Acta Pharmacologica Sinica最新文献

{"title":"Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.","authors":"Yu-Jun Chen, Yu Zhao, Ming-Yue Yao, Ya-Fang Wang, Ming Ma, Cheng-Cheng Yu, Hua-Liang Jiang, Wu Wei, Jie Shen, Xiao-Wei Xu, Cheng-Ying Xie","doi":"10.1038/s41401-025-01479-w","DOIUrl":"10.1038/s41401-025-01479-w","url":null,"abstract":"<p><p>FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification. In this study we investigated the role of p300/CBP in FLT3-ITD AML and evaluated the therapeutic potential of targeting p300/CBP alone or in combination with FLT3 inhibitors. We showed that high expression of p300 was significantly associated with poor prognosis in AML patients and positively correlated with FLT3 expression. We unveiled that the p300/CBP inhibitors A485 or CCS1477 dose-dependently downregulated FLT3 transcription via abrogation of histone acetylation in FLT3-ITD AML cells; in contrast, the FLT3 inhibitor quizartinib reduced the level of H3K27Ac. Concurrent inhibition of p300/CBP and FLT3 enhanced the suppression of FLT3 signaling and H3K27 acetylation, concomitantly reducing the phosphorylation of STAT5, AKT, ERK and the expression of c-Myc, thereby leading to synergistic antileukemic effects both in vitro and in vivo. Moreover, we found that p300/CBP-associated transcripts were highly expressed in quizartinib-resistant AML cells with FLT3-TKD mutation. Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD⁺ AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1390-1403"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BE-43547A₂ exerts hypoxia-selective inhibition on human pancreatic cancer cells through targeting eEF1A1 and disrupting its association with FoxO1.","authors":"Can Liu, Can Liu, Guang-Ju Liu, Meng-Meng Wang, Yan Jiao, Yuan-Jun Sun, Hui Guo, Liang Wang, Ya-Xin Lu, Yue Chen, Ya-Hui Ding","doi":"10.1038/s41401-024-01461-y","DOIUrl":"10.1038/s41401-024-01461-y","url":null,"abstract":"<p><p>Hypoxia is a key feature of the tumor microenvironment that leads to the failure of many chemotherapies and induces more aggressive and resistant cancer phenotypes. Up to date, there are very few compounds and treatments that can target hypoxia. BE-43547A₂ from Streptomyces sp. was one of the most hypoxia-selective compounds against PANC-1, MCF-7, and K562 cell lines. In this study, we investigated the molecular mechanism underlying the hypoxia selectivity of BE-43547A₂ in human pancreatic cancer cells. We showed that BE-43547A₂ displayed hypoxia-selective cytotoxicity in five pancreatic cancer cells (PANC-1, Capan-2, MIA PaCa-2, AsPC-1, and PaTu8988T) with IC₅₀ values under hypoxia considerably lower than those under normoxia. We demonstrated that BE-43547A₂ is directly bound to eEF1A1 protein in PaTu8988T cells under hypoxia. Furthermore, we revealed that hypoxia significantly elevated the expression levels of HIF1α, FoxO1, and eEF1A1 in the five pancreatic cancer cells; eEF1A1 interacted with FoxO1 in the cytoplasm, which was disrupted by BE-43547A₂ followed by the nuclear translocation of FoxO1 and ultimate inhibition of JAK/STAT3 signaling pathway under hypoxia. This study reveals that BE-43547A₂, targeting eEF1A1, disrupts its interaction with FoxO1 in human pancreatic cancer cells under hypoxia. This compound could serve as a potential hypoxia-selective therapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1433-1444"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7.","authors":"Si-Rui Shen, Zhu-Qi Huang, Yu-Die Yang, Ji-Bo Han, Zi-Min Fang, Yue Guan, Jia-Chen Xu, Ju-Lian Min, Yi Wang, Gao-Jun Wu, Zhong-Xiang Xiao, Wu Luo, Zhou-Qing Huang, Guang Liang","doi":"10.1038/s41401-024-01437-y","DOIUrl":"10.1038/s41401-024-01437-y","url":null,"abstract":"<p><p>Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. In this study, we identified the deubiquitinating enzyme Josephin domain-containing protein 2 (JOSD2) as a protective factor and investigated its molecular mechanism in Ang II-induced vascular remodeling. First, we found that JOSD2 was upregulated in aortic smooth muscle cells, but not in endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by vascular smooth muscle cell (VSMC)-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated Ang II-induced fibrosis, proliferation, and migration VSMCs, while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to the TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in the TGFβ-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to remove the K48-linked ubiquitin chains from SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that the JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 may be a novel and potential therapeutic target for hypertensive vascular remodeling.