基甲酸环酶1 knockdown 减弱皮拉鲁素诱导的心脏毒性
Wenqing Zhang1, Zhiyun Shu1, Peng Huang1
1Department of Experimental Pharmacology and Toxicology, School of Pharmaceutical Sciences, Jilin University, Changchun, China.
Clinical and experimental pharmacology & physiology
|September 3, 2024
概括
腺酸环酶1 (ADCY1) 在皮拉鲁比 (THP) 诱导的心脏损伤中起着关键作用. 降低ADCY1水平可以通过调节ADCY1/PKA/GRIN2D通路来保护心脏细胞免受THP毒性.
科学领域:
- 心脏病学 心脏病学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 皮拉鲁比 (THP) 是一种已知会引起心脏毒性的化疗药物.
- 由于THP引起的心肌细胞损伤的确切机制尚未完全理解.
- 腺酸环酶1 (ADCY1) 是一种酶,涉及到各种细胞过程.
研究的目的:
- 研究ADCY1在皮拉鲁比 (THP) 诱导的小鼠心肌细胞损伤中的作用.
- 阐明ADCY1影响THP心脏毒性的分子机制.
主要方法:
- 用THP治疗HL-1细胞以诱导心脏毒性.
- 用CCK-8,Edu,流细胞计和ROS试验来评估细胞活力,增殖,亡和氧化应激.
- 对ADCY1,PKA和GRIN2D的基因和蛋白质表达水平,通过RT-qPCR和西式斑点分析.
- 分子对接被用来预测ADCY1和THP之间的相互作用.
主要成果:
- THP治疗显著降低了HL-1细胞活力,抑制了增殖,诱导了亡,并增加了氧化应激.
- 在THP治疗的细胞中,ADCY1表达显著上调.
- 分子对接表明ADCY1和THP之间存在直接相互作用.
- 观察到ADCY1,蛋白激酶A (p-PKA) 和GRIN2D的水平升高.
- 降低ADCY1减弱的THP诱导心脏毒性.
结论:
- ADCY1参与皮拉鲁比诱导的心脏毒性.
- ADCY1/PKA/GRIN2D通路似乎调解了THP诱导的心肌细胞损伤.
- 向ADCY1可能提供一种治疗策略,以减轻皮拉鲁比辛心脏毒性.
相关概念视频
01:09GPCRs Regulate Adenylyl Cylase Activity
5.4K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.4K
01:19Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
404
The activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) contributes to cardiac remodeling, and inhibiting the RAAS is a pharmacological target in heart failure management. As a result, neurohumoral modulation is a crucial treatment principle for managing heart failure. This approach involves using medications like ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, mineralocorticoid receptor antagonists (MRAs), and neutral...
404
02:34Inhibition of Cdk Activity
4.7K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K
01:26Heart Failure Drugs: Inotropic Agents
545
Positive inotropic agents are commonly used as the first line of treatment for heart failure. One such agent is digoxin, derived from the genus Digitalis, which has been known for centuries but effectively utilized since 1785. However, these cardiac glycosides can have potentially toxic effects due to their mechanism of action, which involves inhibiting Na+/K+-ATPase and increasing contractility. Digoxin is absorbed orally and distributed in various tissues, including the CNS. It has a long...
545
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
147
Receptor tyrosine kinase inhibitors (TKIs) and calcium channel blockers (CCBs) are two critical categories of drugs employed in the treatment of pulmonary artery hypertension (PAH). PAH is a disease that causes high blood pressure in the pulmonary arteries, resulting in chest pain, fatigue, and shortness of breath.
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
147