Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro.
Effects of Midazolam on the Development of Adult Leydig Cells From Stem Cells In Vitro.
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咪达唑仑对干细胞体外发育成体间质细胞的影响
DOI：
10.3389/fendo.2021.765251
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发表时间：
2021
影响因子：
5.2
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Zhao X;Ji M;Wen X;Chen D;Huang F;Guan X;Tian J;Xie J;Shao J;Wang J;Huang L;Lin H;Ye L;Chen H
研究背景咪达唑仑是一种神经系统药物，具有镇静、催眠、降低焦虑、顺行性遗忘、脑介导的肌肉松弛和抗惊厥等多种作用。由于它经常在儿童和青少年中使用很长一段时间，因此有可能影响他们的青春期发育。在这里，我们报告了药物对睾丸中产生睾酮（T）的细胞--间质细胞（LC）发育的潜在影响。方法采用磁激活细胞分选技术分离成年大鼠睾丸干细胞，体外诱导3周分化为睾丸干细胞。向培养基中加入咪达唑仑（0.1-30 μM），并测定对LC发育的影响。结果咪达唑仑对SLC分化有剂量依赖性作用。在低浓度（0.1-5 μM）下，该药物可轻度增加SLC分化（增加T产生），而在较高浓度（15-30 μM）下，它可抑制LC发育（减少T产生）。较低水平下T升高可能是由于清道夫受体B类成员1（SCARB 1）和细胞色素P450 17 A1（CYP 17 A1）上调，而较高水平咪达唑仑下T降低可能是由于多种类固醇生成蛋白的变化。类固醇生成途径蛋白质的不均匀变化，尤其是高咪达唑仑水平下CYP 17 A1的降低，也导致孕酮蓄积。除了T的变化，孕酮的增加可能对男性生殖产生额外的影响。高咪达唑仑水平下类固醇生成蛋白的丢失可能部分由蛋白激酶B/cAMP反应元件结合蛋白（AKT/CREB）信号通路的失活介导。结论在与人类患者血清水平相当的浓度下，咪达唑仑有可能影响成人Leydig细胞（ALC）的发育。需要进一步的研究来测试对人体细胞的影响。
Background Midazolam is a neurological drug with diverse functions, including sedation, hypnosis, decreased anxiety, anterograde amnesia, brain-mediated muscle relaxation, and anticonvulsant activity. Since it is frequently used in children and adolescents for extended periods of time, there is a risk that it may affect their pubertal development. Here, we report a potential effect of the drug on the development of Leydig cells (LCs), the testosterone (T)-producing cells in the testis. Methods Stem LCs (SLCs), isolated from adult rat testes by a magnetic-activated cell sorting technique, were induced to differentiate into LCs in vitro for 3 weeks. Midazolam (0.1–30 μM) was added to the culture medium, and the effects on LC development were assayed. Results Midazolam has dose-dependent effects on SLC differentiation. At low concentrations (0.1–5 μM), the drug can mildly increase SLC differentiation (increased T production), while at higher concentrations (15–30 μM), it inhibits LC development (decreased T production). T increases at lower levels may be due to upregulations of scavenger receptor class b Member 1 (SCARB1) and cytochrome P450 17A1 (CYP17A1), while T reductions at higher levels of midazolam could be due to changes in multiple steroidogenic proteins. The uneven changes in steroidogenic pathway proteins, especially reductions in CYP17A1 at high midazolam levels, also result in an accumulation of progesterone. In addition to changes in T, increases in progesterone could have additional impacts on male reproduction. The loss in steroidogenic proteins at high midazolam levels may be mediated in part by the inactivation of protein kinase B/cAMP response element-binding protein (AKT/CREB) signaling pathway. Conclusion Midazolam has the potential to affect adult Leydig cell (ALC) development at concentrations comparable with the blood serum levels in human patients. Further studies are needed to test the effects on human cells.
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影响因子：
4.5
作者：
Eliveld, Jitske;van Daalen, Saskia K. M.;van Pelt, Ans M. M.
通讯作者：
van Pelt, Ans M. M.
影响因子：
5.1
作者：
Diana, Paolo;Joksimovic, Srdjan M.;Jevtovic-Todorovic, Vesna
通讯作者：
Jevtovic-Todorovic, Vesna
影响因子：
3.7
作者：
Bobjer J;Katrinaki M;Tsatsanis C;Lundberg Giwercman Y;Giwercman A
通讯作者：
Giwercman A
巢蛋白阳性干间质细胞作为治疗睾丸间质细胞功能障碍的潜在来源的表征。
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
5.8
作者：
Malkin, CJ;Pugh, PJ;Jones, TH
通讯作者：
Jones, TH