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1275-1288"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein B100 acts as a tumor suppressor in ovarian cancer via lipid/ER stress axis-induced blockade of autophagy.","authors":"Ze-Yuan Yin, Shi-Min He, Xin-Yuan Zhang, Xiao-Chen Yu, Kai-Xuan Sheng, Tong Fu, Yi-Xue Jiang, Liu Xu, Bing-Xuan Hu, Jing-Bo Zhang, Yan-Yu Li, Qing Wang, Bei-Bei Zhang, Yun-Meng Qi, Joseph Adu-Amankwaah, Xue-Yan Zhou, Qi Qi, Bei Zhang, Cheng-Lin Li","doi":"10.1038/s41401-024-01470-x","DOIUrl":"10.1038/s41401-024-01470-x","url":null,"abstract":"<p><p>Ovarian cancer presents a significant treatment challenge due to its insidious nature and high malignancy. As autophagy is a vital cellular process for maintaining homeostasis, targeting the autophagic pathway has emerged as an avenue for cancer therapy. In the present study, we identify apolipoprotein B100 (ApoB100), a key modulator of lipid metabolism, as a potential prognostic biomarker of ovarian cancer. ApoB100 functioned as a tumor suppressor in ovarian cancer, and the knockdown of ApoB100 promoted ovarian cancer progression in vivo. Moreover, ApoB100 blocked autophagic flux, which was dependent on interfering with the lipid accumulation/endoplasmic reticulum (ER) stress axis. The effects of LFG-500, a novel synthetic flavonoid, on ApoB100 induction were confirmed using proteomics and lipidomics analyses. Herein, LFG-500 induced lipid accumulation and ER stress and subsequently blocked autophagy by upregulating ApoB100. Moreover, data from in vivo experiments further demonstrated that ApoB100, as well as the induction of the lipid/ER stress axis and subsequent blockade of autophagy, were responsible for the anti-tumor effects of LFG-500 on ovarian cancer. Hence, our findings support that ApoB100 is a feasible target of ovarian cancer associated with lipid-regulated autophagy and provide evidence for using LFG-500 for ovarian cancer treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1445-1461"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide CRISPR-Cas9 screening identifies ITGA8 responsible for abivertinib sensitivity in lung adenocarcinoma.","authors":"Xuan-Guang Li, Guang-Sheng Zhu, Pei-Jun Cao, Hua Huang, Yu-Hao Chen, Chen Chen, Pei-Jie Chen, Di Wu, Chen Ding, Zi-He Zhang, Rui-Hao Zhang, Zi-Xuan Hu, Wen-Hao Zhao, Ming-Hui Liu, Yong-Wen Li, Hong-Yu Liu, Jun Chen","doi":"10.1038/s41401-024-01451-0","DOIUrl":"10.1038/s41401-024-01451-0","url":null,"abstract":"<p><p>The emergence of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the prognosis for lung cancer patients with EGFR-driven mutations. However, acquired resistance to EGFR-TKIs poses a significant challenge to the treatment. Overcoming the resistance has primarily focused on developing next-generation targeted therapies based on the molecular mechanisms of resistance or inhibiting the activation of bypass pathways to suppress or reverse the resistance. In this study we developed a novel approach by using CRISPR-Cas9 whole-genome library screening to identify the genes that enhance the sensitivity of lung adenocarcinoma cells to EGFR-TKIs. Through this screening, we revealed integrin subunit alpha 8 (ITGA8) as the key gene that enhanced sensitivity to abivertinib in lung adenocarcinoma. Notably, ITGA8 expression was significantly downregulated in lung adenocarcinoma tissues compared to adjacent normal tissues. Bioinformatics analyses revealed that ITGA8 was positively correlated with the sensitivity of lung adenocarcinoma to abivertinib. We showed that knockdown of ITGA8 significantly enhanced the