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Pulmonary entrapping predicts occult diaphragmatic injury in blunt thoracic trauma with rib fractures

Asian Journal of Surgery 2025年第5期48卷 2859-2865页

作者： Chang, Po-Chih Chen, Chao-Wen Liu, Yu-Wei Chou, Shah-Hwa Chang, Ting-Wei Li, Hsien-Pin Chiang, Hung-Hsing School of Medicine College of Medicine National Sun Yat-sen University Kaohsiung City Taiwan Division of Thoracic Surgery Department of Surgery Kaohsiung Medical University Hospital/Kaohsiung Medical University Kaohsiung City Taiwan Weight Management Center Kaohsiung Medical University Hospital/Kaohsiung Medical University Kaohsiung City Taiwan Department of Sports Medicine College of Medicine Kaohsiung Medical University Kaohsiung City Taiwan Ph. D. Program in Biomedical Engineering College of Medicine Kaohsiung Medical University Kaohsiung City Taiwan Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung City Taiwan Division of Trauma and Surgical Critical Care Department of Surgery Kaohsiung Medical University Hospital/Kaohsiung Medical University Kaohsiung City Taiwan Division of Thoracic Surgery Department of Surgery Kaohsiung Medical University Ganshan Hospital/Kaohsiung Medical University Kaohsiung City Taiwan Ph.D. Program in Environmental and Occupational Medicine College of Medicine Kaohsiung Medical University Kaohsiung City Taiwan

Background: Blunt thoracic trauma (BTT) often leads to rib fractures (RFs), with an increasing trend in surgical stabilization of rib fractures (SSRF) combined with thoracoscopic exploration, revealing previously underestimated occult diaphragmatic injuries (OdIs) that can result in hernias if not promptly addressed. We present our experience managing OdIs following BTT with complex RFs in a tertiary hospital in Southern Taiwan. Methods: We conducted a retrospective study including patients undergoing SSRF for BTT with complex RFs from January 2018 to March 2024. We analyzed demographic data, trauma details, clinical presentations, intraoperative findings, radiological features, and attempted to identify predictive factors for OdIs using logistic regression analysis. We also reviewed previous case series on OdIs. Results: We identified 11 OdIs, primarily detected during thoracoscopic exploration performed concurrently with SSRF (n = 8) or excessive bloody pleural effusion (n = 3). One hundred and twenty-two patients underwent SSRFs for their complex RFs simultaneously. All these patients with incidental OdI findings during SSRF for complex RFs underwent successful diaphragm repair via thoracoscopy. Multivariate logistic regression analysis revealed a significant association between trapped lung and OdI occurrence in patients undergoing SSRF after BTT (odds ratio: 24.423;95 % confidence interval: 2.77–215.369;p = 0.004). Conclusions: Our findings emphasize the importance of considering pulmonary entrapment as a significant predictive factor for OdI after BTT with complex RFs. Routine thoracoscopy during SSRF is crucial for early detection and management of this rare condition. © 2025 Asian Surgical Association and Taiwan Society of Coloproctology

关键词： Blunt injury diaphragm Fracture fixation Pulmonary entrapping Rib fractures Thoracoscopy

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Cytocompatible and antibacterial Fe-, Cu- and Zn-substituted calcium hydroxyapatite materials for skin applications

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Ceramics International 2025年第9期51卷 11286-11296页

作者： Lukaviciute, L. Lukowiak, A. Stankeviciute, Z. Junka, A. Mortimer, M. Zarkov, A. Yang, J.-C. Ganceviciene, R. Kareiva, A. Faculty of Chemistry and Geosciences Vilnius University Naugarduko st. 24 Vilnius03225 Lithuania Institute of Low Temperature and Structure Research Polish Academy of Sciences Okolna 2 Wroclaw50422 Poland Department of Pharmaceutical Microbiology and Parasitology Wroclaw Medical University Borowska 211A Wroclaw50556 Poland Laboratory of Environmental Toxicology National Institute of Chemical Physics and Biophysics Akadeemia tee 23 Tallinn12618 Estonia Graduate Institute of Nanomedicine and Medical Engineering International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Research Center of Biomedical Device Research Center of Digital Oral Science and Technology Taipei Medical University Taiwan Faculty of Medicine Vilnius University M.K. Ciurlionio st. 21 Vilnius03101 Lithuania

