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Corrigendum to "MNAM enhances Blautia abundance and modulates Th17/Treg balance to alleviate diabetes in T2DM Mice" [Biochem. Pharmacol. volume (230), Part 2, Published online October 23, 2024/116593]. “MNAM增强蓝藻丰富度并调节Th17/Treg平衡以缓解T2DM小鼠的糖尿病”[生物化学]的更正。杂志。卷(230),第2部分,10月23日在线发布[2014 /11]。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-09 DOI: 10.1016/j.bcp.2024.116738
Jingfan Zhang, Yu Chen, Ling Li, Ruiqi Liu, Ping Li
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引用次数: 0
Cordycepin alleviates metabolic dysfunction-associated liver disease by restoring mitochondrial homeostasis and reducing oxidative stress via Parkin-mediated mitophagy. 虫草素通过恢复线粒体稳态和通过帕金森介导的线粒体自噬减少氧化应激来减轻代谢功能障碍相关的肝脏疾病。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-08 DOI: 10.1016/j.bcp.2025.116750
Hai-Ying Tian, Dao-Jiang Yu, Teng Xie, Meng-Xia Xu, Yu-Hao Wang, Xi-Lu Sun, Xin-Meng Zhou, Ying-Xuan Han, Qing-Qing Liao, Yu-Jie Zhao, Juan Liao, Mohamed El-Kassas, Xiao-Dong Sun, Yuan-Yuan Zhang

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) keeps rising with only a few drugs available. The present study aims to investigate the effects and mechanisms of cordycepin on MASLD. Male C57BL/6 mice were induced with a 90-day high-fat diet (HFD) and intraperitoneal administration with streptozotocin to establish MASLD murine model. Then they were randomly divided into the HFD and cordycepin groups (15, 30, 45 mg/kg). Cordycepin was orally given for 30 days. Serum total cholesterol (TC), triacylglyceride (TG), and aspartate aminotransferase (AST) levels were measured. L02 cells were induced by oleate acid (OA) or lipopolysaccharides (LPS), and treated with cordycepin or combined with inhibitors including chloroquine, 3-Methyladenine, and compound C. Atg7 and Parkin were knocked down in L02 cells using siRNA. Oil Red O and Nile Red staining for measuring lipid deposition. Mitochondria were visualized by transfection with mCherry-TOMM20-N10. Quantitative real-time PCR, Western blotting, and immunofluorescence staining were used to determine expressions of key molecules in inflammation, lipid metabolism, mitochondria homeostasis, and oxidative stress. Cordycepin significantly mitigated lipid deposition and ballooning in the livers of MASLD mice. Serum TC, TG, and AST levels were decreased by cordycepin. Cordycepin alleviated OA-induced lipid deposition and LPS-induced inflammation in L02 cells, attenuated oxidative stress, promoted autophagy, and maintained the autophagic flux by activating AMP-activated protein kinase (AMPK). Cordycepin reduced the accumulation of impaired mitochondria by enhancing Parkin-dependent mitophagy and promoting mitochondrial biogenesis. Cordycepin alleviates MASLD by restoring mitochondrial homeostasis and reducing oxidative stress via activating the Parkin-mediated mitophagy.