proliferation, migration and invasion of H1975 cells. Conversely, overexpression of ITGA8 reduced the proliferation migration and invasion of H1975/ABIR cells. Furthermore, we demonstrated that ITGA8 sensitized lung adenocarcinoma cells to EGFR-TKIs by attenuating the downstream FAK/SRC/AKT/MAPK signaling pathway. In H1975 cell xenograft mouse models, knockdown of ITGA8 significantly increased tumor growth and reduced the sensitivity to abivertinib, whereas overexpression of ITGA8 markedly suppressed tumor proliferation and enhanced sensitivity to the drug. This study demonstrates that ITGA8 inhibits the proliferation, invasion and migration of lung adenocarcinoma cells, enhances the sensitivity to EGFR-TKIs, improves treatment efficacy, and delays the progression of acquired resistance. Thus, ITGA8 presents a potential therapeutic candidate for addressing acquired resistance to EGFR-TKIs from a novel perspective.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1419-1432"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Humanized dual-targeting antibody-drug conjugates specific to MET and RON receptors as a pharmaceutical strategy for the treatment of cancers exhibiting phenotypic heterogeneity.","authors":"Minghai Wang, Qi Ma, Sreedhar Reddy Suthe, Rachel E Hudson, Jing-Ying Pan, Constantinos Mikelis, Miao-Jin Zhu, Zhi-Gang Wu, Dan-Rong Shi, Hang-Ping Yao","doi":"10.1038/s41401-024-01458-7","DOIUrl":"10.1038/s41401-024-01458-7","url":null,"abstract":"<p><p>Cancer heterogeneity, characterized by diverse populations of tumorigenic cells, involves the occurrence of differential phenotypes with variable expressions of receptor tyrosine kinases. Aberrant expressions of mesenchymal-epithelial transition (MET) and recepteur d'origine nantais (RON) receptors contribute to the phenotypic heterogeneity of cancer cells, which poses a major therapeutic challenge. This study aims to develop a dual-targeting antibody-drug conjugate (ADC) that can act against both MET and RON for treating cancers with high phenotypic heterogeneity. Through immunohistochemical staining, we show that MET and RON expressions are highly heterogeneous with differential combinations in more than 40% of pancreatic and triple-negative breast cancer cases. This expressional heterogeneity provides the rationale to target both receptors for cancer therapy. A humanized bispecific monoclonal antibody specific to both MET and RON (PCMbs-MR) is generated through IgG recombination using monoclonal antibody sequences specific to MET and RON, respectively. Monomethyl auristatin E is conjugated to PCMbs-MR to generate a dual-targeting ADC (PCMdt-MMAE), with a drug-to-antibody ratio of 4:1. Various cancer cell lines were used to determine PCMdt-MMAE-mediated biological activities. The efficacy of PCMdt-MMAE in vivo is evaluated using multiple xenograft tumor models. PCMdt-MMAE shows a favorable pharmacokinetic profile, with a maximum tolerated dose of ~30 mg/kg in mice. Toxicological studies using Sprague-Dawley rats reveal that PCMdt-MMAE is relatively safe with slight-to-moderate, temporary, and reversible adverse events. Functionally, PCMdt-MMAE induces a robust internalization of both MET and RON and causes a large-scale cell death in cancer cell lines exhibiting MET and RON heterogeneous co-expressions. Both in vitro and in vivo studies demonstrate that the dual-targeting approach in the form of an ADC is highly effective with a long-lasting effect against tumors exhibiting MET/RON heterogeneous phenotypes. Hence, we can suggest that a dual-targeting ADC specific to both MET and RON can be employed as a novel therapeutic strategy for tumors with expressional phenotypic heterogeneity.