Predictive value of serum HIF-1α/HIF-2α and YKL-40 levels for vascular invasion and prognosis of follicular thyroid cancer.

OBJECTIVE: This study investigated the significance of serum hypoxia-inducible factor (HIF)-1α/HIF-2 α and Chitinase 3-Like protein 1 (YKL-40) levels in the assessment of vascular invasion and prognostic outcomes in patients with Follicular Thyroid Cancer (FTC). METHODS: This prospective study comprised 83 patients diagnosed with FTC, who were subsequently categorized into a recurrence group (17 cases) and a non-recurrence group (66 cases). The pathological features of tumor vascular invasion were classified. Serum HIF-1α/HIF-2α and YKL-40 were quantified using a dual antibody sandwich enzyme-linked immunosorbent assay, while serum Thyroglobulin (Tg) levels were measured using an electrochemiluminescence immunoassay method. The Spearman test was employed to assess the correlation between serum factors, and the predictive value of diagnostic factors was determined using receiver operating characteristic curve analysis. A Cox proportional hazards regression model was utilized to analyze independent factors influencing prognosis. RESULTS: Serum HIF-1α, HIF-2α, YKL-40, and Tg were elevated in patients exhibiting higher vascular invasion. A significant positive correlation was observed between Tg and HIF-1α, as well as between HIF-1α and YKL-40. The cut-off values for HIF-1α and YKL-40 in predicting recurrence were 48.25 pg/mL and 60.15 ng/mL, respectively. Patients exceeding these cut-off values experienced a lower recurrence-free survival rate. Furthermore, serum levels surpassing the cut-off value, in conjunction with vascular invasion (v2+), were identified as independent risk factors for recurrence in patients with FTC. CONCLUSION: Serum HIF-1α/HIF-2α and YKL-40 levels correlate with vascular invasion in FTC, and the combination of HIF-1α and YKL-40 predicts recurrence in patients with FTC.

KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.

INTRODUCTION: We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). METHODS: This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N = 122) and non-carriers (KL-VSNC; N = 332). RESULTS: Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET. Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC. DISCUSSION: Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET. HIGHLIGHTS: Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes.

Uncovering novel mechanisms of chitinase-3-like protein 1 in driving inflammation-associated cancers.

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that is induced and regulated by multiple factors during inflammation in enteritis, pneumonia, asthma, arthritis, and other diseases. It is associated with the deterioration of the inflammatory environment in tissues with chronic inflammation caused by microbial infection or autoimmune diseases. The expression of CHI3L1 expression is upregulated in several malignant tumors, underscoring the crucial role of chronic inflammation in the initiation and progression of cancer. While the precise mechanism connecting inflammation and cancer is unclear, the involvement of CHI3L1 is involved in chronic inflammation, suggesting its role as a contributing factor to in the link between inflammation and cancer. CHI3L1 can aggravate DNA oxidative damage, induce the cancerous phenotype, promote the development of a tumor inflammatory environment and angiogenesis, inhibit immune cells, and promote cancer cell growth, invasion, and migration. Furthermore, it participates in the initiation of cancer progression and metastasis by binding with transmembrane receptors to mediate intracellular signal transduction. Based on the current research on CHI3L1, we explore introduce the receptors that interact with CHI3L1 along with the signaling pathways that may be triggered during chronic inflammation to enhance tumorigenesis and progression. In the last section of the article, we provide a brief overview of anti-inflammatory therapies that target CHI3L1.

Research advances in serum chitinase-3-like protein 1 in liver fibrosis.

While liver fibrosis remains a serious, progressive, chronic liver disease, and factors causing damage persist, liver fibrosis may develop into cirrhosis and liver cancer. However, short-term liver fibrosis is reversible. Therefore, an early diagnosis of liver fibrosis in the reversible transition phase is important for effective treatment of liver diseases. Chitinase-3-like protein 1 (CHI3L1), an inflammatory response factor that participates in various biological processes and is abundant in liver tissue, holds promise as a potential biomarker for liver diseases. Here, we aimed to review research developments regarding serum CHI3L1 in relation to the pathophysiology and diagnosis of liver fibrosis of various etiologies, providing a reference for the diagnosis, treatment, and prognosis of liver diseases.

