a useful biomarker in the diagnosis and severity evaluation of RA-ILD.

Alcohol drinking modified the effect of plasma YKL-40 levels on stroke-specific mortality of acute ischemic stroke.

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.

α-Chitosan and ß-Oligochitosan Mixtures-Based Formula for In Vitro Assessment of Melanocyte Cells Response.

Chitosan is a natural polymer with numerous biomedical applications. The cellular activity of chitosan has been studied in various types of cancer, including melanoma, and indicates that these molecules can open new perspectives on antiproliferative action and anticancer therapy. This study analyzes how different chitosan conformations, such as α-chitosan (CH) or ß-oligochitosan (CO), with various degrees of deacetylation (DDA) and molar mass (MM), both in different concentrations and in CH-CO mixtures, influence the cellular processes of SK-MEL-28 melanocytes, to estimate the reactivity of these cells to the applied treatments. The in vitro evaluation was carried out, aiming at the cellular metabolism (MTT assay), cellular morphology, and chitinase-like glycoprotein YKL-40 expression. The in vitro effect of the CH-CO mixture application on melanocytes is obvious at low concentrations of α-chitosan/ß-oligochitosan (1:2 ratio), with the cell's response supporting the hypothesis that ß-oligo-chitosan amplifies the effect. This oligochitosan mixture, favored by the ß conformation and its small size, penetrates faster into the cells, being more reactive when interacting with some cellular components. Morphological effects expressed by the loss of cell adhesion and the depletion of YKL-40 synthesis are significant responses of melanocytes. ß-oligochitosan (1.5 kDa) induces an extension of cytophysiological effects and limits the cell viability compared to α-chitosan (400-900 kDa). Statistical analysis using multivariate techniques showed differences between the CH samples and CH-CO mixtures.

Changes in metabolic parameters and serum YKL-40 levels in Chinese rheumatoid arthritis patients during tocilizumab therapy.

OBJECTIVE: To investigate the metabolic changes during therapy of tocilizumab (TCZ) and methotrexate (MTX) in non-diabetic rheumatoid arthritis (RA) patients and for the first time explore the associations between metabolic parameters and serum YKL-40 (sYKL-40) levels. METHODS: We enrolled active non-diabetic RA patients who were refractory to MTX. Patients received intravenous TCZ (8 mg/kg) once every 4 weeks combined with MTX for 24 weeks. Metabolic parameters and sYKL-40 levels were measured before TCZ infusion at baseline, week 4, week 12, and week 24. Correlations were assessed by the Spearman's rank correlation analysis. RESULTS: A total of 91 non-diabetic RA patients were enrolled in this study. At week 24, we observed a significant elevation in body mass index (BMI), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels. In contrast, there was a significant decrease in TC/HDL­C ratio. No apparent changes in insulin resistance were found. Additionally, we detected a significant reduction in sYKL-40 levels during the study. At week 24, changes in sYKL-40 levels showed a significant negative correlation (r = -0.334, p = 0.002) with changes in TC levels. CONCLUSION: The combined therapy of TCZ and MTX resulted in a significant increase in BMI and lipid levels, while an evident decrease in the TC/HDL­C ratio and sYKL-40 levels in RA patients. Additionally, there was a significant correlation between the decrease in sYKL-40 levels and the increase in TC levels during treatment with TCZ and MTX. Key Points • Lipid levels elevated significantly and sYKL-40 levels decreased obviously after therapy of TCZ combined with MTX in Chinese RA patients. • There was a significant correlation between the increase in TC levels and the decrease in sYKL-40 levels during treatment with TCZ and MTX in RA patients.

Evolutionary insights into sequence modifications governing chitin recognition and chitinase inactivity in YKL-40 (HC-gp39, CHI3L1).