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1375-1389"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control.","authors":"Meng-Yun Tian, Ji-Qin Yang, Jin-Chuan Hu, Shan Lu, Yong Ji","doi":"10.1038/s41401-024-01448-9","DOIUrl":"10.1038/s41401-024-01448-9","url":null,"abstract":"<p><p>Diabetic cardiomyopathy causes end-stage heart failure, resulting in high morbidity and mortality in type 2 diabetes mellitus (T2DM) patients. Long-term treatment targeting metabolism is an emerging field in the treatment of diabetic cardiomyopathy. Semaglutide, an agonist of the glucagon-like peptide 1 receptor, is clinically approved for the treatment of T2DM and provides cardiac benefits in patients. However, the cardioprotective mechanism of semaglutide, especially its direct effects on cardiomyocytes (CMs), is not fully understood. Here, we used 8-week diabetic and obese db/db mice treated with semaglutide (200 μg·kg·d^-1, i.p.) to study its direct effect on CMs and the underlying mechanisms. Our results revealed that the consecutive application of semaglutide improved cardiac function. Increased AMPK and ULK1 phosphorylation levels were detected, accompanied by elevated [Ca²⁺]_mito. Seahorse analysis revealed that semaglutide increases ATP production via elevated basal and maximum respiration rates as well as spare respiration capacity in CMs. Transmission electron microscopy revealed improved mitochondrial morphology in the cardiomyocytes of db/db mice. On the other hand, Western blot analysis revealed increased Parkin and LC3 protein expression, indicating mitophagy in CMs. Collectively, our findings demonstrate that semaglutide directly protects CMs from high-glucose damage by promoting AMPK-dependent ATP production as well as ULK1-mediated mitophagy in db/db mice.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1250-1261"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"eIF4A1 exacerbates myocardial ischemia-reperfusion injury in mice by promoting nuclear translocation of transgelin/p53.","authors":"Dan-Yang Li, Xiao-Xi Hu, Zhong-Rui Tian, Qi-Wen Ning, Jiang-Qi Liu, Ying Yue, Wei Yuan, Bo Meng, Jia-Liang Li, Yang Zhang, Zhen-Wei Pan, Yu-Ting Zhuang, Yan-Jie Lu","doi":"10.1038/s41401-024-01467-6","DOIUrl":"10.1038/s41401-024-01467-6","url":null,"abstract":"<p><p>Eukaryotic translation initiation factor 4A1 (eIF4A1) is an ATP-dependent RNA helicase that participates in a variety of biological and pathological processes such as cell proliferation and apoptosis, and cancer. In this study we investigated the role of eIF4A1 in ischemic heart disease. The myocardial ischemia/reperfusion (I/R) model was established in mice by ligation of the left anterior descending artery for 45 min with the subsequent reperfusion for 24 h; cultured neonatal mouse ventricular cardiomyocytes (NMVCs) treated with H₂O₂ (200 μM) or H/R (12 h hypoxia and 12 h reoxygenation) were used for in vitro study. We showed that the expression levels of eIF4A1 were significantly increased in I/R-treated myocardium and in H₂O₂- or H/R-treated NMVCs. In NMVCs, eIF4A1 overexpression drastically enhanced LDH level, caspase 3 activity, and cell apoptosis. eIF4A1 overexpression also significantly reduced anti-apoptotic protein Bcl2 and elevated pro-apoptotic protein Bax expression, whereas eIF4A1 deficiency produced the opposite responses. Importantly, cardiomyocyte-specific eIF4A1 knockout attenuated cardiomyocyte apoptosis, reduced infarct area, and improved cardiac function in myocardial I/R mice. We demonstrated that eIF4A1 directly bound to transgelin (Tagln) to prevent its ubiquitination degradation and subsequent up-regulation of p53, and then promoted nuclear translocation of Tagln and p53. Nuclear localization of Tagln and p53 was increased in H₂O₂-treated NMVCs. Silencing Tagln reversed the pro-apoptotic effects of eIF4A1. Noticeably, eIF4A1 exerted the similar effects in AC16 human cardiomyocytes. In conclusion, eIF4A1 is a detrimental factor in myocardial I/R injury via promoting expression and nuclear translocation of Tagln and p53 and might be a potential target for myocardial I/R injury. This study highlights a novel biological role of eIF4A1 by interacting with non-translational-related factor Tagln in myocardial I/R injury.