A Comprehensive Analysis into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer's Disease, Aging, Cancer, Inflammation, and Diabetes.

Natural products have long been used as drugs to treat a wide array of human diseases. The lead compounds discovered from natural sources are used as novel templates for developing more potent and safer drugs. Natural products produce biological activity by binding with biological macromolecules, since natural products complement the protein-binding sites and natural product-protein interactions are already optimized in nature. Sirtuin 6 (SIRT6) is an NAD+ dependent histone deacetylase enzyme and a unique Sirtuin family member. It plays a crucial role in different molecular pathways linked to DNA repair, tumorigenesis, glycolysis, gluconeogenesis, neurodegeneration, cardiac hypertrophic responses, etc. Thus, it has emerged as an exciting target of several diseases such as cancer, neurodegenerative diseases, aging, diabetes, metabolic disorder, and heart disease. Recent studies have shown that natural compounds can act as modulators of SIRT6. In the current review, a list of natural products, their sources, and their mechanisms of SIRT6 activity modulation has been compiled. The potential application of these naturally occurring SIRT6 modulators in the amelioration of major human diseases such as Alzheimer's disease, aging, diabetes, inflammation, and cancer has also been delineated. Natural products such as isoquercetin, luteolin, and cyanidin act as SIRT6 activators, whereas vitexin, catechin, scutellarin, fucoidan, etc. work as SIRT6 inhibitors. It is noteworthy to mention that quercetin acts as both SIRT6 activator and inhibitor depending on its concentration used. Although none of them were found as highly selective and potent modulators of SIRT6, they could serve as the starting point for developing selective and highly potent scaffolds for SIRT6.

The Biology of Glial Cells and Their Complex Roles in Alzheimer's Disease: New Opportunities in Therapy.

Even though Alzheimer's disease (AD) is of significant interest to the scientific community, its pathogenesis is very complicated and not well-understood. A great deal of progress has been made in AD research recently and with the advent of these new insights more therapeutic benefits may be identified that could help patients around the world. Much of the research in AD thus far has been very neuron-oriented; however, recent studies suggest that glial cells, i.e., microglia, astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells (NG2 glia), are linked to the pathogenesis of AD and may offer several potential therapeutic targets against AD. In addition to a number of other functions, glial cells are responsible for maintaining homeostasis (i.e., concentration of ions, neurotransmitters, etc.) within the central nervous system (CNS) and are crucial to the structural integrity of neurons. This review explores the: (i) role of glial cells in AD pathogenesis; (ii) complex functionalities of the components involved; and (iii) potential therapeutic targets that could eventually lead to a better quality of life for AD patients.

A Closer Look into the Role of Protein Tau in the Identification of Promising Therapeutic Targets for Alzheimer's Disease.

One of the most commonly known chronic neurodegenerative disorders, Alzheimer's disease (AD), manifests the common type of dementia in 60⁻80% of cases. From a clinical standpoint, a patent cognitive decline and a severe change in personality, as caused by a loss of neurons, is usually evident in AD with about 50 million people affected in 2016. The disease progression in patients is distinguished by a gradual plummet in cognitive functions, eliciting symptoms such as memory loss, and eventually requiring full-time medical care. From a histopathological standpoint, the defining characteristics are intracellular aggregations of hyper-phosphorylated tau protein, known as neurofibrillary tangles (NFT), and depositions of amyloid ß-peptides (Aß) in the brain. The abnormal phosphorylation of tau protein is attributed to a wide gamut of neurological disorders known as tauopathies. In addition to the hyperphosphorylated tau lesions, neuroinflammatory processes could occur in a sustained manner through astro-glial activation, resulting in the disease progression. Recent findings have suggested a strong interplay between the mechanism of Tau phosphorylation, disruption of microtubules, and synaptic loss and pathology of AD. The mechanisms underlying these interactions along with their respective consequences in Tau pathology are still ill-defined. Thus, in this review: (1) we highlight the interplays existing between Tau pathology and AD; and (2) take a closer look into its role while identifying some promising therapeutic advances including state of the art imaging techniques.

A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets.

Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide⁺ (NAD⁺) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings of SIRT6 since future research may hold the key to engendering strategies involving SIRT6 that may have significant implications for human health and expand upon possible treatment options. In this review, we are primarily concerned with exploring the latest advances in understanding SIRT6 and how it can alter the course of several life-threatening diseases such as processes related to aging, cancer, neurodegenerative diseases, heart disease, and diabetes (SIRT6 has also shown to be involved in liver disease, inflammation, and bone-related issues) and any recent promising pharmacological investigations or potential therapeutics that are of interest.