代谢功能障碍相关脂肪变性肝病(MASLD)的患病率持续上升,只有少数药物可用。本研究旨在探讨虫草素对MASLD的作用及其机制。采用高脂饮食(HFD)和腹腔注射链脲佐菌素诱导雄性C57BL/6小鼠建立MASLD小鼠模型。然后随机分为HFD组和虫草素组(15、30、45 mg/kg)。口服虫草素30 d。测定血清总胆固醇(TC)、甘油三酯(TG)、天冬氨酸转氨酶(AST)水平。用油酸(OA)或脂多糖(LPS)诱导L02细胞,并用虫草素或与氯喹、3-甲基腺嘌呤和化合物c等抑制剂联合处理。油红O和尼罗河红染色测定脂质沉积。转染mCherry-TOMM20-N10后,线粒体可见。采用实时荧光定量PCR、Western blotting和免疫荧光染色检测炎症、脂质代谢、线粒体稳态和氧化应激中关键分子的表达。冬虫夏草素可显著减轻MASLD小鼠肝脏中的脂质沉积和水肿。虫草素降低血清TC、TG和AST水平。冬虫夏草素可减轻oa诱导的脂质沉积和lps诱导的L02细胞炎症,减轻氧化应激,促进自噬,并通过激活amp活化蛋白激酶(AMPK)维持自噬通量。虫草素通过增强帕金森依赖性线粒体自噬和促进线粒体生物发生来减少受损线粒体的积累。虫草素通过激活帕金森介导的线粒体自噬来恢复线粒体稳态和减少氧化应激,从而减轻MASLD。
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引用次数: 0
Guggulsterone ameliorates psoriasis by inhibiting keratinocyte proliferation and inflammation through induction of miR-17 directly targeting JAK1 and STAT3. gugugulsterone通过诱导直接靶向JAK1和STAT3的miR-17抑制角化细胞增殖和炎症来改善银屑病。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-08 DOI: 10.1016/j.bcp.2025.116745
Lu Xiang, Yangli Shen, Shuangteng Liu, Bowen Fan, Jiafeng Zhan, Yadi Zhou, Baichun Jiang, Molin Wang, Qiao Liu, Xiaofei Liu, Yongxin Zou, Shuna Sun

The pathogenesis of psoriasis involves hyperproliferation of epidermal keratinocytes and abnormal interactions between activated keratinocytes and infiltrating immune cells. Emerging evidence has shown that keratinocytes play essential roles in both the initiation and maintenance of psoriasis, suggesting that exposing keratinocytes to agents with antiproliferative and anti-inflammatory effects may be effective for psoriasis treatment. Guggulsterone (GS), a plant sterol derived from the gum resin of Commiphora wightii, possesses a variety of pharmacological activities. However, the effects of GS on psoriasis and the underlying mechanism have not been elucidated. In this study, we evaluated the therapeutic effect of GS on psoriasis using an imiquimod-induced psoriasis mouse model and investigated the effect of GS on human keratinocytes and the underlying mechanism. We found that GS effectively alleviated psoriasis-like skin lesions in imiquimod-induced psoriasis model mice and that GS suppressed the proliferation, migration, and production of proinflammatory cytokines, chemokines and antimicrobial peptides in keratinocytes. Transcriptome analysis by RNA-seq revealed that the differentially expressed genes (DEGs) induced by GS in keratinocytes were intricately linked to the pathogenesis of psoriasis. Furthermore, STAT3, a key player in the development and pathogenesis of psoriasis, was identified as a critical downstream mediator of GS in keratinocytes. Mechanistically, GS upregulated the expression of miR-17-5p, which directly binds to the 3'-untranslated regions (3'UTRs) of JAK1 and STAT3, leading to the downregulation of JAK1 and STAT3 expression. Collectively, these findings suggest that GS may serve as an effective natural compound for the treatment of psoriasis.

银屑病的发病机制涉及表皮角质形成细胞的过度增生以及活化的角质形成细胞与浸润性免疫细胞之间的异常相互作用。新出现的证据表明,角化细胞在牛皮癣的发生和维持中都起着至关重要的作用,这表明将角化细胞暴露于具有抗增殖和抗炎作用的药物可能对牛皮癣治疗有效。谷草酮(Guggulsterone, GS)是一种植物甾醇,从金缕草的树胶树脂中提取,具有多种药理活性。然而,GS对银屑病的作用及其机制尚未阐明。在本研究中,我们利用吡喹莫德诱导的银屑病小鼠模型评估了GS对银屑病的治疗效果,并探讨了GS对人角质形成细胞的影响及其机制。我们发现,GS能有效缓解吡喹莫特诱导的银屑病模型小鼠的牛皮癣样皮肤病变,并抑制角化细胞中促炎细胞因子、趋化因子和抗菌肽的增殖、迁移和产生。RNA-seq转录组分析显示,角化细胞中GS诱导的差异表达基因(DEGs)与银屑病的发病机制有着复杂的联系。此外,STAT3在银屑病的发展和发病机制中起着关键作用,被确定为角化细胞中GS的关键下游介质。在机制上,GS上调miR-17-5p的表达,miR-17-5p直接结合JAK1和STAT3的3'-非翻译区(3' utrs),导致JAK1和STAT3表达下调。总之,这些发现表明,GS可能作为一种有效的天然化合物治疗牛皮癣。
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引用次数: 0
JOSD2 promotes breast cancer metastasis by deubiquitinating and stabilizing SMAD4. JOSD2通过去泛素化和稳定SMAD4促进乳腺癌转移。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-08 DOI: 10.1016/j.bcp.2025.116748
Jiamin Du, Jiao Wang, Fujing Ge, Hongrui Ma, Hongdao Zhu, Jiangxia Du, Fangjie Yan, Qiaojun He, Bo Yang, Tao Yuan, Hong Zhu