YKL-40, also known as human cartilage glycoprotein-39 (HC-gp39) or CHI3L1, shares structural similarities with chitotriosidase (CHIT1), an active chitinase, but lacks chitinase activity. Despite being a biomarker for inflammatory disorders and cancer, the reasons for YKL-40's inert chitinase function have remained elusive. This study reveals that the loss of chitinase activity in YKL-40 has risen from multiple sequence modifications influencing its chitin affinity. Contrary to the common belief associating the lack of chitinase activity with amino acid substitutions in the catalytic motif, attempts to activate YKL-40 by creating two amino acid mutations in the catalytic motif (MT-YKL-40) proved ineffective. Subsequent exploration that included creating chimeras of MT-YKL-40 and CHIT1 catalytic domains (CatDs) identified key exons responsible for YKL-40 inactivation. Introducing YKL-40 exons 3, 6, or 8 into CHIT1 CatD resulted in chitinase inactivation. Conversely, incorporating CHIT1 exons 3, 6, and 8 into MT-YKL-40 led to its activation. Our recombinant proteins exhibited properly formed disulfide bonds, affirming a defined structure in active molecules. Biochemical and evolutionary analysis indicated that the reduced chitinase activity of MT-YKL-40 correlates with specific amino acids in exon 3. M61I and T69W substitutions in CHIT1 CatD diminished chitinase activity and increased chitin binding. Conversely, substituting I61 with M and W69 with T in MT-YKL-40 triggered chitinase activity while reducing the chitin-binding activity. Thus, W69 plays a crucial role in a unique subsite within YKL-40. These findings emphasize that YKL-40, though retaining the structural framework of a mammalian chitinase, has evolved to recognize chitin while surrendering chitinase activity.

Serum YKL-40 as a Predictive Biomarker of Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage Recurrence.

Background: Neuroinflammation is a major cause of secondary brain injury in intracerebral hemorrhage (ICH). To date, the prognostic value of YKL-40 (chitinase-3-like-1 protein), a biomarker of neuroinflammation, in cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-ICH) remains undiscovered. Objective: To evaluate the relationships between serum YKL-40 and CAA-ICH recurrence. Methods: Clinical and imaging information of 68 first-onset probable CAA-ICH cases and 95 controls were collected at baseline. Serum YKL-40 was measured by Luminex assay. Cox proportional hazards model was used to analyze the associations between YKL-40 level and CAA-ICH recurrence. Results: Serum YKL-40 level was significantly higher in CAA-ICH cases than healthy controls (median [interquartile range, IQR], 46.1 [19.8, 93.4] versus 24.4 [13.9, 59.0] ng/mL, p = 0.004). Higher level of YKL-40 predicted increased risk of CAA-ICH recurrence adjusted for age, ICH volume and enlarged perivascular space score (ePVS) (above versus below 115.5 ng/ml, adjusted hazard ratios 4.721, 95% confidence intervals 1.829-12.189, p = 0.001) within a median follow-up period of 2.4 years. Adding YKL-40 to a model of only MRI imaging markers including ICH volume and ePVS score improved the discriminatory power (concordance index from 0.707 to 0.772, p = 0.001) and the reclassification power (net reclassification improvement 28.4%; integrated discrimination index 11.0%). Conclusions: Serum YKL-40 level might be a candidate prognostic biomarker for CAA-ICH recurrence.

Intracellular Accumulation and Secretion of YKL-40 (CHI3L1) in the Course of DMSO-Induced HL-60 Cell Differentiation.

YKL-40 (CHI3L1) is a matrix glycoprotein stored in human neutrophil-specific granules and released upon activation. While it is implicated in inflammation, cancer progression, and cell differentiation, its exact physiological role remains unclear. This study investigated the intracellular expression and secretion of YKL-40 by untreated and DMSO-treated HL-60 cells in association with surface expression of CD11b and CD66b throughout the differentiation process (up to 120 h). Secreted YKL-40 protein and mRNA levels of YKL-40, CD66b, and CD11b were measured by ELISA and quantitative RT-PCR, respectively. The intracellular YKL-40 and surface CD11b and CD66b expression were assessed by flow cytometry. A significant increase in CD11b expression confirmed DMSO-induced differentiation of HL-60 cells. Upon DMSO stimulation, YKL-40 mRNA expression increased in a time-dependent manner, unlike CD66b. The lack of CD66b (a granulocyte maturation and activation marker) on the surface of HL-60 cells might suggest that DMSO treatment did not induce full maturation or activation. The intracellular YKL-40 protein expression was increasing up to 96 h of DMSO treatment and then declined. YKL-40 secretion into the culture medium was detectable only at later time points (96 and 120 h), which was correlated with a decreased proliferation of DMSO-treated HL-60 cells. These findings suggest sequential changes in YKL-40 production and secretion during DMSO-induced differentiation of HL-60 cells and might contribute to a better understanding of YKL-40's involvement in both physiological processes and disease development, including multiple sclerosis.

