亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

Mechanisms of soft-tissue mineralization induced by the inhibition of the MEK/ERK pathway or the inhibition of fibroblast growth factor receptors

MAPK/ERK通路 MEK抑制剂 化学 重吸收 矿化(土壤科学) 受体 成纤维细胞生长因子 内分泌学 内科学 激酶 生物 医学 生物化学 有机化学 氮气
作者
João Graça
链接
摘要

Currently in development as anti-cancer drugs, MEK/ERK and FGFR inhibitors have induced soft-tissue mineralization and increased plasma Pi and 1,25-dihydroxyvitamin D3 (1,25D3) levels in pre-clinical studies. AstraZeneca in-house data reported softtissue mineralization in stomach, kidney and heart of rats administered for >7d with MEK (MEKi) or FGFR (FGFRi) inhibitors. In this study, I aimed to unravel the mechanisms of soft-tissue mineralization associated with MEK/ERK or FGFR inhibition by assessing key processes for mineral homeostasis in rats treated with these inhibitors. The main findings of this study are: 1) Supporting previous studies, MEKi and FGFRi treatment (8d) resulted in softtissue mineralization and increases in plasma Pi and FGF23. Importantly, similar effects were observed for the first time in animals treated with an ERK inhibitor (ERKi). 2) Renal CaSR expression remained unchanged following MEKi or FGFRi treatment (8d), suggesting that the CaSR is not key for the mineralization induced by these inhibitors. Additionally, CaSR expression was detected throughout the nephron which supports previously hypothesised roles for this receptor in different processes including 1,25D3 production and Pi reabsorption. 3) Acute dosing (6h) with ERKi or FGFRi resulted in reduced plasma FGF23 and altered renal expression of proteins involved in 1,25D3 production (Cyp27b1, Cyp24a1) and Pi reabsorption (NaPiIIa), effects indicative of an impared FGF23 signalling. These results are consistent with MEK/ERK and FGFR inhibition promoting soft-tissue mineralization by analogous mechanisms: a blockage of FGF23 signalling that results in increased 1,25D3 production and in the consequent toxicity. 4) Repeated dosing (8d) with MEKi and FGFRi resulted in increased renal expression of Ca2+-transport (TRPV5, calbindin-D28k, PMCA) and of calcification-inducing (alkaline phosphatase) proteins. These increases may contribute to mineralization by locally raising Ca2+xPi product and inducing a pro-calcifying environment. Since the identified proteins contain VDREs, these effects are likely to be induced by increased plasma 1,25D3 levels.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
科研通AI2S应助科研通管家采纳,获得10
18秒前
1分钟前
1分钟前
1分钟前
小禾一定行完成签到 ,获得积分10
1分钟前
inkoin发布了新的文献求助10
1分钟前
科研通AI2S应助科研通管家采纳,获得10
2分钟前
inkoin完成签到,获得积分10
2分钟前
2分钟前
积极的台灯应助Akitten采纳,获得10
2分钟前
隐形曼青应助务实书包采纳,获得10
3分钟前
3分钟前
3分钟前
爱思考的小笨笨完成签到,获得积分10
4分钟前
GingerF应助科研通管家采纳,获得50
4分钟前
GingerF应助科研通管家采纳,获得50
4分钟前
上官若男应助闫雪采纳,获得10
4分钟前
4分钟前
4分钟前
Akitten发布了新的文献求助10
4分钟前
5分钟前
大写的LV完成签到 ,获得积分10
5分钟前
ffff完成签到 ,获得积分10
5分钟前
zsmj23完成签到 ,获得积分0
6分钟前
Owen应助科研通管家采纳,获得10
6分钟前
Owen应助hongtao采纳,获得10
6分钟前
6分钟前
哈哈哈完成签到 ,获得积分10
6分钟前
7分钟前
liu完成签到 ,获得积分10
7分钟前
33发布了新的文献求助10
7分钟前
7分钟前
阿金啊发布了新的文献求助10
7分钟前
科研通AI2S应助Cong采纳,获得10
8分钟前
科目三应助科研通管家采纳,获得10
8分钟前
8分钟前
8分钟前
务实书包发布了新的文献求助10
8分钟前
8分钟前
8分钟前
高分求助中
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3990219
求助须知:如何正确求助?哪些是违规求助? 3532146
关于积分的说明 11256472
捐赠科研通 3271042
什么是DOI,文献DOI怎么找? 1805190
邀请新用户注册赠送积分活动 882302
科研通“疑难数据库(出版商)”最低求助积分说明 809234