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Emerging Roles of Sirtuin 6 in Alzheimer's Disease

Mohamad Nasir NF, Zainuddin A, Shamsuddin S

J Mol Neurosci, 2018 Feb;64(2):157-161.
PMID: 29260452 DOI: 10.1007/s12031-017-1005-y

Alzheimer's disease (AD) is a neurodegenerative disease that is imposing an increasing burden on society. Currently, AD is the leading cause of senile dementia worldwide. Despite the long existence of AD, there is lack of therapies for AD, suggesting that new and effective treatment strategy must be explored. At present, sirtuin pathway has attracted attention from the researchers due to its promising results in laboratory models of aging. In addition, our understanding in the roles of sirtuin 6 in AD has expanded. It has been identified to be involved in telomere maintenance, DNA repair, genome integrity, energy metabolism, and inflammation, which ultimately regulate life span. Recent findings also demonstrate that sirtuin 6 is lacking in AD patients, proposing that it can be a new potential therapeutic target in AD. Therefore, exploring on how sirtuin 6 is related in AD manifestation may accelerate the research of AD further and benefits future AD patients. Keeping that in mind, this review aims to highlight the possible roles of sirtuin 6 in AD manifestation.

Matched MeSH terms: Sirtuins/metabolism*
Antioxidant Modulation of mTOR and Sirtuin Pathways in Age-Related Neurodegenerative Diseases

Abdullah A, Mohd Murshid N, Makpol S

Mol Neurobiol, 2020 Dec;57(12):5193-5207.
PMID: 32865663 DOI: 10.1007/s12035-020-02083-1

In the human body, cell division and metabolism are expected to transpire uneventfully for approximately 25 years. Then, secondary metabolism and cell damage products accumulate, and ageing phenotypes are acquired, causing the progression of disease. Among these age-related diseases, neurodegenerative diseases have attracted considerable attention because of their irreversibility, the absence of effective treatment and their relationship with social and economic pressures. Mechanistic (formerly mammalian) target of rapamycin (mTOR), sirtuin (SIRT) and insulin/insulin growth factor 1 (IGF1) signalling pathways are among the most important pathways in ageing-associated conditions, such as neurodegeneration. These longevity-related pathways are associated with a diversity of various processes, including metabolism, cognition, stress reaction and brain plasticity. In this review, we discuss the roles of sirtuin and mTOR in ageing and neurodegeneration, with an emphasis on their regulation of autophagy, apoptosis and mitochondrial energy metabolism. The intervention of neurodegeneration using potential antioxidants, including vitamins, phytochemicals, resveratrol, herbals, curcumin, coenzyme Q10 and minerals, specifically aimed at retaining mitochondrial function in the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease is highlighted.

Matched MeSH terms: Sirtuins/metabolism*
Anticancer activities of a benzimidazole compound through sirtuin inhibition in colorectal cancer

Tan YJ, Lee YT, Yeong KY, Petersen SH, Kono K, Tan SC, et al.

Future Med Chem, 2018 Sep 01;10(17):2039-2057.
PMID: 30066578 DOI: 10.4155/fmc-2018-0052

AIM: This study aims to investigate the mode of action of a novel sirtuin inhibitor (BZD9L1) and its associated molecular pathways in colorectal cancer (CRC) cells.
MATERIALS & METHODS: BZD9L1 was tested against metastatic CRC cell lines to evaluate cytotoxicity, cell cycle and apoptosis, senescence, apoptosis related genes and protein expressions, as well as effect against major cancer signaling pathways.
RESULTS & CONCLUSION: BZD9L1 reduced the viability, cell migration and colony forming ability of both HCT 116 and HT-29 metastatic CRC cell lines through apoptosis. BZD9L1 regulated major cancer pathways differently in CRC with different mutation profiles. BZD9L1 exhibited anticancer activities as a cytotoxic drug in CRC and as a promising therapeutic strategy in CRC treatment.

Matched MeSH terms: Sirtuins/metabolism
Benzimidazoles as new scaffold of sirtuin inhibitors: green synthesis, in vitro studies, molecular docking analysis and evaluation of their anti-cancer properties

Yoon YK, Ali MA, Wei AC, Shirazi AN, Parang K, Choon TS

Eur J Med Chem, 2014 Aug 18;83:448-54.
PMID: 24992072 DOI: 10.1016/j.ejmech.2014.06.060

Two series of novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. Among the newly synthesized compounds, compound 4j displayed the best inhibitory activity for SIRT1 (IC50 = 54.21 μM) as well as for SIRT2 (IC50 = 26.85 μM). Cell proliferation assay showed that compound 4j possessed good antitumor activity against three different types of cancer cells derived from colon (HCT-116), breast (MDA-MB-468) and blood-leukemia (CCRF-CEM) with cell viability of 40.0%, 53.2% and 27.2% respectively at 50 μM. Docking analysis of representative compound 4j into SIRT2 indicated that the interaction with receptor was primarily due to hydrogen bonding and π-π stacking interactions.

Matched MeSH terms: Sirtuins/metabolism
BZD9L1 sirtuin inhibitor: Identification of key molecular targets and their biological functions in HCT 116 colorectal cancer cells

Tan YJ, Lee YT, Mancera RL, Oon CE

Life Sci, 2021 Nov 01;284:119747.
PMID: 34171380 DOI: 10.1016/j.lfs.2021.119747

BZD9L1 was previously described as a SIRT1/2 inhibitor with anti-cancer activities in colorectal cancer (CRC), either as a standalone chemotherapy or in combination with 5-fluorouracil. BZD9L1 was reported to induce apoptosis in CRC cells; however, the network of intracellular pathways and crosstalk between molecular players mediated by BZD9L1 is not fully understood. This study aimed to uncover the mechanisms involved in BZD9L1-mediated cytotoxicity based on previous and new findings for the prediction and identification of related pathways and key molecular players. BZD9L1-regulated candidate targets (RCTs) were identified using a range of molecular, cell-based and biochemical techniques on the HCT 116 cell line. BZD9L1 regulated major cancer pathways including Notch, p53, cell cycle, NFκB, Myc/MAX, and MAPK/ERK signalling pathways. BZD9L1 also induced reactive oxygen species (ROS), regulated apoptosis-related proteins, and altered cell polarity and adhesion profiles. In silico analyses revealed that most RCTs were interconnected, and were involved in the modulation of catalytic activity, metabolism and transcription regulation, response to cytokines, and apoptosis signalling pathways. These RCTs were implicated in p53-dependent apoptosis pathway. This study provides the first assessment of possible associations of molecular players underlying the cytotoxic activity of BZD9L1, and establishes the links between RCTs and apoptosis through the p53 pathway.

Matched MeSH terms: Sirtuins/metabolism*