OPEN ACCESS ARTICLE – Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s):  Kenneth Maiese


Background: The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease.

Methods: In light of the significant role circadian rhythm can hold over the body’s normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis.

Results: In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer’s disease and Parkinson’s disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth.

Conclusion: Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.

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Major article contribution by Indian author in the journal Mini-Reviews in Medicinal Chemistry

New Approaches to Target Cancer Stem Cells: Current Scenario

Author(s): Mayank Bashyal Insan and Vikas Jaitak.

Abstract: Resistance towards chemotherapy and radiotherapy as well as relapse of cancer is the major obstacle in the treatment of cancer. The main factor behind is cancer stem cells (CSCs) which are more resistant to conventional chemotherapy, radiotherapy and are quite able to regenerate whole new tumor again if remain alive during treatment. Targeting CSCs along with actively dividing cancer cells may significantly contribute to the solution of the problem of resistance and relapse. Various approaches are implemented to eradicate CSCs which include CSC markers specific compounds, Drugs which disturb niche and various inhibitors/modulators of signaling pathways. Hedgehog (Hh), Wnt and Notch pathways are modulated/inhibited using various agents and shown beneficial results in multiple forms of cancer. Many inhibitors/modulators of these pathways have been entered in the clinical trials. MicroRNAs have also been developed as anti CSCs agents. In this review, we have covered current status of CSC targeting therapy based on CSC markers, CSC niche, Hedgehog, Wnt, Notch pathway along with MicroRNA based targeting strategies and possibility of implementation multi-targeted anti-CSC therapy for the better outcome of the results.

Mini-Reviews in Medicinal Chemistry, 14(1): 20-34.


BSP High Impact Factor Journal:

7-17-2014 8-11-00 AM

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