Calcium hydroxyapatite (C10(PO4)6(OH)2;CHAp) and metal-substituted samples (Fe:CHAp, Cu:CHAp, and Zn:CHAp) were synthesized using a recently developed method. This method involved the wet precipitation of amorphous calcium phosphate (ACP), followed by solid-state reaction synthesis of α-tricalcium phosphate (α-TCP), and finally hydrothermal synthesis of CHAp. The effect of Fe3+, Cu2+, and Zn2+ substitution on the phase purity and antimicrobial properties of CHAp are summarized in this study. Notably, it highlights the phase purity of CHAp and Zn:CHAp (in the presence of Fe3+ and Cu2+ ions, the α- and β-TCP phases have formed) as well as the antimicrobial activity of Zn:CHAp and Cu:CHAp against Staphylococcus aureus and Candida albicans. The synthesized nanosized CHAp, Fe:CHAp, Cu:CHAp, and Zn:CHAp samples were used as additives in the preparation of skin creams. In vitro biological studies of the resulting skin creams demonstrated their antimicrobial activity against Pseudomonas aeruginosa, and showed a reduction in osteoblasts cells viability of in the range of 20–40 %. The addition of zinc enhances antimicrobial efficacy but reduces biocompatibility, while copper maintains both high antimicrobial activity and biocompatibility, making it more suitable for the development of medical or cosmetic materials. dermal creams containing CHAp with copper and iron ions also show significant antimicrobial activity while preserving good cell viability. These results highlight the importance of optimizing the balance between antimicrobial effectiveness and biocompatibility in these materials. © 2024

关键词： Biocompatibility

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Fermentative biohydrogen production potential of sorghum distillers grains using anaerobic microflora at various ph values

Next Energy

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Next Energy 2025年 7卷

作者： Lu, Ching-Chun Lin, Chiu-Yue Ph.D. Program for Infrastructure Planning and Engineering Feng Chia University Taichung Taiwan Department of Environmental Science and Engineering Feng Chia University Taichung Taiwan Green Energy and Biotechnology Industry Research Center Feng Chia University Taichung Taiwan

Sorghum distillers grains (SdGs) are rich in proteins, vitamins, and minerals and are a good feedstock for anaerobically generating biogases such as biohydrogen and biomethane. The present work aims to investigate the anaerobic biohydrogen production potential of SdG to explore its added value. ph is an important operating factor affecting biological reactions and was tested at values of 5.0, 5.5, 6.0, and 6.5. The experimental results show that the hydrogen production rate (HPR) is less ph.d.pendent, but the hydrogen yield (HY) is rather ph.d.pendent with near-neutral conditions favoring biohydrogen production. ph 6.5 resulted in an HPR of 4.9 L/L-d (188 mmol/L-d) and peak HY of 81 mL/g chemical oxygen demand. It is shown that SdG is a new and prospective biomass source for biohydrogen production, and with this application, the problem of treating kaoliang liquor SdG could be reduced. Approaches to increase biohydrogen production and applications of the experimental results were also elucidated. © 2025 The Author(s)

关键词： Anaerobic fermentation Biohydrogen Hydrogen production rate Hydrogen yield ph effect Sorghum distillers grains

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development of BACE2-IN-1/tranylcypromine-based compounds to induce steroidogenesis-dependent neuroprotection

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Biomedicine and pharmacotherapy 2025年 183卷 117851-117851页

作者： Banerjee, Suddhasatwa Hsu, Ying-Ting Nguyen, duc-Hieu Yeh, Shiu-Hwa Liou, Ke-Chi Liu, Jr-Jiun Liou, Jing-Ping Chuang, Jian-Ying School of Pharmacy Taipei Medical University Taipei 11031 Taiwan Ph.D. Program in Medical Neuroscience Taipei Medical University and National Health Research Institutes Taipei 11031 Taiwan Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Miaoli County 35053 Taiwan TMU Research Center for Drug Discovery Taipei Medical University Taipei 11031 Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei 110 Taiwan International Master Program in Medical Neuroscience Taipei Medical University New Taipei City 23564 Taiwan TMU Research Center of Neuroscience Taipei Medical University Taipei 11031 Taiwan Department of Biomedical Science and Environmental Biology Kaohsiung Medical University Kaohsiung 80780 Taiwan

Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet. Revelations from single-cell RNA sequencing (scRNA-seq) performed to determine cell-type heterogeneity and gene expression changes in brain tissue indicated that brain trauma increases the expression of lysine-specific demethylase 1 (LSd1) and secretase 2 (BACE2). To capitalize on this finding, a medicinal chemistry campaign was conducted to pragmatically insert tranylcypromine, an LSd1 inhibitor, into a carefully designed BACE2 inhibitory template (BACE2-IN-1). Additionally, tranylcypromine was structurally modified to enhance the effects of LSd1 inhibition in TBI. As a result, a tractable neuroprotective agent, BACE2-IN-1/tranylcypromine-based compound 4, was identified, showing potential to maintain Neuro-2a cell survival by alleviating mitochondrial damage after oxidative stress. Compound 4 also restored TBI-mediated inhibition of the cholesterol biosynthetic pathway (mevalonate pathway) and damage of redox metabolism, increasing neuroprotective effects. Furthermore, behavioral assays, including nest-building and cognitive performance tests, demonstrated significant improvement in mice post-TBI following treatment with compound 4. Taken together, the outcomes of this study validate the favorable effects of inhibiting LSd1 and beta-secretase in mitigating mitochondrial stress and promoting neurometabolic recovery in TBI. These findings pave the way for the development of rationally designed inhibitors as promising neuroprotective agents, potentially addressing unmet clinical needs in TBI treatment. © 2025 The Authors

关键词： Beta-secretase LSd1 Oxidative stress Sterol biosynthesis Tranylcypromine Traumatic brain injury

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Association of long-term ozone exposure with the incidence and progression of hypertension, diabetes, and chronic kidney disease: A national retrospective cohort study

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Science of the Total Environment 2025年 975卷 179209页

作者： Li, Yu-Ling Chang, Po-Ya Chuang, Ting-Wu Hsieh, Yi-Chen Wang, Bo-Sian Chen, Szu-Ying Chiou, Hung-Yi Institute of Population Health Sciences National Health Research Institutes Miaoli County Zhunan Taiwan Department of Leisure Industry and Health Promotion National Taipei University of Nursing and Health Sciences Taipei Taiwan Department of Molecular Parasitology and Tropical Diseases School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei Taiwan Master Program in Applied Epidemiology College of Public Health Taipei Medical University Taipei Taiwan

Evidence suggests that ozone is associated with an increased risk of hypertension, diabetes, or chronic kidney disease (CKd). However, the associations of ozone exposure with the dynamic progression of these diseases among Asian population remain unknown. This study included 9,256,945 participants from Taiwan's National Health Insurance Research database between 2006 and 2021. Multimorbidity was defined as the coexistence of CKd and either hypertension or diabetes. The ordinary kriging method was used to estimate daily concentrations of ozone, sulfur dioxide, carbon monoxide, nitrogen dioxide, suspended fine particles, and suspended particles. Then, five-year average concentrations of pollutants were calculated. We performed multi-state survival models to analyze the association between ozone and dynamic progression of these diseases. during follow-up, 3,555,498 participants experienced hypertension, diabetes, or CKd;656,515 experienced multimorbidity;and 792,555 died. Ozone exposure was significantly associated with incidence of the results in all transitions. The hazard ratios of each IQR (3.57 ppb) increment in ozone for the transition to incident disease were 1.016 [95 % confidence interval (CI): 1.014, 1.017], for the transition to death were 1.04 [95 % CI: 1.036, 1.043], for the transition to multimorbidity were 1.015 [95 % CI: 1.012, 1.017]. Furthermore, with each IQR increase of ozone, the hazard ratios for transition from the disease incidence to death and from multimorbidity to death were 1.03 [95 % CI: 1.026, 1.033] and 1.007 [95 % CI: 1.002, 1.013], respectively. Our results suggest long-term exposure to ozone might be an important determinant for the incidence and dynamic progression of hypertension, diabetes, and CKd in Taiwan. © 2025 Elsevier B.V.

