Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Punjab, Moga, India.
Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA.
J Mol Med (Berl). 2023 Feb;101(1-2):9-49. doi: 10.1007/s00109-022-02272-6. Epub 2022 Dec 7.
The cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade is a pleiotropic pathway that involves receptor subunit multimerization. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine-threonine kinase that perceives and integrates a variety of intracellular and environmental stimuli to regulate essential activities such as cell development and metabolism. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a prototypical metabolic nuclear receptor involved in neural differentiation and axon polarity. The JAK-STAT, mTOR, and PPARγ signaling pathways serve as a highly conserved signaling hub that coordinates neuronal activity and brain development. Additionally, overactivation of JAK/STAT, mTOR, and inhibition of PPARγ signaling have been linked to various neurocomplications, including neuroinflammation, apoptosis, and oxidative stress. Emerging research suggests that even minor disruptions in these cellular and molecular processes can have significant consequences manifested as neurological and neuropsychiatric diseases. Of interest, target modulators have been proven to alleviate neuronal complications associated with acute and chronic neurological deficits. This research-based review explores the therapeutic role of JAK-STAT, mTOR, and PPARγ signaling modulators in preventing neuronal dysfunctions in preclinical and clinical investigations.
细胞因子激活的 Janus 激酶 (JAK)-信号转导和转录激活因子 (STAT) 级联反应是一个多效途径，涉及受体亚基的多聚化。哺乳动物雷帕霉素靶蛋白 (mTOR) 是一种广泛表达的丝氨酸-苏氨酸激酶，它感知和整合各种细胞内和环境刺激，以调节细胞发育和代谢等基本活动。过氧化物酶体增殖物激活受体-γ (PPARγ) 是一种参与神经分化和轴突极性的典型代谢核受体。JAK-STAT、mTOR 和 PPARγ 信号通路是一个高度保守的信号枢纽，协调神经元活动和大脑发育。此外，JAK/STAT、mTOR 的过度激活和 PPARγ 信号的抑制与各种神经并发症有关，包括神经炎症、细胞凋亡和氧化应激。新出现的研究表明，即使这些细胞和分子过程的微小中断也可能产生明显的后果，表现为神经和神经精神疾病。有趣的是，已经证明靶向调节剂可以减轻与急性和慢性神经功能缺陷相关的神经元并发症。本研究型综述探讨了 JAK-STAT、mTOR 和 PPARγ 信号调节剂在预防临床前和临床研究中神经元功能障碍方面的治疗作用。