CHI3L1 on fibrinolytic system imbalance in chronic rhinosinusitis with nasal polyp.

Background: Chronic rhinosinusitis (CRS) is an inflammatory disease affecting more than 10% of the global adult population. It is classified into Th1, Th2, and Th17 endotypes and eosinophilic and non-eosinophilic types. Th2-based inflammation and eosinophilic CRS (ECRS) are associated with tissue remodeling and fibrinolytic system impairment. Objective: To elucidate the role of eosinophils in inducing fibrin deposition in CRS nasal polyp tissues and explore potential regulatory mechanisms. Methods: We analyzed the expression of genes related to the serpin family and fibrinolytic system using Gene Expression Omnibus and Next-generation sequencing data. Differentially expression genes (DEGs) analysis was used to compare control and nasal polyp tissues, followed by KEGG and Gene ontology (GO) analysis. We measured the expression and correlation of plasminogen activator-1 (PAI-1), tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and urokinase plasminogen activator surface receptor (u-PAR) in CRS tissues, and evaluated the effect of eosinophils on the fibrinolytic system using a cytokine array and co-culture. Results: Nasal polyp tissues showed upregulated PAI-1, u-PA, and u-PAR expression and downregulated t-PA expression. Fibrinolytic system-related genes positively correlated with Th2 cytokines, except for t-PA. Eosinophil-derived Chitinase-3-like protein 1 (CHI3L1) increased PAI-1 expression and decreased t-PA levels in fibroblasts and epithelial cells. The inhibition of CHI3L1 suppresses these alterations. Conclusion: CHI3L1 contributes to fibrin deposition by impairing the fibrinolytic system during nasal polyp formation. The regulation of CHI3L1 expression may inhibit fibrin deposition and edema in ECRS, presenting a potential treatment for this condition.

Chitinase-3-like protein 1, matrix metalloproteinase-9, and monocyte chemoattractant protein-1 as potential biomarkers and treatment targets of adenomyosis.

OBJECTIVE: This study aimed to investigate the levels of chitinase-3-like protein-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and monocyte chemoattractant protein-1 (MCP-1) in adenomyosis, as compared to normal myometrial tissue. These biomarkers may be useful for determining potential treatment targets. METHODS: This was a correlative, analytical, and observational study with a cross-sectional design. Participants with a diagnosis of moderate-to-severe adenomyosis, as determined through transvaginal ultrasonography and histological examination, and who underwent laparotomy or laparoscopic surgery for the treatment of adenomyosis, were enrolled in the study. Unlike other studies that recruited healthy women as controls, our study used adenomyotic and healthy nonadenomyotic myometria obtained from the same individual. The levels of CHI3L1, MMP-9, and MCP-1 in the biopsy samples were determined using enzyme-linked immunoassay kits, according to the manufacturer's protocol. RESULTS: A highly significant increase in the levels of CHI3L1, MMP-9, and MCP-1 was found in adenomyotic tissues compared to non-adenomyotic tissues (P<0.001). A significant positive correlation was found between CHI3L1 and MMP-9 levels (r=0.463; P=0.008), CHI3L1 and MCP-1 levels (r=0.594; P<0.001), and MCP-1 and MMP-9 levels (r=0.680; P<0.001) in adenomyotic tissues. CONCLUSION: CHI3L1 may play a role in the pathogenesis of adenomyosis via the regulation of the MCP-1 and MMP-9 pathways. Therefore, these molecules may serve as biomarkers and potential therapeutic targets for adenomyosis.

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.

The role of the Chitinase 3-Like 1 (CHI3L1) genes in the preeclampsia pathophysiology

SUMMARY OBJECTIVE: The aim of this study was to investigate the relationship between Chitinase 3-Like 1 gene polymorphisms and the occurrence of preeclampsia in a selected cohort of pregnant women. METHODS: A total of 75 pregnant women participated in the study, 35 of whom were diagnosed with preeclampsia, while 40 served as healthy controls. The preeclamptic group was subdivided based on severity. Real-time polymerase chain reaction was employed to analyze the serum samples for variations in Chitinase 3-Like 1 gene polymorphisms. RESULTS: The rs880633 polymorphism was found to be significantly more frequent in the control group (80%) compared with the overall preeclamptic group (60%) (p<0.05). In the severity-based subgroups, rs880633 appeared in 57.1% of non-severe and 61.9% of severe preeclamptics. Contrarily, the heterozygous form of rs7515776 polymorphism showed a significantly higher prevalence in the preeclamptic cohort (p<0.05), without distinctions in severity subgroups. CONCLUSION: The study suggests that the rs880633 polymorphism may serve a protective role against the development of preeclampsia, whereas the rs7515776 polymorphism may be associated with an elevated risk. Further research is warranted to elucidate the clinical implications of these findings.