关键词： Health insurance

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Structural optimization and biological evaluation of indolin-2-one derivatives as novel CdK8 inhibitors for idiopathic pulmonary fibrosis

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Biomedicine and pharmacotherapy 2025年 184卷 117891-117891页

作者： Hsu, Jui-Yi Hsu, Kai-Cheng Chou, Ching-Hsuan He, Tzu-Ying Lin, Tony Eight Sung, Tzu-Ying Yen, Shih-Chung Hsieh, Jui-Hua Yang, Chia-Ron Huang, Wei-Jan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University and Academia Sinica Taipei Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan Cancer Center Wan Fang Hospital Taipei Medical University Taipei Taiwan School of Pharmacy College of Medicine National Taiwan University Taipei Taiwan Warshel Institute for Computational Biology School of Medicine The Chinese University of Hong Kong (Shenzhen) Shenzhen China Division of Translational Toxicology National Institute of Environmental Health Sciences National Institutes of Health Durham NC United States School of Pharmacy Taipei Medical University Taipei Taiwan

Cyclin-dependent kinase 8 (CdK8) plays a crucial role in the transforming growth factor beta (TGF-β) signaling pathway, which is critical to the pathology of idiopathic pulmonary fibrosis (IPF). CdK8 promotes the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition, making it a promising target for IPF treatment. This study focused on optimizing F059–1017, a previously identified CdK8 inhibitor, to enhance its potency. Through integrated structure-based modifications, a series of compounds was synthesized, and their inhibitory effects on CdK8 were tested. Results indicated that substituting with cyclopentanone significantly improved the inhibitory activity, and compound 4j demonstrated the best potency (IC₅₀ = 16 nM). Notably, compared to F059–1017, its potency increased 35-fold, and kinase profiling revealed that the compound was selective for CdK8. Compound 4j inhibited the TGF-β1-induced EMT, cell migration, and morphological changes in A549 cells at a concentration of 0.1 μM and inhibited ECM and EMT protein expressions. In addition, the compound blocked TGF-β1-induced transcriptional changes and inhibited Smad3 and RNA polymerase II phosphorylation. These results highlight the potential of the optimized CdK8 inhibitor as a prospective drug for IPF treatment. © 2025 The Authors

关键词： Cyclin-dependent protein kinase 8 Epithelial-mesenchymal transition Indolin-2-one, Idiopathic pulmonary fibrosis Structural optimization Transforming growth factor beta

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Comparative metabolomics of acetylcholinesterase and α-glucosidase inhibitors in pericarp of Garcinia mangostana L

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Botanical studies 2025年第1期66卷 13页

作者： Yun-Han Wang Ta-Wei Liu Sui-Wen Hsiao Man-Hsiu Chu Tzong-Huei Lee Su-Jung Hsu Shih Yin Chen Ching-Kuo Lee Ph.D. Program in Clinical Drug Development of Herbal Medicine Taipei Medical University 250 Wu Xin Street Taipei 110 Taiwan. School of Pharmacy Taipei Medical University 250 Wu Xin Street Taipei 110 Taiwan. Ph.D. Program in Drug Discovery and Development Industry Taipei Medical University 250 Wu Xin Street Taipei 11031 Taiwan. Institute of Fisheries Science National Taiwan University Taipei City Taiwan. School of Pharmacy Taipei Medical University 250 Wu Xin Street Taipei 110 Taiwan. juliahsu@ntu.edu.tw. Institute of Fisheries Science National Taiwan University Taipei City Taiwan. juliahsu@ntu.edu.tw. Xantho Biotechnology Co. Ltd. Rm ER15 17F.-1 No. 3 Yuanqu St. Nangang Dist. Taipei City 11503 Taiwan (R.O.C.). Ph.D. Program in Clinical Drug Development of Herbal Medicine Taipei Medical University 250 Wu Xin Street Taipei 110 Taiwan. cklee@tmu.edu.tw. School of Pharmacy Taipei Medical University 250 Wu Xin Street Taipei 110 Taiwan. cklee@tmu.edu.tw. Ph.D. Program in Drug Discovery and Development Industry Taipei Medical University 250 Wu Xin Street Taipei 11031 Taiwan. cklee@tmu.edu.tw. Graduate Institute of Pharmacognosy Taipei Medical University 250 Wu Xin Street Taipei 11031 Taiwan. cklee@tmu.edu.tw. School of Food Safety Taipei Medical University 250 Wu Xin Street Taipei 11031 Taiwan. cklee@tmu.edu.tw. Department of Chemistry Chung Yuan Christian University 200 Zhongbei Road Zhongli District Taoyuan 32023 Taiwan. cklee@tmu.edu.tw.