Breast cancer is one of the most common malignant tumors among women worldwide, and its high degree of metastasis significantly impacts treatment effectiveness leading to poor prognosis. The potential molecular mechanisms underlying breast cancer metastasis remain to be further elucidated. In this study, via database analysis, we revealed that the deubiquitinase josephin domain containing 2 (JOSD2) was abnormally amplified in patients with metastatic breast cancer, and was significantly negatively correlated with patient prognosis. By integrating data from the Gene Expression Omnibus (GEO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis, we found that the transforming growth factor beta (TGF-β) signaling pathway was significantly activated in breast cancer patients with increased JOSD2 expression. Further studies revealed that JOSD2 interacted with and stabilized SMAD family member 4 (SMAD4) by removing polyubiquitin chains. Inhibition of JOSD2 by RNA interference effectively inhibited the metastasis of breast cancer cells both in vitro and in vivo. In conclusion, our study not only reveals the role of JOSD2 in promoting breast cancer metastasis for the first time, but also indicates promising directions for the future development of deubiquitinase inhibitors, which could yield significant therapeutic benefits. Nevertheless, extensive research and development are required to fully realize this potential.

乳腺癌是世界范围内女性最常见的恶性肿瘤之一,其转移程度高,严重影响治疗效果,导致预后不良。乳腺癌转移的潜在分子机制仍有待进一步阐明。本研究通过数据库分析发现,转移性乳腺癌患者脱泛素酶josephin结构域2 (JOSD2)异常扩增,且与患者预后呈显著负相关。通过整合Gene Expression Omnibus (GEO)数据库数据和京都基因与基因组百科全书(KEGG)信号通路富集分析,我们发现JOSD2表达升高的乳腺癌患者转化生长因子β (TGF-β)信号通路显著激活。进一步的研究表明,JOSD2通过去除多泛素链与SMAD家族成员4 (SMAD4)相互作用并稳定SMAD4。RNA干扰抑制JOSD2在体内和体外均能有效抑制乳腺癌细胞的转移。总之,我们的研究不仅首次揭示了JOSD2在促进乳腺癌转移中的作用,也为未来去泛素酶抑制剂的开发指明了有希望的方向,这些抑制剂可能会产生显著的治疗效益。然而,要充分发挥这一潜力,还需要进行广泛的研究和开发。
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引用次数: 0
Cynanchum wallichii Wight and CW1 reversed docetaxel resistance effects by inhibiting P-gp and promoting PI3K/Akt-mediated apoptosis in prostate cancer. Cynanchum wallichii Wight和CW1通过抑制P-gp和促进PI3K/ akt介导的前列腺癌细胞凋亡逆转多西他赛耐药效应。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-07 DOI: 10.1016/j.bcp.2025.116749
Qian Feng, Jin-Xiu Zhi, Xue-Yu Wang, Yi-Di Chen, Guan-Cheng Liu, Cai-Yan Wang, Xia Yang, Fang-Ju Feng, Rong Zhang, Zhong-Qiu Liu, Rong-Rong Zhang

