Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis

Background To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Methods FLS from RA patients were activated with interleukin (IL)-1β in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). Results HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1β. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1β. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. Conclusion Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential.This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number:HI14C1277); the Ministry of Science, ICT and Future Planning (NRF2020M3E5E2037430, 2019M3A9A8065574); and the Chong Kun Dang Pharmaceutical Corp. TP was supported by the DFG (FOR2722)

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient-derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice11Nsciescopu

SnO2:NGO ???????????? ?????? ????????????????????? ???????????? ?????? ??????

Due to high electron mobility, excellent charge selective behavior with a large band gap of 3.76 eV, and low temperature processibility, tin oxide (SnO2) is commonly used as an electron transport layer in perovskite solar cells (PeSCs). Since the electrical and optical properties vary depending on the oxidation state of Sn, it is necessary to control the oxygen vacancies in the SnO2 layer in order to reach highly efficient SnO2-based PeSCs, This study demonstrates that PeSCs based on SnO2 can be enhanced by introducing nitrogen doped graphene oxide (NGO) as an oxidizing agent for SnO2. Since NGO changes the oxidation state of the Sn in SnO2 from Sn2+ to Sn4+, the oxygen vacancies in SnO2 can be reduced using NGO. Multiple devices are fabricated and various techniques are analyzed to define their performance, including X-ray photoelectron spectroscopy, dark current analysis, and the change of the open circuit voltage depending on light intensity. PeSCs with SnO2:NGO composite layers show superior Voc with less deviation compared to the average power conversion efficiency (PCE) of control devices. Therefore, introducing NGO in a SnO2 layer can be treated as an simple method of controlling the oxidation state of SnO2 to enhance the performance of PeSCs

Comprehensive Computed Tomography Radiomics Analysis of Lung Adenocarcinoma for Prognostication

Background. In this era of personalized medicine, there is an expanded demand for advanced imaging biomarkers that reflect the biology of the whole tumor. Therefore, we investigated a large number of computed tomography-derived radiomics features along with demographics and pathology-related variables in patients with lung adenocarcinoma, correlating them with overall survival. Materials and Methods. Three hundred thirty-nine patients who underwent operation for lung adenocarcinoma were included. Analysis was performed using 161 radiomics features, demographic, and pathologic variables and correlated each with patient survival. Prognostic performance for survival was compared among three models: (a) using only clinicopathological data; (b) using only selected radiomics features; and (c) using both clinicopathological data and selected radiomics features. Results. At multivariate analysis, age, pN, tumor size, type of operation, histologic grade, maximum value of the outer 1/3 of the tumor, and size zone variance were statistically significant variables. In particular, maximum value of outer 1/3 of the tumor reflected tumor microenvironment, and size zone variance represented intratumor heterogeneity. Integration of 31 selected radiomics features with clinicopathological variables led to better discrimination performance. Conclusion. Radiomics approach in lung adenocarcinoma enables utilization of the full potential of medical imaging and has potential to improve prognosis assessment in clinical oncology (c) AlphaMed Press 201

Effects of Backbone Planarity and Tightly Packed Alkyl Chains in the Donor-Acceptor Polymers for High Photostability

The photostability of donor-acceptor (D-A) polymers remains a critical issue despite recent improvements in the power conversion efficiencies (PCEs) of organic photovoltaic (OPV) cells. We report the synthesis of three highly photostable polymers (PDTBDT-BZ, PDTBDT-BZF, and PDTBDT-BZF(2)) and their suitability for use in high-performance OPV cells. Under 1 sunlight of illumination in air for 10 h, these polymer films demonstrated remarkably high photostability compared to that of PTB7, a representative polymer in the OPV field. While the PDTBDT-BZ, PDTBDT-BZF, and PDTBDT-BZF2 polymer films maintained 97, 90, and 96% photostability, respectively, a PTB7 film exhibited only 38% photo stability under the same conditions. We ascribed the high photostability of the polymers to both the intrinsically photostable chemical moieties and the dense packing of alkyl side chains and planar backbone polymer chains, which prevents oxygen diffusion into the PDTBDT-BZ films. This work demonstrates the high photostability of planar PDTBDT-BZ series polymers composed of photostable DTBDT and BZ moieties and suggests a design rule to synthesize highly photostable photovoltaic material