BACKGROUNd:Mangosteen (Garcinia mangostana L.) pericarp extract has demonstrated potential against Alzheimer's disease (Ad) and diabetes mellitus (dM). This study introduces a rapid dereplication and comparative approach to identify and characterize acetylcholinesterase (AChE) and α-glucosidase inhibitors in mangosteen pericarp. Using protein-subtraction, MS profiling, and computational modeling is effective for screening, identifying, and analyzing enzyme-inhibiting compounds from plant sources, and quantitative analysis of the main components has been performed. RESULTS:The Mangosteen pericarp extract observed significant inhibitory activity against α-glucosidase and AChE, with IC50 values of 31.02 and 70.56 µg/mL, respectively. By comparing profiles of protein-subtracted extracts with non-treated extracts, eight potential inhibitors for each enzyme were identified: 8-desoxygartanin, gartanin, 3-isomangostin, β-mangostin, 9-hydroxycalabaxanthone, γ-mangostin, α-mangostin, and garcinone E. The α-mangostin was the most abundant, comprising 39.589% of the extract. Molecular docking revealed these inhibitors target the peripheral anionic site of AChE and the active site of α-glucosidase, forming key hydrogen bonds and pi-pi stacking interactions. CONCLUSION:This study emphasizes mangosteen pericarp as a promising natural source of these inhibitors, with potential for use in developing nutraceuticals and pharmaceuticals. The study validated a systems biology approach by applying dereplication and comparative UPLC-ESI-MS/MS metabolomics profiling to identify target-binding molecules in both protein-treated and untreated plant extracts. Further confirmation was obtained through molecular docking predictions, mechanism analysis, and compound quantification assays.

关键词： Acetylcholinesterase Comparative metabolomics dereplication Mangosteen (Garciniaman gostana L) α-glucosidase

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double-sided niche regulation in skin stem cell and cancer: mechanisms and clinical applications

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Molecular Cancer 2025年第1期24卷 1-61页

作者： pham, Trang Thao Quoc Kuo, Yung-Che Chang, Wei-Ling Weng, Hao-Jui Huang, Yen-Hua International Ph.D. Program in Cell Therapy and Regenerative Medicine College of Medicine Taipei Medical University Taipei Taiwan TMU Research Center for Cell Therapy and Regeneration Medicine Taipei Medical University Taipei Taiwan Department of Dermatology Taipei Medical University-Shuang Ho Hospital New Taipei City Taiwan Department of Dermatology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Biochemistry and Molecular Cell Biology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei Taiwan

The niche microenvironment plays a crucial role in regulating the fate of normal skin stem cells (SSCs) and cancer stem cells (CSCs). Therapeutically targeting the CSC niche holds promise as an effective strategy; however, the dual effects of shared SSC niche signaling in CSCs have contributed to the aggressive characteristics of tumors and poor survival rates in skin cancer patients. The lack of a clear underlying mechanism has significantly hindered drug development for effective treatment. This article explores recent advances in understanding how niche factors regulate cell fate determination between skin stem cells and skin CSCs, along with their clinical implications. The dual roles of key components of the adhesive niche, including the dermo-epidermal junction and adherens junction, various cell types—especially immune cells and fibroblasts—as well as major signaling pathways such as Sonic hedgehog (Shh), Wingless-related integration site (Wnt)/β-catenin, YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PdZ-binding motif), and Notch, are highlighted. Additionally, recent advances in clinical trials and drug development targeting these pathways are discussed. Overall, this review provides valuable insights into the complex interactions between skin cancer stem cells and their microenvironment, laying the groundwork for future research and clinical strategies.

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Short-Chain dense Brush Pegylation on Rigid Nanocarriers Overcomes Anti-Peg Antibody Recognition for Immune-Stealth drug delivery

SSRN

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SSRN 2025年

作者： Chen, Ting-Yu Chang, Chi-Yuan Wen, Ting-Chun Xu, Li Lin, Yu-Han Peng, Cheng-Liang Yeh, Yi-Qi Chen, Chueh-Hsuan Chuang, Kuo-Hsiang Wu, Si-Han Graduate Institute of Pharmacognosy Taipei Medical University Taipei11031 Taiwan Graduate Institute of Nanomedicine and Medical Engineering Taipei Medical University Taipei11031 Taiwan Department of Isotope Application National Atomic Research Institute Taoyuan Taiwan National Synchrotron Radiation Research Center Hsinchu Science Park Hsinchu30076 Taiwan Research Center for Applied Science Academia Sinica Taiwan PhD Program in Clinical Drug Development of Chinese Herbal Medicine Taipei Medical University Taipei Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan