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OBJECTIVES: To explore the role and potential mechanisms of chitinase-3-like protein 1 (CHI3L1) in coronary artery lesions in a mouse model of Kawasaki disease (KD)-like vasculitis. METHODS: Four-week-old male SPF-grade C57BL/6 mice were randomly divided into a control group and a model group, with 10 mice in each group. The model group mice were intraperitoneally injected with 0.5 mL of lactobacillus casei cell wall extract (LCWE) to establish a mouse model of KD-like vasculitis, while the control group mice were injected with an equal volume of normal saline. The general conditions of the mice were observed on the 3rd, 7th, and 14th day after injection. Changes in coronary artery tissue pathology were observed using hematoxylin-eosin staining. The level of CHI3L1 in mouse serum was measured by enzyme-linked immunosorbent assay. Immunofluorescence staining was used to detect the expression and localization of CHI3L1, von Willebrand factor (vWF), and α-smooth muscle actin (α-SMA) in coronary artery tissue. Western blot analysis was used to detect the expression of CHI3L1, vWF, vascular endothelial cadherin (VE cadherin), Caspase-3, B cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), nuclear factor κB (NF-κB), and phosphorylated NF-κB (p-NF-κB) in coronary artery tissue. RESULTS: The serum level of CHI3L1 in the model group was significantly higher than that in the control group (P<0.05). Compared to the control group, the expression of CHI3L1 in the coronary artery tissue was higher, while the expression of vWF was lower in the model group. The relative expression levels of CHI3L1, Bax, Caspase-3, NF-κB, and p-NF-κB were significantly higher in the model group than in the control group (P<0.05). The relative expression levels of vWF, VE cadherin, and Bcl-2 were lower in the model group than in the control group (P<0.05). CONCLUSIONS: In the LCWE-induced mouse model of KD-like vasculitis, the expression levels of CHI3L1 in serum and coronary arteries increase, and it may play a role in coronary artery lesions through endothelial cell apoptosis mediated by inflammatory reactions.

Serum YKL-40 in coronary heart disease: linkage with inflammatory cytokines, artery stenosis, and optimal cut-off value for estimating major adverse cardiovascular events.

Objective: YKL-40, previously known as chitinase-3-like protein 1 (CHI3L1), is an inflammation-related glycoprotein that promotes atherosclerosis, but its application and optimal cut-off value as a prognostic biomarker in coronary heart disease (CHD) require more clinical evidence. Thus, this prospective study aimed to evaluate the linkage of serum YKL-40 with disease features, inflammatory cytokines, and major adverse cardiovascular events (MACEs) in CHD patients. Methods: A total of 410 CHD patients were enrolled for serum YKL-40 determination via enzyme-linked immunosorbent assay. Meanwhile, serum YKL-40 levels in 100 healthy controls (HCs) were also quantified. Results: YKL-40 level was higher in CHD patients compared with that in HCs (P < 0.001). YKL-40 was positively linked with hyperlipidemia (P = 0.014), diabetes mellitus (P = 0.001), fasting blood glucose (P = 0.045), C-reactive protein (P < 0.001), the Gensini score (P < 0.001), and stenosis degree (graded by the Gensini score) (P < 0.001) in CHD patients. In addition, an elevated YKL-40 level was associated with increased levels of tumor necrosis factor alpha (P = 0.001), interleukin (IL)-1ß (P = 0.001), IL-6 (P < 0.001), and IL-17A (P = 0.002) in CHD patients. The 1-/2-/3-year cumulative MACE rates of CHD patients were 5.5%, 14.4%, and 25.0%, respectively. Regarding the prognostic capability, YKL-40 ≥100 ng/ml (the median cut-off value) (P = 0.003) and YKL-40 ≥150 ng/ml (the third interquartile cut-off value) (P = 0.021) reflected an elevated accumulating MACE rate, whereas accumulating MACE was not different between CHD patients with YKL-40 ≥80 and <80 ng/ml (the first interquartile cut-off value) (P = 0.083). Conclusion: Serum YKL-40 is positively linked with inflammatory cytokines and the Gensini score, whose high expression cut-off by 100 and 150 ng/ml estimates a higher MACE risk in CHD patients.