Cynanchum wallichii (CW) is a traditional Chinese medicine which is widely used for treating arthrophlogosis, traumatic injury, and other conditions. Herein, we investigate the effects and mechanisms of CW and its bioactive constituent CW1 in reversing docetaxel (DTX) resistance in prostate cancer (PCa) cells. We investigated the reversal effects of CW and its bioactive constituent CW1 on 22Rv1/DTX cells in vitro and in vivo. We also explored the underlying mechanism by evaluating drug sensitivity, cell proliferation, efflux transporter P-glycoprotein (P-gp), and molecular signaling involved in apoptosis-related protein expression. CW and its bioactive constituent CW1 reversed DTX resistance in PCa 22Rv1/DTX cells by directly binding to the efflux transporter P-gp and by inhibiting the expression of P-gp. This significantly increased the intracellular concentration of DTX and inhibited the malignant proliferation of 22Rv1/DTX cells. In addition, DTX + CW/CW1 co-treatment significantly increased the apoptosis effects in 22Rv1/DTX cells by regulating the relative expressions of BAX, Bcl2, cytochrome C, and caspase 3/9. Furthermore, both CW and CW1 enhanced the in vivo therapeutic effect of DTX in the 22Rv1/DTX cell xenograft while alleviating the side effects of liver and kidney damage caused by DTX. Our results suggest that CW and its bioactive constituent CW1 enhance the antitumor activity of DTX by reducing P-gp expression and promoting phosphoinositide 3-kinase/Akt-mediated apoptosis in vitro and in vivo. Our results firstly confirm that CW1, as a natural bioactive substance, holds promise as an adjuvant drug for treating high-load metastatic and castration-resistant PCa.

金银花(Cynanchum wallichii, CW)是一种中药,广泛用于治疗关节炎、创伤性损伤等疾病。在此,我们研究了CW及其生物活性成分CW1在逆转前列腺癌(PCa)细胞多西他赛(DTX)耐药中的作用和机制。我们在体外和体内研究了CW及其生物活性成分CW1对22Rv1/DTX细胞的逆转作用。我们还通过评估药物敏感性、细胞增殖、外排转运蛋白p -糖蛋白(P-gp)和参与凋亡相关蛋白表达的分子信号来探讨其潜在机制。CW及其生物活性成分CW1通过直接结合外流转运体P-gp并抑制P-gp的表达,逆转了PCa 22Rv1/DTX细胞对DTX的抗性。这显著增加了细胞内DTX浓度,抑制了22Rv1/DTX细胞的恶性增殖。此外,DTX + CW/CW1共处理通过调节BAX、Bcl2、细胞色素C和caspase 3/9的相对表达,显著增强了22Rv1/DTX细胞的凋亡效应。此外,CW和CW1在22Rv1/DTX细胞异种移植中均增强了DTX的体内治疗效果,同时减轻了DTX引起的肝肾损害的副作用。我们的研究结果表明,在体外和体内,CW及其生物活性成分CW1通过降低P-gp表达和促进磷酸肌苷3-激酶/ akt介导的细胞凋亡来增强DTX的抗肿瘤活性。我们的研究结果首先证实了CW1作为一种天然生物活性物质,有望作为治疗高负荷转移性和去势抵抗性PCa的辅助药物。
{"title":"Cynanchum wallichii Wight and CW1 reversed docetaxel resistance effects by inhibiting P-gp and promoting PI3K/Akt-mediated apoptosis in prostate cancer.","authors":"Qian Feng, Jin-Xiu Zhi, Xue-Yu Wang, Yi-Di Chen, Guan-Cheng Liu, Cai-Yan Wang, Xia Yang, Fang-Ju Feng, Rong Zhang, Zhong-Qiu Liu, Rong-Rong Zhang","doi":"10.1016/j.bcp.2025.116749","DOIUrl":"10.1016/j.bcp.2025.116749","url":null,"abstract":"<p><p>Cynanchum wallichii (CW) is a traditional Chinese medicine which is widely used for treating arthrophlogosis, traumatic injury, and other conditions. Herein, we investigate the effects and mechanisms of CW and its bioactive constituent CW1 in reversing docetaxel (DTX) resistance in prostate cancer (PCa) cells. We investigated the reversal effects of CW and its bioactive constituent CW1 on 22Rv1/DTX cells in vitro and in vivo. We also explored the underlying mechanism by evaluating drug sensitivity, cell proliferation, efflux transporter P-glycoprotein (P-gp), and molecular signaling involved in apoptosis-related protein expression. CW and its bioactive constituent CW1 reversed DTX resistance in PCa 22Rv1/DTX cells by directly binding to the efflux transporter P-gp and by inhibiting the expression of P-gp. This significantly increased the intracellular concentration of DTX and inhibited the malignant proliferation of 22Rv1/DTX cells. In addition, DTX + CW/CW1 co-treatment significantly increased the apoptosis effects in 22Rv1/DTX cells by regulating the relative expressions of BAX, Bcl2, cytochrome C, and caspase 3/9. Furthermore, both CW and CW1 enhanced the in vivo therapeutic effect of DTX in the 22Rv1/DTX cell xenograft while alleviating the side effects of liver and kidney damage caused by DTX. Our results suggest that CW and its bioactive constituent CW1 enhance the antitumor activity of DTX by reducing P-gp expression and promoting phosphoinositide 3-kinase/Akt-mediated apoptosis in vitro and in vivo. Our results firstly confirm that CW1, as a natural bioactive substance, holds promise as an adjuvant drug for treating high-load metastatic and castration-resistant PCa.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116749"},"PeriodicalIF":5.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
GAS41 promotes ITGA4-mediated PI3K/Akt/mTOR signaling pathway and glioma tumorigenesis. GAS41促进itga4介导的PI3K/Akt/mTOR信号通路和胶质瘤的发生。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-07 DOI: 10.1016/j.bcp.2025.116747
Guanglei Shang, Wenju Zhang, Yanjie Jia, Donglei Ji, Enwei Wei, Chunfeng Gao, Caroline Zeng, Chunyu Wang, Nan Liu, Pengfei Ge, Yunqian Li, Lei Zeng