YKL-40 Knockdown Decreases Oxidative Stress Damage in Ovarian Granulosa Cells.

Background: Oxidative stress has been implicated in the pathogenesis of polycystic ovarian syndrome (PCOS). To develop novel antioxidant drugs, it is necessary to explore the key regulatory molecules involved in oxidative stress in PCOS. Plasma YKL-40 levels are elevated in patients with PCOS; however, its role remains unclear. Methods: The follicular fluids of 20 women with PCOS and 12 control subjects with normal ovarian function were collected, and YKL-40 in follicular fluids was measured by enzyme-linked immunosorbent assay. A letrozole-induced PCOS rat model was established and the expression level of YKL-40 in the ovaries was detected by immunohistochemistry. KGN cells were treated with H2O2 to generate an ovarian granulosa cell (OGC) model of oxidative stress. The siRNA was transfected into the cells for knockdown. The effect of YKL-40 knockdown on H2O2-treated KGN cells was evaluated by measuring proliferation, apoptosis, activities of T-SOD, GSH-Px, and CAT, levels of MDA, IL-1ß, IL-6, IL-8, and TNF-α, and the PI3K/AKT/NF-κB signaling pathway. Results: YKL-40 levels were elevated in the follicular fluids of women with PCOS compared with control subjects with normal ovarian function. The expression level of YKL-40 in the ovaries of rats with PCOS is obviously higher than that in the ovaries of the control group rats. H2O2 treatment enhanced YKL-40 mRNA expression and protein secretion. YKL-40 knockdown enhanced cell proliferation and antioxidant capacity while decreasing apoptosis and inflammatory factor levels in KGN cells following H2O2 treatment. The knockdown activated the PI3K/AKT signaling pathway and suppressed NF-κB nuclear translocation from the cytoplasm. Conclusion: YKL-40 levels were elevated in the follicular fluids of women with PCOS and the ovaries of rats with PCOS. YKL-40 expression can be induced by oxidative stress, and YKL-40 knockdown can decrease oxidative stress damage in OGCs.

Strong YKL-40 expression in the invasive tumor front of colorectal cancer-A pilot study.

Тhe poor prognosis of patients initially diagnosed at an advanced stage of colorectal cancer (CRC) and the heterogeneity within the same tumor stage define the need for additional predictive biomarkers. Tumor buds are proposed as a poor prognostic factor for CRC, however, they are still not implemented into routine pathology reporting. In turn, the chitinase-3-like protein 1 (CHI3L1) also known as YKL-40, is regarded as a candidate circulating biomarker and therapeutic target in CRC. The aim of our study was to investigate tissue YKL-40 localization and tumor budding in CRC. Thirty-one CRC patients and normal colonic tissues were examined. The correlation between YKL-40 levels, tumor budding and clinocopathological parameters was evaluated by polychoric correlation analysis. The immunohistochemical assessment revealed high YKL-40 expression in CRC in contrast to normal mucosa. Specifically, intense YKL-40 staining was detected in the front of tumor invasion compared with tumor parenchyma and noncancerous tissue. We present novel data for increased YKL-40 expression in tumor buds within the front of tumor invasion. We assume that the combination of this morphological parameter with the tissue level of the pleotropic YKL-40 glycoprotein could serve as a future prognostic biomarker for CRC stratification and treatment.