5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury.

Rationale: Liver resection and transplantation surgeries are accompanied by hepatic ischemia-reperfusion (HIR) injury that hampers the subsequent liver recovery. Given that the liver is the main organ for metabolism and detoxification, ischemia-reperfusion in essence bestows metabolic stress upon the liver and disrupts local metabolic and immune homeostasis. Most of the recent and current research works concerning HIR have been focusing on addressing HIR-induced hepatic injury and inflammation, instead of dealing with the metabolic reprogramming and restoration of redox homeostasis. As our previous work uncovers the importance of 5-aminolevulinate (5-ALA) synthesis during stress adaptation, here we evaluate the effects of supplementing 5-ALA to mitigate HIR injury. Methods: 5-ALA was supplemented into the mice or cultured cells during the ischemic or oxygen-glucose deprivation (OGD) phase. Following reperfusion or reoxygenation, cellular metabolism and energy homeostasis, mitochondrial production of reactive oxygen species (ROS) and transcriptomic changes were evaluated in HIR mouse models or cultured hepatocytes and macrophages. Liver injury, hepatocytic functional tests, and macrophagic M1/M2 polarization were assessed. Results: Dynamic changes in the expression of key enzymes in 5-ALA metabolism were first confirmed in donor and mouse liver samples following HIR. Supplemented 5-ALA modulated mouse hepatic lipid metabolism and reduced ATP production in macrophages following HIR, resulting in elevation of anti-inflammatory M2 polarization. Mechanistically, 5-ALA down-regulates macrophagic chemokine receptor CX3CR1 via the repression of RelA following OGD and reoxygenation (OGD/R). Cx3cr1 KO mice demonstrated milder liver injuries and more macrophage M2 polarization after HIR. M2 macrophage-secreted chitinase-like protein 3 (CHIL3; CHI3L1 in human) is an important HIR-induced effector downstream of CX3CR1 deficiency. Addition of CHIL3/CHI3L1 alone improved hepatocellular metabolism and reduced OGD/R-inflicted injuries in cultured mouse and human hepatocytes. Combined treatment with 5-ALA and CHIL3 during the ischemic phase facilitated lipid metabolism and ATP production in the mouse liver following HIR. Conclusion: Our results reveal that supplementing 5-ALA promotes macrophagic M2 polarization via downregulation of RelA and CX3CR1 in mice following HIR, while M2 macrophage-produced CHIL3/CHI3L1 also manifests beneficial effects to the recovery of hepatic metabolism. 5-ALA and CHIL3/CHI3L1 together mitigate HIR-induced mitochondrial dysfunction and hepatocellular injuries, which may be developed into safe and effective clinical treatments to attenuate HIR injuries.

Association of Non-Invasive Markers with Significant Fibrosis in Patients with Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study.

Purpose: The identification of significant fibrosis is critical for predicting the prognosis of non-alcoholic fatty liver disease (NAFLD). This study aimed to compare the predictive value of chitinase-3-like protein 1 (CHl3L1) and other non-invasive biomarkers, as well as to establish a novel non-invasive diagnostic model for assessing the risk of significant fibrosis in NAFLD. Patients and Methods: A total of 71 patients with confirmed NAFLD based on liver biopsy were included in this study. Serum CHI3L1 levels and other non-invasive fibrosis assessment measures were determined. The aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 Index (FIB-4) were calculated to assess the diagnostic superiority of serum CHI3L1 compared to other non-invasive fibrosis assessment measures. Multivariate logistic regression analysis was conducted to identify relevant variables for constructing a diagnostic model. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of each index, including the area under ROC curve (AUC), sensitivity, and specificity. A nomogram was established based on the logistic regression model. Results: Serum CHI3LI levels were found to be higher in NAFLD patients with significant fibrosis compared to those without significant fibrosis. Multivariate logistic regression analysis revealed that aspartate aminotransferase (AST), type IV collagen (IV-C), CHI3L1, and liver stiffness measurement (LSM) were identified as potential independent risk factors associated with significant fibrosis in patients. The AUC of CHI3L1 for diagnosing significant liver fibrosis was 0.716 (0.596,0.836), with the optimal cut-off point of 125.315. The nomogram incorporating CHI3LI, AST, IV-C, and LSM further improved the potential predictive value, with an AUC for diagnosing significant fibrosis of 0.864 (0.766,0.962). This was superior to IV-C, CHI3L1, LSM, and APRI (all p < 0.05). Conclusion: The diagnostic model constructed by CHI3L1 combined with the existing non-invasive markers AST, IV-C, and LSM can help assess the risk of significant liver fibrosis in NAFLD.