Glioma Amplified Sequence 41 (GAS41) is a chromatin-associated protein that belongs to the YEATS domain family of proteins and is frequently amplified in various tumors. However, its biological function and carcinogenic mechanism in gliomas are not fully understood. In this study, we revealed that GAS41 was upregulated in human glioma tissues and cell lines, and higher expression of GAS41 was significantly associated with poor clinical prognosis. Genetic depletion and chemical inhibition of GAS41 remarkably inhibited glioma cell proliferation and metastasis abilities and induced cellular apoptosis. Furthermore, functional annotation identified that GAS41 was involved in stimulating the expression of membrane protein ITGA4 to activate the downstream PI3K/Akt/mTOR signaling pathway in glioma cell lines. In addition, we synthesized and evaluated a series of small molecules targeting the GAS41 YEATS domain, which yielded effective anti-proliferative activities in glioma cells. Molecular docking revealed that these compounds bound to the GAS41 YEATS domain pocket in a manner similar to Compounds 9 and 3b, providing a structural basis for exploring the selective inhibition of GAS41 as part of an essential molecular framework. Overall, our study illustrates the crucial role of GAS41 in glioma progression and the malignant phenotype and suggests that targeting GAS41 may be a promising therapeutic treatment strategy for gliomas.

胶质瘤扩增序列41 (Glioma Amplified Sequence 41, GAS41)是一种染色质相关蛋白,属于YEATS结构域蛋白家族,在各种肿瘤中经常被扩增。然而,其在胶质瘤中的生物学功能和致癌机制尚不完全清楚。在本研究中,我们发现GAS41在人胶质瘤组织和细胞系中表达上调,GAS41的高表达与不良临床预后显著相关。基因缺失和化学抑制可显著抑制胶质瘤细胞的增殖和转移能力,诱导细胞凋亡。此外,功能注释发现GAS41参与刺激膜蛋白ITGA4的表达,激活胶质瘤细胞系下游PI3K/Akt/mTOR信号通路。此外,我们合成并评估了一系列靶向GAS41 YEATS结构域的小分子,这些小分子在胶质瘤细胞中具有有效的抗增殖活性。分子对接发现,这些化合物与GAS41 YEATS结构域口袋结合的方式与化合物9和3b相似,为探索GAS41选择性抑制的基本分子框架提供了结构基础。总的来说,我们的研究说明了GAS41在胶质瘤进展和恶性表型中的关键作用,并表明靶向GAS41可能是一种有希望的胶质瘤治疗策略。
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引用次数: 0
CBD and the 5-HT1A receptor: A medicinal and pharmacological review. CBD和5-HT1A受体:医学和药理学综述。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-06 DOI: 10.1016/j.bcp.2025.116742
Claire Alexander, Jiyoon Jeon, Kyle Nickerson, Shayne Hassler, Maryam Vasefi

Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms. It has the ability to bind to multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD's pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated. This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling. A comprehensive survey of the literature underscores CBD's multifaceted neurotherapeutic effects, which include antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR. Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.

