A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL-13Rα2-mediated JNK-AP-1 signals.

Our previous big data analyses showed a high level of association between chitinase 3 like1 (CHI3L1) expression and lung tumor development. In the present study, we investigated whether a CHI3L1-inhibiting chemical, 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284), could inhibit lung metastasis and studied its mechanism of action. We investigated the antitumor effect of K284 both in vitro and in vivo. K284 (0.5 mg·kg-1 body weight) significantly inhibited lung metastasis in in vivo models after injection of murine melanoma cells (B16F10) or adenocarcinomic human alveolar basal epithelial cells (A549). K284 significantly and concentration-dependently also inhibited cancer cell proliferation and migration in the A549 and H460 lung cancer cell lines. We found that the binding of K284 to the chitin-binding domain (CBD) of CHI3L1 prevented the binding of CHI3L1 to its receptor, interleukin-13 receptor subunit alpha-2 (IL-13Rα2), thereby suppressing the CHI3L1 signal. This blocking of the CHI3L1-IL-13Rα2 signal caused the inhibition of c-Jun N-terminal kinase (JNK)-activator protein 1 (AP-1) signals, resulting in the prevention of lung metastasis and cancer cell growth. Our data demonstrate that K284 may serve as a potential candidate anticancer compound targeting CHI3L1.

Adiponectin and the steatosis marker Chi3L1 decrease following switch to raltegravir compared to continued PI/NNRTI-based antiretroviral therapy.

BACKGROUND: People with HIV are at for metabolic syndrome (MetS) and fatty liver disease, but the role of Antiretroviral therapy (ART) is poorly understood. MetS and fatty liver disease been associated with changes in adiponectin, soluble ST2 (sST2), chitinase 3-like 1 (Chi3L1), hyaluronic acid (HA), tissue inhibitor of metalloproteinase-1 (TIMP-1), lysyl oxidase-like-2 (LOXL2) and transforming growth factor ß (TGF-ß) concentrations in HIV-uninfected populations. Protease (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) may contribute to these comorbidities, but the effects of switching from PI- or NNRTI to raltegravir (RAL) on these biomarkers is unknown. METHODS: Cryopreserved plasma was obtained from a completed, prospective trial of HIV-infected women with central adiposity on NNRTI- or PI-based ART during which they were randomized to remain on their current ART or switch to a RAL based regimen. Biomarker concentrations were quantified using ELISA and Multiplex assays at baseline and 24 weeks after randomization. Wilcoxon-signed rank test evaluated within-group changes, Spearman and linear regression models evaluated correlations between biomarkers and clinical covariates. RESULTS: Participants had a median age of 43 years, CD4+ T lymphocyte count 558 cells/mm3 and BMI 32 kg/m2; 35% met criteria for MetS. At baseline, higher adiponectin levels correlated with higher Chi3L1 levels (r = 0.42, p = 0.02), as did declines after 24 weeks (r = 0.40, p = 0.03). Changes in sST2 correlated with changes in Chi3L1 (r = 0.43, p = 0.02) and adiponectin (r = 0.40, p = 0.03). Adiponectin and Chi3L1 levels decreased significantly in women switched to RAL vs continue PI/NNRTI. CONCLUSION: In women with HIV and central obesity, the hepatic steatosis/fibrosis marker Chi3L1 and adiponectin decrease in conjunction with sST2 decreases following switch to RAL. Whether switching from NNRTI/PI-based regimens to RAL can improve hepatic steatosis and dysmetabolism requires further study. TRIAL REGISTRATION: Clinicaltrials.gov NCT00656175.

The role of YKL40 in the pathogenesis of CRS with nasal polyps.

BACKGROUND: Many Chinese patients who experience chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to exhibit specifically enhanced TH1/TH17 responses and excessive neutrophil accumulation without demonstrating significant eosinophilia. These patients may be subject to different pathologies and therapies compared to Western patients. YKL40 can be produced by neutrophil and is associated with many inflammatory diseases, while its role in the pathogenesis of chronic rhinosinusitis (CRS) has yet to be determined. OBJECTIVE: The aim of this study was to investigate the relationship between the expression level and biologic role of YKL40 in CRS. METHODS: YKL40 expression was examined via quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry, and Western blot. Human nasal epithelia cells (HNECs) were isolated to detect YKL40 expression in response to specific inflammatory stimulation. RESULTS: YKL40 expression levels were significantly higher in NP patients compared to the turbinates of CRSsNP/CRSwNP and the control group and can be strongly activated by stimulation with IL-4 in vitro and suppressed by the other pro-inflammatory cytokines; lipopolysaccharide (LPS) and dexamethasone also caused significant decreases in YKL40 expression in HNECs. CONCLUSIONS: YKL40 may play a significant role in Chinese patients with CRSwNP. The molecular mechanisms identified here may aid in the design of new therapeutic strategies for improving the clinical outcomes of Chinese patients.