Astrocytic Chitinase-3-like protein 1 in neurological diseases: Potential roles and future perspectives.

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein characterized by its ability to regulate multiple biological processes, such as the inflammatory response and gene transcriptional signaling activation. Abnormal CHI3L1 expression has been associated with multiple neurological disorders and serves as a biomarker for the early detection of several neurodegenerative diseases. Aberrant CHI3L1 expression is also reportedly associated with brain tumor migration and metastasis, as well as contributions to immune escape, playing important roles in brain tumor progression. CHI3L1 is synthesized and secreted mainly by reactive astrocytes in the central nervous system. Thus, targeting astrocytic CHI3L1 could be a promising approach for the treatment of neurological diseases, such as traumatic brain injury, ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and glioma. Based on current knowledge of CHI3L1, we assume that it acts as a molecule mediating several signaling pathways driving the initiation and progression of neurological disorders. This narrative review is the first to introduce the potential roles of astrocytic CHI3L1 in neurological disorders. We also equally explore astrocytic CHI3L1 mRNA expression under physiological and pathological conditions. Inhibiting CHI3L1 and disrupting its interaction with its receptors through multiple mechanisms of action are briefly discussed. These endeavors highlight the pivotal roles of astrocytic CHI3L1 in neurological disorders and could contribute to the development of effective inhibitors based on the strategy of structure-based drug discovery, which could be an attractive therapeutic approach for neurological disease treatment.

The Potential Roles of CHI3L1 in Failed Autologous Arteriovenous Fistula in End-Stage Renal Disease.

Autologous arteriovenous fistula (AVF) is commonly placed for hemodialysis treatment. Recent studies show that increased baseline serum level of Chitinase-3-like protein 1 (CHI3L1) is independently associated with a higher risk of the early failure of forearm AVFs. However, the changes and mechanisms of CHI3LI in local vascular tissues of failed AVF have not be revealed. This study aims to conduct the expression and mechanism of CHI3L1 in vascular tissues from patients. Immunoreactivity of CHI3L1, matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor-A (VEGF-A) were detected in vascular tissues collected from nine patients with AVF surgery. Due to the significant stenosis clinically, six of the nine patients received arteriovenous fistula reconstruction. The expression differences of CHI3L1 between the initial vascular tissues and failed AVF are significant (P < 0.05). Failed AVF due to stenosis shows intraluminal thrombus, collagen fiber rupture, fibrous connective tissue hyperplasia, tube wall thickening, neovascularization, scattered inflammatory cell infiltration in the tunica media as well as high CHI3L1 expression level, and the expression of MMP-2 (r = 0.9022, P = 0.0139) and VEGF-A (r = 0.8355, P = 0.0393) was positively correlated with CHI3L1. CHI3L1 expression in vascular tissues possibly plays an important role in AVF failure. MMP-2 and VEGF-A may participate in venous stenosis with CHI3L1.

Conserved YKL-40 changes in mice and humans after postoperative delirium.

Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence (14%-50%) and likely association with inflammation, the exact mechanisms that underpin postoperative delirium are unclear. This project aimed to characterize systemic and central nervous system (CNS) inflammatory changes following surgery in mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the "Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults" (INTUIT; NCT03273335) study were compared to murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well established orthopedic surgical model in the FosTRAP reporter mouse we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing evidence for a YKL-40 role in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were similarly increased after surgery, with a trend toward a greater postoperative plasma YKL-40 increase in patients with delirium. However, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in the blood-brain barrier (BBB) as early as 9 h after surgery in mice, which warrants more detailed and acute evaluations of BBB integrity following surgery in humans. Together, these results provide a nuanced understanding of neuroimmune interactions underlying postoperative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.