大麻二酚(CBD)是一种植物大麻素,已成为解决各种症状的有希望的候选者。它具有结合多种蛋白质和受体的能力,包括5-HT1AR,瞬时受体电位香草素1 (TRPV1)和大麻素受体。然而,CBD与5-HT1AR的药效学相互作用及其疗效仍存在争议。本文回顾了最近的文献来阐明这些问题,强调了这种药效学相互作用的神经治疗结果,并提出了CBD使5-HT1AR信号脱敏的机制的信号通路。对文献的全面调查强调了CBD多方面的神经治疗作用,包括抗抑郁、抗焦虑、神经保护、抗精神病、止吐、抗异动、抗癫痫、抗退行性和成瘾治疗特性,部分归因于其与5-HT1AR的相互作用。此外,有证据表明CBD和5-HT1AR之间的药效学相互作用取决于剂量。此外,我们提出CBD可以通过同源和异源机制诱导5-HT1AR脱敏。同源脱敏涉及G蛋白偶联受体激酶2 (GRK2)和β-阻滞蛋白的募集,导致受体内吞作用。相反,异源脱敏是通过细胞内钙水平升高或蛋白激酶(如c-Jun n -末端激酶(JNK))的激活,通过其他受体的活性介导的。
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引用次数: 0
Identification of a dual JAK3/TEC family kinase inhibitor for atopic dermatitis therapy. 双重JAK3/TEC家族激酶抑制剂治疗特应性皮炎的鉴定。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-05 DOI: 10.1016/j.bcp.2025.116740
Yiwen Du, Longling Wang, Jingmei Zhou, Wenxiang Hong, Xuanyan Cai, Hongbo Ma, Zonghui Wei, Wenwen Nie, Hong Zhu, Bo Yang, Qiaojun He, Binhui Chen, Jiajia Wang, Qinjie Weng

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by recurrent eczematous lesions and severe itching, for which clinical treatments are limited. Selectively inhibiting Janus Kinase 3 (JAK3) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases is proposed as a promising strategy to treat AD with possible reduced side effects and enhanced efficacy. In this study, we developed a dual JAK3/TEC family kinase inhibitor ZZB, which demonstrated potent inhibitory activity with IC50 values of 0.89 nM against JAK3 and 11.56 nM against TEC kinase interleukin-2-inducible T-cell kinase (ITK). Docking studies revealed that ZZB forms a covalent bond with the unique cysteine residue at position 909 (Cys909) in JAK3 and Cys442 in ITK. Utilizing human peripheral blood mononuclear cells, we discovered ZZB selectively inhibits JAK3-dependent cytokines signaling and ITK-mediated CD4+ T cell activation. Moreover, in vitro studies indicated ZZB significantly suppresses the proliferation and differentiation of CD4+ T cells, as well as the cytolytic function of CD8+ T cells and NK cells. We then conducted a pharmacokinetic study in mice and observed a favorable pharmacokinetic profile for ZZB. In a mouse model of AD induced by repeated application of 2,4-dinitrochlorobenzene to the shaved dorsal skin, oral administration of ZZB (100 mg/kg) markedly improved skin condition and reduced immune cell infiltration, matching the efficacy of the positive drug dexamethasone. We conclude that the JAK3/TEC kinase inhibitor ZZB is a highly promising candidate for the treatment of AD.