The immunogenicity of polyethylene glycol (PEG) remains a critical challenge in nanomedicine, as pre-existing anti-PEG antibodies can compromise therapeutic efficacy through accelerated blood clearance (ABC) and life-threatening hypersensitivity. Here, we address this challenge by engineering the PEG architecture, creating short-chain dense brush PEGylation (PEG500) on rigid mesoporous silica nanoparticles (MSNs). Unlike conventional PEG2000-liposomes, MSN-PEG500 evades antibodies via three synergistic mechanisms: (1) short-chain PEG500 reduces epitope accessibility, (2) high grafting density (4.43 chains/nm2, according to TGA) forms an dense steric shield, and (3) the rigid silica surface prevents PEG burial. ELISA studies demonstrated that, at equivalent nanoparticle concentrations, MSN-PEG500 exhibits a 26-fold reduction in anti-PEG IgG (6.3) binding and a 1000-fold reduction in anti-PEG IgM (AGP3) binding compared to Lipodox (PEG2000), both of which target the PEG backbone. Furthermore, radiolabeled MSN-PEG500 achieved prolonged circulation and 25% tumor accumulation (Id/g) at 24 hours. In strongly immunized mice, doxorubicin-loaded MSN-PEG500 preserved therapeutic efficacy and 100% survival, whereas Lipodox induced fatal hypersensitivity. Mechanistic investigations revealed that complement activation drives PEG2000 immunotoxicity, and pretreatment with the C3 inhibitor compstatin effectively mitigated temperature drops from 10°C to 2°C in immunized hosts. By demonstrating that nanoscale control of polymer conformation dictates immunological fate, this work provides a clinically translatable blueprint for developing immune-evasive nanomedicines. © 2025, The Authors. All rights reserved.

关键词： Silica nanoparticles

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Identification of pyrazole scaffold inhibitors targeting cyclin-dependent kinase 8 for potential use in pulmonary fibrosis

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Biochemical pharmacology 2025年 237卷

作者： Lin, Tony Eight Hsu, Kai-Cheng Chou, Ching-Hsuan Tsai, En-Yun Wu, Yi-Wen Sung, Tzu-Ying Hsu, Jui-Yi Hsieh, Jui-Hua Yen, Shih-Chung Chang, Yu-Wei Pan, Shiow-Lin Huang, Wei-Jan Yang, Chia-Ron Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei Taiwan Cancer Center Wan Fang Hospital Taipei Medical University Taipei Taiwan School of Pharmacy College of Medicine National Taiwan University Taipei Taiwan Division of Translational Toxicology National Institute of Environmental Health Sciences National Institutes of Health Durham NC United States Warshel Institute for Computational Biology The Chinese University of Hong Kong (Shenzhen) Guangdong Shenzhen China Department of Traditional Chinese Medicine Chang Gung Memorial Hospital Keelung Medical Center Keelung Taiwan School of Pharmacy Taipei Medical University Taipei Taiwan

Idiopathic Pulmonary Fibrosis (IPF) is a disease that includes inflammation and scarring of the lung tissues. Cyclin-dependent kinase 8 (CdK8) is a target of interest due to its role in inflammatory pathways. CdK8 can also modulate the TGF-β/Smad signaling associated with IPF. Herein, a structure-based virtual screening (SBVS) campaign led to the identification of three CdK8 inhibitors. Testing of candidate inhibitors in protein and cellular assays confirmed CdK8 inhibition, with the most potent inhibitor producing an IC₅₀ value of 398.8 nM. Computational analysis identified pharmacological interactions that lead to CdK8 inhibition. No significant cytotoxicity was observed when the inhibitor was treated in vitro. Further results showed that the inhibitor can disrupt proteins associated with the epithelial-mesenchymal transition (EMT) and reduce cell migration. Additionally, the inhibitor can disrupt the TGF- β1/Smad signaling axis in the nucleus, potentially impacting the transcription of IPF related protein expression, when treated in cells at 5 µM. Comparisons to structures of known CdK8 inhibitors showed the identified inhibitor to be structurally novel. When tested against a panel of kinases at 1 µM, the most potent inhibitor demonstrated a favorable CdK8 selectivity profile. The identification of the CdK8 inhibitors in this study can be used in future drug design studies and as CdK8 probes to explore alternative therapeutics for IPF. © 2025 The Author(s)

关键词： Cyclin-dependent kinase 8 Inflammation Pulmonary fibrosis Small-molecule inhibitor Structure-based virtual screening

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