CHI3L1 predicted in malignant entities is associated with glioblastoma immune microenvironment.

Effective immunotherapies for patients with glioblastoma (GBM) are urgently needed. Chitinase-3 like-protein-1 (CHI3L1) play important roles in the development of gliomas. However, its role in glioma-related immune responses remains unclear. We aimed to comprehensively investigate its biological features and clinical value in glioma, especially in GBM. Transcriptome, proteome and single-cell RNA-sequencing databases were enrolled in the study. Immunostaining and immunoblotting were performed for validation. CHI3L1 was highly correlated with clinical and molecular features, suggesting that high CHI3L1 expression is more likely to be predicted as malignant entities. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed CHI3L1 closely associated with immune responses and inflammatory activities in GBM. In addition, CHI3L1 also correlated with immune cell infiltration and immune checkpoints. Our study suggests that inhibition of CHI3L1 may help to reduce immunosuppression and overcome immunotherapy resistance, which would be an therapeutic area for the treatment of GBM.

Analysis of Chitinase-3-Like Protein 1, IL-1-Alpha, and IL-6 as Novel Inflammatory Biomarkers for COVID-19.

The aim of our study was to investigate the potential role of IL-1-alpha, IL-6, and chitinase 3-like protein-1 (CHI3L1) as potential biomarkers for COVID-19. Sixty adult SARS Cov-2 PCR-positive patients (22 mild, 25 moderate, and 13 severe) and 50 healthy controls were included in this study. The serum levels of CHI3L1, IL-1-alpha, and IL-6 for all study participants were measured by protein-specific ELISAs. Mean serum CHI3L1 levels in patients with severe disease (7,185.5 ± 1,109.4) were significantly higher than in the moderate (3,977.4 ± 1,260.3), mild (1,379.5 ± 598.8), and control (329.5 ± 128.4) groups (P = 0.001). There was no difference in IL-1-alpha levels between the patient and control groups (P = 0.083). IL-6 levels differed significantly, being lowest in the control group (35.9 ± 13.7), 89.1 ± 23.4 in the mild group, 156.2 ± 29.6 in the moderate group, and the highest in the severe group (214.9 ± 28.1) (P = 0.001). A strong significant correlation was found between disease severity and serum IL-6 and CHI3L1 values (r = 0.894 and r = 0.905, respectively, and P < 0.001 for both). Serum CHI3L1 and IL-6 levels exhibited a linear correlation with the clinical course of COVID-19 infection. These results indicate that inhibitors of IL-6 and/or CHI3L1 may provide useful treatments for COVID-19.

The Value of Serum CHI3L1 for the Diagnosis of Chronic Liver Diseases.

Objective: To explore the value of chitinase-3-like protein 1 (CHI3L1) for the diagnosis of patients with chronic liver diseases such as chronic viral hepatitis B, liver cirrhosis and hepatocellular carcinoma (HCC), and analyze the correlation between serum CHI3L1 level and Child-Pugh grading of chronic liver diseases. Methods: The serum CHI3L1 levels of 154 cases of chronic viral hepatitis B, 132 cases of liver cirrhosis and 88 cases of HCC were detected by ELISA, and 92 healthy subjects were taken as the control. Results: The -serum CHI3L1 levels in HCC group, liver cirrhosis group and chronic viral hepatitis B group were higher than in healthy control group (P < 0.001). Serum CHI3L1 level showed a trend of increase in patients with chronic hepatitis to liver cirrhosis and to HCC. The diagnostic efficacy of serum CHI3L1 level on liver cirrhosis showed the sensitivity of 64.4% and the specificity of 96.7%. The diagnostic efficacy of serum CHI3L1 level on HCC showed the sensitivity of 86.8% and the specificity of 97.8%. Serum CHI3L1 level was higher in Child-Pugh grade B and C patients than in Child-Pugh grade A patients, and was positively correlated with Child-Pugh grading of liver function (rs = 0.301, P < 0.001). Conclusion: Serum CHI3L1 level increased in chronic liver diseases and showed an increase trend with the progression of liver diseases. Serum CHI3L1 could be a biomarker for the auxiliary diagnosis of chronic liver diseases.