特应性皮炎(AD)是一种慢性炎症性皮肤疾病,其特征是反复发作的湿疹病变和严重的瘙痒,临床治疗有限。选择性抑制Janus Kinase 3 (JAK3)和酪氨酸激酶在肝细胞癌(TEC)家族激酶中的表达,被认为是治疗AD的一种有希望的策略,可能减少副作用并提高疗效。在本研究中,我们开发了JAK3/TEC家族双激酶抑制剂ZZB,对JAK3和TEC激酶的IC50值分别为0.89 nM和11.56 nM。对接研究发现,ZZB与JAK3中909位(Cys909)和ITK中Cys442位独特的半胱氨酸残基形成共价键。利用人外周血单个核细胞,我们发现ZZB选择性地抑制jak3依赖性细胞因子信号和itk介导的CD4+ T细胞活化。此外,体外研究表明,ZZB显著抑制CD4+ T细胞的增殖和分化,以及CD8+ T细胞和NK细胞的细胞溶解功能。然后,我们在小鼠身上进行了药代动力学研究,并观察到ZZB具有良好的药代动力学特征。2,4-二硝基氯苯反复应用于剃除的背侧皮肤诱导的AD小鼠模型中,口服ZZB (100 mg/kg)可显著改善皮肤状况,减少免疫细胞浸润,其疗效与阳性药物地塞米松相当。我们得出结论,JAK3/TEC激酶抑制剂ZZB是治疗AD的极有希望的候选药物。
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引用次数: 0
Advancements in understanding the role and mechanism of sirtuin family (SIRT1-7) in breast cancer management. sirtuin家族(SIRT1-7)在乳腺癌治疗中的作用及机制研究进展
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-04 DOI: 10.1016/j.bcp.2025.116743
Deepak Sharma, Muthukumaran Panchaksaram, Rajiniraja Muniyan

Breast cancer (BC) is the most prevalent type of cancer in women worldwide and it is classified into a few distinct molecular subtypes based on the expression of growth factor and hormone receptors. Though significant progress has been achieved in the search for novel medications through traditional and advanced approaches, still we need more efficacious and reliable treatment options to treat different types and stages of BC. Sirtuins (SIRT1-7) a class III histone deacetylase play a major role in combating various cancers including BC. Studies reveal thateach sirtuin has a unique and well-balanced biology, indicating that it regulates a variety of biological processes that result in the initiation, progression,and metastasis of BC. SIRT also plays a major role in numerous vital biological functions, including apoptosis, axonal protection, transcriptional silencing, DNA recombination and repair, fat mobilization, and aging. As per the current demand, we wish to outline the structural insights into sirtuin's catalytic site, substantial variations among all SIRT types, and their mechanism in BC management. Additionally, this review will focus on the application of SIRT modulators along with their clinical significance, hurdles, and future perspective to develop successful SIRT-based drug candidates to conquer the BC problem.

乳腺癌(BC)是全世界女性中最常见的癌症类型,根据生长因子和激素受体的表达,它被分为几个不同的分子亚型。尽管在通过传统和先进方法寻找新型药物方面取得了重大进展,但我们仍然需要更有效和可靠的治疗方案来治疗不同类型和阶段的BC。Sirtuins (SIRT1-7)是III类组蛋白去乙酰化酶,在对抗包括BC在内的多种癌症中发挥重要作用。研究表明,每种sirtuin都具有独特且平衡良好的生物学特性,表明它调节了导致BC发生、进展和转移的多种生物学过程。SIRT还在许多重要的生物学功能中发挥重要作用,包括细胞凋亡、轴突保护、转录沉默、DNA重组和修复、脂肪动员和衰老。根据目前的需求,我们希望概述sirtuin催化位点的结构见解,所有SIRT类型之间的实质性差异,以及它们在BC管理中的机制。此外,本文将重点介绍SIRT调节剂的应用及其临床意义、障碍和未来发展前景,以成功开发基于SIRT的候选药物来克服BC问题。
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引用次数: 0
Peptide-based CAR-NK cells: A novel strategy for the treatment of solid tumors. 基于肽的CAR-NK细胞:治疗实体瘤的新策略。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-04 DOI: 10.1016/j.bcp.2025.116741
Qianqian Wang, Xin Yuan, Cuijuan Liu, Ying Huang, Lin Li, Yimin Zhu

