The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis

Background Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. Results HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Conclusions Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.This work was supported by grants from the National Research Foundation of Korea, (NRF-2018R1A5A2025286, NRF-2020R1A2C3013255, NRF-2020M2D9A2093974, NRF-2020R1I1A1A01070841, NRF-2020M2D9A2093976 and NRF-2022R1A2C3011611), funded by the Korean government (Ministry of Science and ICT)

Changes in the Prevalence of Childhood Asthma in Seoul from 1995 to 2008 and Its Risk Factors

PURPOSE: To investigate the prevalence of asthma and determine its risk factors in elementary school students in Seoul. METHODS: A modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used to survey 4,731 elementary school students from five areas in Seoul between April and October, 2008. RESULTS: In elementary school children, the lifetime and recent 12-month prevalence of wheezing were 11.7% and 5.6%, respectively. The lifetime prevalence of asthma diagnosis was 7.9%, and the recent 12-month prevalence of asthma treatment was 2.7%. Male sex (adjusted odds ratio [aOR], 1.90; 95% confidence interval [CI], 1.36-2.66), history of atopic dermatitis (AD) (aOR, 2.76; 95% CI, 1.98-3.84), history of allergic rhinitis (AR) (aOR, 3.71; 95% CI, 2.61-5.26), history of bronchiolitis before 2 years of age (aOR, 2.06; 95% CI, 1.39-3.07), use of antibiotics during infancy for >3 days (aOR, 1.88; 95% CI, 1.35-2.62), parental history of asthma (aOR, 2.83; 95% CI, 1.52-5.27), exposure to household molds during infancy (aOR, 1.84; 95% CI, 1.18-2.89), and the development or aggravation of asthma symptoms within 6 months after moving to a new house (aOR, 11.76; 95% CI, 5.35-25.86) were the independent risk factors for wheezing within 12 months. CONCLUSIONS: The prevalence of wheezing and asthma in elementary school students in 2008 was similar to that in the past decade. Male sex, history of AD, history of AR, history of bronchiolitis before 2 years of age, parental asthma, use of antibiotics during infancy, exposure to molds in the house during infancy, and development or aggravation of asthma symptoms within 6 months after moving to a new house, could be risk factors for wheezing within 12 months.ope

Effects of Chrysoeriol on Adipogenesis and Lipolysis in 3T3-L1 Adipocytes

We examined the effect of chrysoeriol on adipogenesis and lipolysis and elucidated the underlying molecular mechanisms. Chrysoeriol inhibited fat deposition in adipocytes. Treatment with chrysoeriol suppressed the expression of peroxisome proliferator-activated receptor γ, fatty acid synthase, fatty acid-binding protein, CCAAT/enhancer-binding proteins (C/EBP) α, C/EBPβ, and sterol regulatory element-binding protein-1. In addition, chrysoeriol significantly elevated the activation of 5′-adenosine monophosphate-activated protein kinase. Moreover, chrysoeriol increased free glycerol and fatty acid levels and promoted lipolysis in adipocytes. Overexpression of adipose triglyceride lipase and hormone-sensitive lipase by chrysoeriol led to increased lipolysis in 3T3-L1 adipocytes. Taken together, chrysoeriol showed anti-adipogenic and lipolytic properties in adipocytes

Synthetic TGF-β Signaling Agonist-Treated Dendritic Cells Induce Tolerogenicity and Antirheumatic Effects

The newly synthesized compound TGF-β signaling agonist (T74) is a small molecule associated with the TGF-β receptor signaling pathway. Tolerogenic dendritic cells (tDCs) have been used to examine immunosuppressive and anti-inflammatory effects in multiple autoimmune disease models. The aim of this study was to investigate whether treatment of DCs with T74 has an antirheumatic effect in a mouse model of collagen-induced arthritis (CIA). Bone marrow-derived cells were obtained from DBA/1J mice and differentiated into DCs. T74-treated DCs (T74-DCs) were generated by treating bone marrow-derived DCs with LPS, type II collagen, and T74. T74-DCs expressed lower levels of surface molecules and inflammatory cytokines associated with antigen presentation and T cell stimulation. The ability of T74-DCs to differentiate effector T cells was lower than that of T74-untreated DCs (NT-DCs), but T74-DCs increased the regulatory T (Treg) cell differentiation in vitro. DBA/1J mice received two subcutaneous (s.c.) injections of type II collagen to establish CIA. Mice then received two s.c. injections of T74-DCs or NT-DCs. Joint inflammation was ameliorated in the paws of T74-DC-treated mice. Additionally, Treg populations in T74-DC-treated mice were higher than in NT-DC-treated or PBS-treated CIA mice. Taken together, these results demonstrate that T74 induces tolerance in DCs, and that T74-mediated DCs exert antirheumatic effects via induction of Tregs