Expression of chitinase-3-like protein 1 in different TCM syndromes and its correlation with liver fibrosis.

BACKGROUND: We aimed to explore the expression of chitinase-3-like protein 1 (CHI3L1) in different traditional Chinese medicine (TCM) syndromes and its correlation with liver fibrosis. METHODS: A total of 95 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who were diagnosed by pathological examination of liver biopsy specimens were selected as study subjects. According to different TCM syndrome types, 47 cases were divided into damp-heat moderate resistance type, and 48 cases were liver depression and spleen-deficiency type. Serum samples of the 2 groups were collected, then the levels of CHI3L1 were detected by enzyme-linked immunosorbent assay (ELISA). Hyaluronic acid (HA), laminin (LN), fibronectin (FN), collagen type IV (CIV), and N-terminal procollagen III propeptide (PIIINP) were measured by chemiluminescence. The levels of CHI3L1 was studied to explore the correlations between the 2 types of TCM syndromes and liver fibrosis. RESULTS: The serum CHI3L1 level of the 2 groups increased with increasing fibrosis stage and peaked at the S4 stage. The serum CHI3L1 levels of liver depression and spleen deficiency type patients in the S0-S1, S2-S3, and S4 stages were higher than those of patients with damp-heat moderate resistance type, and the difference was significant (P<0.01). The levels of HA, LN, FN, CIV, and PIIINP in the 2 groups increased with the increase of fibrosis stage and reached the highest level at the S4 stage. Compared to patients with damp-heat syndrome, the levels of HA, LN, FN, CIV, and PIIINP in patients with liver depression and spleen deficiency syndrome were lower, and the difference was statistically significant (P<0.05). There were positive correlations between CHI3L1 and HA, LN, FN, CIV, and PIIINP (all <0.05). CONCLUSIONS: The expression level of CHI3L1 in HBeAg-positive chronic hepatitis B patients was higher than expected. The levels of CHI3L1, HA, LN, FN, CIV, and PIIINP in liver depression and spleen deficiency type patients were lower than those in damp-heat moderate resistance type patients. These findings indicated that CHI3L1 is correlated with HA, LN, FN, CIV, PIIINP liver fibrosis indexes, and the syndrome of stagnation of spleen deficiency has a better correlation.

Peripheral inflammatory markers associated with brain volume reduction in patients with bipolar I disorder.

BACKGROUND: Neuroinflammation and brain structural abnormalities are found in bipolar disorder (BD). Elevated levels of cytokines and chemokines have been detected in the serum and cerebrospinal fluid of patients with BD. This study investigated the association between peripheral inflammatory markers and brain subregion volumes in BD patients. METHODS: Euthymic patients with bipolar I disorder (BD-I) aged 20-45 years underwent whole-brain magnetic resonance imaging. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), chitinase-3-like protein 1 (also known as YKL-40), fractalkine (FKN), soluble tumour necrosis factor receptor-1 (sTNF-R1), interleukin-1ß, and transforming growth factor-ß1 were measured on the day of neuroimaging. Clinical data were obtained from medical records and interviewing patients and reliable others. RESULTS: We recruited 31 patients with a mean age of 29.5 years. In multivariate regression analysis, plasma level YKL-40, a chemokine, was the most common inflammatory marker among these measurements displaying significantly negative association with the volume of various brain subareas across the frontal, temporal, and parietal lobes. Higher YKL-40 and sTNF-R1 levels were both significantly associated with lower volumes of the left anterior cingulum, left frontal lobe, right superior temporal gyrus, and supramarginal gyrus. A greater number of total lifetime mood episodes were also associated with smaller volumes of the right caudate nucleus and bilateral frontal lobes. CONCLUSIONS: The volume of brain regions known to be relevant to BD-I may be diminished in relation to higher plasma level of YKL-40, sTNF-R1, and more lifetime mood episodes. Macrophage and macrophage-like cells may be involved in brain volume reduction among BD-I patients.