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1236-1249"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAI-TargetFisher: A proteome-wide drug target prediction method synergetically enhanced by artificial intelligence and physical modeling.","authors":"Shi-Wei Li, Peng-Xuan Ren, Lin Wang, Qi-Lei Han, Feng-Lei Li, Hong-Lin Li, Fang Bai","doi":"10.1038/s41401-024-01444-z","DOIUrl":"10.1038/s41401-024-01444-z","url":null,"abstract":"<p><p>Computational target identification plays a pivotal role in the drug development process. With the significant advancements of deep learning methods for protein structure prediction, the structural coverage of human proteome has increased substantially. This progress inspired the development of the first genome-wide small molecule targets scanning method. Our method aims to localize drug targets and detect potential off-target effects early in the drug discovery process, thereby improving the success rate of drug development. We have constructed a high-quality database of protein structures with annotated potential binding sites, covering 82% of the protein-coding genome. On the basis of this database, to enhance our search capabilities, we have integrated computational techniques, including both artificial intelligence-based and biophysical model-based methods. This integration led to the development of a target identification method called Multi-Algorithm Integrated Target Fisher (MAI-TargetFisher). MAI-TargetFisher leverages the complementary strengths of various methods while minimizing their weaknesses, enabling precise database navigation to generate a reliably ranked set of candidate targets for an active query molecule. Importantly, our work is the first comprehensive scan of protein surfaces across the entire human genome, aimed at evaluating potential small molecule binding sites on each protein. Through a series of evaluations on benchmark and a target identification task, the results demonstrate the high hit rates and good reliability of our method under the validation of wet experiments. We have also made available a freely accessible web server at https://bailab.siais.shanghaitech.edu.cn/mai-targetfisher for non-commercial use.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1462-1475"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gentiopicroside ameliorates psoriasis-like skin lesions in mice via regulating the Keap1-Nrf2 pathway and inhibiting keratinocyte activation.","authors":"Jing Ren, Xin Chen, Hao-Yu Wang, Tao Yang, Kai-Rong Zhang, Shu-Yue Lei, Lu-Yao Qi, Chun-Lan Feng, Rong Zhou, Hu Zhou, Wei Tang","doi":"10.1038/s41401-024-01449-8","DOIUrl":"10.1038/s41401-024-01449-8","url":null,"abstract":"<p><p>Psoriasis is a chronic, systemic immune-mediated skin disease. Although many new strategies for psoriasis treatment have been developed, there is great need in clinic for treating psoriasis. Gentiopicroside (GPS), derived from Gentiana manshurica Kitagawa, has multiple pharmacological activities including anti-inflammatory, anti-oxidative and antiviral activities. In this study, we investigated the potential effects of GPS in imiquimod (IMQ)-induced psoriasis mouse model and the underlying mechanisms. The mice were sensitized on their shaved back with IMQ cream for 7 days with or without topical application of 1% or 2% GPS cream. We showed that the application of GPS cream significantly ameliorated psoriasis-like skin lesions; GPS effect was better than that of calcipotriol. GPS rectified the immune cells infiltration and keratinocytes activation in the skin lesions, and significantly inhibited TNF-α/IFN-γ stimulated human keratinocyte (HaCaT) activation in vitro. Proteomic analysis from keratinocytes with and without GPS treatment prompted that GPS regulated the Keap1-Nrf2 pathway, which was the most important pathway in regulating oxidative stress and inflammation. We demonstrated that GPS regulated the protein expression of p62 and Keap1, induced Nrf2 nuclear translocation followed by transcription of Nrf2 downstream antioxidant genes in HaCaT cells. Furthermore, the antioxidant effects of GPS were abolished in Nrf2^-/- keratinocytes. Simultaneously, Nrf2^-/- mice showed increased psoriasiform symptoms with a diminished protective effect in response to GPS treatment. Collectively, the study discloses that GPS inhibits keratinocyte activation and ameliorates psoriasis-like skin lesions in an Nrf2-dependent manner.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1361-1374"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}