CAR-T cell therapy has been proven to be effective on hematological tumors, although graft-versus-host disease and cytokine release syndrome(CRS) limit its application to a certain extent. However, CAR-T therapy for solid tumors met challenges, among which the lack of tumor-specific antigens (TSA) and immunosuppressive tumor microenvironment (TME) are the most important factors. CAR-NK could be a good alternative to CAR-T in some ways since they can induce mild CRS and are independent of HLA-matching, but the efficacy of CAR-NKs remains limited in solid tumors. CAR cells armed with multiple tumor targeting molecules may obtain higher therapeutic efficacy against solid tumors. Due to large molecular weight, multivalent scFvs cannot be displayed efficiently on T cells and the high affinity of scFv to the target makes it easy to cause on-target, off-tumor(OTOT) toxicity. Peptides with low molecular weight and slightly lower affinity than scFvs allow immune cells to display multiple peptides to increase killing ability and reduce OTOT toxicity. In our study, peptide-based CAR-NK cells were designed to solve the dilemma of CAR-T in solid tumors. Firstly, the peptide-based CAR-NK92MI cells with A1 peptide were constructed and their inhibitory effects on the growth of A549 tumor cells were identified. Secondly, the tri-specific CAR-NK92MI cells with peptides that simultaneously targeted PD-L1, EGFR and VEGFR2 were developed for the combinatory therapy. Tri-specific CAR-NK92MI exhibited comparable killing activities to scFv-based CAR-NK92MI. Moreover, peptide-based CAR NK92MI mitigated OTOT toxicity. Our study implied that peptide-based CAR-NKs could behave as promising tools in solid tumor.

CAR-T细胞疗法已被证明对血液系统肿瘤有效,但移植物抗宿主病和细胞因子释放综合征(CRS)在一定程度上限制了其应用。然而,CAR-T治疗实体肿瘤面临挑战,其中肿瘤特异性抗原(tumor-specific antigens, TSA)的缺乏和免疫抑制肿瘤微环境(immunosuppressive tumor microenvironment, TME)是最重要的因素。CAR-NK在某些方面可能是CAR-T的良好替代品,因为它们可以诱导轻度CRS并且不依赖于hla匹配,但CAR-NK在实体瘤中的疗效仍然有限。携带多种肿瘤靶向分子的CAR细胞可以获得更高的实体肿瘤治疗效果。由于分子量大,多价scFv不能在T细胞上有效展示,且scFv对靶标的高亲和力使其容易引起靶外肿瘤(OTOT)毒性。低分子量和亲和力略低于scFvs的多肽可使免疫细胞显示多肽,从而提高杀伤能力,降低OTOT毒性。在我们的研究中,我们设计了基于肽的CAR-NK细胞来解决CAR-T在实体肿瘤中的困境。首先构建含有A1肽的肽基CAR-NK92MI细胞,并鉴定其对A549肿瘤细胞生长的抑制作用。其次,开发具有同时靶向PD-L1、EGFR和VEGFR2肽的三特异性CAR-NK92MI细胞用于联合治疗。三特异性CAR-NK92MI表现出与基于scfv的CAR-NK92MI相当的杀伤活性。此外,基于肽的CAR NK92MI减轻了OTOT毒性。我们的研究表明,基于肽的CAR-NKs可以作为实体肿瘤治疗的有前途的工具。
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Biochemical pharmacology
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