Interrupting specific hydrogen bonds between ELF3 and MED23 as an alternative drug resistance-free strategy for HER2-overexpressing cancers

Introduction: HER2 overexpression induces cancer aggression and frequent recurrences in many solid tumors. Because HER2 overproduction is generally followed by gene amplification, inhibition of protein–protein interaction (PPI) between transcriptional factor ELF3 and its coactivator MED23 has been considered an effective but challenging strategy. Objectives: This study aimed to determine the hotspot of ELF3-MED23 PPI and further specify the essential residues and their key interactions in the hotspot which are controllable by small molecules with significant anticancer activity. Methods: Intensive biological evaluation methods including SEAP, fluorescence polarization, LC-MS/MS-based quantitative, biosensor, GST-pull down assays, and in silico structural analysis were performed to determine hotspot of ELF3-MED23 PPI and to elicit YK1, a novel small molecule PPI inhibitor. The effects of YK1 on possible PPIs of MED23 and the efficacy of trastuzumab were assessed using cell culture and tumor xenograft mouse models. Results: ELF3-MED23 PPI was found to be specifically dependent on H-bondings between D400, H449 of MED23 and W138, I140 of ELF3 for upregulating HER2 gene transcription. Employing YK1, we confirmed that interruption on these H-bondings significantly attenuated the HER2-mediated oncogenic signaling cascades and exhibited significant in vitro and in vivo anticancer activity against HER2-overexpressing breast and gastric cancers even in their trastuzumab refractory clones. Conclusion: Our approach to develop specific ELF3-MED23 PPI inhibitor without interfering other PPIs of MED23 can finally lead to successful development of a drug resistance-free compound to interrogate HER2 biology in diverse conditions of cancers overexpressing HER2

Design of ITER divertor VUV spectrometer and prototype test at KSTAR tokamak

Design and development of the ITER divertor VUV spectrometer have been performed from the year 1998, and it is planned to be installed in the year 2027. Currently, the design of the ITER divertor VUV spectrometer is in the phase of detail design. It is optimized for monitoring of chord-integrated VUV signals from divertor plasmas, chosen to contain representative lines emission from the tungsten as the divertor material, and other impurities. Impurity emission from overall divertor plasmas is collimated through the relay optics onto the entrance slit of a VUV spectrometer with working wavelength range of 14.6–32 nm. To validate the design of the ITER divertor VUV spectrometer, two sets of VUV spectrometers have been developed and tested at KSTAR tokamak. One set of spectrometer without the field mirror employs a survey spectrometer with the wavelength ranging from 14.6 nm to 32 nm, and it provides the same optical specification as the spectrometer part of the ITER divertor VUV spectrometer system. The other spectrometer with the wavelength range of 5–25 nm consists of a commercial spectrometer with a concave grating, and the relay mirrors with the same geometry as the relay mirrors of the ITER divertor VUV spectrometer. From test of these prototypes, alignment method using backward laser illumination could be verified. To validate the feasibility of tungsten emission measurement, furthermore, the tungsten powder was injected in KSTAR plasmas, and the preliminary result could be obtained successfully with regard to the evaluation of photon throughpu

Design of ITER divertor VUV spectrometer and prototype test at KSTAR tokamak

Design and development of the ITER divertor VUV spectrometer have been performed from the year 1998, and it is planned to be installed in the year 2027. Currently, the design of the ITER divertor VUV spectrometer is in the phase of detail design. It is optimized for monitoring of chord-integrated VUV signals from divertor plasmas, chosen to contain representative lines emission from the tungsten as the divertor material, and other impurities. Impurity emission from overall divertor plasmas is collimated through the relay optics onto the entrance slit of a VUV spectrometer with working wavelength range of 14.6–32 nm. To validate the design of the ITER divertor VUV spectrometer, two sets of VUV spectrometers have been developed and tested at KSTAR tokamak. One set of spectrometer without the field mirror employs a survey spectrometer with the wavelength ranging from 14.6 nm to 32 nm, and it provides the same optical specification as the spectrometer part of the ITER divertor VUV spectrometer system. The other spectrometer with the wavelength range of 5–25 nm consists of a commercial spectrometer with a concave grating, and the relay mirrors with the same geometry as the relay mirrors of the ITER divertor VUV spectrometer. From test of these prototypes, alignment method using backward laser illumination could be verified. To validate the feasibility of tungsten emission measurement, furthermore, the tungsten powder was injected in KSTAR plasmas, and the preliminary result could be obtained successfully with regard to the evaluation of photon throughpu